Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19][C:4]1=2)[CH3:2].C([Sn](CCCC)(CCCC)[C:33]1[CH:34]=[N:35][NH:36][CH:37]=1)CCC.[Cl-].[Li+]>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([CH:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18]([C:33]3[CH:34]=[N:35][NH:36][CH:37]=3)=[N:19][C:4]1=2)[CH3:2]
Reactant: CCC1c2ncccc2C(=O)N(C)c2ccc(OS(=O)(=O)C(F)(F)F)nc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn[nH]c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC1c2ncccc2C(=O)N(C)c2ccc(-c3cn[nH]c3)nc21
Temperature: 120 °C
Yield: 15 %

Procedure:
A mixture of 5,11-dihydro-11-ethyl-2-trifluoromethanesulfonyloxy-5-methyl-dipyrido[3,2-b:2',3'-e]azepine-6-one (0.084 g), 4-tributylstannylpyrazole (0.096 g), lithium chloride (0.052 g) and Pd(Ph3P)2Cl2 (0.009 g) in dimethylformamide (1 mL) was heated at 120° C. in a sealed tube 16 hours. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. Chromatography of the residue over silica gel (ethyl acetate/hexane) gave 5,11-dihydro-11-ethyl-2-(4-pyrazolyl)-5-methyl-dipyrido[3,2-b:2',3'-e]azepine-6-one (0.010 g).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH2:7].C(N(CC)CC)C.[O:22]1[CH2:27][CH2:26][N:25]([C:28]([C:30]([S:33]([CH2:36][C@@H:37]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:38](O)=[O:39])(=[O:35])=[O:34])([CH3:32])[CH3:31])=[O:29])[CH2:24][CH2:23]1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.ON1C=CC=CC1=O.C(#N)C>[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH:7][C:38](=[O:39])[C@@H:37]([CH2:36][S:33]([C:30]([CH3:31])([C:28]([N:25]1[CH2:26][CH2:27][O:22][CH2:23][CH2:24]1)=[O:29])[CH3:32])(=[O:34])=[O:35])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: CC(C)(C(=O)N1CCOCC1)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=c1ccccn1O
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C(=O)N1CCOCC1
Reaction time: 18 h
Yield: 101 %

