Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9](=[O:23])[CH2:10][CH2:11][C:12]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]=2[CH:21]=O)[CH2:3]1.[CH2:24]([S:26]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])[CH2:32]2)(=[O:28])=[O:27])[CH3:25]>>[CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9](=[O:23])[CH2:10][CH2:11][C:12]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]=2/[CH:21]=[C:32]2\[C:33](=[O:38])[NH:34][C:35]3[C:31]\2=[CH:30][C:29]([S:26]([CH2:24][CH3:25])(=[O:27])=[O:28])=[CH:37][CH:36]=3)[CH2:3]1
Reactant: CCS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CC1CN(C(=O)CCc2c(C=O)[nH]c3c2CCCC3)CC(C)N1
Product: CCS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCC(=O)N1CC(C)NC(C)C1)CCCC3)C(=O)N2
Yield: 46 %

Procedure:
3-[3-(3,5-Dimethylpiperazin-1-yl)-3-oxo-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde, prepared as described in Example 3 above, was condensed with 5-ethylsulfonyloxindole following the same procedure used in example 1 to give the desired product (72 mg, 46% yield).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:39](OC=O)(=[O:41])C>C(OCC)(=O)C>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([N:17]([CH:39]=[O:41])[CH2:18][CH2:19][CH3:20])[C:14]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:25][CH:26]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CCCNC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(OCCC)cc1
Reactant: CC(=O)OC=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCOc1ccc(C2=NN(C(=O)Nc3ccc(C(F)(F)F)cc3)CC2N(C=O)CCC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To 3.0 g (6.7 mmole) of N-(4-trifluoromethylphenyl)-3-(4-propoxyphenyl)-4-(N-propylamino)-4,5,-dihydro-1H-pyrazole-1-carboxamide (Example 586) dissolved in 25 ml of ethyl acetate and cooled to 0° C., was added 2.4 g (30 mmole) of pyridine and 4.0 g (28 mmole) of formic acetic anhydride mixture (Example 621a). After 30 minutes, the reaction mixture was washed with water and brine, concentrated in vacuo, and chromatographed over silica gel using hexanes and ethyl acetate to yield 2.5 g of the desired compound, mp 161°-163° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:24]1(B(O)O)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:32]2[C:33]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:29]=[CH:30][CH:31]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1cccc2ccccc12
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccc(Cl)cc3)c2c1O
Product: CCOC(=O)c1nc(-c2cccc3ccccc23)c2snc(-c3ccc(Cl)cc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-bromo-3-(4-chloro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and 1-naphthylboronic acid: MS (m/z) 461.0 (M+1).
Reaction SMILES: N#N.[Si:3]([O:10][CH2:11][C:12]1[N:13]=[C:14](/[CH:17]=C/C2C=CC=CC=2)[O:15][CH:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[OH2:25]>CC(C)=O>[Si:3]([O:10][CH2:11][C:12]1[N:13]=[C:14]([CH:17]=[O:25])[O:15][CH:16]=1)([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:4])[CH3:5]
Reactant: O
Reactant: CC(C)(C)[Si](C)(C)OCc1coc(/C=C/c2ccccc2)n1
Agent: N#N
Solvent: CC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1coc(C=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of NaIO4 (726 mg, 3.33 mmol) in water (6.6) mL was slowly added to a vigorously stirred suspension of silica gel (4.46 g) in acetone (13.2 mL). The mixture was then concentrated under reduced pressure and the lumpy solid slurried in CH2Cl2 and the solvent was evaporated under reduced pressure. CH2Cl2 (16.5 mL) was added and the reaction mixture was treated at rt with (E)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-styryloxazole (350 mg, 1.1 mmol) and RuCl3 hydrate (7.8 mg, 0.03 mmol). The reaction mixture was stirred at rt in the dark overnight, filtered through silica gel and concentrated under reduced pressure to give the title compound as a red oil. TLC: rf (1:3 EA-Hept)=0.51. LC-MS-conditions 07: tR=0.64 min.
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]2=[O:20].C([Sn](CCCC)(CCCC)[C:28]#[C:29][C:30]([CH3:32])=[CH2:31])CCC>C1(C)C=CC=CC=1.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>[CH:12]1([N:10]2[C:11]3[C:6](=[CH:5][C:4]([F:21])=[C:3]([F:22])[C:2]=3[C:28]#[C:29][C:30]([CH3:32])=[CH2:31])[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9]2)[CH2:14][CH2:13]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Br)c(F)c(F)cc2c1=O
Reactant: C=C(C)C#C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C(C)C#Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c12
Yield: 80.1 %

