Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1)(=O)=O)([O-])=O.CN1CCOCC1.[N:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[C:53]([OH:55])=O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C=O)C>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][NH:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]([CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)[C:53](=[O:55])[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][N:47]=2)=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(c1ccccn1)N(Cc1ccc(CNCc2ccccn2)cc1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 131.1 %

Procedure:
To a stirred solution of N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (209 mg, 0.39 mmol) in dry DMF (1 mL) was added N-methylmorpholine (0.5 mL, 4.45 mmol), picolinic acid (64 mg, 0.52 mmol), 1-hydroxybenzotriazole (57 mg, 0.42 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (85 mg, 0.44 mmol). The reaction mixture was allowed to stir at room temperature for further 18 hours and then concentrated. The residue was diluted with ethylacetate (300 mL) and washed with saturated aqueous NaHCO3, then brine, dried (Na2SO4) and evaporated. Purification of the crude material by column chromatography on silica gel (1.5×20 cm, 50:50 EtOAc/CH2Cl2) gave the desired amide (237 mg, 94%) as a yellow oil.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH:16][C:17](=[O:29])[C@@H:18]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[CH3:21][CH:20]([CH3:22])[CH2:19][C@H:18]([N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)[C:17]([NH:16][C@H:13]1[C@H:11]2[C@H:10]([CH2:9][NH:8][CH2:12]2)[CH2:15][CH2:14]1)=[O:29]
Reactant: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N1CCOCC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CNC[C@H]21)N1CCOCC1