Procedure:
2.5 g (10.5 mmol) of histidine methyl ester dihydrochloride, 10 ml of acetonitrile and 2.9 ml (148 mmol) of triethylamine were stirred at 20° for 20 hours. 3.8 g (10 mmol) of (S)-α[[[1-(morpholinocarbonyl)-1-methylethyl]sulphonyl]methyl]hydrocinnamic acid, 0.11 g (1 mmol) of 1-hydroxy-2(1H)-pyridone and 20 ml of ethyl acetate were subsequently added. After 15 minutes a solution of 2.2 g (10.5 mmol) of dicyclohexylcarbodiimide in 15 ml of ethyl acetate was added within 30 minutes. The reaction had finished after stirring at 20° for 18 hours. The solid (dicyclohexylurea) was filtered off under suction and the filtrate was washed with aqueous sodium bicarbonate solution and water. 5.4 g of N-[(S)-α-[[[1-methyl-1-(morpholinocarbonyl)ethyl]sulphonyl]methyl]hydrocinnamoyl]-L-histidine methyl ester were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2[S:28][C:29]([CH2:33]O)=[C:30]([CH3:32])[N:31]=2)[CH:23]=[CH:24][C:25]=1[F:26].ClC1C=C(C=CC=1F)C(N)=S.ClC(C(C)=O)C(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:33][C:29]2[S:28][C:27]([C:22]3[CH:23]=[CH:24][C:25]([F:26])=[C:20]([Cl:19])[CH:21]=3)=[N:31][C:30]=2[CH3:32])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1nc(-c2ccc(F)c(Cl)c2)sc1CO
Agent: CCOC(=O)C(Cl)C(C)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: NC(=S)c1ccc(F)c(Cl)c1
Product: CCOC(=O)C(Cc1ccc(OCc2sc(-c3ccc(F)c(Cl)c3)nc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with [2-(3-chloro-4-fluoro-phenyl)-4-methyl-thiazol-5-yl)-methanol (prepared from 3-chloro-4-fluoro-thiobenzamide and ethyl 2-chloro-acetoacetate in analogy to the procedures described in examples 33 a] and 33 b]) in the presence of triphenylphosphine and diethyl azodicarboxylate to yield [rac]-3-{4-[2-(3-chloro-4-fluoro-phenyl)-4-methyl-thiazol-5-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester as light yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:19]=1[C:20](Cl)=[O:21]>>[F:17][C:18]1[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: O=C(Cl)c1c(F)ccc(F)c1F
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3c(F)ccc(F)c3F)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 2,3,6-trifluorobenzoyl chloride (30 μL, 0.229 mmol) and mixing for 24 h, 47.7 mg (>100%) of the title compound were recovered.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[C:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:4].[H-].[Na+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C)C=O>[CH2:35]([O:34][C:32]([CH2:31][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=2)[C:10]([C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[C:11]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:33])[CH3:36]
Reactant: CCOC(=O)CBr
Reactant: COC(=O)C1=C(c2c(-c3ccccc3)[nH]c3cc(C(=O)O)ccc23)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(-c2ccccc2)c(C2=C(C(=O)OC)CCC2)c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3-(2-methoxycarbonyl-cyclopent-1-enyl)-2-phenyl-1H-indole-6-carboxylic acid on Wang resin (100 mg; compound 7-3, prepared according to the is procedure outlined in Example 7) in dimethylformamide (1.5 mL) was added sodium hydride (60% in mineral oil; 20 mg) and the mixture was stirred at room temperature for 30 min. Ethyl bromoacetate (0.1 mL) was added and the mixture was stirred for 3 h. The mixture was filtered, washed with water (1×1.5 mL), tetrahydrofuran (2×1.5 mL), dichloromethane (2×1.5 mL), and dried. The product was cleaved from the resin by treatment with 1:1 trifluoroacetic acid/dichloromethane for 1 h; 1H NMR (DMSO-d6) δ 1.13 (t, J=7.1 Hz, 3 H), 1.80 (m, 2 H), 2.50 (m, 2 H), 2.63 (m, 2 H), 3.33 (s, 3 H), 4.09 (q, J=7.1 Hz, 7.30 (m, 2 H), 7.39 (d, J=8.5 Hz, 1 H), 7.48 (m, 3 H), 7.71 (d, J=7.2 Hz, 1 H), 8.11 (s, 1 H).
Reaction SMILES: Cl.[CH2:2]([O:4][P:5]([CH:10]([C:18]#[N:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:9])[O:6][CH2:7][CH3:8])[CH3:3]>CCO.[Pt]=O>[CH2:7]([O:6][P:5]([CH:10]([CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[CH2:18][NH2:19])(=[O:9])[O:4][CH2:2][CH3:3])[CH3:8]
Reactant: CCOP(=O)(OCC)C(C#N)Cc1ccccc1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: CCOP(=O)(OCC)C(CN)CC1CCCCC1

Procedure:
Platinum oxide and conc.HCl were added to a solution of diethyl(1-cyano-2-phenylethyl)phosphonate in EtOH, for overnight stirring under hydrogen atmosphere, to obtain diethyl[2-amino-1-(cyclohexylmethyl)ethyl]phosphonate.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([O:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C>CO.[OH-].[Na+]>[C:16]([NH:15][O:14][CH:5]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([OH:23])=[O:3])([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17]
Reactant: CCOC(=O)C(CCc1ccccc1)ONC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NOC(CCc1ccccc1)C(=O)O
Yield: 101.6 %

Procedure:
A solution of the compound from Step 9b (950 mg, 3 mmol) in MeOH (20 mL) and 2 N NaOH (4 mL) were stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, acidified to pH ˜2.0 with 2 N HCl. The resulting mixture was extracted with EtOAc (3×50 mL), dried (Na2SO4) and filtered. The solvent was removed under reduced pressure and residue was purified by flash chromatography (CH2Cl2; CH2Cl2/MeOH=10/1) giving 900 mg (86%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([S:28](C)(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C[Si]([N-:36][Si](C)(C)C)(C)C.[Na+].[OH-].[Na+].O.O.O.C([O-])(=O)C.[Na+].NOS(O)(=O)=O>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:36])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(O)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: CC(=O)[O-]
Agent: NOS(=O)(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 17.9 %