Procedure:
1.86 g of ethyl 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 2.8 g of 1-tributylstannyl-3-methyl-but-3-en-1-ine and 0.29 g of tetrakis(triphenylphosphine)palladium(0) are refluxed for 6 hours in 20 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is filtered under hot conditions and concentrated, and the residue is stirred with hexane. After filtration with suction and drying, 1.43 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-methyl-but-3-en-1-inyl)-4-oxo-3-quinolinecarboxylate are obtained (80% of theory).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[CH3:14][CH:15]([CH:17]=O)[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[N:6]=[CH:14][CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CC(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Product: CC(C)C=Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,6-Diisopropylaniline (9.4 mL, 50 mmol, Aldrich) was mixed with isobutyric aldehyde (9.1 mL, 100 mmol, Aldrich), p-toluenesulfonic acid (0.48 g, 2.5 mmol, Aldrich), chloroform (50 mL) and MgSO4 (12 g, 100 mmol). The mixture was stirred for 2 h at RT. Assay by 1H-NMR (crude reaction mixture) showed the presence of product and starting material (8/1 ratio). The reaction mixture was filtered, the precipitate washed with chloroform (50 mL), and 5 Å molecular sieves were added. After stirring for 20 h at RT the solution was filtered, the molecular sieves were washed with chloroform (2×50 mL), the solvent was evaporated, and the residue distilled at reduced pressure. After a few drops of forerun (67–76° C./27 Pa) product was collected at 76–77° C./27 Pa as a colorless oil, 8.66 g (74.8%). 1H NMR (CDCl3) 7.60 (d, 1H; J=4.8 Hz); 7.20–7.05 (m, 3H); 3.00 (septet, 2H; J=6.8 Hz); 2.78 (d of septets, 1H; J=4.8; 6.7 Hz); 1.33 (d, 6H; J=6.7 Hz); 1.23 (d, 12H; J=6.8 Hz).
Reaction SMILES: [CH3:1][Si](Cl)(C)C.[NH2:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([F:19])[C:8]=1[F:20]>CO>[NH2:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]([C:11]([O:13][CH3:1])=[O:12])=[C:9]([F:19])[C:8]=1[F:20]
Reactant: C[Si](C)(C)Cl
Reactant: Nc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1F
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Yield: 91.4 %

Procedure:
TMSCl (132 g, 1.21 mol, 2.0 equiv) was added over 5 minutes to a slurry of 4-amino-2,3-difluoro-5-nitrobenzoic acid (3) (132.3 g, 0.607 mol, 1 equiv) in 325 mL of MeOH. The mixture was heated at reflux for 15 hours. Once the reaction was complete by HPLC, the reaction mixture was cooled in an ice-water bath for 45 minutes. Then the reaction mixture was filtered and the cake was washed with 65 mL of MeOH. The wet cake was dried overnight at 55° C. under high vacuum to provide 128.8 g (92%) of 4-amino-2,3-difluoro-5-nitrobenzoic acid methyl ester (4). HPLC was 97.9 a % (220 nm) and 99.2 a % (254 nm). 1H NMR (400 MHz, d6 DMSO) δ 3.84 (3H, s, OMe), 8.1 (2H, br s, NH2), 8.43 (1H, apparent dd, J 1.9, 7.2, Ar—H). 19F NMR (376 MHz, d6 DMSO) δ−153.6, −129.2. 13C NMR (100 MHz, d6 DMSO) δ 52 (CH3O), 105 (C, d, J 10), 125 (CH, t, J 2.7), 128 (CH, d, J 5), 140 (C—F, dd, J 244, 15), 141 (C, dd, J 14, 5), 152 (C—F, dd, J 263, 11), 162 (COO, t, J 3). IR vmax/cm−1 3433, 3322, 1699, 1637, 1548, 1342, 1234. MS APCI (−) m/z 231 (M−1) detected.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][CH2:28][N:29]([CH2:40][CH2:41][OH:42])[S:30]([C:33]1[S:34][C:35]([Cl:39])=[C:36]([NH2:38])[CH:37]=1)(=[O:32])=[O:31]>>[OH:26][CH2:27][CH2:28][N:29]([CH2:40][CH2:41][OH:42])[S:30]([C:33]1[S:34][C:35]([Cl:39])=[C:36]([NH:38][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:37]=1)(=[O:31])=[O:32]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cc(S(=O)(=O)N(CCO)CCO)sc1Cl
Product: O=C(Nc1cc(S(=O)(=O)N(CCO)CCO)sc1Cl)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 4-amino-5-chloro-thiophene-2-sulfonic acid bis-(2-hydroxy-ethyl)-amide (example B.5) according to general procedure II. Light yellow solid. MS (ISP) 640.3 [(M+H)+]; mp 216° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]([C:25]([F:28])([F:27])[F:26])([O:20][Si](C)(C)C)[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([Cl:17])[C:11]=1[O:18][CH3:19])([CH3:9])[CH3:8])[CH3:2].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[CH2:1]([O:3][C:4](=[O:29])[C:5]([C:25]([F:26])([F:27])[F:28])([OH:20])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([Cl:17])[C:11]=1[O:18][CH3:19])([CH3:8])[CH3:9])[CH3:2]
Reactant: CCOC(=O)C(CC(C)(C)c1ccc(C)c(Cl)c1OC)(O[Si](C)(C)C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(O)(CC(C)(C)c1ccc(C)c(Cl)c1OC)C(F)(F)F
Temperature: 25 °C
Yield: 34 %