Procedure:
(S)—N-((3aS,4R,6aR)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-yl)-4-methyl-2-morpholinopentanamide (0.400 g, 1.001 mmol) from Step B of Example 249 and ethanol (40 mL) were added to 20% Pd(OH)2 on carbon, wet (0.080 g, 0.570 mmol) in a 250 mL stainless steel pressure bottle and stirred for 16 hours under 30 psi hydrogen at 55° C. The mixture was filtered through a nylon membrane and the solvent removed in vacuo to give (S)-4-methyl-2-morpholino-N-((3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl)pentanamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.46 (d, J=6.9, 1H), 4.46-4.38 (m, 1H), 3.74 (s, 4H), 3.45 (dd, J=2.0, 11.3, 1H), 3.31-3.21 (m, 2H), 3.10 (dd, J=7.0, 11.0, 1H), 2.89 (dd, J=2.3, 11.0, 1H), 2.83-2.77 (m, 2H), 2.76-2.67 (m, 4H), 2.09 (td, J=6.0, 11.8, 1H), 1.95-1.87 (m, 1H), 1.84 (dq, J=6.0, 9.7, 2H), 1.71-1.57 (m, 2H), 1.49 (ddt, J=6.3, 9.1, 12.5, 1H), 0.94 (dd, J=6.3, 11.2, 6H); MS (ESI+) m/z 310 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[F:21][C:22]1([F:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.Cl.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:25]3[CH2:26][CH2:27][C:22]([F:28])([F:21])[CH2:23][CH2:24]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: FC1(F)CCNCC1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cn1c(CCN2CCC(F)(F)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 37 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (60 mg, 0.20 mmol) in DCE (10 mL) was added 4,4-difluoropiperidine.HCl (42 mg, 0.26 mmol), triethylamine (0.04 mL, 0.26 mmol), powdered 4 Å molecular sieves and sodium triacetoxyborohydride (86 mg, 0.41 mmol). The reaction mixture was stirred at room temperature for 5 h, the reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by column chromatography (Si—PCC, 0-5% MeOH in DCM) to give the title compound as a pale yellow oil (30 mg, 37%). LCMS (Method H): RT=2.61 min, [M+H]+ 401.5
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[CH3:32][C:33]([OH:50])([CH3:49])[CH2:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:38]3[CH:37]=[N:36][N:35]([CH2:34][C:33]([OH:50])([CH3:49])[CH3:32])[CH:39]=3)[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3cnn(CC(C)(C)O)c3)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (see US2011/76291) gave 228. 1H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 8.04 (s, 1H), 7.88 (s, 1H), 4.88 (dd, J=10.0, 3.9 Hz, 1H), 4.69-4.42 (m, 1H), 4.39-4.24 (m, 1H), 4.17-3.95 (m, 4H), 3.77 (s, 3H), 2.15-2.05 (m, 1H), 1.89-1.68 (m, 3H), 1.10 (d, J=4.4 Hz, 6H). LCMS (ES+) m/z 478 (M+1).
Reaction SMILES: C([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:10]2([C:29]3[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:31])[CH:9]1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[F:39])=[O:7])(C)(C)C.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:17]([O:16][CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13][CH:11]1[C:10]2([C:29]3[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:31])[CH:9]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])[CH:8]([C:6]([OH:7])=[O:5])[NH:12]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OCC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
A solution of rac-(2′S,3′R,4′S,5′R)-2′-(3-acetoxy-2,2-dimethyl-propyl)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (0.24 g, 0.41 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 g). The reaction mixture was stirred at room temperature for 18 h, then concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried in vacuo to give rac-(2′S,3′R,4′S,5′R)-2′-(3-acetoxy-2,2-dimethyl-propyl)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid as a yellow solid (0.25 g, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][S:27][C:21]=2[N:20]=[C:19]1[CH:28]([NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH2:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][S:27][C:21]=2[N:20]=[C:19]1[CH:28]([N:31]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:29][CH3:30])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCC(NCCN(C)C)c1nc2sccc2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(c1nc2sccc2c(=O)n1Cc1ccccc1)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of 4-bromobenzoyl chloride (8 mg, 0.035 mmol, 1 equiv) in dichloromethane (1 mL) was added to a solution of 3-benzyl-2-(1-{[2-(dimethylamino)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one (3-1, 13 mg, 0.035 mmol, 1 equiv) and N,N-diisopropylethylamine (5 mg, 0.035 mmol, 1 equiv) in dichloromethane (1 mL), and the resulting mixture was stirred under ambient conditions for 1 h. The reaction mixture was washed with saturated aqueous NaHCO3 solution, and brine, then dried (MgSO4) and concentrated. The residue was purified by flash chromatography. Elution with CH2Cl2 to 5% NH3-EtOH/CH2Cl2 gave N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]-4-bromo-N-[2-(dimethylamino)ethyl]benzamide (3-2) as an off-white foam. 1H NMR (500 MHz, CDCl3) δ 7.53 (m, 3H), 7.31 (m, 5H), 7.14 (m, 2H), 6.09 (d, J=15.6 Hz, 1H), 5.94 (m, 1H), 5.10 (d, J=15.6 Hz, 1H), 3.40 (m, 2H), 2.11 (m, 1H), 2.03 (m, 2H), 1.87 (m, 1H), 1.79 (s, 6H), 0.66 (t, J=6.6 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:23]([NH2:24])=[C:6]2[C:7]([O:21][CH3:22])=[CH:8][CH:9]=[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])[N:5]2[N:4]=1)[CH3:2].[CH3:25][CH2:26][C:27](=O)[CH2:28][CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH2:1]([C:3]1[C:23]([NH:24][CH:27]([CH2:28][CH3:29])[CH2:26][CH3:25])=[C:6]2[C:7]([O:21][CH3:22])=[CH:8][CH:9]=[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])[N:5]2[N:4]=1)[CH3:2]
Reactant: CCC(=O)CC
Reactant: CCc1nn2c(-c3c(C)cc(C)cc3OC)ccc(OC)c2c1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCc1nn2c(-c3c(C)cc(C)cc3OC)ccc(OC)c2c1NC(CC)CC
Reaction time: 3 h

