Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C:8]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=2[CH3:25])[C:12]2[N:26]=[C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[S:28][C:11]=2[C:10](=[O:35])[N:9]=1)(=O)C.Cl>CO>[OH:6][CH2:7][C:8]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[C:16]=2[CH3:25])[C:12]2[N:26]=[C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[S:28][C:11]=2[C:10](=[O:35])[N:9]=1
Reactant: CC(=O)OCc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(C(F)(F)F)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(Cn2c(CO)nc(=O)c3sc(N4CCOCC4)nc32)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydroxide (0.166 mL, 0.166 mmol) was added to a solution of [4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-2-(4-morpholinyl)-7-oxo-4,7-dihydro[1,3]thiazolo[4,5-d]pyrimidin-5-yl]methyl acetate (80 mg, 0.166 mmol) in Methanol (1.5 mL). The reaction was stirred at RT for 30 min. 1N HCl was added to adjust to pH=5. The mixture was partitioned between DCM and NaCl solution. The organic layer was concentrated to give the titled compound, 65 mg (90%). LC/MS (ES) m/z 441.0 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.65 (m, 1H), 7.36 (m, 1H), 6.87 (m, 1H), 5.60 (s, 2H), 4.15 (m, 2H), 3.66 (m, 4H), 3.56 (m, 4H), 2.49 (s, 3H)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:32]=[C:21]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[O:23])[C:20]([OH:33])=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:22](=[O:23])[C:21]2[CH:32]=[C:17]([Br:16])[CH:18]=[CH:19][C:20]=2[O:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:30][CH:29]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Br)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(Br)cc3C(=O)Nc3ccc(Cl)cc3)c2cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 5-bromo-4′-chlorosalicylanilide (653 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (59 mg, yield 23%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[CH:25]=[CH:24][CH:23]=[CH:22][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=1)=O>O1CCOCC1>[NH2:7][C:8]1[CH:25]=[CH:24][CH:23]=[CH:22][C:9]=1[CH2:10][NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=1
Reactant: COc1ccc(NC(=O)c2ccccc2N)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1ccc(NCc2ccccc2N)cc1F
Temperature: 25 °C

Procedure:
To a stirred suspension of lithium aluminum hydride (121 mg, 3.2 mmol) in 2 mL dioxane at reflux under nitrogen was added 2-amino-N-(3-fluoro-4-methoxyphenyl)benzamide (260 mg, 1 mmol) as a solution in 2 mL dioxane. After refluxing overnight the reaction was cooled to room temperature and quenched by sequential treatment with H2O (150 μL), 15% NaOH (150 μL) and H2O (450 μL). After stirring for several minutes, the heterogeneous mixture was filtered through GF/F filter paper with dioxane and concentrated to a brown residue (246 mg, 100%). 1H NMR (400 MHz, CDCl3) δ 7.14 (m, 2H), 6.86 (m, 1H), 6.74 (m, 2H), 6.60 (dd, 1H), 6.42 (dd, 1H), 4.15 (d, 2H), 4.12 (br s, 2H), 3.83 (s, 3H), 3.54 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[C:23]([F:31])[CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:19][C:4]2[CH:5]=[N:6][C:7]([O:8][C:9]3[N:10]=[CH:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:2]([Cl:1])[CH:3]=2)(=[O:28])=[O:29])=[C:23]([F:31])[CH:22]=1
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Product: O=S(=O)(Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1)c1ccc(Cl)cc1F

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 4-chloro-2-fluorobenzene-1-sulfonyl chloride.
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH:3]1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1.[ClH:28]>O1CCOCC1>[ClH:28].[F:27][C:24]([F:25])([F:26])[O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH:3]2[NH:4][CH2:5][CH2:6][CH2:7][NH:8][C:2]2=[O:1])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCNC(=O)C1Cc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1NCCCNC1Cc1ccc(OC(F)(F)F)cc1

Procedure:
tert-Butyl hexahydro-3-oxo-2-[4-(trifluoromethoxy)benzyl]-1H-1,4-diazepine-1-carboxylate was dissolved in 4M hydrogen chloride in dioxane and after 2.5 h evaporated to yield the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:29][CH2:28][N:11]2[C:12](=[O:27])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:15][C:14]=3[C:23]([F:26])([F:25])[F:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:29][CH2:28][N:11]2[C:12](=[O:27])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:15][C:14]=3[C:23]([F:25])([F:26])[F:24])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)=Cc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)Cc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Reaction time: 2 h
Yield: 45.3 %

