Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([CH2:18][C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])=[C:15]([CH3:17])[N:16]=2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>C(#N)C>[CH3:17][C:15]1[N:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:7][CH:8]=2)[S:13][C:14]=1[CH2:18][C:19](=[O:20])[N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1nc(-c2ccc(OCCCCl)cc2)sc1CC(=O)N1CCCCC1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc(-c2ccc(OCCCN3CCCCC3)cc2)sc1CC(=O)N1CCCCC1
Yield: 67 %

Procedure:
A suspension of 1-({2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazol-5-yl}acetyl)piperidine i104 (0.18 g, 0.51 mmol, 1 eq), potassium carbonate (0.14 g, 1.02 mmol, 2 eq) and sodium iodide (16 mg, 0.03 mmol, 0.2 eq) in acetonitrile (3 ml) is stirred at 80° C. for 20 minutes before addition of piperidine (0.15 ml, 0.51 mmol, 1.03 eq). The mixture is then stirred at reflux overnight, concentrated under vacuum and the residue is taken up in ethyl acetate (50 ml). The organic layer is washed with water (3×25 ml), brine, dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure to obtain an orange solid. Purification by chromatography over silicagel (eluent: dichloromethane/methanol/ammonia 90:10:1) affords 150 mg of 1-(3-{4-[4-methyl-5-(2-oxo-2-piperidin-1-ylethyl)-1,3-thiazol-2-yl]phenoxy}propyl)piperidine 127.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].[CH:31]([C:33]1[CH:53]=[CH:52][C:36]([O:37][CH2:38][C:39]2([NH:44]C(=O)OC(C)(C)C)[CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1)=O>>[NH2:44][C:39]1([CH2:38][O:37][C:36]2[CH:52]=[CH:53][C:33]([CH2:31][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[C@@H:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:34][CH:35]=2)[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(COc2ccc(C=O)cc2)CCCC1
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1cc(NCCCc2ccc(OCC3(N)CCCC3)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 93.1 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and tert-butyl [1-(4-formylphenoxymethyl)cyclopentyl]carbamate (74 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (24 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=C[N:6]3[C:12]([CH3:15])=[N:13][N:14]=[C:5]3[C:4]=2[CH:3]=1.[OH-].[K+].Cl>>[NH2:8][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=1[C:5]1[NH:14][N:13]=[C:12]([CH3:15])[N:6]=1
Reactant: Cc1nnc2c3cc(Cl)ccc3ncn12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1n[nH]c(-c2cc(Cl)ccc2N)n1

Procedure:
To a flask containing 5 gms. of 9-chloro-3-methyl-1,2,4-triazolo[4,3-c]quinazoline is added 100 ml. of a 10% KOH solution and the resulting mixture heated to reflux. A gentle reflux is maintained for a period of 51/2 hours after which time the mixture is neutralized to pH 7.0 with cooling and stirring by adding dropwise a 1:1 HCl solution. The aqueous layer is washed 3 or 4 times with ethyl acetate, washed once with H2O, dried and evaporated in vacuo to dryness. The residue is recrystallized from ether to obtain 5-(2-amino-5-chlorophenyl)-3-methyl-s-triazole, m.p. 190°-195° C.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([N:39]=[C:40]=[O:41])=[O:38])=[CH:32][CH:31]=1>O1CCCC1.C(N(C(C)C)CC)(C)C>[CH3:26][N:24]([CH3:25])[CH2:23][CH2:22][N:19]1[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:40]([NH:39][C:37](=[O:38])[CH2:36][C:33]4[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=4)=[O:41])=[CH:28][CH:27]=3)[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:21][CH2:20]1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3)ccn2)CC1
Reaction time: 8 h
Yield: 29 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(2-dimethylaminoethyl)piperazin-1-yl]carbonylamino}pyridine (86.7 mg) in tetrahydrofuran (2.5 ml) were added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 5.4 ml) and diisopropylethylamine (0.235 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5) to provide the titled compound (36.2 mg, 29%) as white powder.
Reaction SMILES: N1CCCCC1.C(O)=O.CC1(C)[O:18][C:16](=[O:17])[CH2:15][C:13](=O)O1.C(=O)[C:21]1[CH:30]=[CH:29][C:26]([O:27][CH3:28])=[C:23]([O:24][CH3:25])[CH:22]=1>>[CH3:25][O:24][C:23]1[CH:22]=[C:21]([CH2:13][CH2:15][C:16]([OH:18])=[O:17])[CH:30]=[CH:29][C:26]=1[O:27][CH3:28]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1ccc(C=O)cc1OC
Solvent: C1CCNCC1
Solvent: O=CO
Product: COc1ccc(CCC(=O)O)cc1OC

