Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:37]([CH3:39])[CH3:38])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34](O)=O)[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.[C:46]([C:50]1[CH:51]=[C:52]([NH2:57])[C:53]([NH2:56])=[CH:54][CH:55]=1)([CH3:49])([CH3:48])[CH3:47].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:46]([C:50]1[CH:55]=[CH:54][C:53]2[NH:56][C:34]([CH2:33][CH2:32][CH:30]3[CH2:31][CH:28]([N:27]([CH2:26][C@@H:18]4[C@H:19]5[O:23][C:22]([CH3:24])([CH3:25])[O:21][C@H:20]5[C@H:16]([N:13]5[C:9]6[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]7[CH:40]=[CH:41][C:42]([O:44][CH3:45])=[CH:43][C:3]=7[O:2][CH3:1])[C:8]=6[CH:15]=[CH:14]5)[CH2:17]4)[CH:37]([CH3:38])[CH3:39])[CH2:29]3)=[N:57][C:52]=2[CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo [2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanoic acid (490 mg, 0.79 mmol) and 4-tert-butylbenzene-1,2-diamine (155 mg, 0.946 mmol) in N,N-Dimethylformamide (8.1 ml) was treated with N,N-Diisopropylethylamine (0.453 ml, 2.60 mmol) dropwise followed by N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (449 mg, 1.18 mmol) in one portion. The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated under high vacuum and the residue was partitioned between 50 ml EtOAc and 50 ml 1/1 H2O/sat NaHCO3. The aqueous phase was extracted with 30 ml EtOAc and the combined organic phase was washed with 30 ml portions of H2O and brine. The organic phase was dried over Na2SO4, filtered and concentrated to give a glass/stiff foam. The crude material was purified by flash chromatography (SiO2, eluting with 4% 7N NH3 in CH3OH/CH2Cl2) to give the desired intermediate as a mixture of amide regioisomers (400 mg). A solution of intermediate (0.40 g) in Acetic acid (15 ml) was heated at 65° C. for 2.5 h, the reaction mixture was cooled and placed under high vacuum to remove the acetic acid. The residue was taken up in 60 ml CH2Cl2 and washed with 40 ml portions of sat NaHCO3 and 2% Na2CO3 solution. The organic phase was dried over Na2SO4, filtered and concentrated to yield a glass/stiff foam. The material was placed on high vacuum and used directly in the next step (380 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]1[NH:10][CH2:9]1>>[C:2]1([NH:1][CH2:8][CH2:9][NH2:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CN1
Reactant: Nc1ccccc1
Product: NCCNc1ccccc1
Yield: 13 %

Procedure:
It is known to produce certain unsymetrically substituted 1,2-ethanediamines. Current processes, however, have proven unacceptable. For example, G. I. Braz et al. disclosed that the aminoethylation of aniline with ethyleneimine afforded only a 13 percent yield of N-phenyl-1,2-ethanediamine. The remaining product comprised polyamino ethyl compounds of high molecular weight. Dokl. Akad. Nauk., 59, 489 (1948), Chem. Abstr., 42, 6747 (1948).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH:3]1[OH:9].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:9][CH:3]2[CH:4]([CH3:8])[CH2:5][CH2:6][CH2:7][CH:2]2[CH3:1])=[O:19])=[CH:13][CH:12]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CC1CCCC(C)C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1CCCC(C)C1OC(=O)Cc1ccc(O)cc1
Yield: 51 %

