Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[C:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:39]>CN(C=O)C>[Cl:39][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:25]=1[CH2:24][N:9]1[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])=[N:8]1
Reactant: Clc1cccc(OCc2ccccc2)c1CBr
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccn(Cc2c(Cl)cccc2OCc2ccccc2)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,6-difluoro-N-(1H-pyrazol-3-yl)benzamide (for a preparation see Intermediate 9) (0.360 g, 1.61 mmol) and potassium carbonate (0.308 g, 2.23 mmol) was added a solution 2-(bromomethyl)-1-chloro-3-[(phenylmethyl)oxy]benzene (for a preparation see Intermediate 8)(0.50 g, 1.61 mmol) in DMF (5 ml). The suspension was stirred overnight at ambient temperature. The suspension was partitioned between ethyl acetate (30 ml) and water (30 ml). The phases were separated and the organic phase washed with ethyl acetate (30 ml). The combined organic extracts were washed with brine (30 ml) and the solvent removed in vacuo. The residue was loaded in dichloromethane and purified on silica 50 g using 0-50% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (0.212 g); LCMS: (System 1) MH+=455, tRET=3.59 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N:34]1[CH2:38][CH2:37][O:36][C:35]1=[O:39]>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:20])[CH3:21])=[O:24])=[C:28]([N:34]2[CH2:38][CH2:37][O:36][C:35]2=[O:39])[CH:29]=1
Reactant: NCc1ccc(F)cc1N1CCOC1=O
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1CCOC1=O)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and 3-(2-(aminomethyl)-5-fluorophenyl)oxazolidin-2-one, derived from reduction of intermediate 117, 4-fluoro-2-(2-oxooxazolidin-3-yl)benzonitrile. 1H NMR (400 MHz, MeOD) δ ppm: 9.48 (1H, dd, J=8.6, 6.5 Hz), 7.41 (2H, m), 7.32 (3H, m), 7.22 (1H, dd, J=9.6, 2.5 Hz), 7.08 (1H, td, J=8.6, 2.7 Hz), 5.21 (2H, s), 4.57 (2H, t, J=7.7 Hz), 4.50 (2H, s), 4.07 (4H, m), 3.99 (2H, m), 1:61 (6H, s). LCMS (M+H)+ m/z 523.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10](SC)[N:11]=[N:12][CH:13]=1.[NH2:16][NH2:17]>CO.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH:16][NH2:17])[N:11]=[N:12][CH:13]=1
Reactant: NN
Reactant: CSc1nncc(-c2ccccc2F)n1
Solvent: C1CCOC1
Solvent: CO
Product: NNc1nncc(-c2ccccc2F)n1

Procedure:
To a solution of 27.6 g. of 5-(o-fluorophenyl)-3-(methylthio)-1,2,4-triazine in 100 ml. of 1:1 methanol-tetrahydrofuran is added 6.4 ml. of 95% hydrazine. The mixture is refluxed for about 22 hours and then cooled. The solid is recovered by filtration, giving 5-(o-fluorophenyl)-3-hydrazino-1,2,4-triazine as yellow crystals.
Reaction SMILES: [CH3:1][C:2]([NH:14][C:15]1[C:16](=[O:39])[N:17]([C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)[C@@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)[CH:19]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[N:5]=1)[CH3:3].C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:3][C:2]([NH:14][C@@H:15]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:28])[F:29])[CH:21]=2)[N:17]([C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)[C:16]1=[O:39])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:11])[F:12])[N:5]=1)[CH3:1]
Reactant: CC(C)(NC1=C[C@H](c2cccc(OC(F)(F)F)c2)N(c2ccc(C#N)cc2)C1=O)c1cccc(C(F)(F)F)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(N[C@@H]1C[C@H](c2cccc(OC(F)(F)F)c2)N(c2ccc(C#N)cc2)C1=O)c1cccc(C(F)(F)F)n1
Reaction time: 1 h
Yield: 70.6 %