Procedure:
After dropping 20.4 g (23.7 ml, 0.24 mol) of piperidine to 27.6 g (22.6 ml, 0.6 mol) of formic acid under stirring and cooling, 7.2 g (0.05 mol) of Meldrum's acid and 8.3 g (0.05 mol) of veratraldehyde were added to the above mixture, then the procedure of Example 35 was followed.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O.C(#N)N(C)C>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)=[O:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(C(=O)c3ccc(Cl)c(Cl)c3)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C#N
Product: O=C(c1ccc(-c2ccc(CBr)cc2)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 5.0 g of 3,4-dichlorophenyl 4'-methyl-4-biphenylyl ketone, 2.7 g of N-bromosuccinimide and 20 mg of azaisobutyronitrile in 70 ml of carbon tetrachloride is heated to boiling under reflux. The precipitated material is filtered and the filtrate is evaporated. The residue is recrystallized from toluene/cyclohexane. 3,4-Dichlorophenyl 4'-bromomethyl-4-biphenylyl ketone is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].N1C=CC=CC=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:20]=1[C:21](Cl)=[O:22]>ClCCl>[Cl:18][C:19]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:20]=1[C:21]([NH:7][C:6]1[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])=[O:22]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)ccc1[N+](=O)[O-])c1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Reaction time: 72 h
Yield: 86.2 %

Procedure:
5-Chloro-2-nitroaniline (1 g; 5.8 mmol) and pyridine (0.64 ml; 8.1 mmol) were dissolved in dichloromethane (10 ml) and cooled to 0° C. This was added dropwise over 5 minutes to a solution of 2-chloro-5-nitrobenzoyl chloride (1.34 g; 6.1 mmol) in dichloromethane (5 ml). The reaction was stirred at room temperature for 72 hours before adding further acid chloride (1.34 g) and pyridine (0.64 ml). After 30 minutes, the solvent was evaporated and the bisacylated residue treated with 1:1 concentrated ammonia/acetonitrile (10 ml). All the solvent was removed after 5 minutes and the residue crystallised from 1:1 chloroform/heptane (30 ml) to give 2-chloro-N-(5-chloro-2-nitro-phenyl)-5-nitro-benzamide (1.78 g, 86%)
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:7]([CH3:8])[O:6][C:5](=[O:9])[O:4]1.[F:10][C:11]1[CH:12]=[C:13]([NH:22][C:23]([C@@H:25]2[N:34]([C:35]([C@@H:37]3[CH2:40][C@H:39]([C:41]([OH:43])=[O:42])[CH2:38]3)=[O:36])[CH2:33][CH2:32][C:31]3[N:30]=[C:29]([O:44][CH3:45])[CH:28]=[CH:27][C:26]2=3)=[O:24])[CH:14]=[C:15]2[C:19]=1[C:18]([CH3:21])([CH3:20])[CH2:17][CH2:16]2.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:10][C:11]1[CH:12]=[C:13]([NH:22][C:23]([C@@H:25]2[N:34]([C:35]([C@@H:37]3[CH2:40][C@H:39]([C:41]([O:43][CH2:2][C:3]4[O:4][C:5](=[O:9])[O:6][C:7]=4[CH3:8])=[O:42])[CH2:38]3)=[O:36])[CH2:33][CH2:32][C:31]3[N:30]=[C:29]([O:44][CH3:45])[CH:28]=[CH:27][C:26]2=3)=[O:24])[CH:14]=[C:15]2[C:19]=1[C:18]([CH3:20])([CH3:21])[CH2:17][CH2:16]2
Reactant: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@@H](C(=O)O)C1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Reactant: CC1OC(=O)OC1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@@H](C(=O)OCc3oc(=O)oc3C)C1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 48 %

