Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[N:6][CH:7]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][C:19]=1/[CH:32]=[CH:33]/[C:34]([O:36][CH2:37][CH3:38])=[O:35].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O>[CH2:25]([S:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:2]2[CH:7]=[N:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=3)=[CH:4][C:3]=2[O:15][CH3:16])=[C:19](/[CH:32]=[CH:33]/[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:20]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Reactant: COc1cc(-c2cccc(F)c2)ncc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1cnc(-c2cccc(F)c2)cc1OC
Temperature: 90 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
A 40-mL vial containing 5-bromo-2-(3-fluorophenyl)-4-methoxypyridine (0.420 g, 1.489 mmol), (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (0.560 g, 1.787 mmol), Xantphos (0.172 g, 0.298 mmol), cesium carbonate (0.679 g, 2.084 mmol), and Pd2(dba)3 (0.136 g, 0.149 mmol) was flushed with N2 and charged with CPME (3 mL). After stirring overnight at 90° C., additional Pd2(dba)3 (0.136 g, 0.149 mmol) and Xantphos (0.172 g, 0.298 mmol) was added. After stirring an additional 4 h, the reaction was cooled to rt, quenched with H2O and extracted thrice with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to a brown-black oil. Column chromatography (50 g Snap Ultra column, 0% to 80% EtOAc/hept) afforded (E)-ethyl 3-(5-(benzylthio)-2-((6-(3-fluorophenyl)-4-methoxypyridin-3-yl)amino)phenyl)acrylate (0.615 g, 1.195 mmol, 80% yield) as a yellow oil. m/z (ESI) 515.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16]2[C@@H:15]3[CH2:17][C@@H:14]3[CH2:13][C:12]=2[C:11]([C:18](Cl)=[O:19])=[N:10]1.[C:21]([C:25]1[O:29][N:28]=[C:27]([NH2:30])[CH:26]=1)([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[C:21]([C:25]1[O:29][N:28]=[C:27]([NH:30][C:18]([C:11]2[C:12]3[CH2:13][C@H:14]4[CH2:17][C@H:15]4[C:16]=3[N:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[N:10]=2)=[O:19])[CH:26]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(Cl)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Reactant: CC(C)(C)c1cc(N)no1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(NC(=O)c2nn(-c3ccc(F)cc3F)c3c2C[C@H]2C[C@@H]32)no1
Temperature: 23 °C
Reaction time: 2.5 h
Yield: 72 %

Procedure:
(1aR,5aR)-2-(2,4-difluorophenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl chloride (40 mg, 0.136 mmol) was added to a solution of 5-tert-butylisoxazol-3-amine (19.03 mg, 0.136 mmol), triethylamine (0.038 mL, 0.271 mmol), and DMAP (1.658 mg, 0.014 mmol) in dichloromethane (1 mL). The orange solution was stirred at 23° C. for 2.5 h. The mixture was purified by silica gel flash chromatography to give the title compound (39 mg) as a white solid. LCMS m/z=399.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.52 (td, J=4.8, 3.3 Hz, 1H), 1.20 (td, J=7.8, 4.9 Hz, 1H), 1.36 (s, 9H), 2.14-2.20 (m, 1H), 2.29-2.35 (m, 1H), 2.98 (d, J=16.9 Hz, 1H), 3.08 (dd, J=16.6, 6.4 Hz, 1H), 6.79 (s, 1H), 7.01-7.08 (m, 2H), 7.63-7.69 (m, 1H), 9.17 (s, 1H).
Reaction SMILES: O[CH:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.S(Cl)([Cl:20])=O>>[Cl:20][CH:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: OC(CCc1ccc(Cl)cc1)Cn1ccnc1
Reactant: O=S(Cl)Cl
Product: Clc1ccc(CCC(Cl)Cn2ccnc2)cc1

Procedure:
1-[2-Hydroxy-4-(4-chlorophenyl)-n-butyl]imidazole (2.0 g) in thionyl chloride (10 ml) was warmed for one hour at 65° C. The excess thionyl chloride was removed in vacuo and the residue dissolved in dichloromethane (75 ml) and shaken with excess aqueous potassium carbonate. The organic layer was washed with water, dried (MgSO4), evaporated and the residue evacuated to remove all traces of dichloromethane to afford 1-[2-chloro-4-(4-chlorophenyl)-n-butyl]imidazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[NH2:7][CH2:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:11][CH2:10]1>CO>[CH3:1][O:2][C:3]([CH2:4][CH2:5][N:7]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:11][CH2:10]1)=[O:6]
Reactant: NCC1COc2ccccc2C1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCN(CCC(=O)OC)CC1COc2ccccc2C1
Reaction time: 16 h
Yield: 95 %