Procedure:
To a solution of 2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl- -propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (139 mg, 0.309 mmol) and di-t-butylazodicarboxylate (71.2 mg, 0.309 mmol) in THF (25 mL) at −78° C. was added dropwise a 1M solution of NaHMDS (0.93 mL, 0.928 mmol) in THF. After addition the reaction was stirred another 45 min at −78° C. (or until TLC indicated a disappearance of starting material) and then was treated with 1N NaOH (20 mL). The reaction mixture was stirred at room temperature for the next 18 h. Sodium acetate trihydrate (758 mg, 5.57 mmol) was added followed by addition of hydroxylamine-O-sulphonic acid (630 mg, 5.57 mmol) and H2O (50 mL). The resulting mixture was stirred at ambient temperature for the next 18 hours and then extracted with EtOAc. The extract was washed with water, brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography (silica gel, 1:1 hexanes-EtOAc) to provide the title compound (yield: 25 mg; 18%). mp 65–69° C; 1H NMR (300 MHz, DMSO-d6) δ 1.0 (s, 6H), 4.2 (s, 2H), 4.56 (s, 1H), 7.51 (m, 3H), 7.6 (m, 1H), 7.85 (m, 1H), 7.95 (s, 4H), 8.21 (s, 1H); MS (DCI/NH3) m/z 451 (M+H)+, 467 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)[N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=2)[CH:6]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:24])=[O:33])=[CH:19][CH:18]=2)[N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2cc(C)cn2-c2ccc(S(N)(=O)=O)cc2)cc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2ccc(S(C)=O)cc2)n(-c2ccc(S(N)(=O)=O)cc2)c1
Reaction time: 1 h
Yield: 61.4 %

Procedure:
0.35 g (1.0 mmol) of 4-methyl-2-(4-methylthiophenyl)-1-(4-sulfamoylphenyl)pyrrole (prepared as described in Example 66) was dissolved in 50 ml of chloroform, and 0.27 g (1.1 mmol) of 70% m-chloroperbenzoic acid was added to the resulting solution in several portions, whilst ice-cooling, after which the mixture was stirred for 1 hour, whilst ice-cooling. The reaction mixture was then diluted with chloroform and was washed with a 10% w/v aqueous solution of sodium thiosulfate and with a saturated aqueous solution of sodium hydrogencarbonate twice each, in that order. The organic layer was then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue thus obtained was applied to a silica gel chromatography column and eluted with a 95:5 by volume mixture of methylene chloride and methanol, to give 0.23 g (yield 63%) of the title compound as a pale orange-colored powder, melting at 222-226° C.
Reaction SMILES: [C:1]([Mg]Cl)#[CH:2].[O:5]1[CH:11]2[CH:6]1[CH2:7][N:8]([C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10]2>C1COCC1.OS(O)(=O)=O>[C:12]([N:8]1[CH2:9][CH2:10][CH:11]([OH:5])[CH:6]([C:1]#[CH:2])[CH2:7]1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C#C[Mg]Cl
Reactant: O=C(c1ccccc1)N1CCC2OC2C1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: C#CC1CN(C(=O)c2ccccc2)CCC1O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a solution of ethynyl magnesium chloride in THF (5 mmole) at 0° C., is added dropwise a solution of 40 (5.8 mmole) in THF. The mixture is allowed to stir at 0-10° C. for 1 hour, then at room temperature for an additional hour and then heated with gentle reflux for 30 mm. The reaction mixture is added to ice-water and the formed precipitate, Mg(OH)2, is dissolved in 30% H2SO4. The product formed is extracted repeatedly with methylene chloride. Standard work-up and flash chromatography affords 54.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:4])[CH2:2][CH3:3].P([O-])([O-])(O)=O.[Na+].[Na+].[Br:19]Br>O.C(O)(=O)C>[C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Br:19])=[CH:8][N:7]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Nc1ccccn1
Reactant: BrBr
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC(=O)Nc1ccc(Br)cn1
Reaction time: 4 h
Yield: 84.7 %