Procedure:
A mixture of 2,6-dimethylcyclohexyl alcohol (11.4 g), 4-hydroxyphenylacetic acid (9.12 g), p-toluenesulfonic acid (1 g) and benzene (300 mL) was refluxed with continuous water separation for 20 hours. The mixture was filtered and the filtrate was washed with a 10% Na2CO3 solution, then with water. Drying over MgSO4 and evaporation in vacuo afforded 8.02 g of 2,6-dimethylcyclohexyl 4-hydroxyphenylacetate. That product has the structural formula: ##STR26##
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[N:10]12[CH2:17][CH2:16][CH:13]([CH2:14][CH2:15]1)[C@@H:12]([NH:18][C:19](=[O:27])[O:20][CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)[CH2:11]2>CCOC(C)=O>[Cl-:1].[O:4]=[C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][N+:10]12[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17]1)[C@@H:12]([NH:18][C:19]([O:20][CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)=[O:27])[CH2:11]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)OCc1cccs1
Reactant: O=C(CCl)c1cccs1
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1C[N+]2(CC(=O)c3cccs3)CCC1CC2)OCc1cccs1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
2-Chloro-1-(thiophen-2-yl)ethanone (30.2 mg, 0.19 mmol) was added to a solution of (R)-thiophen-2-ylmethyl quinuclidin-3-ylcarbamate (50.0 mg, 0.19 mmol) in EtOAc (3 ml). The reaction was stirred at room temperature overnight. The solvent was removed, and the residue was triturated in Et2O, filtered and dried to give (R)-1-(2-oxo-2-(thiophen-2-yl)ethyl)-3-((thiophen-2-ylmethoxy)carbonylamino)-1-azoniabicyclo[2.2.2]octane chloride (60 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([CH3:11])C(O)=O)[CH2:2]1.Cl.CN(C)CCCN=C=NCC.[NH2:24][C:25]1[CH:26]=[C:27]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:40]([NH2:42])=[O:41])[CH:38]=3)[N:33]([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)[N:32]=2)[CH:28]=[CH:29][CH:30]=1.CN(C)[CH:51]=[O:52]>ClCCl>[O:44]1[CH2:45][CH2:46][CH2:47][CH2:48][CH:43]1[N:33]1[C:34]2[C:39](=[CH:38][C:37]([C:40]([NH2:42])=[O:41])=[CH:36][CH:35]=2)[C:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([NH:24][C:51](=[O:52])[CH2:11][CH2:7][CH:3]3[CH2:4][CH2:5][CH2:6][NH:1][CH2:2]3)[CH:26]=2)=[N:32]1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: CC(C(=O)O)C1CCCNC1
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: NC(=O)c1ccc2c(c1)c(-c1cccc(NC(=O)CCC3CCCNC3)c1)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-piperidylpropanoic acid (0.102 g, 0.65 mmol) in 6 mL of dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) (0.135 g, 0.71 mmol). After 10 min at room temperature, 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (0.200 g, 0.59 mmol) was then added as a solid followed by 2 mL of dimethyl formamide. The reaction mixture was stirred at room temperature overnight. The crude mixture was partitioned between water and ethyl acetate. The crude was not purified (yield not calculated). ES-MS (m/z) 476 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=2)[CH:4]=1.CN(C)C=O.P(Cl)(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=2)[CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cnc(Nc2cc(CO)ccn2)s1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cnc(Nc2cc(CCl)ccn2)s1

Procedure:
2-(4-Hydroxymethyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (0.883 g, 3.80 mmol) was stirred in anhydrous CH2Cl2 (12 mL) under N2. Dimethylformamide (0.354 mL, 3.80 mmol, 1 equiv) was added followed by the addition of phosphorous oxychloride (0.294 mL, 3.80 mmol). After 4 hours the reaction was concentrated and quenched by the addition of saturated NaHCO3 (aq). A precipitate formed which was filtered and washed with water to provide the titled compound. 1H NMR (DMSO-d6) δ 12.35 (bs, 1H), 8.40 (d, 1H, J=5.3 Hz), 8.28 (s, 1H), 7.20 (s, 1H), 7.12 (d, 1H, J=5.3 Hz), 4.82 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14](O)[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:17]1([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:17]1([CH:23]2[CH2:24][CH2:25][N:26]([CH:14]3[C:15]4[C:10](=[N:9][C:8]5[C:3]([C:2]=4[NH2:1])=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH2:11][CH2:12][CH2:13]3)[CH2:27][CH2:28]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1c2c(nc3ccccc13)CCCC2N1CCC(c2ccccc2)CC1