Procedure:
3.03 g (35.2 mmol) of acrylic acid methyl ester are added to a solution of 2.61 g (16 mmol) of 3-aminomethylchroman in 20 ml of methanol. The reaction solution is stirred for 16 hours at 50° and, after cooling, is concentrated by evaporation in vacuo. 5.1 g (95%) of N,N-bis(2-methoxycarbonylethyl)-N-(chroman-3-ylmethyl)-amine are obtained in the form of a reddish oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:10][CH:9]=[CH:8][C:7]=1[OH:25].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCOCC>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][O:25][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:6]=1/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:26])[CH3:35]
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)/C=C/c1c(O)cccc1C#CCCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(=O)CCCOc1cccc(C#CCCCCOC2CCCCO2)c1/C=C/C(=O)OC
Temperature: 25 °C
Reaction time: 23 h
Yield: 102.9 %

Procedure:
A mixture of 7.16 g (20 mmol) of rac-(E)-3-[2-hydroxy-6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenyl]-2-propenoic acid methyl ester (preceding example), 4.37 g (22.4 mmol) of ethyl 4-bromobutyrate, 8.32 g (60.29 mmol) of anhydrous, granular potassium carbonate, and 50 mL of dry dimethyl sulfoxide was stirred at room temperature for 23 hr. The resulting mixture was diluted with ether and worked-up in the usual manner. There was obtained 9.73 g of rac-(E)-4-[2-(3-methoxy-3-oxo-1-propenyl)-3-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenoxy]butanoic acid ethyl ester as a yellow oil containing ca. 10% of ethyl 4-bromobutyrate (NMR analysis). This material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[O:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:7]1[CH2:18]OS(C)(=O)=O.[CH3:30][NH2:31]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[O:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C@@H:7]1[CH2:18][NH:31][CH3:30]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2cc(F)cc([N+](=O)[O-])c2)[C@H]1COS(C)(=O)=O
Reactant: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC[C@@H]1[C@@H](Oc2cc(F)cc([N+](=O)[O-])c2)CCN1C(=O)OC(C)(C)C
Temperature: 55 °C

Procedure:
To a solution of (2R,3S)-tert-butyl 3-(3-fluoro-5-nitrophenoxy)-2-((methylsulfonyloxy)methyl)pyrrolidine-1 -carboxylate (1.0 equiv) in THF (0.4 M) was added 40% aq. methylamine (90 equiv). The resulting solution was heated to 55° C. overnight. The reaction mixture was cooled to room temperature and diluted with EtOAc (20 volume equivalents) and washed twice with sat. aq. NaHCO3 and once with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a dark oil with 147% mass balance; the material was used without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1)=O.[CH3:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH2:15][C:16](=[O:22])[NH:17]2>>[O:10]1[C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[C:15]3[C:14]4[C:18](=[CH:19][CH:20]=[CH:21][C:13]=4[CH3:12])[NH:17][C:16]3=[O:22])=[CH:11][C:7]=2[CH2:8][CH2:9]1
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: Cc1cccc2c1CC(=O)N2
Product: Cc1cccc2c1C(=Cc1ccc3c(c1)CCO3)C(=O)N2

Procedure:
2,3-Dihydro-5-formylbenzofuran (commercially available) was condensed with 4-methyl-2-oxindole to give 0.25 g of 3-(2,3-dihydrobenzofuran-5-ylmethylene)-4-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH3:26]>C(#N)C>[CH3:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:25][CH3:26])[CH2:14][CH2:13]1
Reactant: Cc1c(C2CCNCC2)cccc1S(C)(=O)=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(c2cccc(S(C)(=O)=O)c2C)CC1