Procedure:
To a stirring degassed solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-methyl-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (60 mg, 0.15 mmol) and 10% palladium on carbon (5 mg) in MeOH (2 mL) was added hydrogen (1 atm). After 2 h, the reaction was filter and the solid washed with methanol. The organic layers were combined and conc. in vacuo to a colorless oil. The oil was purified by flash chromatography (silica gel, 0-50% EtOAc in hexanes) to give 28 mg of the desired product as a white solid. MS (ESI) 413 (M+H).
Reaction SMILES: C[Mg+].[Br-].[OH:4][C:5]1[C:6]([C:11]([OH:13])=O)=[N:7][CH:8]=[CH:9][CH:10]=1.[CH2:14](N(CC)CC)C.C(OC)=O.Cl>C1COCC1>[OH:4][C:5]1[C:6]([C:11](=[O:13])[CH3:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ncccc1O
Agent: C[Mg+]
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: COC=O
Product: CC(=O)c1ncccc1O
Temperature: 60 °C
Reaction time: 2 h
Yield: 26.5 %

Procedure:
A solution of MeMgBr (390 mL of 1.4 M in toluene/THF (75:25), 540 mmol) was heated at 60° C. and a solution of 3-hydroxypyridine-2-carboxylic acid (15 g, 110 mmol) and triethylamine (15 mL, 110 mmol) in THF (75 mL) was added dropwise over 3 hours. The resulting mixture was then stirred for 2 hours at 60° C. The reaction mixture was cooled on an ice/brine bath and methyl formate (13 mL, 220 mmol) was added keeping the internal temperature below 20° C. The reaction mixture was then acidified to pH 5-6 with 1M aqueous HCl, and the layers were separated, and the aqueous layer was extracted with ethyl acetate (3×). The organic phases were combined, washed with brine, dried over sodium sulfate and evaporated to dryness to afford 1-(3-hydroxypyridin-2-yl)ethanone (4.0 g, 27%). ESI-MS m/z calc. 137.1, found 138.3 (M+1)+; Retention time: 0.62 minutes (3 min run).
Reaction SMILES: [C:1]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:49])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:48])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[S:28][C:29]([C:33](=[O:47])[N:34]([CH2:36][CH2:37][N:38](C(OC(C)(C)C)=O)[CH3:39])[CH3:35])=[C:30]([CH3:32])[CH:31]=2)[CH3:19])[CH2:12][CH2:11]1.Cl.CO>C1(C)C=CC=CC=1>[C:1]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:49])[O:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[C:20](=[O:48])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[S:28][C:29]([C:33](=[O:47])[N:34]([CH3:35])[CH2:36][CH2:37][NH:38][CH3:39])=[C:30]([CH3:32])[CH:31]=2)[CH2:14][CH2:15]1
Reactant: Cc1cc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)sc1C(=O)N(C)CCN(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: CNCCN(C)C(=O)c1sc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
The compound (153 mg, 0.201 mmol) obtained in Example 89d was dissolved in 2 N hydrochloric acid-methanol (2.01 mL, 4.01 mmol), and the mixture was stirred at room temperature for 2 hours. Toluene was added to the reaction mixture, the solvent was evaporated under reduced pressure, the resulting residue was dissolved in ethyl acetate, and the mixture was adjusted to pH 10 with a 1 N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate (×2) and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=100:0→methylene chloride:methanol=10:1, v/v) to give the title compound (122 mg; yield, 92%) as a white solid.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[CH3:59][O:60][C:61]1[CH:62]=[C:63]([CH:67]=[C:68]([O:72][CH3:73])[C:69]=1[O:70][CH3:71])[C:64](Cl)=[O:65]>>[CH3:57][CH:56]([CH3:58])[C@H:51]([N:46]1[CH2:45][C:44]2[C:48](=[CH:49][C:41]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:64](=[O:65])[C:63]4[CH:62]=[C:61]([O:60][CH3:59])[C:69]([O:70][CH3:71])=[C:68]([O:72][CH3:73])[CH:67]=4)=[CH:40][CH:39]=3)=[CH:42][CH:43]=2)[C:47]1=[O:50])[C:52]([O:54][CH3:55])=[O:53]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cc(OC)c(OC)c(OC)c4)cc3)cc2C1=O
Yield: 89 %