Procedure:
9-Amino-1,2,3,4-tetrahydroacridin-1-ol (5.36 g) was refluxed for 48 hours in 300 ml of toluene that contained 4-phenylpiperidine (8.06 g) and p-toluenesulfonic acid monohydrate (9.5 g). At the end of this time the reaction mixture was concentrated and the residue purified by flash chromatography (5% Et3N/toluene) to give, after concentration of theproduct-containing fractions and recrystallization from EtOAc/pentane, 3.22g of analytically pure product, m.p. 189°-190°.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[NH:4][CH2:5][CH2:6][CH2:7][N:8]=1.[OH-].[Na+].[O-:11]S([O-])(=O)=O.[Na+].[Na+].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1[N:26]=[C:27]=[O:28]>C1COCC1>[OH2:11].[ClH:18].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1[NH:26][C:27]([NH:2][C:3]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]=1)=[O:28].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1[NH:26][C:27]([NH:2][C:3]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]=1)=[O:28].[ClH:1]
Reactant: O=S(=O)([O-])[O-]
Reactant: NC1=NCCCN1
Reactant: Cc1cccc(Cl)c1N=C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cccc(Cl)c1NC(=O)NC1=NCCCN1
Product: O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 8.14 g (0.060 mol) of 2-amino-1,4,5,6-tetrahydropyrimidine hydrochloride, 6.0 g (0.075 mol) of 50% NaOH and 75 ml of THF was stirred for 0.5 hours at room temperature and then 15 g Na2SO4 was added. After stirring for 0.5 hours, a solution of 6.70 g (0.040 mol) of 2-chloro-6-methylphenyl isocyanate in 50 ml of THF was added over a period of 0.5 hours. After stirring for 1 hour, the reaction mixture was filtered, the filtrate evaporated in vacuo and the residue dissolved in 25 ml of 10% HCl and 25 ml of H2O with warming. After filtration through diatomaceous earth chilling in ice gave the crystalline hydrochloride which was recrystallized from cold H2O after treatment with charcoal affording 7.15 g (59%). This material was dried in vacuo (20° C., 5 mm Hg) to constant weight to give 7.11 g (59%) of pure N-(2-chloro-6-methylphenyl)-N'-(1,4,5,6-tetrahydropyrimidin-2-yl)urea monohydrochloride hemihydrate, m.p. (190) 215°-220° C. melts, then forms a new solid; m.p. 243°-245° C.; IR(CHCl3) 3224, 1713, 1677, 1641, 1543 cm-1 ; UV max. (MeOH) 236 (ε16,200) and 217 nm infl (ε21,500).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:18])[CH2:14][O:15][CH2:16][CH3:17])[CH2:9]1)=O)(C)(C)C.F[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.[H-].[Na+].CCO>CN(C=O)C.Cl>[CH2:16]([O:15][CH2:14][C@@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[O:18][C:28]1[C:29]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][CH:27]=1)[CH3:17]
Reactant: Fc1cccc2ccccc12
Reactant: CCOC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC[C@H](Oc1cccc2ccccc12)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-2-Ethoxy-1-hydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (200 mg, 0.8 mmol) and 1-fluoronaphthalene were dissolved in DMF (2.7 mL). NaH (27.8 mg, 1.2 mmol) was added and the mixture was stirred at room temperature for 15 minutes, then heated at 120° C. for 4 hours. The mixture was then cooled to room temperature. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (19 mL, 23 mmol) and stirred overnight at room temperature. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (125 mg, 94% purity). MS m/z: [M+H]+ calcd for C18H23NO2, 286.17. found 286.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([S:29]([C:20]1[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=1)(=[O:31])=[O:30])[CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CN1CC=C(c2c[nH]c3c(F)cc(F)cc23)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccc4ccccc4c3)c3c(F)cc(F)cc23)CC1

Procedure:
(5.1 mg, 29%); from 5,7-difluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4g, 10 mg, 0.04 mmol) and 2-naphthalenesulfonyl chloride (13.6 mg, 0.06 mmol) with 1M NaN(TMS)2 (60 μL, 0.06 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]1([C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[C:22]([O:24][CH3:25])=[O:23]>C(Cl)Cl>[CH3:25][O:24][C:22]([N:18]1[CH2:17][CH:16]=[C:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:20][CH2:19]1)=[O:23]
Reactant: COC(=O)Cl
Reactant: C1=C(c2ccccc2)CCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CC=C(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 105.2 %

Procedure:
Triethylamine (2.6 mL, 19.15 mmol) was added to a suspension of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (1.50 g, 7.66 mmol) in DCM (30 mL). The resulting mixture was stirred for 5 minutes until complete dissolution of the solids, then was cooled to 0° C., and methyl chloroformate (0.65 mL, 8.43 mmol) was added dropwise. A thick white precipitate formed. The reaction mixture was warmed to room temperature and stirred for 1 hour, then was quenched by addition of water, and extracted with DCM. The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure to give 1.75 g of 4-phenyl-3,6-dihydro-2H-pyridine-1-carboxylic acid methyl ester as a pale yellow oil. This crude product (7.66 mmol) was dissolved in chloroform (30 mL) and 3-chloroperoxybenzoic acid (77%, 2.22 g, 9.95 mmol) was added. The resulting solution was stirred at room temperature for 18 hours. An aqueous solution of Na2SO3 (20%, 30 mL) was added and the resulting mixture was vigorously stirred for 1 hour. The phases were separated and the aqueous layer was extracted with DCM. The combined organic extracts were washed with a saturated aqueous solution of NaHCO3, dried over MgSO4, filtered and evaporated under reduced pressure to give a pale yellow oil. This crude oil was purified by flash chromatography (10% to 20% of EtOAc in hexane) to give 1.68 g (94% 2 steps yield) of 6-phenyl-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid methyl ester as a colorless oil.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.S(OC)([O:19][CH3:20])(=O)=O.[CH3:23]N(C)C=O>CCCCCC.O1CCCC1>[CH:20]([C:10]1[S:6][C:7]([C:11]2[S:12][C:13]([CH3:23])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)=[O:19]
Reactant: CN(C)C=O
Reactant: c1csc(-c2cccs2)c1
Reactant: COS(=O)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(-c2ccc(C=O)s2)s1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 132.4 %