Procedure:
Dissolve 4-[(R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-2-oxo-5-(3-trifluoromethoxy-phenyl)-2,5-dihydro-pyrrol-1-yl]-benzonitrile (1.06 g, 1.94 mmol) in acetic acid (19.4 mL) and add sodium cyanoborohydride (609 mg. 9.70 mmol). Stir 1 hr. at ambient temperature. Concentrate under reduced pressure. Dissolve the residue in dichloromethane and concentrate. Partition the residue between dichloromethane and 5% NaHCO3 solution and extract with dichloromethane. Combine dichloromethane extracts, dry over magnesium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography (25% ethyl acetate-hexane) to obtain 4-[(3R,5R)-3-[1-Methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-2-oxo-5-(3-trifluoromethoxy-phenyl)-pyrrolidin-1-yl]-benzonitrile (751 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 7.80-7.76 (m, 2H), 7.50-7.46 (m, 3H), 7.38 (d, J=8.8 Hz, 2H), 7.29-7.23 (m, 1H), 7.05 (t, J=7.3 Hz, 2H), 6.95 (s, 1H), 4.98 (dd, J=6.2, 9.7 Hz, 1H), 3.46 (dd, J=8.1, 10.8 Hz, 1H), 2.83-2.74 (m, 1H), 1.85-1.76 (m, 1H), 1.54 (d, J=7.0, 6H). LC-MS ESI m/z: 549.0 (M+H)+, Tr=2.285 min., method 2.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH:21]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:21][C:10]=3[S:11][CH:12]=2)=[CH:15][CH:16]=1
Reactant: C1CCNC1
Reactant: Fc1ccc(-c2csc3cc(OCCCBr)ccc23)cc1
Product: Fc1ccc(-c2csc3cc(OCCCN4CCCC4)ccc23)cc1

Procedure:
In analogy to example 3.1, 6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and pyrrolidine were converted to yield 1-{3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl-pyrrolidine as colorless oil, MS: 356 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]([CH3:25])([CH3:24])[CH2:10]2)[N:5]=[C:4]([O:26][CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[N:30]([O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:29]([CH3:43])([CH3:42])[CH2:28]2)[N:3]=1.[CH2:44]([CH2:46][NH2:47])[OH:45]>>[OH:45][CH2:44][CH2:46][NH:47][C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][C:13]([CH3:15])([CH3:16])[N:12]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]([CH3:25])([CH3:24])[CH2:10]2)[N:5]=[C:4]([O:26][CH:27]2[CH2:32][C:31]([CH3:33])([CH3:34])[N:30]([O:35][CH:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]3)[C:29]([CH3:43])([CH3:42])[CH2:28]2)[N:3]=1
Reactant: NCCO
Reactant: CC1(C)CC(Oc2nc(Cl)nc(OC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Product: CC1(C)CC(Oc2nc(NCCO)nc(OC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)oxy]-1,3,5-triazine with ethanolamine.
Reaction SMILES: [C:1]([C:3]1([CH3:18])[CH2:8][CH2:7][CH:6]([CH2:9][NH:10]C(=O)OC(C)(C)C)[CH2:5][CH2:4]1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH2:10][CH2:9][CH:6]1[CH2:7][CH2:8][C:3]([CH3:18])([C:1]#[N:2])[CH2:4][CH2:5]1
Reactant: CC1(C#N)CCC(CNC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C#N)CCC(CN)CC1
Reaction time: 3 h

Procedure:
To a solution of EXAMPLE 366A (480 mg) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL). The mixture was stirred for 3 hours. The mixture was then concentrated under vacuum and was used directly in the next reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=4)[N:19]=3)[N:14](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:13]=1)[CH2:5]2.[NH:52]1[C:56](B(O)O)=[CH:55][CH:54]=[N:53]1.C([O-])([O-])=O.[Na+].[Na+].[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>O1CCOCC1>[CH:30]([S:27]([C:24]1[CH:23]=[CH:22][C:21]([C:18]2[N:19]=[C:20]3[C:12]([N:6]4[CH2:5][C:4]5[C:8](=[CH:9][CH:10]=[C:2]([C:54]6[NH:53][N:52]=[CH:56][CH:55]=6)[CH:3]=5)[C:7]4=[O:11])=[CH:13][NH:14][C:15]3=[N:16][CH:17]=2)=[CH:26][CH:25]=1)(=[O:28])=[O:29])([CH3:31])[CH3:32]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N2Cc4cc(Br)ccc4C2=O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: OB(O)c1ccn[nH]1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]cc(N4Cc5cc(-c6ccn[nH]6)ccc5C4=O)c3n2)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 21.2 %