Procedure:
Preparation according to Example 1: 4-[2-methyl-3-(methyl-sulfonyl)phenyl]piperidine (0.17 g, 0.67 mmol), acetonitrile (20 ml), potassium carbonate (0.23 g, 1.67 mmol) and 1-iodoethane (0.065 ml, 0.74 mmol). Yield: 0.12 g (64%). MS m/z (relative intensity, 70 eV) 281 (M+, 22), 267 (17), 266 (bp), 129 (12), 115 (24).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[S:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH2:52][C:53](O)=[O:54].CCN(C(C)C)C(C)C>O.CN(C)C=O>[CH3:44][O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH2:52][C:53]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[S:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:54]
Reactant: COc1ccccc1CC(=O)O
Reactant: Nc1nccc2scc(-c3ccc4c(c3)CCN4)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccccc1CC(=O)N1CCc2cc(-c3csc4ccnc(N)c34)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
To a 4 mL screw cap vial was added 3-(2,3-dihydro-1H-indol-5-yl)thieno[3,2-c]pyridin-4-amine (100 mg, 0.374 mmol) followed by HATU (142 mg, 0.374 mmol), 2-methoxyphenylacetic acid (62.2 mg, 0.374 mmol) and DIEA (0.261 mL, 1.496 mmol). N,N-Dimethylformamide (DMF) (2 mL) was added and the reaction was sealed and left to stir at room temperature overnight. The reaction mixture was poured into water (4 mL) and extracted with EtOAc (5 mL). The organics were dried over Na2SO4 and concentrated. The residue was taken up in DCM and purified via normal phase chromatography (0-10% MeOH/DCM). Fractions were collected and concentrated to afford 3-(1-{[2-(methyloxy)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)thieno[3,2-c]pyridin-4-amine (40.6 mg) as a white solid. LC/MS (ES) m/z=416.2 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 3.25 (t, 2H) 3.74-3.84 (m, 5H) 4.27 (t, 2H) 6.01 (br. s., 2H) 6.93 (t, 1H) 7.01 (d, J=7.83 Hz, 1H) 7.20 (dd, J=7.33, 1.52 Hz, 1H) 7.22-7.31 (m, 2H) 7.36 (s, 1H) 7.42 (d, J=6.06 Hz, 1H) 7.57 (s, 1H) 7.84 (d, J=6.06 Hz, 1H) 8.14 (d, J=8.08 Hz, 1H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]1[C:31]2C(=CC=CC=2)[CH2:25][CH:24]1N>>[CH2:5]1[C:4]2[C:3](=[CH:31][CH:23]=[CH:24][CH:25]=2)[CH2:2][CH:1]1[NH:6][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: NC1Cc2ccccc2C1
Product: Cc1nc(NCc2ccccn2)nc(NC2Cc3ccccc3C2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 2,3-dihydro-1H-inden-2-ylamine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.86 (s, 3H), 2.11 (s, 3H), 2.76 (bs, 2H), 2.99 (bs, 2H), 4.49 (bs, 2H), 4.61 (bs, 1H), 6.23 (bs, 1H), 6.72-6.79 (m, 1H), 7.12 (bs, 4H), 7.216-7.23 (m, 1H), 7.21-7.29 (m, 1H), 7.65-7.73 (m, 1H), 8.41 (bs, 1H); MS (ESI) m/z 346.8 (M+1)+.
Reaction SMILES: C(N(CC)CC)C.[O:8]([C@H:16]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:18]([CH:28]=[O:29])[CH2:17]1)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[N+:30]([CH3:33])([O-:32])=[O:31]>>[O:8]([C@H:16]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:18]([CH:28]([OH:29])[CH2:33][N+:30]([O-:32])=[O:31])[CH2:17]1)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)C[N+](=O)[O-]
Reaction time: 15 h
Yield: 65.5 %

Procedure:
Triethylamine (1.27 ml, 9.55 mmol) was added to a solution of (2S,4R)-4-tert-butyldimethylsiloxy-N-tert-butoxycarbonylprolinal (19.1 g, 57.87 mmol) in nitromethane (95 ml) under stirring and cooling with ice. This solution was left to stand at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakogel™ C-300, 350 g, hexane-ethyl acetate 9:1) to obtain oily (2S,4R)-4-tert-butyldimethylsiloxy-N-tert-butoxycarbonyl-2-(1-hydroxy-2nitroethyl)pyrrolidine (14.81 g, yield: 65.5%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH2:19])[CH2:17][CH3:18].[BH4-].[Na+]>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:16]([NH:19][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)[CH2:17][CH3:18]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCNCc1cccc(Oc2ccccc2)c1
Temperature: 80 °C
Yield: 57.3 %