Procedure:
4-Chloromethyl-5-methyl-1,3-dioxolan-2-one (0.026 mL, 0.24 mmol) was added to a mixture of cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutanecarboxylic acid (100 mg, 0.20 mmol) and potassium carbonate (33.5 mg, 0.24 mmol) in DMF (2.0 mL) at room temperature, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20→50% ethyl acetate/hexane) to give the title compound (58.2 mg, 0.096 mmol, 47.5%) as a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][CH2:22][C:23]([N:25]3[CH:29]([CH3:30])[CH2:28][CH2:27][CH:26]3[CH3:31])=[O:24])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[C:10]3=[N:18][CH:19]=[CH:20][N:9]23)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:51][N:52]([CH3:56])[CH2:53][CH2:54]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][CH2:22][C:23]([N:25]3[CH:26]([CH3:31])[CH2:27][CH2:28][CH:29]3[CH3:30])=[O:24])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:54][CH2:53][N:52]([CH3:56])[CH3:51])[CH:15]=3)[C:10]3=[N:18][CH:19]=[CH:20][N:9]23)=[CH:4][CH:3]=1
Reactant: CN(C)CCO
Reactant: CC1CCC(C)N1C(=O)CCC1(c2ccc(Cl)cc2)c2cc(O)ccc2-c2nccn21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1CCC(C)N1C(=O)CCC1(c2ccc(Cl)cc2)c2cc(OCCN(C)C)ccc2-c2nccn21

Procedure:
To a solution of 5-(4-chlorophenyl)-5-[3-(2,5-dimethylpyrrolidin-1-yl)-3-oxopropyl]-5H-imidazo[2,1-a]isoindol-7-ol (30 mg) in dry THF (0.5 mL) was added triphenylphosphine (27 mg), 2-dimethylaminoethanol (11 μL), then DIAD (21 μL) at room temperature. After 3 h additional triphenylphosphine (27 mg), 2-dimethylaminoethanol (11 μL), and DIAD (21 μL) were added and stirring continued. After 24 h the mixture was concentrated. The crude material was purified by preparative reversed-phase HPLC (20×150 mm Waters Sunfire, 5-50% ACN/water containing 0.1% TFA over 20 min. at 20 mL/min). Fractions containing the product were pooled then passed through Dowex 1×2-400 ion exchange resin (prewashed with 1M NaOH, H2O, MeOH) washing with MeOH. The filtrate was concentrated to give a white solid (20 mg): 1H-NMR (500 MHz, CDCl3) δ 7.73 (dd, J=2.2 and 6.1 Hz, 1 H), 7.29-7.24 (m, 3 H), 7.12 (m, 2 H), 6.93 (m, 2 H), 6.78 (dd, J=2.2 and 3.9 Hz, 1 H), 4.04-3.90 (m, 3 H), 3.40 (m, 1 H), 3.11-2.79 (m, 2 H), 2.69 (t, J=5.37 Hz, 1 H), 2.32 (s, 6 H), 2.02-1.75 (m, 2 H), 1.66-1.49 (m, 5 H), 1.16 (dd, J=6.35 and 11.96 Hz, 3 H), 0.88 (dd, J=6.32 and 27.1 Hz, 3 H); HRMS (M+H)+ calculated 507.2521. found 507.2508.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:16][CH3:17])=[CH:5][C:6]=1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14].N1C=CC=CC=1.[CH3:24][CH2:25][O:26]CC.C(Cl)(=O)C>O>[C:25]([NH:1][C:2]1[S:3][C:4]([CH2:16][CH3:17])=[CH:5][C:6]=1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])(=[O:26])[CH3:24]
Reactant: CCOCC
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(N)s1
Solvent: O
Solvent: CC(=O)Cl
Solvent: c1ccncc1
Product: CCc1cc(C(=O)c2ccccc2Cl)c(NC(C)=O)s1