Procedure:
To a solution of 2-ethyl-4-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-amine (100 mg) in acetic acid (10 mL) there was added 3-pentanone (0.04 mL), and then sodium triacetoxyborohydride (85.0 mg) was slowly added at room temperature and the mixture was stirred for 3 hours. A 5 N aqueous sodium hydroxide solution was added while cooling on ice, and then extraction was performed with ethyl acetate, the organic layer washed with saturated aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (10 g), and the title compound (69 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]([CH3:31])([CH3:30])[C:14]([NH:16][NH:17][C:18]1[N:19]=[N:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:22][CH:23]=1)=O)=[CH:8][CH:7]=2>C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]([C:14]1[N:19]3[N:20]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:22]=[CH:23][C:18]3=[N:17][N:16]=1)([CH3:31])[CH3:30])=[CH:8][CH:7]=2
Reactant: COc1cnc2ccc(C(C)(C)C(=O)NNc3ccc(-c4ccccc4)nn3)cc2c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc2ccc(C(C)(C)c3nnc4ccc(-c5ccccc5)nn34)cc2c1

Procedure:
A solution of 2-(3-methoxyquinolin-6-yl)-2-methyl-N′-(6-phenylpyridazin-3-yl)propanehydrazide (270 mg, 653 μmol) in TFA (2 mL) was heated to 150° C. in microwave (6 bar; 20W) for 2 h. LCMS suggests very good conversion: 89425-17-1. Reaction concentrated under reduced pressure then partitioned between CHCl3/IPA (50 mL) and 1M NaOH (50 mL). Aqueous further extracted with CHCl3/IPA (15 mL) and combined organics dried over MgSO4, concentrated, then dissolved in ACN (2 mL). Crystallized solid washed with ACN (1 mL) and dried under reduced pressure. MS (ESI pos. ion) m/z: 396 (MH+). Calc'd exact mass for C24H21N5O: 395.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[C:10]([NH:11][C:12]2[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[N:15]=[C:14]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=3[F:29])[N:13]=2)=[CH:9][CH:8]=[N:7][CH:6]=1)C.[OH-].[Na+]>CO>[Cl:28][C:26]1[CH:25]=[CH:24][C:23]([F:29])=[C:22]([C:14]2[N:13]=[C:12]([NH:11][C:10]3[C:5]([C:4]([OH:30])=[O:3])=[CH:6][N:7]=[CH:8][CH:9]=3)[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[N:15]=2)[CH:27]=1
Reactant: CCOC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1CCCC2
Temperature: 25 °C
Yield: 94.6 %

Procedure:
To a suspension of 4-[2-(5-chloro-2-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-4-ylamino]-nicotinic acid ethyl ester (150 mg, 0.35 mmol, 1 eq) in MeOH (5 ml) was added a 1N NaOH(aq) solution (423 μl, 0.42 mmol, 1.2 eq) and the reaction mixture was refluxed for 1 h. The solution was cooled to rt and concentrated in vacuo. Water (20 ml) was added to the crude material and the aqueous layer was acidified to pH 4. The solid was filtered, washed with water (2×5 ml) and dried overnight to give 4-[2-(5-chloro-2-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-4-ylamino]-nicotinic acid, 50 (132 mg, 94%) as a cream colored solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[N:12]([CH2:16][CH3:17])[N:13]=[CH:14][CH:15]=2)=[O:10])[C:5](F)=[N:6][CH:7]=1.N.C([N:22](C(C)C)CC)(C)C>>[NH2:22][C:5]1[C:4]([C:9]([C:11]2[N:12]([CH2:16][CH3:17])[N:13]=[CH:14][CH:15]=2)=[O:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCn1nccc1C(=O)c1cc(Br)cnc1F
Agent: N
Product: CCn1nccc1C(=O)c1cc(Br)cnc1N
Temperature: 90 °C
Reaction time: 18 h
Yield: 50.2 %

