Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[H-].[Na+].Cl[C:12]1[C:17]([CH3:18])=[CH:16][C:15]([N+:19]([O-:21])=[O:20])=[CH:14][N:13]=1>CN(C)C=O>[CH3:18][C:17]1[C:12]([O:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:13][CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[CH:16]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: OCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cnc1OCc1ccccn1
Temperature: -20 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
2-Pyridylcarbinol (1.96 g, 18 mmol) in dry dimethylformamide (20 ml) was cooled to −20° C. and treated with sodium hydride (0.48 g of 80% dispersion in mineral oil, 16 mmol). The mixture was stirred under argon at −20° C. for one hour then a solution of 2-chloro-3-methyl-5-nitropyridine (2.07 g, 12 mmol) in dry dimethylformamide (10 ml) was added and the mixture was allowed to warn to room temperature over 16 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane (3×100 ml) and 10% aqueous sodium hydroxide solution(75 ml). The combined organics were dried (Na2SO4) and evaporated in vacuo to a residue which was subjected to flash column chromatography with 1:1 ethyl acetate/petroleum ether as eluant to afford the title compound (1.47 g, 51%) as lemon yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH:23]1([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[C:34]([CH3:41])=[C:35]([CH:39]=O)[NH:36][C:37]=3[CH3:38])[CH2:28][CH2:27]2)[CH2:25][CH2:24]1>>[CH:23]1([N:26]2[CH2:27][CH2:28][N:29]([CH2:32][C:33]3[C:34]([CH3:41])=[C:35](/[CH:39]=[C:16]4\[C:17](=[O:22])[NH:18][C:19]5[C:15]\4=[CH:14][C:13]([S:10]([CH2:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=5)[NH:36][C:37]=3[CH3:38])[CH2:30][CH2:31]2)[CH2:24][CH2:25]1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CN1CCN(C2CC2)CC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CN1CCN(C2CC2)CC1

Procedure:
5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (178 mg) was condensed with 4-(4-cyclopropyl-piperazin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (125 mg) to give the titled compound.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[Br:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:15]([Br:14])[CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1cccc(Br)c1
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Temperature: 190 °C
Reaction time: 2.5 h

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (107 mg, 0.87 mmol) (described in a previous experimental) and 3-bromoaniline (0.75 mL, 7.8 mmol) is stirred under N2 at 190° C. for 2.5 h, and the precipitate which appears on cooling is recrystallized from PriOH. 1H NMR (DMSO) δ 9.91 (1H, brs), 9.34 (1H, s), 8.45 (1H, s), 8.19 (1H, s), 7.84 (1H, d, J=8.0 Hz), 7.34 (1H, t, J=8.0 Hz), 7.29 (1H, d, J=8.2 Hz), 6.68 (2H, brs), 6.45 (1H, s).
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[N:11]=[CH:12][S:13][CH:14]=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[C:33]([O:37][C:38](=[O:63])[NH:39][CH2:40][C:41]1[N:42]([CH2:59][CH:60]([CH3:62])[CH3:61])[C:43](=[O:58])[C:44]2[C:49]([C:50]=1[O:51][CH2:52][CH2:53][CH2:54][CH3:55])=[CH:48][C:47]([CH:56]=O)=[CH:46][CH:45]=2)([CH3:36])([CH3:35])[CH3:34].O>CN(C)C=O>[C:33]([O:37][C:38](=[O:63])[NH:39][CH2:40][C:41]1[N:42]([CH2:59][CH:60]([CH3:61])[CH3:62])[C:43](=[O:58])[C:44]2[C:49]([C:50]=1[O:51][CH2:52][CH2:53][CH2:54][CH3:55])=[CH:48][C:47](/[CH:56]=[CH:9]/[C:10]1[N:11]=[CH:12][S:13][CH:14]=1)=[CH:46][CH:45]=2)([CH3:36])([CH3:34])[CH3:35]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C=O)cc12
Reactant: c1ccc([P+](Cc2cscn2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(/C=C/c3cscn3)cc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 81.7 %

Procedure:
A mixture of triphenyl(1,3-thiazol-4-ylmethyl)phosphonium chloride (0.44 g, 1.1 mmol), potassium carbonate (15 g, 1.1 mmol) and tert-butyl(4-butoxy-6-formyl-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.47 g, 1.1 mol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 10 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from ethyl acetate-diisopropyl ether to give tert-butyl{4-butoxy-2-isobutyl-1-oxo-6-[(E)-2-(1,3-thiazol-4-yl)ethenyl]-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.46 g, 80.7%) as crystals.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:3][CH2:2]1.Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:21]([CH3:23])[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:15]=23)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3ccc(OC)cc3OCC3CC3)ccnc12
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3ccc(OC)cc3OCC3CC3)ccnc12