Procedure:
Under a nitrogen atmosphere 25 mL of 2.6M solution of n-butyllithium in hexane was added to a stirred, cold (-78° C.) solution of 9.8 grams (0.058 mole) of 2,2'-bithiophene in 150 mL of tetrahydrofuran. After addition, the mixture was stirred at -78° C. for 15 minutes and then was allowed to warm to 0° C. and stirred at this temperature for one hour. Dimethyl sulfate (5.8 mL, 0.061 mole) was added, and the mixture was allowed to warm to room temperature and stir for approximately 16 hours. This mixture was cooled to -78° C., and 25 mL of 2.6M solution of n-butyllithium was added. The reaction mixture was stirred at -78° C. for fifteen minutes and was then allowed to warm to 0° C. and stirred for one hour. While maintaining a temperature of 0° C., 5.3 mL (0.068 mole) of N,N-dimethylformamide was added. After addition, the mixture was allowed to warm to room temperature and stir for two hours. The mixture was quenched with 180 mL of 10% hydrochloric acid. After stirring for 20 minutes, the organic phase was removed and diluted with diethyl ether. The aqueous phase was retained. This organic phase was washed with 10% hydrochloric acid and an aqueous solution saturated with sodium chloride. The aqueous phase from above was extracted with chloroform. This extract was washed with an aqueous solution saturated with sodium chloride and then combined with the washed organic phase. This organic mixture was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving an oil. This oil was purified by column chromatography on silica gel to yield 16.0 grams of 5-formyl-5'-methyl [2,2'-bithienyl] as an oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[O:14][C:13]([C:15]([C:17]2[CH:18]=[N:19][C:20]([Cl:24])=[C:21]([Cl:23])[CH:22]=2)=[O:16])=[N:12][N:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].CC(O)=O>O1CCCC1.C(O)C>[Si:1]([O:8][CH2:9][C:10]1[O:14][C:13]([CH:15]([C:17]2[CH:18]=[N:19][C:20]([Cl:24])=[C:21]([Cl:23])[CH:22]=2)[OH:16])=[N:12][N:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCc1nnc(C(=O)c2cnc(Cl)c(Cl)c2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1nnc(C(O)c2cnc(Cl)c(Cl)c2)o1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 101.7 %

Procedure:
To a solution of (5-((tert-butyldimethylsilyloxy)methyl)-1,3,4-oxadiazol-2-yl)(5,6-dichloropyridin-3-yl)methanone (70) (1.75 g, 4.51 mmol) in tetrahydrofuran (8.8 mL) and ethanol (8.8 mL) was added sodium tetrahydroborate (0.085 g, 2.25 mmol) at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 15 min. AcOH was added to the reaction flask and the mixture was extracted with ethyl acetate (50 mL×2). The resulting organic layer was washed with H2O, brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 1.79 g of the product (71) as a pale yellow oil (quant.).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:21]4[CH2:22][NH:23][CH2:24][CH2:25][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)=[C:5]([C:26]([F:29])([F:28])[F:27])[CH:4]=1.C(N(C(C)C)CC)(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>CN(C=O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:21]4[CH2:22][N:23]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:24][CH2:25][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)=[C:5]([C:26]([F:29])([F:27])[F:28])[CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1n[nH]c2c1CNCC2)N1CCC(c2ccc(F)cc2C(F)(F)F)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4ccc(F)cc4C(F)(F)F)CC3)c2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.6 %