Procedure:
5-bromo-2-[2-(4-isopropylsulfonylphenyl)-5-trityl-pyrrolo[2,3-b]pyrazin-7-yl]isoindolin-1-one (100 mg, 0.1327 mmol), 1H-pyrazol-5-ylboronic acid (17.81 mg, 0.1592 mmol) and Na2CO3 (200 μL of 2 M aqueous solution, 0.40 mmol) combined in 1,4-dioxane (1.5 mL). Mixture de-gassed (×3 vacuum-N2 cycles). Pd(tBu3P)2 (6.782 mg, 0.01327 mmol) added and mixture de-gassed (×3 cycles) then heated overnight at 60° C. Reaction mixture partitioned between DCM and water. Aqueous phase extracted with DCM. Combined organics dried and concentrated. Residue taken up in DCM (2 mL) and Et3SiH (106.0 μL, 0.6635 mmol) then TFA (0.3 mL) added under N2. Mixture stirred for 48 h then concentrated and residue azeotroped with DCM (×3). Residue purified by hplc to give the title compound (14 mg, 21%); 1H NMR (400 MHz, DMSO) 1.22 (6H, d), 3.50 (1H, sep), 5.58 (2H, s), 6.90 (1H, d), 7.83-7.87 (2H, m), 8.00 (2H, d), 8.05 (1H, d), 8.25 (1H, s), 8.53-8.57 (3H, m), 9.11 (1H, s), 12.33 (1H, vbrs), 13.10 (1H, s); MS (ES+) 499.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=3)=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(Nc3ccc(C(F)(F)F)cn3)cc2)COC1(C)C
Temperature: 110 °C
Reaction time: 1 h
Yield: 37.9 %

Procedure:
In a pressure tube, (S)-4-[2-(4-amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (100 mg), 2-chloro-5-(trifluoromethyl)pyridine (57 mg) and potassium carbonate (431 mg) were combined with toluene (1 ml) to give a yellow solution. The mixture was degassed by bubbling through argon for several minutes. BINAP (12 mg) and palladium(II)acetate (2 mg) were then added and the tube was sealed. The reaction mixture was stirred at 110° C. for 1 hour. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (SiO2; gradient: 0% to 40% EtOAc in hexane) to afford (S)-2,2-dimethyl-4-{2-[4-(5-trifluoromethyl-pyridin-2-ylamino)-phenyl]-ethyl}-oxazolidine-3-carboxylic acid tert-butyl ester (55 mg, 38%) as a yellow amorphous solid. MS (ISP): 466.3 ([M+H]+), 410.2 ([M+H—C4H8]+), 366.2 ([M+H—C4H8—CO2]+).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[S:20][C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:26]=3[N:27]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1.[F:28][C:29]([F:35])([F:34])[CH2:30][C:31](Cl)=[O:32]>>[F:28][C:29]([F:35])([F:34])[CH2:30][C:31]([N:23]1[CH2:24][CH2:25][C:26]2[N:27]=[C:19]([NH:18][C:8]3[CH:9]=[CH:10][C:11]([N:12]4[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]4)=[C:6]([O:5][CH3:4])[CH:7]=3)[S:20][C:21]=2[CH2:22]1)=[O:32]
Reactant: COc1cc(Nc2nc3c(s2)CNCC3)ccc1-n1cnc(C)c1
Reactant: O=C(Cl)CC(F)(F)F
Agent: Cl
Product: COc1cc(Nc2nc3c(s2)CN(C(=O)CC(F)(F)F)CC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 45 from 90 mg (0.2 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-amine trihydrochloride and 30 mg (0.2 mmol) 3,3,3-trifluoropropionylchloride yielding 29 mg (32%) 3,3,3-trifluoro-1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl}-propan-1-one as a light yellow solid. MS ISP (m/e): 452.0 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.33 (s, 1H), 7.65 (S, 1 h), 7.47 (S, 1 h), 7.30-7.25 (m, 2H), 7.02 (s, 1H), 4.57 (br s, 2H), 3.85-3.59 (br m, 2H), 3.78 (s, 3H), 2.75 (m, 1H), 2.62 (m, 1H), 2.14 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[CH3:12][S:13]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([NH:21][NH2:22])=[O:20])(=[O:15])=[O:14]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](/[C:8](=[N:22]/[NH:21][C:19](=[O:20])[C:18]2[CH:23]=[CH:24][CH:25]=[C:16]([S:13]([CH3:12])(=[O:14])=[O:15])[CH:17]=2)/[CH3:9])[CH:7]=1
Reactant: CS(=O)(=O)c1cccc(C(=O)NN)c1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(C)(=O)=O)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 63.5 %