Procedure:
To a mixture of 46.4 g of 2-amino-3-(o-chlorobenzoyl)-5-ethylthiophene, 46.4 g of pyridine and 1160 ml of anhydrous ether is added dropwise 46.4 g of acetyl chloride. Then the reaction mixture is stirred under reflux for 2 hours. After cooling, the reaction mixture is poured into water. The ether layer is separated and washed with water, and dried over sodium sulfate. The solvent is removed under reduced pressure to give crystals of 2-acetylamino-3-(o-chlorobenzoyl)-5-ethylthiophene, which are recrystallized from ethanol-ether to give crystals having a melting point of 132° - 134°C; yield 42.44 g (79%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[C:5](=[O:16])[N:4]([CH2:17][CH2:18][CH3:19])[C:3]=1[C:20]([OH:22])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:56][C:57]1[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=1)[CH2:60][NH2:61]>C(Cl)Cl>[F:56][C:57]1[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=1)[CH2:60][NH:61][C:20]([C:3]1[N:4]([CH2:17][CH2:18][CH3:19])[C:5](=[O:16])[C:6]2[C:11]([C:2]=1[CH3:1])=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:15])[F:14])[CH:7]=2)=[O:22]
Reactant: CCCn1c(C(=O)O)c(C)c2ccc(C(F)(F)F)cc2c1=O
Reactant: NCc1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCn1c(C(=O)NCc2cccc(F)c2)c(C)c2ccc(C(F)(F)F)cc2c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 27.3 %

Procedure:
A solution of 360 mg (1.1 mmol) 4-methyl-1-oxo-2-propyl-7-(trifluoromethyl)-1,2-dihydroisoquinoline-3-carboxylic acid in DCM (20 ml) was cooled to 0° C. and 870 mg (2.3 mmol) HATU and 0.8 ml (4.6 mmol) DIPEA were added. After stirring at 0° C. for 10 min, 0.2 ml (1.7 mmol) 3-fluoro-benzylamine was added and the RS was stirred at RT for 1 h. The mixture was then diluted with DCM (40 ml) and the organic layer was separated, washed with a sat. aq. NaHCO3-sol. (25 ml), a sat. aq. NH4Cl-sol. (20 ml), water (20 ml) and brine (20 ml), dried over Na2SO4 and concentrated in vacuo. The residue obtained was purified by CC (acetone/hexan 1:9) to yield 120 mg (0.3 mmol, 25%) N-(3-fluorobenzyl)-4-methyl-1-oxo-2-propyl-7-(trifluoromethyl)-1,2-dihydroisoquinoline-3-carboxamide (example 2). [M+H]+ 421.1.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][C:7]1[C:8]([C:12]([OH:14])=[O:13])=[CH:9][S:10][CH:11]=1.IC>O1CCCC1>[CH3:1][C:9]1[S:10][CH:11]=[C:7]([CH3:6])[C:8]=1[C:12]([OH:14])=[O:13]
Reactant: [Li]CCCC
Reactant: Cc1cscc1C(=O)O
Solvent: CI
Solvent: C1CCOC1
Product: Cc1csc(C)c1C(=O)O
Temperature: -78 °C
Yield: 82.3 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 18.6 mL, 46 mmol) was added to a pre-cooled solution of 4-methylthiophene-3-carboxylic acid (3.0 g, 21 mmol) in dry tetrahydrofuran (THF, 35 mL) at −62° C. The reaction mixture was stirred at −78° C. for an hour, allowed to warm to −40° C. and re-cooled to −78° C. before adding iodomethane (3.28 mL, 7.49 g, 53 mmol). After addition, the reactants were stirred at −78° C. for an hour and then allowed to warm to room temperature over 14 hours and quenched with water (20 mL). The organic phase was extracted with dilute sodium hydroxide (0.2 N, 3×30 mL). The combined aqueous extracts were washed with ether (2×30 mL), cooled in an ice bath and acidified to pH 3 using concentrated hydrochloric acid. The resultant precipitate was extracted with ether (3×50 mL). The combined ethereal extracts were washed with water (50 mL) and brine (50 mL), dried over magnesium sulphate, concentrated under reduced pressure and recrystallised from ethyl acetate/hexane to give product as an amorphous white solid (2.7 g, 82%): mp 164-165° C.; 1H NMR (CDCl3) δ 6.65 (q, 1H), 2.73 (s, 3H), 2.43 (d, 3H); EI/MS 156 m/e (M+); IR (liq film) 1664 cm−1; Calcd for C7H8O2S: C, 53.8; H, 5.16; Found: C, 53.8; H, 5.11.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[H-].[Na+].[C:17]([O:20][NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])(=[O:19])[CH3:18]>>[C:17]([O:20][N:21]([S:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:13])=[O:12])[C:22](=[O:23])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)ONC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: CC(=O)ON(C(=O)OCc1ccccc1)S(=O)(=O)c1ccccc1S(C)(=O)=O