Procedure:
The compound of example 143 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 3,4,5-trimethoxy benzoyl chloride.
Reaction SMILES: C(N(CC)CC)C.O=[C:9]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[CH2:10][C:11]#[N:12].Cl.[CH:20]([NH:23][NH2:24])([CH3:22])[CH3:21]>C(O)C>[CH3:21][CH:20]([N:23]1[C:11]([NH2:12])=[CH:10][C:9]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:24]1)[CH3:22]
Reactant: N#CCC(=O)C1CCOCC1
Reactant: CC(C)NN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)n1nc(C2CCOCC2)cc1N
Reaction time: 1 h
Yield: 81.6 %

Procedure:
0.43 ml of triethylamine is added to a solution of 640 mg of 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanenitrile and 347 mg of isopropylhydrazine hydrochloride in 8 ml of ethanol under an argon atmosphere. The mixture is refluxed with magnetic stirring for 1 h and then concentrated to dryness under reduced pressure. The residue is taken up in 100 ml of ethyl acetate and the organic phase is washed twice with 40 ml of a saturated sodium hydrogen carbonate solution. The combined aqueous phases are extracted twice with 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure, so as to obtain 536 mg of 1-(propan-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine.
Reaction SMILES: O=[C:2]1[CH2:7][O:6][C@H:5]([C:8]2[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=2[F:16])[C@@H:4]([NH:17]C(=O)OC(C)(C)C)[CH2:3]1.[F:25][C:26]([F:38])([F:37])[C:27]1[N:28]=[CH:29][C:30]2[CH2:36][CH2:35][NH:34][CH2:33][C:31]=2[N:32]=1.[B][B][B][B][B][B][B][B][B][B].[ClH:49]>CO>[ClH:49].[ClH:49].[F:38][C:26]([F:25])([F:37])[C:27]1[N:28]=[CH:29][C:30]2[CH2:36][CH2:35][N:34]([C@H:2]3[CH2:7][O:6][C@H:5]([C:8]4[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=4[F:16])[C@@H:4]([NH2:17])[CH2:3]3)[CH2:33][C:31]=2[N:32]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(=O)CO[C@@H]1c1cc(F)c(F)cc1F
Reactant: FC(F)(F)c1ncc2c(n1)CNCC2
Agent: Cl
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: N[C@H]1C[C@@H](N2CCc3cnc(C(F)(F)F)nc3C2)CO[C@@H]1c1cc(F)c(F)cc1F
Reaction time: 8 h

Procedure:
To a solution of 45 mg (0.13 mmol) of tert-butyl [(2R,3S)-5-oxo-2-(2,4,5-trifluorophenyl) tetrahydro-2H-pyran-3-yl]carbamate and 27 mg (0.13 mmol) of 2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine in 2.0 mL of dry methanol was added 5.0 mg (0.039 mmol) of decaborane. The reaction mixture was stirred overnight and concentrated in vacuo, then purified by preparative thin layer chromatography using an Analtech® 1000 micron plate (5% methanol/methylene chloride, 1% concentrated ammonium hydroxide) to give the product which was stirred with hydrochloric acid in methanol (1.3M, 4 mL) for 1 h to give the title product. LC/MS 432.93 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]#[N:15].[H][H]>[Co].CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][NH2:15]
Reactant: [H][H]
Reactant: Cc1oc(-c2ccccc2)nc1CC#N
Agent: [Co]
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCN
Yield: 101.4 %