Procedure:
(5-Bromo-2-fluoro-pyridin-3-yl)-(2-ethyl-2H-pyrazol-3-yl)-methanone (685 mg, 2.29 mmol) was combined with ammonia (0.5M in dioxane, 30 ml, 15.00 mmol) and di-iso-propylethylamine (4 ml, 23.43 mmol). The mixture was stirred for 18 hours at 90° C. The reaction mixture concentrated in vacuo. The crude material was combined with a saturated aqueous solution of sodium bicarbonate, and ethyl acetate and the biphasic mixture was stirred for 1 hour. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography (0 to 100% [10% methanol in ethyl acetate] in hexanes) to give 339 mg (50%) of (2-amino-5-bromo-pyridin-3-yl)-(2-ethyl-2H-pyrazol-3-yl)-methanone. 1H-NMR (250 MHz, d6-DMSO) δ 8.35 (d, J=2.3 Hz, 1H), 7.99 (d, J=2.5 Hz, 1H), 7.68 (s, 2H), 7.61 (d, J=1.8 Hz, 1H), 6.71 (d, J=1.8 Hz, 1H), 4.35 (quart., J=7.0 Hz, 2H), 1.37 (t, J=7.3 Hz, 3H); MS: m/z 295.1+297.1 (M+H+).
Reaction SMILES: O[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)[C:3]#[N:4].N1C=CC=CC=1.S(Cl)([Cl:22])=O>C(OCC)C>[Cl:22][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)[C:3]#[N:4]
Reactant: O=S(Cl)Cl
Reactant: N#CC(O)c1cccc([N+](=O)[O-])c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: N#CC(Cl)c1cccc([N+](=O)[O-])c1
Yield: 88.7 %

Procedure:
A solution of 2-hydroxy-2-(3-nitrophenyl)acetonitrile (Preparation 113, 1.0 g, 5.62 mmol) in diethyl ether (10 ml) was stirred at room temperature and treated with pyridine (0.1 ml, 1.24 mmol) followed by thionyl chloride (0.82 ml, 11.2 mmol) dropwise over 5 minutes. The mixture was gently heated under reflux and after 30 min the solvent was removed by evaporation to give a pale yellow solid. This was purified by column chromatography on silica gel eluting with hexane:ethyl acetate (3:1 and then 2:1) to give the title compound as a white crystalline solid (980 mg, 89%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=3[CH3:23])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1>[Pd].CO>[NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=3[CH3:23])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=O)c1csc2c(N)ncnc12
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(N)cc1NC(=O)c1csc2c(N)ncnc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 16.9 %

Procedure:
The compound (1 g, 3.0 mmol) obtained in Step 2 of Example 39 was added to methanol (15 mL) and Pd/C (200 mg), and stirred under H2 atmosphere for 14 hours at room temperature. The reaction mixture was filtered using Celite and concentrated to obtain the title compound (152 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][S:4][C:3]1=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][S:4][C:3]1=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1
Reactant: CC(C(=O)O)c1ccc(C=C2SCCCC2=O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C(=O)O)c1ccc(C=C2SCCCC2O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
2-[4-(3-Oxothian-2-ylidenemethyl)phenyl]propionic acid (80 mg) obtained in Example 4 was dissolved in methanol (1.0 ml), and to the solution was added sodium borohydride (11 mg) under ice cooling. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was acidified with 10% aqueous citric acid, and extracted with chloroform. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (24 mg, 30%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[S:6]/[C:5]/1=[N:13]\[C:14](=[O:24])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23].[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[C:9]([C:7]1[S:6]/[C:5](=[N:13]\[C:14](=[O:24])[C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])/[N:4]([CH2:3][CH2:2][NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[CH:8]=1)([CH3:11])([CH3:12])[CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
A solution of Example 12A (0.29 g, 0.79 mmol) in tetrahydrofuran (10 mL) was treated with methanesulfonyl chloride (0.6 mL, 0.79 mmol) and triethylamine (0.33 mL, 0.24 mmol) and stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, washed with water, brine, dried with MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (SiO2, eluting with a gradient from 0 to 100% ethyl acetate in hexane over 600 mL then isocratic for 300 mL) to provide the title compound (0.28 g, 0.63 mMol, 80% yield). MS (DCI/NH3) m/z 446.1 (M+H)+. 1H NMR (300 MHz, CDCl3) δ ppm 1.36 (s, 9 H) 2.78 (s, 3 H) 3.62 (ddd, J=6.94, 5.55, 4.16 Hz, 2 H) 3.92 (s, 3 H) 4.33-4.39 (m, 2 H) 5.80 (t, J=5.35 Hz, 1 H) 6.70 (s, 1 H) 6.93 (d, J=9.12 Hz, 1 H) 7.35 (dd, J=9.12, 2.78 Hz, 1 H) 7.89 (d, J=2.78 Hz, 1 H).
Reaction SMILES: [C:1]([CH:3]1[CH2:32][CH2:31][N:6]2[C:7]3[C:12]([C:13]([C:14]4[C:15](=[O:30])[O:16][C:17](=O)[C:18]=4[C:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]([CH3:28])[CH:20]=4)=[C:5]2[CH2:4]1)=[CH:11][CH:10]=[CH:9][CH:8]=3)#[N:2].C[N:34](C)C=O>N>[C:1]([CH:3]1[CH2:32][CH2:31][N:6]2[C:7]3[C:12]([C:13]([C:14]4[C:15](=[O:30])[NH:34][C:17](=[O:16])[C:18]=4[C:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]([CH3:28])[CH:20]=4)=[C:5]2[CH2:4]1)=[CH:11][CH:10]=[CH:9][CH:8]=3)#[N:2]
Reactant: CN(C)C=O
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(C#N)C4)C(=O)OC2=O)c2ccccc21
Agent: N
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(C#N)C4)C(=O)NC2=O)c2ccccc21