Procedure:
To 47.5g of an aqueous solution containing 0.2 mol of 2-propionamido pyridine (Ie), a solution containing 71 g (0.5 ml) of disodium hydrogenphosphate dissolved in 450 g of water was added. To this mixture, a solution containing 49.2 g (0.31 mol) of bromine dissolved in 50 g of acetic acid was added with stirring at 10°-15° C. for 4 hours. After having been stirred at room temperature for one hour and then at 60° C. for one hour, the mixture was cooled. The crystal precipitated thereby was filtered. After the crystal was washed with water and dried, 38.8 g (yield: 84.7%) of 2-propionamido-5-bromopyridine (IIe) was obtained as a dark white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:14](#[N:17])[CH:15]=[CH2:16]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:16][CH2:15][C:14]#[N:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CC#N
Reactant: Clc1ccc(C2CCCN2)cc1Cl
Solvent: CO
Product: N#CCCN1CCCC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.7 %

Procedure:
To the solution of 2.4 g (11.2 mmol) 2-(3,4-dichlorophenyl)pyrrolidine in 13 ml abs. methanol dropwise under stirring at room temperature 2.21 ml (33.6 mmol) acrylonitrile is added. The reaction mixture is stirred for 3 days at room temperature, then evaporated. The residue is purified by column chromatography using at first chloroform, then chloroform:methanol 100:1 ratio mixture as eluent, to obtain 2.1 g title compound in the form of an oil. LC-MS[MH+]=269 (C13H14Cl2N2 269.14).
Reaction SMILES: C([O-])=O.[NH4+].[C:5]([O:9][C:10]([N:12]([CH3:46])[CH2:13][CH2:14][O:15][CH2:16][C:17]1[CH:18]=[C:19]([CH:43]=[CH:44][CH:45]=1)[CH2:20][CH2:21][NH:22][C:23]1[C:24](=[O:42])[N:25]([CH2:31][C:32]([O:34]CC2C=CC=CC=2)=[O:33])[C:26]([CH3:30])=[C:27](Cl)[N:28]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>[Pd].CO>[C:5]([O:9][C:10]([N:12]([CH3:46])[CH2:13][CH2:14][O:15][CH2:16][C:17]1[CH:18]=[C:19]([CH:43]=[CH:44][CH:45]=1)[CH2:20][CH2:21][NH:22][C:23]1[C:24](=[O:42])[N:25]([CH2:31][C:32]([OH:34])=[O:33])[C:26]([CH3:30])=[CH:27][N:28]=1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: Cc1c(Cl)nc(NCCc2cccc(COCCN(C)C(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cnc(NCCc2cccc(COCCN(C)C(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)O
Temperature: 25 °C
Yield: 77.4 %

Procedure:
Ammonium formate (368 mg, 5.83 mmol), followed by 10% palladium on charcoal (200 mg), were added to a solution of benzyl 2-[3-{[3-({2-[(tert-butoxycarbonyl)(methyl)amino]ethoxy}methyl)phenethyl]amino}-5-chloro-6-methyl-2-oxo-1(2H)-pyrazinyl]acetate (preparation 113) (350 mg, 0.58 mmol) in methanol (10 ml), and the reaction stirred at room temperature ovemight. The reaction mixture was filtered through Whatman® fibre, and the filtrate concentrated under reduced pressure. The residue was triturated with dichloromethane, the resulting suspension filtered again through Whatman® fibre, then through celite, and this filtrate evaporated under reduced pressure. The residual solid was dissolved in dichloromethane, the solution washed with water, brine, then dried over MgSO4 and evaporated under reduced pressure to give the desired product as a gum, (213 mg, 79%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:3]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C([O-])=O.[NH4+]>CCO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:3]=1[N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)[NH2:8]
Reactant: Cc1cc([N+](=O)[O-])cc(CN2CCCC2)c1N1CCOCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1cc(N)cc(CN2CCCC2)c1N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
4-[2-Methyl-4-nitro-6-(pyrrolidin-1-ylmethyl)phenyl]morpholine (62 mg, 0.20 mmol) was hydrogenated using ammonium formate (128 mg, 2.00 mmol) and Pd/C (10% Pd, 21 mg, 0.02 mmol) in 2 mL of EtOH. The mixture was stirred overnight at room temperature and then filtered through a celite pad. The filtrate was evaporated and the residue was dissolved in DCM and washed with a saturated aqueous solution of Na2CO3. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated to yield expected compound as a pale yellow oil (55 mg, 99% yield); m/z (ESI) 276.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[CH3:46][O:47][C:48]([N:50]=[C:51]=S)=[O:49].C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C.C1C=CC=CC=1>[CH3:40][O:39][C:8]1[CH:9]=[C:10]([CH:37]=[CH:38][C:7]=1[NH:6][C:4]([C:3]1[C:2]2[N:1]=[C:51]([NH:50][C:48]([O:47][CH3:46])=[O:49])[NH:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)=[O:5])[C:11]([N:13]([CH3:36])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:28])=[O:12]
Reactant: COC(=O)N=C=S
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: c1ccccc1
Product: COC(=O)Nc1nc2c(C(=O)Nc3ccc(C(=O)N(C)c4ccc(C)cc4OCCCCCC(=O)N4CCN(C)CC4)cc3OC)cccc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49.8 %