Procedure:
3-Phenoxybenzaldehyde (2.00 mL, 2.29 g, 11.6 mmol), n-propylamine (0.95 mL, 0.68 g, 11.5 mmol), and p-toluenesulfonic acid monohydrate (15 mg, 0.08 mmol) were dissolved in absolute ethanol (15 mL), then heated to 80° C. in a sealed tube for 2.5 hours. The reaction was cooled to room temperature, transfered to a round-bottom flask, then sodium borohydride (440 mg, 11.6 mmol) was added, followed by heating under reflux for 2.5 hours. The reaction was concentrated, the residue partitioned between water and EtOAc, the EtOAc layer washed with water and brine. After drying with Na2SO4, filtration, and concentration, the residue was purified by chromatography on silica gel eluting with 4:6 followed by 3:7 hexane-EtOAc to give 1.59 g (57%) of the title compound as a light yellow oil. 1H NMR (CDCl3) δ 7.30 (m, 3H), 7.08 (m, 2H), 7.00 (m, 3H), 6.88 (dd, 1H), 3.77 (s, 2H), 2.60 (t, 2H), 1.53 (m, 2H), 0.92 (t, 3H). MS (DCl/NH3) m/e 242 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8](=O)[CH3:9])=[CH:3][CH:2]=1.BrBr.[N:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[NH:19][C:20]([NH2:22])=[S:21]>O1CCOCC1>[CH3:9][C:8]1[N:22]=[C:20]([NH:19][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][N:13]=2)[S:21][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: CC(=O)Cc1ccncc1
Reactant: NC(=S)Nc1cnccn1
Agent: BrBr
Solvent: C1COCCO1
Product: Cc1nc(Nc2cnccn2)sc1-c1ccncc1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 1-pyridin-4-yl-propan-2-one (0.1 g, 0.812 mmol) in dioxane (7 ml) is added bromine (0.029 ml, 0.569 mmol) dropwise. After 45 minutes, the solvent is removed in vacuo and the crude product is dissolved in ethanol (15 ml). The solution is treated with pyrazin-2-yl-thiourea (0.125 g, 0.812 mmol) and the reaction mixture is heated at 60° C. for 3 hours. The solvent is removed in vacuo and purification by chromatography on silica, eluting with ethyl acetate-methanol affords the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([C@H:19]([C:30](OCC)=[O:31])[CH2:20][CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][C@H:12]1[CH3:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].CO.S([O-])(O)(=O)=O.[K+]>O1CCCC1.C(OCC)(=O)C.CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([C@H:19]([CH2:30][OH:31])[CH2:20][CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][C@H:12]1[CH3:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@H](CCOCc1ccccc1)N1C[C@@H](C)N(C(=O)OCc2ccccc2)CCC1=O
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H]1CN([C@H](CO)CCOCc2ccccc2)C(=O)CCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 65.3 %

Procedure:
A solution of 3.90 g (8.10 mmol) of (R)-4-((S)-3-benzyloxy-1-ethoxycarbonyl-propyl)-2-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester in 73 ml of tetrahydrofuran was treated at 0° C. with 4.44 ml (8.90 mmol, 2 M solution in tetrahydrofuran) of lithium borohydride. The reaction was stirred 10 min at 0° C. and 4 h at room temperature, again treated with 3.64 ml (7.30 mmol, 2 M solution in tetrahydrofuran) of lithium borohydride. After 16 h, 5.2 ml of methanol was added and the reaction was neutralized with cold 10% aq. potassium hydrogensulfate solution and extracted with ethyl acetate (3×). The organic phases were washed with 10% aq. potassium hydrogensulfate solution, 10% aq. sodium chloride solution, dried over Na2SO4 and evaporated to yield after flash silica gel column (ethyl acetate/n-heptane 1:1 to ethyl acetate, then ethyl acetate/methanol 98:2) 2.33 g (65%) of the title compound as off-white oil. MS: 441.4 (MH+).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[CH:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:39]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:40])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C3CCCCC3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (13 mg, 28 μmol) was dissolved in abs. pyridine (0.65 ml). At room temperature, cyclohexanecarbonyl chloride (8.3 mg, 57 μmol, 2 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Kromasil C18 column, 20×50 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (12.5 mg, 83% of theory).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][C@H:13]([CH3:28])[C@:14]2([OH:27])[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[F:36]C(F)(F)C([O-])=O.[Na+].FF.S([O-])([O-])(=O)=S.[Na+].[Na+]>N1C=CC=CC=1.FC(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@:21]2([F:36])[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][C@H:13]([CH3:28])[C@:14]2([OH:27])[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3C[C@H](C)[C@]2(O)C(C)=O)C1
Reactant: O=C([O-])C(F)(F)F
Agent: FF
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: FC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4C[C@H](C)[C@](O)(C(C)=O)[C@@]4(C)CC[C@@]32F)C1
Yield: 50 %