Procedure:
A solution of 400 mg of 3-[8-cyano-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 12 ml of dimethylformamide and 12 ml of 33% aqueous ammonia was heated to 140° C. for 3 hours. The mixture was cooled and the resulting solid was filtered off and dried to give 275 mg of 3-[8-cyano-6,7,8,9-tetrahydropyrido-[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 312°-313° C.
Reaction SMILES: BrC1C=CC2OCCN3C=C(I)N=C3C=2C=1.C=O.O.N1CCCC1.C[Si](N[Si](C)(C)C)(C)C.Br[C:35]1[CH:36]=[CH:37][C:38]2[O:44][CH2:43][CH2:42][N:41]3[C:45]([CH2:51][N:52]4[CH2:56][CH2:55][CH2:54][CH2:53]4)=[C:46]([C:48]([NH2:50])=[O:49])[N:47]=[C:40]3[C:39]=2[CH:57]=1.[CH3:58][C:59]([OH:63])([C:61]#[CH:62])[CH3:60]>C(O)(=O)C.ClCCl.CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:63][C:59]([CH3:60])([CH3:58])[C:61]#[C:62][C:35]1[CH:36]=[CH:37][C:38]2[O:44][CH2:43][CH2:42][N:41]3[C:45]([CH2:51][N:52]4[CH2:56][CH2:55][CH2:54][CH2:53]4)=[C:46]([C:48]([NH2:50])=[O:49])[N:47]=[C:40]3[C:39]=2[CH:57]=1
Reactant: C#CC(C)(C)O
Reactant: NC(=O)c1nc2n(c1CN1CCCC1)CCOc1ccc(Br)cc1-2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Brc1ccc2c(c1)-c1nc(I)cn1CCO2
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(CN3CCCC3)n1CCO2
Yield: 18 %

Procedure:
10-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (300 mg, 0.77 mmol, 1.00 equiv), HCHO/H2O (312 mg, 4.00 equiv), pyrrolidine (332 mg, 4.67 mmol, 6.00 equiv) in acetic acid (4 mL) was stirred overnight at 55° C. The resulting solution was diluted with dichloromethane, washed with saturated aqueous NaHCO3 solution, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/MeOH (10/1). This resulted in 200 mg of 10-bromo-2-iodo-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineas yellow oil that was used without further purification or characterization. Similar to as described in Example 10 (carbonylative amidation), a solution of this intermediate (200 mg, 0.42 mmol, 1.00 equiv), HMDS (135 mg, 0.84 mmol, 2.00 equiv), Pd(dppf)Cl2(34 mg, 0.05 mmol, 0.10 equiv) in N,N-dimethylformamide (2 mL) was stirred overnight at 70° C. under an atmosphere of CO (g). The resulting solution was diluted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (1:10). This resulted in 80 mg (48%) of 10-bromo-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide as a yellow solid. Similar to as described in General Procedure G, 10-bromo-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a yellow solid (14 mg, 18%).