Procedure:
Starting from ethyl 7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (example D.a4) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is prepared as pale yellow viscous oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].CS([CH2:41][CH2:42][O:43][CH2:44][C:45]1[O:46][CH:47]=[CH:48][CH:49]=1)(=O)=O>O>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]([CH2:41][CH2:42][O:43][CH2:44][C:45]3[O:46][CH:47]=[CH:48][CH:49]=3)[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: CS(=O)(=O)CCOCc1ccco1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCCN(c2nc3ccccc3n2CCOCc2ccco2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Combine 1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (1.6 mmol) and tetrahydrofuran (10 mL). Cool to -78° C. Add dropwise, a solution of potassium bis(trimethylsilyl)amide (3.6 mL, 0.5 M in toluene, 1.8 mmol). After 30 minutes, add fur-2-ylmethyl 2-methanesulfonylethyl ether (1.8 mmol). Warm to ambient temperature and heat to reflux. After 18 hours, cool to ambient temperature and add water. Separate the organic layer and extract the aqueous layer with dichloromethane. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give 1-ethoxycarbonyl-4-(1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.7 %

Procedure:
To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (24.4 g, 0.14 mol) in 200 mL DMF was added morpholine (25.7 mL, 0.28 mol), followed by the addition of K2CO3 (23.6 g, 0.17 mol). The mixture was stirred at room temperature for 48 h. The mixture was poured into 0.7 L H2O and the precipitate was collected by filtration. The precipitate was further rinsed with 0.5 L H2O. The resulting solid was air dried by purging with a flow of air for 24 h, thus affording 29.3 g of 4-(3-methoxy-4-nitrophenyl)morpholine (0.12 mol, 86%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[S:7]1(=[O:24])=[O:23].[CH:25]1([NH2:28])[CH2:27][CH2:26]1.Cl>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[CH2:11][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:28][CH:25]2[CH2:27][CH2:26]2)[S:7]1(=[O:24])=[O:23]
Reactant: NC1CC1
Reactant: O=S1(=O)N(CCCCBr)Cc2ccccc2N1c1ccccc1F
Agent: Cl
Product: O=S1(=O)N(CCCCNC2CC2)Cc2ccccc2N1c1ccccc1F
Yield: 92 %

Procedure:
In an analogous manner to Example 11 step 5, 3-(4-bromobutyl)-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.11 g, 0.26 mmol) was reacted to cyclopropylamine and then treated with HCl to provide N-{4-[1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]butyl}cyclopropanamine (0.099 g, 92%) as a white solid:
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[CH:16][C:15]=2[F:34])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].[NH2:35][NH2:36]>O1CCOCC1>[C:1]([C:4]1[C:5]([NH:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[CH:16][C:15]=2[F:34])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1[NH:35][NH2:36])(=[O:3])[NH2:2]
Reactant: NN
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2c(F)cc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)n1
Solvent: C1COCCO1
Product: CSc1nc(NN)c(C(N)=O)c(Nc2c(F)cc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product of Example 16E (380 mg, 0.74 mmol) in 1,4-dioxane (10 mL) was added hydrazine (185 mg, 3.68 mmol) and the mixture was stirred at ambient temperature for 3 hours. The mixture was concentrated and the residue was recrystallized from ethanol to give the title compound. MS: 495 (M+H+).
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:6]=2[C:5]1=[O:17].[CH3:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][C:29](=[O:35])[NH:30]2.N1CCCCC1>C(O)C>[OH:1][C@@H:2]([CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:11][C:12](/[CH:15]=[C:28]3\[C:29](=[O:35])[NH:30][C:31]4[C:27]\3=[C:26]([CH3:25])[CH:34]=[CH:33][CH:32]=4)=[C:13]([CH3:14])[C:6]=2[C:5]1=[O:17]
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CCC2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cccc2c1/C(=C/c1[nH]c3c(c1C)C(=O)N(C[C@@H](O)CN1CCOCC1)CCC3)C(=O)N2
Temperature: 45 °C
Reaction time: 16 h
Yield: 62.8 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 78f (40 mg, 0.12 mmol 1) and 4-methyl-1,3-dihydro-indol-2-one (18 mg, 0.12 mmol) were dissolved in 1.5 ml of ethanol, and added with 6 μl of piperidine to the solution at room temperature. Upon completion of the addition, the reaction mixture was stirred at 45° C. for 16 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (1 ml×2) and dried to obtain the title compound (S,Z)-5-(2-hydroxy-3-morpholinopropyl)-3-methyl-2-((4-methyl-2-oxoindolin-3-ylidene)methyl)-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 83 (35 mg, yield 63.6%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([CH:13]([CH2:19][CH2:20][CH3:21])[C:14](OCC)=[O:15])[CH2:8]1.O1CCCC1.[BH4-].[Li+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([CH:13]([CH2:19][CH2:20][CH3:21])[CH2:14][OH:15])[CH2:8]1
Reactant: CCCC(C(=O)OCC)N1CC(COc2cccc(Cl)c2)OC1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(CO)N1CC(COc2cccc(Cl)c2)OC1=O
Yield: 53.4 %

