Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:32]([N:34]([CH2:36][C:37]([NH:39][C@H:40]([C:62]([NH:64][CH2:65][C:66]([OH:68])=[O:67])=[O:63])[CH2:41][CH2:42][CH2:43][NH:44][C:45](=[NH:61])[NH:46][S:47]([C:50]1[C:59]([CH3:60])=[C:57]([CH3:58])[C:54]([O:55][CH3:56])=[CH:53][C:51]=1[CH3:52])(=[O:49])=[O:48])=[O:38])[CH3:35])=[O:33])[CH2:11][S:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[NH:69]1[C:73](=[O:74])[CH2:72][CH2:71][C@H:70]1[C:75](O)=[O:76]>>[NH:69]1[C:73](=[O:74])[CH2:72][CH2:71][C@H:70]1[C:75]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:32]([N:34]([CH2:36][C:37]([NH:39][C@H:40]([C:62]([NH:64][CH2:65][C:66]([OH:68])=[O:67])=[O:63])[CH2:41][CH2:42][CH2:43][NH:44][C:45](=[NH:61])[NH:46][S:47]([C:50]1[C:59]([CH3:60])=[C:57]([CH3:58])[C:54]([O:55][CH3:56])=[CH:53][C:51]=1[CH3:52])(=[O:49])=[O:48])=[O:38])[CH3:35])=[O:33])[CH2:11][S:12][C:13]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:76]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)CN(C)C(=O)[C@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@@H](N)CC(N)=O)C(=O)NCC(=O)O)c(C)c1C
Product: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)CN(C)C(=O)[C@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H]2CCC(=O)N2)C(=O)NCC(=O)O)c(C)c1C

Procedure:
The coupling and Nα -deprotection processes were repeated in the same manner to prepare H-Asn-Cys(Trt)-Sar-Arg(Mtr)-Gly-resin, followed by another coupling process using pGlu-OH to obtain pGlu-Asn-Cys(Trt)-Sar-Arg(Mtr)-Gly-resin. After drying, the resin was stirred in TFA-anisolethiophenol (10-1-1 ml) for 4 hours, filtered and washed with TFA.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[O:3].N[C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19].C([N:28](CC)CC)C.C(O)C>CN1C(=O)CCC1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:28][C:23]2[CH:24]=[CH:25][CH:15]=[CH:16][C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)(=[O:3])[CH3:1]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CN1CCCC1=O
Solvent: CCO
Product: CCOC(=O)c1ccccc1Nc1ccc(C(C)=O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 938.3 %

Procedure:
A mixture 1b (11.0 g, 60.2 mmol), ethyl 3-aminobenzoate (9.9 g, 6.2 mmol) and triethylamine (8.34 ml, 60.2 mmol) in anhydrous NMP (5 ml) was heated to 130° C. with stirring under a stream of nitrogen for 4 hours. The cooled mixture was poured into ice-water (100 ml). Ethanol (10 ml) was added and the mixture was stirred until crystallization was completed. The precipitate was filtered off, washed with water and dried to yield ethyl (4-acetyl-2-nitrophenyl)aminobenzoate (19.1 g, 97%). This ester was hydrogenated quantitatively in a mixture of ethanol (400 ml) and dichloromethane (100 ml) using Pd (5% on activated carbon) as the catalyst. The resulting diamine was heated to reflux in formic acid (100 ml) for 1 hour. The cooled mixture was poured into ice-water (400 ml) and the precipitate was filtered off, washed with water and dried to yield 5-acetyl-1-(3-ethoxycarbonyl)phenylbenzimidazole (16.4 9, 91%).
Reaction SMILES: Cl.[C:2]([S:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]([CH3:17])[CH2:14][CH2:13][CH2:12]2)(O)=O.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([NH2:27])=[C:24]([NH2:26])[CH:25]=1.N>Cl>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]2[N:27]=[C:2]([S:5][CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:16]=3[N:15]([CH3:17])[CH2:14][CH2:13][CH2:12]4)[NH:26][C:24]=2[CH:25]=1
Reactant: COc1ccc(N)c(N)c1
Reactant: CN1CCCc2cccc(CSC(=O)O)c21
Agent: Cl
Agent: N
Product: COc1ccc2nc(SCc3cccc4c3N(C)CCC4)[nH]c2c1
Yield: 14.7 %