Procedure:
Benzyl (acetyloxy){[2-(methylsulfonyl)phenyl]sulfonyl}carbamate (50) is prepared from 2-methylsulfonylbenzenesulfonyl chloride, sodium hydride and [(benzyloxy) carbonyl]amino acetate according to Scheme 2. (0.33 g, 28%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.21-8.47 (2H, m), 7.79-7.88 (1H, m), 7.65-7.74 (1H, m), 7.30-7.41 (3H, m), 7.16-7.24 (2H, m), 5.18 (2H, br. s.), 3.31 (3H, s), 2.29 (3H, s).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH2:29][O:30][P:31](=[O:48])([O:40]CC6C=CC=CC=6)[O:32]CC6C=CC=CC=6)[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]>CO.CCOC(C)=O>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH2:29][O:30][P:31](=[O:32])([OH:40])[OH:48])[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CCOP(=O)(OCc4ccccc4)OCc4ccccc4)c3)ccc1-2
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CCOP(=O)(O)O)c3)ccc1-2

Procedure:
Phosphoric acid dibenzyl ester 2-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-ethyl ester (180 mg, 0.26 mmol) was dissolved in methanol:EtOAc (1:1, 6 mL) and the solution was flushed with bubbling nitrogen. Palladium hydroxide (5% on carbon, 40 mg) was added and the reaction mixture was placed under hydrogen atmosphere (1 atm, balloon) overnight while rapidly stirred. Filtration over celite and concentration of the filtrate gave 482. Lyophilization of a solution in acetonitrile and 1% NH4OH in water gave 482 as the bis-ammonium salt.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15](C(CC)(CC)C([O-])([O-])[O-])[CH3:16]>C(O)C>[C:1]1([N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=[C:15]2[CH3:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: CCO
Product: Cc1nc2ccccc2n1-c1ccccc1
Yield: 106.6 %

Procedure:
A solution of 10 g (0.054, mole) of N-phenyl-1,2phenylenediamine and 9.94 ml (0.054 mole) of triethylorthoacetate in 200 ml of ethanol was heated to reflux for 4 hours. The solvent was removed and the residue partitioned between chloroform and water. The organic layer was separated, dried and removed to give 11.99 g of product as an oil.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH2:8]([NH:15][C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]1[OH:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ccccc1
Reactant: C1CCC2OC2C1
Solvent: O
Product: O[C@@H]1CCCC[C@H]1NCc1ccccc1