Procedure:
4.4 g (9.67 mmol) of (rac.) 4-(3-chloro-2-methoxy-4-methylphenyl)-4-methyl-2-(trifluoromethyl)-2-trimethylsilyloxy-pentanoic acid ethyl ester is dissolved in 56 ml of tetrahydrofuran and mixed with 3.05 g (9.67 mmol) of tetrabutylammonium fluoride trihydrate and stirred for one and one-half hours at room temperature. The reaction mixture is diluted with water and extracted twice with diethyl ether. The organic phases are washed with water and with brine. After drying, the solvent is spun off, and the remaining residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 1.26 g of the desired compound is isolated.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H:9]1([NH2:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1>>[CH2:1]([NH:19][C@@H:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@H]1CCCc2ccccc21
Product: c1ccc(CN[C@H]2CCCc3ccccc32)cc1

Procedure:
Benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=3)=[O:11])=[C:7]([NH:20][C:21]([C@H:23]3[CH2:28][CH2:27][C@H:26]([N:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]3)=[O:22])[C:6]=2[CH:32]=1.[C:33]([O:36][CH2:37][C:38](Cl)=[O:39])(=[O:35])[CH3:34].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[C:33]([O:36][CH2:37][C:38]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=3)=[O:11])=[C:7]([NH:20][C:21]([C@H:23]3[CH2:28][CH2:27][C@H:26]([N:29]([CH3:30])[CH3:31])[CH2:25][CH2:24]3)=[O:22])[C:6]=2[CH:32]=1)=[O:39])(=[O:35])[CH3:34]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(N)cc23)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Trans-5-amino-3-[4-(dimethylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (100 mg) obtained in Example 180 is dissolved in dichloromethane (8 ml), and thereto are added acetoxy acetylchloride (36 mg) and pyridine (36 μl) under ice-cooling, and the mixture is stirred at room temperature for 17 hours. To the reaction solution is poured a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is washed with a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: chloroform, then chloroform/methanol=50/1) to give trans-5-acetoxyacetylamino-3-[4-(dimethylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (110 mg). A portion of this product is dissolved in ethanol, and treated with 4N hydrogen chloride in ethyl acetate to give the title compound (16 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl:29][C:30]1[C:35](Cl)=[N:34][CH:33]=[CH:32][N:31]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[Cl:29][C:30]1[C:35]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)=[N:34][CH:33]=[CH:32][N:31]=1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: Clc1nccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2nccnc2Cl)C3)cc1