Procedure:
1-(5-Chloro-2-hydroxyphenyl)ethanone (55 mg, 0.322 mmol) and 3-(methylsulfonyl)benzohydrazide (69.1 mg, 0.322 mmol) were dissolved in methanol (5 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (3% CH3OH/CH2Cl2) affording the title compound (75 mg, 63.4% yield) as a solid. 1H NMR (400 MHz, CD3OD): δ 8.49 (s, 1H), 8.26 (d, 1H, J=8.4 Hz), 8.18 (d, 1H, J=7.6 Hz), 7.80 (t, 1H, J=7.6 Hz), 7.60 (d, 1H, J=2.4 Hz), 7.27 (m, 1H), 6.93 (d, 1H, J=8.8 Hz), 3.19 (s, 3H), 2.49 (s, 3H). ESI-MS: 367.8 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:16]=1)[C:8](N(OC)C)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Mg]Br.Cl>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([C:8](=[O:9])[CH3:22])[CH:14]=[C:15]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:16]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Mg]Br
Reactant: COCCOc1cc(C(=O)N(C)OC)cc(C(C)(C)C)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1cc(C(C)=O)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-tert-Butyl-N-methoxy-5-(2-methoxyethoxy)-N-methylbenzamide (O3.043; 1.35 g) was dissolved in THF (40 ml), methylmagnesium bromide (3.05 ml, 3 M in ether) was added dropwise at 0° C. and then the mixture was stirred at RT for 2 h. Then the mixture was admixed with 1 N hydrochloric acid (50 ml), diluted with water and extracted by shaking three times with EA. Then the combined EA phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel (40 g cartridge, n-heptane/EA gradient of 0-30% in 30 min). 1.0 g of the title compound were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[N:6][CH:7]=1.[C:13]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:5]1[N:6]=[CH:7][C:2]([CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]([O:21][CH2:22][CH3:23])=[O:20])=[CH:3][CH:4]=1
Reactant: Brc1ccc(C2OCCO2)nc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(C2OCCO2)nc1
Temperature: 25 °C
Yield: 72 %

Procedure:
To a solution of 5-bromo-2-(1,3-dioxolan-2-yl)pyridine (2.00 g) in 1,4-dioxane (30 mL) were added diethyl malonate (1.6 mL), palladium acetate (II) (195 mg), di-tert-butyl(2′-methylbiphenyl-2-yl)phosphane (600 mg) and tripotassium phosphate (4.30 g), and the mixture was heated under reflux under argon atmosphere overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography, and the title compound (1.95 g, yield 72%) was obtained as a brown oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 310 (MH+).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8]([C:13]#[N:14])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[CH3:24][S:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29].C([O-])(O)=O.[Na+]>CC#N>[Cl:12][C:10]1[CH:9]=[C:8]([C:13]#[N:14])[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:26]([S:25][CH3:24])[CH:27]=2)[N:11]=1
Reactant: CSc1cccc(N)c1
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(SC)c1
Temperature: 60 °C
Reaction time: 48 h
Yield: 32.1 %

Procedure:
A mixture of methyl 2,6-dichloro-4-cyanonicotinate (340.8 mg, 1.475 mmol), DIPEA (0.3 mL, 1.718 mmol) and 3-(methylthio)aniline (234.8 mg, 1.687 mmol) in CH3CN (5 mL) was stirred at 60° C. for 2 days. After the mixture was cooled, saturated aq NaHCO3 (30 mL) was added and the mixture was extracted with EtOAc (2×30 mL). The organic layers were washed with saturated aq NaHCO3 (20 mL), water (20 mL) and brine (20 mL), were dried over anhydrous Na2SO4, and then filtered through SiO2. The filtrate was concentrated under reduced pressure and the residue was washed with IPE and filtered to give the title compound as a yellow solid (157.8 mg). The filtrate was purified by column chromatography (SiO2, hexanes/EtOAc=8/1) to give another crop (135.5 mg) of the title compound as a yellow oil of (total 293 mg, 60%). 1H-NMR (CDCl3) δ ppm 2.52 (s, 3H), 4.05 (s, 3H), 7.00 (s, 1H), 7.03-7.05 (m, 1H), 7.25-7.32 (m, 2H), 7.66-7.67 (m, 1H), 10.51 (br s, 1H). [M+H] calc'd for C15H13ClN3O2S, 334. found, 334.
Reaction SMILES: I[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C1(C=CC(O)=CC=1)O.Br[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN(C)C=O.[Zn].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].ClCCl>[N:27]1[CH:28]=[CH:29][C:24]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:25][CH:26]=1
Reactant: Brc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: Oc1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccncc2)CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Dichloromethane (0.1 ml) was added to a suspension of zinc (2 g, 31.7 mmol) in N,N-dimethylformamide (5 ml), and the mixture warmed until gas evolution occurred. tert-Butyl 4-iodo-1-piperidinecarboxylate (EP 1078928) (4.9 g, 15.8 mmol), and hydroquinone (35 mg, 0.32 mmol) in N,N-dimethylformamide (5 ml) was added, and the mixture warmed until an exotherm was evident. 4-Bromopyridine (1 g, 6.33 mmol), tris(dibenzylideneacetone)dipalladium (0) (73 mg, 0.127 mmol) and tri(2-furyl)phosphine (59 mg, 0.25 mmol) in N,N-dimethylformamide (5 ml) were added, and the reaction stirred at 60° C. for 30 minutes. The cooled mixture was partitioned between water (100 ml) and diethyl ether (50 ml), and the layers separated. The aqueous phase was extracted with diethyl ether (2×50 ml), the combined organic solutions washed with brine (50 ml), dried (MgSO4) and evaporated under reduced pressure, to give a brown oil. This was purified by column chromatography on silica gel using ethyl acetate:pentane (50:50) as eluant to afford the title compound as a yellow oil, 1.1 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:19][S:20]([OH:22])=[O:21].CNCCNC>CS(C)=O>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([S:20]([CH3:19])(=[O:22])=[O:21])[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]=2[C:6]([CH3:14])=[CH:7]1)([CH3:13])[CH3:12]
Reactant: CS(=O)O
Reactant: COC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Agent: CNCCNC
Solvent: CS(C)=O
Product: Cc1cn(C(C)C)c2cc(S(C)(=O)=O)cc(C(=O)O)c12
Temperature: 165 °C
Yield: 25.3 %