Procedure:
A procedure similar to that described in Preparation 5 was repeated, except that 4.31 g of ethyl 2-[5-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]pentanoate (polar isomer), obtained as described in Preparation 96, 40 ml of anhydrous tetrahydrofuran, 0.42 g of lithium borohydride and 0.31 g of anhydrous methanol were used, to give 2.03 g of the title compound, melting at 98° C. to 102° C., from the polar diastereomer.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[CH2:4][CH2:3]1.[BH4-].[Na+]>CO.O>[CH3:1][C:2]1([CH3:14])[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH:5]([OH:13])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=O)c2ccccc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)CCC(O)c2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8,8-dimethyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one (29.20 g, 155.1 mmol) in methanol (150 ml) was added sodium borohydride (5.87 g, 155 mmol) by small portions under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction solution was diluted with water and extracted twice with ethyl acetate. The recovered organic layer was-dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-6/1) to give the objective substance.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([CH:13]([F:15])[F:14])[CH:10]=[C:9]([C:16]3[CH:17]=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=3)[N:8]=2)[CH:6]=1.[C:26]([NH:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[CH:35]=[CH:36][CH:37]=[C:38]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[N:12]=[C:11]([CH:13]([F:15])[F:14])[CH:10]=[C:9]([C:16]4[CH:17]=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=4)[N:8]=3)[CH:6]=2)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(-n2cnc(I)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)cn2)c1

Procedure:
3-{1-[4-Difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonic acid tert-butylamide was prepared from 2-(4-iodo-imidazol-1-yl)-4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.8) (0.47 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure III. Obtained as light yellow solid (0.06 g), which was subsequently deprotected.
Reaction SMILES: C[N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[OH:20][CH2:21][C:22]([NH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2)=[O:23]>>[OH:20][CH2:21][C:22]([NH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])/[C:28]/2=[CH:16]\[C:13]1[NH:12][C:8]2[CH2:9][CH2:10][CH2:11][N:5]([CH2:4][CH2:3][NH:2][CH3:19])[C:6](=[O:18])[C:7]=2[C:14]=1[CH3:15])=[O:23]
Reactant: O=C(CO)Nc1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Product: CNCCN1CCCc2[nH]c(/C=C3\C(=O)Nc4ccc(NC(=O)CO)cc43)c(C)c2C1=O
Yield: 50.5 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 23 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c obtained from step 3 of Example 23 and 2-hydroxy-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide 44b as starting materials to obtain (Z)-2-hydroxy-N-{3-[3-methyl-5-(2-methylamino-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-acetamide 44 (52 mg, yield 50.5%) as an orange solid.
Reaction SMILES: [C:1]1([N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:11]2[CH:12]=[CH:13][C:8]([N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:9][CH:10]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Brc1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 80 °C

Procedure:
A mixture of 4-diphenylaminophenyl boronic acid (2.57 g, 8.9 mmol), 4-bromo-iodobenzene (5.03 g, 17.8 mmol), Pd(PPh3)4 (0.58 g, 0.5 mmol) and K2CO3 (3.0 g, 22 mmol) in dioxane/water (80 mL/15 mL) was degassed and heated at about 80° C. for about 20 hours. The whole was mixed with water/dichloromethane, the organic phase was collected and washed with brine, dried over Na2SO4, loaded on silica gel, and purified by flash column (hexanes to hexanes/dichloromethane 30:1). The desired fraction was collected, and concentrated to give a white solid (Compound 12), which was filtered and washed with methanol (2.70 g, in 76% yield).
Reaction SMILES: Cl.N1C=CC=CC=1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:16][C:17]2[C:22]([C:23](=[O:25])[CH:24]=1)=[C:21]([O:26]C)[CH:20]=[C:19]([O:28]C)[C:18]=2[C@@H:30]1[CH2:34][CH2:33][N:32]([CH3:35])[C@H:31]1[CH2:36][OH:37].C(=O)([O-])[O-].[Na+].[Na+]>CO>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:16][C:17]2[C:22]([C:23](=[O:25])[CH:24]=1)=[C:21]([OH:26])[CH:20]=[C:19]([OH:28])[C:18]=2[C@@H:30]1[CH2:34][CH2:33][N:32]([CH3:35])[C@H:31]1[CH2:36][OH:37]
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccccc4Cl)oc23)[C@@H]1CO
Temperature: 180 °C
Reaction time: 0.5 h