Procedure:
To a solution of (4-(4-fluoro-2-(trifluoromethyl)phenyl) piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone hydrochloride (38 mg, 0.088 mmol) and diisopropylethylamine (35 μL, 0.20 mmol) in DMF (2.0 mL) was added methanesulfonyl chloride (9 L, 0.12 mmol). The mixture was stirred for 16 h at ambient temperature. The solvent was removed under reduced pressure and the residue diluted with H2O (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The obtained solids were chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 100% (10% CH30H in CH2Cl2 with 0.01% NH4OH) in CH2Cl2) and freeze dried to give (4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone as a white solid (4 mg, 10%): 1H NMR (300 MHz, DMSO-d6) δ 13.05 (s, 1H), 7.73-7.69 (m, 1H), 7.57-7.46 (m, 2H), 5.28-5.24 (m, 1H), 4.70-4.65 (m, 1H), 4.38-4.33 (m, 2H), 3.51-3.45 (m, 2H), 3.22-3.10 (m, 2H), 2.94 (s, 3H), 2.84-2.70 (m, 3H), 1.73 (br s, 4H); ESI MS m/z 475 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[C:4](C#C)=[C:5]([CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=1)[C:6]([O:8]CC)=[O:7].[Cl-].[NH+]1C=CC=[CH:26][CH:25]=1.Cl.[CH3:31]N(C=O)C>>[CH3:31][C:15]1[CH:16]=[CH:17][C:18]([C:19]2[O:2][C:3]3[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:11]=[CH:12][C:13]=3[CH:14]=2)=[CH:26][CH:25]=1
Reactant: c1cc[nH+]cc1
Reactant: C#Cc1c(C(=O)OCC)ccc(-c2ccc(C)cc2)c1OC
Reactant: CN(C)C=O
Agent: Cl
Agent: [Cl-]
Product: Cc1ccc(-c2cc3ccc(C(=O)O)cc3o2)cc1
Temperature: 200 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 3-methoxy-4-(4-methylphenyl)-ethynylbenzoate (1.5 g) and pyridinium chloride (9.0 g) was stirred at 200° C. for 2 hours, and then cooled to 100° C. To the mixture was added DMF (20 ml), and the mixture was cooled to room temperature. To the mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the precipitated crystals were collected by filtration, which were washed with diethylether and hexane to give pale yellow crystals of 2-(4-methylphenyl)benzofuran-6-carboxylic acid (0.84 g).
Reaction SMILES: [CH2:1]([Sn:5](=O)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:11]([SH:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O>[CH2:1]([Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([S:23][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[S:23][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](=O)CCCC
Reactant: CCCCCCCCCCCCS
Solvent: O
Product: CCCCCCCCCCCCS[Sn](CCCC)(CCCC)SCCCCCCCCCCCC

Procedure:
This compound was prepared from di-n-butyltin-oxide and 1 dodecanethiol by azeotropic removal of water using the method described in U.S. Pat. No. 2,648,650. All spectroscopic and analytical data were consistent with the proposed structure.
Reaction SMILES: [N+:1]([C:4]1[C:5](C#N)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O.C[CH2:17][O:18][C:19]([CH3:21])=[O:20]>[Pd]>[CH3:5][CH2:4][CH2:9][CH:8]([CH3:10])[CH3:7].[CH3:17][O:18][C:19]([C:21]1[C:4]([NH2:1])=[CH:9][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:7][N:6]=1)=[O:20]
Reactant: N#Cc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CCCC(C)C
Product: COC(=O)c1ncc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Nitro-5-trifluoromethyl-pyridine-2-carbonitrile (6.5 g, 29.9 mmol) was dissolved in EtOAc (150 ml) to give a pale yellow solution. 10% Palladium on activated carbon (3.19 g, 2.99 mmol) was added and the reaction mixture stirred under an atmosphere of hydrogen for 18 hours. The reaction mixture was filtered and concentrated in vacuo. The crude residue was dissolved in HCl conc. (45 ml) and heated to reflux for 24 hours. The reaction mixture was allowed to cool to RT and concentrated in vacuo. The solid was dissolved in MeOH (200 ml) and sulfuric acid (8 ml) was added. The resulting solution was heated at reflux for 84 hours. The reaction was allowed to cool to RT, then neutralised by addition of 10% NaHCO3(aq) (600 ml). The product was extracted into DCM (3×200 mL) and the combined organic phases were washed with water (200 ml), brine (50 mL), (MgSO4) and concentrated in vacuo. The resulting solid was purified by chromatography on silica: Eluant gradient: isohexane (500 ml), 10% EtOAc in isohexane (1000 mL), 20% EtOAc in isohexane (1500 mL) to afford the titled compound as a pale yellow solid 1H-NMR: [400 MHz, DMSO-d6] δ 8.13 (1H, d, J=1.7 Hz, ArH), 7.60 (1H, d, J=1.3 Hz, ArH), 7.01 (2H, br, NH2), 3.85 (3H, s, ArOCH3), m/z 221.1 [M+H]+