Procedure:
To a 30-mL microwave tube were added methyl 6-bromo-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (490 mg, 1.580 mmol), methanesulfinic acid (212 mg, 2.054 mmol), DMSO (7 mL), N,N′-dimethyl-1,2-ethanediamine (18.10 mg, 0.205 mmol), and the mixture was degassed for 5 min by bubbling N2. Copper(I) trifluoromethanesulfonate benzene complex (63.6 mg, 0.126 mmol) was added and the tube was sealed. The mixture was heated at 165° C. overnight with stirring. The mixture was allowed to cool, filtered and purified using reverse-phase HPLC (Gemini 5u C18(2) 100A, AXIA; 30×100 mm 5 micron; 30 mL/min, 30% ACN/H2O, 0.1% formic acid to 60% ACN/H2O, 0.1% formic acid) to give the title compound (118 mg, 25%) as a white solid. 1H NMR (400 MHz, DMSO-d6) ppm 1.47 (d, J=8.00 Hz, 6 H), 2.30-2.41 (m, 3 H), 4.94 (quin, J=6.63 Hz, 1 H), 7.80 (s, 1 H), 7.88 (d, J=1.77 Hz, 1 H), 8.24 (d, J=1.52 Hz, 1 H), 13.17 (br. s., 1 H). MS: (M+H)+=296.3.
Reaction SMILES: [O:1]=[C:2]([CH3:16])[CH2:3][C:4]([NH:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5].[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)#[N:18].N1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.O>[C:2]([C:3](=[CH:23][C:22]1[CH:25]=[CH:26][C:19]([C:17]#[N:18])=[CH:20][CH:21]=1)[C:4]([NH:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5])(=[O:1])[CH3:16]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(=O)CC(=O)NCC=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CC(=O)C(=Cc1ccc(C#N)cc1)C(=O)NCC=Cc1ccccc1

Procedure:
600 mg (2.76 mmol) of 3-oxo-N-(3-phenyl-2-propene-1-yl)butyramide, 362 mg (2.76 mmol) of 4-cyanobenzaldehyde and 23.5 mg (0.276 mmol) of piperidine were heated under reflux in the presence of a catalytic amount of p-toluenesulfonic acid in 30 ml of benzene for 6 hours while water was removed. Benzene was evaporated under reduced pressure. Ethyl acetate was added to the reaction mixture. After washing with 1 N hydrochloric acid and then with a saturated aqueous sodium hydrogencarbonate solution, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=5/1) to obtain the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:9].I[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[C:15]([O:14][C:12]([CH2:11][N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH:2]([NH2:1])[C:3]1=[O:9])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)CI
Reactant: NC1CCCCNC1=O
Product: CC(C)(C)OC(=O)CN1CCCCC(N)C1=O

Procedure:
3-Aminoperhydro-2-azepinone (R. Pellegata, et al., Synthesis, 1978, 614-616) was alkylated with t-butyl iodoacetate as described in Example 1, Step B, to afford 1-t-butoxycarbonylmethyl-3-aminoperhydro-2-azepinone.