Procedure:
Molten pyridine hydrochloride (4.1 g, 0.0354 mol) was added to (+)-trans-2-(2-chlorophenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one (0.4 g, 0.0009 mol) and heated at 180° C. for 1.5 h. The reaction mixture was cooled to 25° C., diluted with methanol (10 mL) and basified using sodium carbonate to pH 10. The mixture was filtered and the organic layer was concentrated. The residue was suspended in water (5 mL), stirred for 30 minutes, filtered and dried to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]([C:21]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:22]=1[C:23](O)=[O:24])([CH3:20])[CH2:3][C@:4]([O:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])([C:8]([F:11])([F:10])[F:9])[CH2:5][C:6]#[CH:7].[N:31]1C=CC=CC=1.S(Cl)(Cl)=O.N>C(Cl)Cl>[CH3:1][C:2]([C:21]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:22]=1[C:23]([NH2:31])=[O:24])([CH3:20])[CH2:3][C@:4]([O:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])([C:8]([F:11])([F:10])[F:9])[CH2:5][C:6]#[CH:7]
Reactant: c1ccncc1
Reactant: C#CC[C@@](CC(C)(C)c1ccc(F)cc1C(=O)O)(O[Si](CC)(CC)CC)C(F)(F)F
Agent: N
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: C#CC[C@@](CC(C)(C)c1ccc(F)cc1C(N)=O)(O[Si](CC)(CC)CC)C(F)(F)F
Reaction time: 0.42 h
Yield: 53.1 %

Procedure:
To a solution of 14.2 g of 2-((S)-1,1-dimethyl-3-triethylsilanyloxy-3-trifluoromethylhex-5-ynyl)-5-fluorobenzoic acid (0.030 mol) in 400 mL of DCM was added 4.6 mL of pyridine (0.057 mol) followed by 3.3 mL of thionyl chloride (0.045 mol). The reaction was stirred for 25 minutes then carried on to next step. The crude acid chloride was cannulated into a flask containing ammonia (7 M in MeOH, 185 mL, 1.30 mol). The mixture was stirred for 40 minutes then quenched with saturated aqueous sodium bicarbonate solution. The mixture was then diluted with 20 mL of ethyl acetate, washed with two 100 mL portions of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude mixture was chromatographed on silica gel using 0-50% ethyl acetate/hexanes to afford 7.1 g (50%) of 2-((S)-1,1-dimethyl-3-triethylsilanyloxy-3-trifluoromethylhex-5-ynyl)-5-fluorobenzamide.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH:24]([C:25]2[NH:26][CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:29]=2)[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)=O)(C)(C)C>>[C:30]1([C:28]2[N:29]=[C:25]([CH:24]3[CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][NH:15]3)[NH:26][CH:27]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2CC1c1nc(-c2ccccc2)c[nH]1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2c[nH]c(C3Cc4ccccc4CN3)n2)cc1
Temperature: 25 °C

Procedure:
Triflouroacetic acid (TFA) (4mL) was cooled in a test tube to about 0° C. To the cool solvent was then added the product prepared in Step B (0.75 g, 2 mmol) above. The reaction mixture was allowed to warm to room temperature over about 45 minutes. Excess TFA was removed under a stream of N2 gas. The residue was partitioned between dichloromethane (15 mL) and saturated NaHCO3. The aqueous phase was then re-extracted with a second portion of dichloromethane and the organic phases combined, dried over MgSO4 and filtered, to yield the title compound in dichloromethane solution. The filtrate was used in the next step without further purification or isolation.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[H-].[Na+]>CN(C=O)C>[CH2:14]([O:13][C:11](=[O:12])[C:10](=[O:16])[CH2:2][C:1](=[O:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:15]
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)CC(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
A stirred solution of acetophenone (5 g, 0.0416 mole), diethyl oxalate (7.23 g, 0.0416 mole) in DMF (40 mL) was cooled to 0° C. for 10 minutes. NaH (60% w/w dispersion in oil) (2.0 g, 0.083 mole) was then added, and the resulting mixture was stirred at the same temperature for 30 minutes, then stirred at ambient temperature for 1 hour. The mixture was then heated at 50° C. for 30 minutes. The reaction mixture was quenched with iced water, acidified with aqueous 2.4N HCl solution and the resulting precipitate was isolated by filtration and dried to afford 3.8 g (42%) of 2,4-dioxo-4-phenyl-butyric acid ethyl ester. LCMS: 221.07 (M+1)+, 85.2%.