Procedure:
1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0496 g, 0.130 mmol) and 2,3-Dichloropyrazine (0.0204 mL, 0.196 mmol) were combined then added dry N,N-Dimethylformamide (0.910 mL, 11.8 mmol) followed by N,N-Diisopropylethylamine (0.0456 mL, 0.262 mmol). The reaction was microwaved on 200 watts, 120° C. for 30 minutes on a CEM microwave. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.30 (d, J=2.5, 1H), 8.21 (d, J=8.8, 2H), 8.01 (d, J=2.5, 1 H), 7.49 (d, J=8.8, 2H), 6.15 (t, J=5.6, 1H), 4.55 (d, J=15.7, 2H), 3.82-3.63 (m, 6H), 3.56-3.45 (m, 4H), 3.17-3.07 (m, 2H), 2.86 (s, 2H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+495.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]1[C:18](=[O:19])[CH2:17][N:16]=[C:15]([N:20]3[CH:24]=[C:23]([CH2:25][CH3:26])[N:22]=[CH:21]3)[CH:14]=[C:9]12)(=[O:3])[CH3:2].[BH3-]C#N.[Na+]>CO.C(Cl)Cl>[CH2:25]([C:23]1[N:22]=[CH:21][N:20]([C:15]2[CH:14]=[C:9]3[C:10]4[C:5]([CH2:6][CH2:7][N:8]3[C:18](=[O:19])[CH2:17][N:16]=2)=[C:4]([CH:1]([OH:3])[CH3:2])[CH:13]=[CH:12][CH:11]=4)[CH:24]=1)[CH3:26]
Reactant: CCc1cn(C2=NCC(=O)N3CCc4c(C(C)=O)cccc4C3=C2)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCc1cn(C2=NCC(=O)N3CCc4c(cccc4C(C)O)C3=C2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 4.8 %

Procedure:
Example 115. A solution of 9-acetyl-2-(4-ethyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (210 mg, 0.36 mmol) in MeOH (20 mL) was treated with NaBH3CN (23 mg, 0.36 mmol) and the mixture was stirred at RT for 10 min. The mixture was then concentrated in vacuo and the residue obtained was taken up in DCM and washed with H2O. The org layer was then dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, heptane to AcOEt to AcOEt/MeOH 85:15) and preparative TLC (SiO2, DCM/MeOH 95:5) afforded the title compound (6 mg). UPLC-MS: MS 351.2 (M+H+); UPLC rt 0.65 min. 1H NMR (400 MHz, CD3OD): δ ppm 1.16-1.27 (m, 3 H); 1.44 (d, J=6.26 Hz, 3 H); 2.58 (q, J=7.56 Hz, 2 H); 2.97-3.17 (m, 2 H); 3.80 (m, 1 H); 3.88-4.00 (m, 2 H); 4.31-4.36 (m, 2 H); 5.14 (d, J=6.65 Hz, 1 H); 6.95 (s, 1 H); 7.34 (s, 1 H); 7.37-7.49 (m, 1 H); 7.67 (d, J=7.43 Hz, 1 H); 7.77 (d, J=7.82 Hz, 1 H); 8.11 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:10](Cl)(Cl)=[O:11]>C(COC)OC>[CH3:9][S:8][C:4]1[CH:3]=[C:2]([N:1]=[C:10]=[O:11])[CH:7]=[CH:6][CH:5]=1
Reactant: CSc1cccc(N)c1
Reactant: O=C(Cl)Cl
Solvent: COCCOC
Product: CSc1cccc(N=C=O)c1

Procedure:
m-Aminothioanisole (27.8 g., 0.2 mole) in 100 ml dry dimethoxyethane is added to a saturated solution of phosgene in 200 ml dry dimethoxyethane. Phosgene is passed into the refluxing mixture for a further 4 hr. and then the mixture is heated under nitrogen for 21 hours. Solvent is removed in vacuo to afford m-methylthiophenyl isocyanate as an amber oil which is dissolved in benzene for use in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7](Cl)[N:8]=[CH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:14][NH2:15].C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:15][CH3:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Clc1cc2ccc(Br)cc2cn1
Reactant: CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: O
Product: CNc1cc2ccc(Br)cc2cn1
Temperature: 150 °C
Reaction time: 60 h
Yield: 86.5 %