Procedure:
3β-Acetoxy-17α-hydroxy-16β-methyl-5α-pregnan-20-one (1g, prepared by treatment of the corresponding 3β-ol with acetic anhydride in pyridine) was dissolved in fluorotrichloromethane (250 ml) and chloroform (200 ml) containing sodium trifluoroacetate (ca. 2g) and sodium fluoride (ca. 2g). The resulting solution was cooled to -78° and vigourously stirred, whereupon fluorine from four 750 cc bottles (8-10% v/v fluorine in nitrogen) was added over 9-10 hours. The reaction solution was then poured into aqueous sodium thiosulphate and the organic layer was separated, washed with water, dried over potassium carbonate and evaporated to dryness. The residue was purified by liquid chromatography, eluting with cyclohexane containing 30% v/v ethyl acetate and 0.1% v/v pyridine, to yield 3β-acetoxy-9α-fluoro-17α-hydroxy-16β-methyl-5α-pregnan-20-one (50%); m.p. 150° (after recrystallisation from acetone); PMR spectrum includes signals at δ 2.20 (21-Me), 2.00 (3-0.CO.CH3), 0.92 (19-Me) and 0.87 (18-Me); FMR φ* + 179.5 ppm. (Found: C, 70.51; H, 9.20; F, 4.48; C24H37FO4 requires C, 70.55; H, 9.13; F, 4.65%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[CH:11](O)=O>>[Br:1][C:2]1[C:3]2[N:10]=[CH:11][NH:9][C:4]=2[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=CO
Reactant: Nc1cc(F)cc(Br)c1N
Product: Fc1cc(Br)c2nc[nH]c2c1
Temperature: 110 °C

Procedure:
A mixture of 3-bromo-5-fluorobenzene-1,2-diamine (10.1 g, 49 mmol) in formic acid (20 mL) was heated at 110° C. overnight. The reaction mixture was concentrated, and to the residue was added MeOH (5 mL) to form a precipitate. The precipitate was filtered and washed with MeOH (2 mL) to afford 4-bromo-6-fluoro-1H-benzo[d]imidazole as a yellow solid (10 g, yield, 73%). MS (ESI): m/z=215 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[C:4]([CH3:23])[CH:3]=1.Br[C:25]1[CH:30]=[N:29][C:28]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu](I)I>[CH3:35][O:34][CH2:33][CH2:32][O:31][C:28]1[N:29]=[CH:30][C:25]([O:1][C:2]2[CH:3]=[C:4]([CH3:23])[C:5]([C:9]3[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[S:12][CH:13]=3)=[C:6]([CH3:8])[CH:7]=2)=[N:26][CH:27]=1
Reactant: COCCOc1cnc(Br)cn1
Reactant: Cc1cc(O)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cnc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cn1
Temperature: 100 °C
Yield: 25.8 %

Procedure:
A mixture of 5-3 (0.50 g, 1.54 mmol), 2-bromo-5-(2-methoxyethoxy)pyrazine (22-2, 0.540 g, 2.32 mmol), copper iodide (15.0 mg, 0.080 mmol), and potassium carbonate (0.64 g, 4.63 mmol) in 3.1 mL of DMF was heated at 100° C. for 6.0 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (EtOAc:hexanes=5:1 as eluant) to give N-(4-(4-{(5-(2-methoxyethoxy)pyrazin-2-yl)oxy}-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (22, 0.19 g) as brown solids: 1H NMR (500 MHz, CDCl3) δ 8.77 (d, J=4.5 Hz, 2 H), 7.91 (d, J=1.0 Hz, 1 H), 7.88 (d, J=1.0 Hz, 1 H), 7.73 (d, J=5.5 Hz, 2 H), 6.79 (s, 1 H), 6.63 (s, 2 H), 4.46 (t, J=4.5 Hz, 2 H), 3.75 (t, J=4.5 Hz, 2 H), 3.43 (s, 3 H), 1.98 (s, 6 H). ESI-MS: m/z 478.2 (M+H)+.