Procedure:
8-Carboxythiomethyl-1-methyl-1,2,3,4-tetrahydroquinoline hydrochloride (27.9 g) and 5-methoxy-o-phenylenediamine (13.8 g) in 4N hydrochloric acid (100 ml) were refluxed for 40 minutes. The reaction mixture was cooled, neutralized with aqueous ammonia and extracted with chloroform. After drying the extract, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography [eluent:n-hexane-ethyl acetate (4:1)] to give 8-(5-methoxy-2-benzimidazolyl)thiomethyl-1-methyl-1,2,3,4-tetrahydroquinoline (5.0 g).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C([O-])([O-])=O.[Na+].[Na+].[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)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.COCCOC>[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Reactant: Cc1ccccc1B(O)O
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: [Na+]
Solvent: COCCOC
Product: Cc1ccccc1-c1cccc2c1/C(=C/c1ccc[nH]1)C(=O)N2
Temperature: 100 °C

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (30 mg, 0.089 mmol) (Starting Material 1), 2M aqueous Na2CO3 solution (89 μL, 0.178 mmol), (Ph3P)4Pd (3 mg, 0.003 mmol) (Aldrich), and 2-methylphenylboronic acid (15 mg, 0.110 mmol) (Aldrich) in 3 mL of a 3:1 mixture of 1,2-dimethoxyethane:distilled water was heated at 100° C. under a nitrogen atmosphere for 18 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 25% ethyl acetate-hexanes elution) to provide a crude yellow oil containing product. Recrystallization from chloroform-pentane yielded pure (Z)-1,3-dihydro-4-(2-methylphenyl)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (yield 20 mg, 75%) as yellow needle-like crystals (mp 195-197° C.).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].CO.[Cl:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13](F)=[CH:12][C:11]=1[F:20].O>C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([O:4][CH3:2])=[CH:12][C:11]=1[F:20]
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])c1cc(Cl)c(F)cc1F
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(F)c(Cl)cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 51.8 %

Procedure:
To a suspension of potassium tert-butoxide (15.07 g, 134.3 mmol) in toluene (100 mL), and the appropriate alcohol, in this case methanol (3.80 g, 118.7 mmol), was added at 0° C. and stirred for 15 minutes. A solution of the appropriate 1-substituted 2,4-difluoro-5-nitrobenzene, in this case 1-chloro-2,4-difluoro-5-nitrobenzene (20.0 g, 103.3 mmol), in toluene (50 mL) was added at 0° C. and stirred for 5 hours at room temperature. Water (1000 mL) was added and the mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with water (150 mL), brine (150 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by column chromatography on neutral silica gel using 5-10% EtOAc in hexane to give the title compound (11.0 g, 52%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH2:12][CH:13]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[CH2:34][CH2:33][C:32]4[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=4[NH:30][C:29]3=[O:39])[CH2:24][CH2:23]2)=[O:21])[C:14]([O:16]CC)=[O:15])=[CH:4][C:3]=1[Cl:40].[OH-].[Na+]>CCO>[NH2:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5]([CH2:12][CH:13]([NH:19][C:20]([N:22]2[CH2:23][CH2:24][CH:25]([N:28]3[CH2:34][CH2:33][C:32]4[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=4[NH:30][C:29]3=[O:39])[CH2:26][CH2:27]2)=[O:21])[C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[Cl:40]
Reactant: CCOC(=O)C(Cc1cc(Cl)c(N)c(C(F)(F)F)c1)NC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(Cl)cc(CC(NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 13.00 g (22.34 mmol) ethyl 3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyl]-amino}-propionate (Intermediate product 59) in 100 mL EtOH was added 45 mL aqueous NaOH (1 M) and the mixture was stirred for 16 hours at RT. EtOH was evaporated i. vac., 45 mL aqueous HCl (1M) was added and 15 minutes stirred. The precipitate formed was filtered off, washed with water and dried i. vac. at 75° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][C:16]#N)[N:10]=[CH:9]2)C=CC=CC=1.[C:30]1([CH2:36][CH2:37][CH2:38][Mg]Br)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+].C([O:45]CC)C>O1CCCC1>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][C:16](=[O:45])[CH2:38][CH2:37][CH2:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:10]=[CH:9]1
Reactant: Br[Mg]CCCc1ccccc1
Reactant: N#CCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCOCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(CCCc1ccccc1)CCCc1c[nH]cn1