Procedure:
A mixture of cyclohexene oxide (1) (19 mL, 0.2 mol, Aldrich cat #C10,280-4) and benzylamine (27) (21 mL, 0.2 mol, Aldrich cat #407712) in water (5 mL) was refluxed for 3 hours. The cooled reaction mixture was partitioned between 4M aq NaOH (100 mL) and methyl t-butyl ether (150 mL). The aqueous layer was further extracted with methyl t-butyl ether (2×100 mL), and the combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give trans-2-benzylaminocyclohexan-1-ol (28) as a low melting point solid (39.4 g, 96% yield); 1H-NMR (300 MHz, CDCl3) δ: 7.31-7.22 (m, 5H, Ar), 3.91 (d, J 13 Hz, 1H, CH2aN), 3.65 (d, J 13 Hz, 1H, CH2bN), 3.18 (dt, J 5 Hz, J 10 Hz, CH), 2.28 (dt, J 5 Hz, J 10 Hz, CH), 2.15-2.10 (m, 1H, CH), 2.00-1.94 (m, 1H, CH), 1.70-1.60 (m, 2H, CH2), 1.31-1.12 (m, 3H, CH2 & CH), 1.03-0.90 (m, 1H, CH); 13C-NMR (75 MHz, CDCl3) δ: 140.44 (+), 128.31 (−), 128.00 (−), 126.87 (−), 73.62 (−), 62.97 (−), 50.71 (+), 33.35 (+), 30.36 (+), 24.96 (+), 24.28 (+), 19.32 (+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[CH:17]=[C:18]([N:22]5[CH2:27][CH2:26][CH:25]([NH:28]C(=O)OC(C)(C)C)[CH2:24][CH2:23]5)[CH:19]=[N:20][CH:21]=4)=[N:14][N:13](C4CCCCO4)[C:10]3=[CH:11][N:12]=2)[CH:2]=1.C(Cl)Cl.FC(F)(F)C(O)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[CH:17]=[C:18]([N:22]5[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]5)[CH:19]=[N:20][CH:21]=4)=[N:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(c2cncc(-c3n[nH]c4cnc(-c5cccnc5)cc34)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
To a solution of tert-butyl 1-(5-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate in methylene chloride (1.00 mL, 15.6 mmol) was added trifluoroacetic Acid (0.3109 mL, 4.036 mmol). The reaction was stirred at RT for 18 hours. The reaction was concentrated then submitted for rHPLC (reverse phase HPLC) to give 158 (10 mg, 33% yield). ESI MS m/z=372.1 (M+1). 1H NMR (400 MHz, DMSO) δ 9.39 (s, 1H), 9.24 (s, 1H), 8.72 (s, 1H), 8.61-8.52 (m, 3H), 8.42 (s, 1H), 7.83 (s, 1H), 7.55-7.48 (m, 1H), 3.85 (d, J=13.0 Hz, 2H), 2.98-2.76 (m, 3H), 1.91-1.81 (m, 2H), 1.42 (dd, J=20.7, 10.2 Hz, 2H)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>>[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: Nc1ccccn1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Nc5ccccn5)nc34)cc21
Temperature: 150 °C
Yield: 29 %

Procedure:
Prepared similarly to that described in Example 82 using 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 154 mg, 0.517 mmol), pyridin-2-amine (58.4 mg, 0.621 mmol, Aldrich), BrettPhos precat (Strem, Newburyport, Mass.; 21.90 mg, 0.026 mmol), Brettphos (Strem, Newburyport, Mass.; 15.12 mg, 0.026 mmol), and LHMDS (1.0M in THF; 1138 μl, 1.138 mmol), heating at 150° C. for 30 min in a microwave reactor (Biotage Initiator). Purification by silica gel (100% DCM to 5% MeOH/DCM) provided 2-(2-(pyridin-2-ylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (29% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.92 (t, J=6.75 Hz, 2H) 3.45 (td, J=6.80, 2.25 Hz, 2H) 6.96 (br. s., 1H) 6.99 (d, J=2.15 Hz, 1H) 7.02 (dd, J=6.85, 5.48 Hz, 1H) 7.36 (t, J=7.73 Hz, 1H) 7.54 (d, J=8.80 Hz, 1H) 7.58 (d, J=8.22 Hz, 1H) 7.63 (d, J=7.24 Hz, 1H) 7.76 (td, J=6.85, 1.96 Hz, 1H) 8.02 (dd, J=6.46, 0.98 Hz, 1H) 8.20 (d, J=9.00 Hz, 1H) 8.41 (dd, J=4.89, 1.37 Hz, 1H) 10.16 (s, 1H) 12.72 (br. s., 1H). MS (ESI, pos. ion) m/z: 356.1 (M+1).