Procedure:
6.00 g (30 mmol) of (5-Methyl-2-phenyl-oxazol-4-yl)-acetonitrile were hydrogenated in the presence of 0.60 g of wet Raney Cobalt catalyst (Grace Davison Catalysts, Worms, Germany, Type Nr. 2700) in 54 mL of methanol in a 185 mL stainless steel autoclave under 9 bar of hydrogen pressure at 80° C. for 4 h. Removal of the catalyst by filtration, evaporation of the solvents and drying (45° C./10 mbar/2 h) afforded 6.15 g of 2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamine with a purity of 87.7% (HPLC area %).
Reaction SMILES: [OH:1][N:2]1[CH:6]=[C:5]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:4]=[N:3]1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18]>>[C:9]1([C:8]#[C:7][C:5]2[CH:4]=[N:3][N:2]([O:1][C:17](=[O:18])[N:16]([CH3:15])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:6]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: On1cc(C#Cc2ccccc2)cn1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)On1cc(C#Cc2ccccc2)cn1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-4-phenylethynylpyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (40%, yellow crystals).
Reaction SMILES: [Li]CCCC.N12CCN(CC1)CC2.[F:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.CN(C)[CH:23]=[O:24]>C(OCC)C.O>[CH:23]([C:16]1[C:15]([F:14])=[CH:20][CH:19]=[CH:18][N:17]=1)=[O:24]
Reactant: Fc1cccnc1
Reactant: CN(C)C=O
Agent: C1CN2CCN1CC2
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: O=Cc1ncccc1F
Temperature: -20 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
Dry ethyl ether (500 mL), n-BuLi (1.6M in hexane, 62.5 mL, 0.1 mol), and dry 1,4-diazabicyclo[2.2.2]octane (DABCO) (11.56 g, 0.1 mol) were introduced into a 1 L flask under a dry N2 stream at -60° C. and the resulting cloudy solution was stirred for 1 hour at -20° C. The mixture was then cooled to -75° C. and an ethyl ether (50 mL) solution of 3-fluoropyridine (9.81 g, 0.1 mol) was added dropwise and stirring continued for 1 1/2 hours at -60° C. The mixture was recooled to -75° C., dry N,N-dimethylformamide (8.52 mL, 0.11 mol) dissolved in ethyl ether (50 mL) was added dropwise and the mixture stirred for 2 hours at -75° C. Water (175 mL) was introduced slowly at -10° C., the aqueous layer extracted with ethyl acetate (5×200 mL), and the combined extracts were dried over anhydrous sodium sulfate. Solvent removal produced a dark brown oil which after vacuum distillation and purification by chromatography on silica gel provided 4.4 g (35%) of the titled product as an off-white crystalline solid:
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:5][C:4]=1OS(C(F)(F)F)(=O)=O)#[N:2].[F:24][C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:24][C@@H:25]1[CH2:29][CH2:28][N:27]([C:4]2[CH:5]=[C:6]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[CH:7]=[C:8]([CH3:9])[C:3]=2[C:1]#[N:2])[CH2:26]1
Reactant: Cc1cc(N2CCOCC2)cc(OS(=O)(=O)C(F)(F)F)c1C#N
Reactant: F[C@@H]1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cc1cc(N2CCOCC2)cc(N2CC[C@@H](F)C2)c1C#N
Temperature: 90 °C
Reaction time: 16 h
Yield: 50.8 %