Procedure:
To a stirred solution of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (145 mg) in a mixture of acetonitrile and benzene [1:4(v/v)] was added methoxycarbonyl isothiocyanate (36 mg) and the reaction mixture was stirred at ambient temperature for 5 minutes. After being added 1,3-dicyclohexylcarbodiimide (73 mg) to the solution, the resulting mixture was stirred at reflux temperature for 5 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in chloroform. The solution was washed with saturated aqueous sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel (chromatorex) eluting with chloroform and preparative thin-layer chromatography (chloroform-methanol=10:1) to give 3-methoxy-4-(2-methoxycarbonylamino-1H-benzimidazol-4-yl)carbonylamino-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (82 mg) as a powder.
Reaction SMILES: [ClH:1].C(OCC)(=O)C.[CH2:8]([O:15][C:16]1[C:17]([F:34])=[C:18]([C:31]([OH:33])=[O:32])[C:19]([NH:23]C(OC(C)(C)C)=O)=[CH:20][C:21]=1[F:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[ClH:1].[NH2:23][C:19]1[C:18]([C:31]([OH:33])=[O:32])=[C:17]([F:34])[C:16]([O:15][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:21]([F:22])[CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(OCc2ccccc2)c(F)c1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1cc(F)c(OCc2ccccc2)c(F)c1C(=O)O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
4N Hydrochloric acid-ethyl acetate (35 mL) was added to 3-benzyloxy-6-tert-butoxycarbonylamino-2,4-difluorobenzenecarboxylic acid (3.53 g), and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled down to room temperature, and the resultant precipitated solid was collected by filtration and dried to give 6-amino-3-benzyloxy-2,4-difluorobenzenecarboxylic acid hydrochloride (2.08 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:17])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1.CO>CN(C=O)C>[CH2:15]([C:13]1[S:14][C:10]2[C:9]3[CH:8]=[CH:7][C:6]([O:17][CH2:25][CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[NH:29][CH:28]=4)=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)[CH3:16]
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: CCc1nc2c(N)nc3cc(O)ccc3c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCc1nc2c(N)nc3cc(OCCc4c[nH]c5ccccc45)ccc3c2s1
Temperature: 60 °C

Procedure:
A scintillation vial was charged with 4-amino-2-ethylthiazolo[4,5-c]quinolin-7-ol (1.0 eq., 1.0 mmol) and anhydrous DMF (2 mL). The mixture was warmed until a solution was obtained. An additional amount of DMF (1 mL) was added. To this stirred orange solution was added cesium carbonate (3.0 eq., 3.0 mmol) and a solution of 3-(2-bromoethyl)indole (1.0 eq., 1.0 mmol) dissolved in DMF (2 mL). Additional DMF (1 mL) was used to rinse the vial. The vial was capped and heated to 60° C. overnight. The reaction was monitored by HPLC. The reaction was quenched by adding the reaction mixture drop-wise to water (60 ml) with stirring. A precipitate formed. The solid was collected by vacuum filtration. The solid was then dissolved in methanol and adsorbed onto silica gel (6 g) for purification by HPFC (0-15% CMA in chloroform, 1440 mL). Pure fractions were combined and concentrated; the resulting solid was recrystallized from methanol to provide a peach colored crystalline solid, mp 218-220° C. MS (APCI) m/z 389 (M+H)+. Anal. calcd for C22H20N4OS.0.8 CH3OH: C, 66.13; H, 5.65; N, 13.53. Found: C, 66.43; H, 5.03; N, 13.90.