Procedure:
A mixture of 7-bromo-3-chloroisoquinoline (100 mg, 0.4 mmol), methylamine hydrochloride (139 mg, 2.06 mmol), and potassium carbonate (456 mg, 3.30 mmol) in 1-methoxy-2-(2-methoxyethoxy)ethane (1 mL) was heated to 150° C. and stirred for 60 hours. Additional methylamine hydrochloride (100 mg, 1.5 mmol) and potassium carbonate (200 mg, 1.4 mmol) were added and heating was continued for another 40 hours. The reaction was cooled to room temperature and diluted with water. The mixture was stirred for 30 minutes. The resulting solid was filtered off, rinsed with water and dried under vacuum. Purification by flash column chromatography (10-30% ethyl acetate/heptanes) gave the title compound (82 mg) as a pale yellow solid. −APCI (M−H+1) 237.8; 1H NMR (400 MHz, CDCl3, δ): 8.70 (s, 1H), 7.84 (d, J=1.95 Hz, 1H), 7.48 (dd, J=8.97, 2.15 Hz, 1H), 7.38 (d, J=8.97 Hz, 1H), 6.39 (s, 1H), 2.92 (s, 3H).
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH3:16][C:17]1[CH:18]=[C:19]([O:23][CH2:24][CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=1>>[CH2:24]([O:23][C:19]1[CH:20]=[CH:21][C:22]([CH:9]=[O:10])=[C:17]([CH3:16])[CH:18]=1)[CH:25]=[CH2:26]
Reactant: CN(C=O)c1ccccc1
Reactant: C=CCOc1cccc(C)c1
Solvent: O=P(Cl)(Cl)Cl
Product: C=CCOc1ccc(C=O)c(C)c1
Temperature: 70 °C
Reaction time: 0.42 h
Yield: 81 %

Procedure:
N-methyl formanilide 19.4 ml (158 mmole), was chilled to 13° C., where it began to solidify. Phosphorus oxychloride, 13.7 ml (147 mmole), was added with stirring, under nitrogen. After 25 minutes, the temperature was 45° C. and the reaction had again begun to solidify. The compound of Step A, 14 g (95 mmole), was added and the mixture was stirred and heated in a 70° C. oil bath. The reaction exothermed to 95° C. Stirring was continued under nitrogen for 30 minutes. The bath was removed and when the temperature reached 35°, the mixture was dissolved in chloroform. Ice was added and the layers were separated and washed once with water, twice with saturated sodium bicarbonate, once again with water and once with brine. The organic layer was chromatographed on 450 ml silica, eluting with chloroform to give 13.54 g (81%) of subtitled product which was used without further purification.
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].CCO.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.CCO>O>[C:14]1([C@@H:13]2[NH:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][S:6]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)C1CS[C@H](c2ccccc2)N1
Reaction time: 2.5 h
Yield: 102.5 %

Procedure:
To the suspension of L-cysteine hydrochloride monohydrate (99.24 g, 565.1 mmol) in H2O (535 mL) were added EtOH (420 mL) and benzaldehyde (83.1 mL, 818 mmol) under stirring. After a few minutes, the mixture became a thick cream, which could not be stirred. Enough H2O/EtOH (3:2) solution was added to assist in stiffing the mixture. After 2.5 hrs, the mixture was filtered and the solid was washed with H2O and hexane successively. Upon drying under high vacuum, white powder (121.19 g) was obtained, which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:6]=2[CH:13]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[O:12])=[CH:7][C:6]=2[CH:13]=1
Reactant: O=C(O)c1cc2cc(Br)ccc2o1
Reactant: CN1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2cc3cc(Br)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.3 %

Procedure:
5-Bromo-benzofuran-2-carboxylic acid (0.346 g) in THF (7 mL) was treated with carbonyldiimidazole (0.214 g) and stirred at ambient temperature for 2 h whereupon methyl-piperazine (0.129 g) was added. The mixture was stirred at ambient temperature for 18 h and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution, whereupon the organic portion was separated out, dried over sodium sulfate and filtered. The solvent was evaporated, and the residue was purified via silica gel chromatography (5% 2 M ammonina in methanol/dichloromethane) to afford the title compound (0.222 g). 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J=1.9 Hz, 1H), 7.45 (dd, J=8.8, 1.9 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 3.83 (br s, 4H), 2.48 (t, J=4.8 Hz, 4H), 2.33 (s, 3H). 13C NMR (400 MHz, CDCl3) δ 159.4, 153.4, 150.3, 129.6, 129.0, 124.9, 116.8, 113.5, 111.3, 55.3, 54.9, 46.8, 46.1, 42.9.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24]([OH:26])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][O:37][CH:36]([CH2:40][NH2:41])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][O:37][CH:36]([CH2:40][NH:41][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[NH:23][CH:22]=2)=[O:26])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCOC(CN)C1
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: CC(C)(C)OC(=O)N1CCOC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A67) and 2-aminomethyl-morpholine-4-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.