Procedure:
A solution of affording trifluoro-methanesulfonic acid (2-cyano-3-methyl-5-morpholin-4-yl-phenyl)ester (0.43 g, 1.22 mmol), (3R)-3-fluoro-pyrrolidin (0.19 g, 1.47 mmol) and caesium carbonate (1.6 g, 4.92 mmol) in tetrahydrofuran (25 ml) is degassed and flushed with Argon for 30 min followed by the addition of palladium(II) acetate (6.0 mg, 0.03 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (23 mg, 0.04 mmol). The resulting mixture is stirred at 90° C. for 16 h. After completion of the reaction (monitored by TLC), the mixture is poured onto water (30 ml) and extracted with ethyl acetate (3×50 ml).The combined organic layers are washed with water (2×20 ml), brine (2×20 ml), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by flash column chromatography (silica gel, 15% ethyl acetate/hexane) affording 2-[(3R)-3-fluoro-pyrrolidin-1-yl]-6-methyl-4-morpholin-4-yl-benzonitrile (0.18 g, 0.62 mmol, 50%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([S:18](Cl)(=[O:20])=[O:19])[C:15]([Cl:22])=[CH:14][C:13]=2[Cl:23])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].CN.[NH:26]1[CH:30]=CC=N1.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[C:3]([C:12]2[C:13]([Cl:23])=[CH:14][C:15]([Cl:22])=[C:16]([S:18]([NH:26][CH3:30])(=[O:20])=[O:19])[CH:17]=2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9]
Reactant: c1cn[nH]c1
Reactant: Cn1nc(-c2cc(S(=O)(=O)Cl)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Agent: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 4-chloro-3-(5-chlorosulfonyl-2,4-dichlorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole (0.43 g, 1 mmole) in 2 ml tetrahydrofuran was added dropwise to a 40% aqueous methylamine solution dissolved in 20 ml tetrahydrofuran to react the pyrazole derivative with methylamine. After the addition was finished, the reaction was continued further for 30 minutes at room temperature. Then ethyl acetate was added to the reaction product solution to extract the objective product. The extract solution was washed with water, dehydrated, and evaporated to dryness, giving the title compound (0.42 g) in paste form, yield 100%.
Reaction SMILES: [N:1]1([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:31])C(=O)C1.O>CN(C=O)C>[Br:31][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]([CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]1)[CH2:2][CH2:3][CH2:4]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCc3ccccc32)CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCCc3cc(Br)ccc32)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A solution of tert-butyl 4-(3,4-dihydroquinolin-1(2H)-yl)piperidine-1-carboxylate (0.85 g, 2.69 mmol) in 15 mL of DMF was cooled to 0° C. then treated dropwise with NBS (478 mg, 2.69 mmol) in 12 mL DMF. The reaction was stirred at 0° C. for 1 hour then treated with 100 mL H2O. The suspension was extracted with 2×75 mL of ethyl acetate. The combined organic layer was rinsed with brine (2×50 mL), dried over Na2SO4, filtered and concentrated to give a light brown oil. This residue was subjected to silica gel chromatography using the Biotage purification system (25+M column, 0-20% ethyl acetate/hexanes over 10 column volumes) to give a viscous oil which solidified to give a white solid (852 mg, 80.4%). 1H-NMR (CDCl3) δ 7.10 (dd, J=2.4 Hz, 8.7 Hz, 1H), 7.05-7.04 (m, 1H), 6.51 (d, J=9.0 Hz, 1H), 4.33-4.19 (m, 2H), 3.71-3.64 (m, 1H), 3.14 (t, J=6.0 Hz, 2H), 2.82-2.74 (m, 2H), 2.69 (t, J=6.3 Hz, 2H), 1.91-1.77 (m, 2H), 1.61-1.57 (m, 4H), 1.47 (s, 9H). MS (ESI): 395.1 and 377.1 (M+1).
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:28][CH:29]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>ClCCl.CO>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:28][CH:29]=2)=[O:23])=[CH:16][CH:17]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(Oc3ccccc3)nc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(Oc3ccccc3)nc2)cc1)C(=O)O
Yield: 67.6 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-butyl-3-[4-[2-(2-phenoxypyridine-5-carbonylamino)ethoxy]phenyl]propionate (215 mg), which is the product of Example 55, was reacted with aqueous sodium hydroxide solution (1N, 1.32 ml) and the reaction mixture was treated to afford the crude free acid which was subjected to chromatography on a silica gel thin layer plate using dichloromethane/methanol=10/1 as the eluant to give the title compound (137 mg) as colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[H][H].[ClH:11].CC1CC(C)CNC1.[OH-].[Na+]>C(O)C.[Rh].O>[ClH:11].[CH3:8][C@H:3]1[CH2:4][C@@H:5]([CH3:7])[CH2:6][NH:1][CH2:2]1
Reactant: [H][H]
Reactant: Cc1cncc(C)c1
Agent: [Rh]
Agent: CC1CNCC(C)C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: C[C@@H]1CNC[C@H](C)C1
Temperature: 5 °C

Procedure:
3,5-Lutidine (6475.0 g.) is hydrogenated under 1000 psi hydrogen pressure in ethanol using 1665 g. of 5% rhodium on carbon catalyst (50% H2O) at room temperature. The catalyst is filtered off and anhydrous hydrogen chloride bubbled into the filtrate at a temperature below 40° C. until the solution is strongly acidic. The solution is then concentrated in vacuo to a thick slurry which is diluted with 40 liters of hexane. The crystalline material is filtered off and dried in the atmosphere to give 8.9 kg. of crude product. The crude 3,5-dimethylpiperidine hydrochloride is dissolved in 14 liters of water and the pH of this solution adjusted to7.0 with dilute sodium hydroxide solution. The mixture is washed with 7 1. and then with 3 1. of chloroform to remove unreduced 3,5lutidine. The aqueous solution is then adjusted to pH 12-13 by the addition of 40% sodium hydroxide solution and extracted with 6 1. and then with 3 1. of chloroform. The combined chloroform extract is dried over anhydrous magnesium sulfate and chilled to 5° C. in an ice bath. Anhydrous hydrogen chloride is then injected until the solution is strongly acidic. The chloroform solution is concentrated in vacuo as benzene is continuously added. When most of the chloroform has been replaced, the product is filtered from about 36 1. of benzene. The filter cake is washedwith cold benzene and hexane, and air dried, to obtain 4.8 kg. of product, m.p. 222°-224° C.