Procedure:
5 mmol of 4-(1-(triphenylmethyl)imidazol-4-yl)butanenitrile are introduced into a solution of 3-phenylpropylmagnesium bromide in 300 ml of diethyl ether and 100 ml of tetrahydrofuran and the mixture is brought to reflux for 6 h. Hydrolysis is carried out with an ammonium chloride solution, the organic phase is separated and the aqueous phase is stirred with dichloromethane. The combined and concentrated organic phases are brought to boiling point for 2 h in a 2N aqueous/alcohol (ethanol/water) hydrochloric acid solution. The ethanol is removed under vacuum, filtration is carried out and basification is carried out. The title compound is stirred in dichloromethane and recrystallized in the hydrogenmaleate form from ethanol/diethyl ether.
Reaction SMILES: C1N2CN3CN(C2)C[N:2]1C3.[CH3:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[C:20]2[CH2:23][CH2:24][NH:25][C:26](=[O:29])[CH2:27]Br)=[CH:15][CH:14]=1.C(Cl)(Cl)[Cl:31]>>[ClH:31].[CH3:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[C:20]2[CH2:23][CH2:24][NH:25][C:26](=[O:29])[CH2:27][NH2:2])=[CH:15][CH:14]=1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: COc1ccc2cccc(CCNC(=O)CBr)c2c1
Reactant: ClC(Cl)Cl
Product: COc1ccc2cccc(CCNC(=O)CN)c2c1
Product: Cl

Procedure:
0.012 mol of hexamethylenetetramine is dissolved under magnetic agitation in 15 ml of chloroform, and 0.01 mol of N-[2-(7-methoxynaphth-1-yl)ethyl]-2-bromoacetamide obtained in Example 9 dissolved in 20 ml of chloroform are introduced. The mixture is refluxed for 100 hours, spun down and dried. The precipitate is introduced into a ground glass flask and 150 ml of alcohol and 30 ml of concentrated hydrochloric acid are added. The mixture is refluxed for two hours, and then the solvent is evaporated and the residue is recrystallized in alcohol at 90° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:6]=1[C:7](O)=[S:8])(=[O:3])[CH3:2].CCN(CC)CC.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:33][C:34]1[C:35]([C:40]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][N:44]=2)=[O:41])=[N:36][CH:37]=[CH:38][CH:39]=1>ClCCl>[C:1]([O:4][C:5]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:6]=1[C:7]([NH:33][C:34]1[C:35]([C:40]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][N:44]=2)=[O:41])=[N:36][CH:37]=[CH:38][CH:39]=1)=[S:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C)ccc1C(O)=S
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc(C)ccc1C(=S)Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Reaction time: 1 h

Procedure:
To a 0° C. mixture of 2-acetoxy-4-methylthiobenzoic acid (5 g, 22.1 mmol), dichloromethane (75 mL), NEt3 (3.1 mL, 22.1 mmol) and DMF (17 μL, 0.221 mmol) was added oxalyl chloride (1.92 mL, 22.1 mL) at a rate to give gentle bubbling. The mixture was stirred for 1 h and then was concentrated in vacuo. The resulting residue was dissolved in dichloromethane (75 mL). To this solution was added 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide (5.5 g, 22.1 mmol) followed by NEt3 (3.1 mL, 22.1 mmol). The reaction mixture was stirred for 18 h, concentrated to a slurry in dichloromethane and chromatographed (75 g silica gel; 100% dichloromethane to 100% EtOAc) to give the title compound as an impure solid (8.5 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[F:11][C:12]([F:19])([F:18])[C:13](OCC)=[O:14]>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[NH:1][C:13](=[O:14])[C:12]([F:19])([F:18])[F:11]
Reactant: NC1Cc2ccccc2C1
Reactant: CCOC(=O)C(F)(F)F
Product: O=C(NC1Cc2ccccc2C1)C(F)(F)F

Procedure:
Preferably in Step (i), 2-aminoindan is reacted with ethyl trifluoroacetate to form N-(2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](O)=[O:6].Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([N:15]([O:16][CH3:17])[CH3:14])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(F)c(F)c(F)c1

Procedure:
Following the procedure of Example 29, step (b), reaction of 3,4,5-trifluoro-benzoic acid with N,O-dimethylhydroxylamine HCl in present of HOBT, EDA, TEA in DCM followed the column purification gave the title compound; Calcd MW 219.16. Found MH+ 220.1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:54])[CH2:29][C:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[N:38]=[C:39]([CH2:45][O:46]C3CCCCO3)[S:40][C:41]=2[CH2:42][CH2:43][CH3:44])[CH:32]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:28](=[O:54])[CH2:29][C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]4[N:38]=[C:39]([CH2:45][OH:46])[S:40][C:41]=4[CH2:42][CH2:43][CH3:44])[CH:32]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CCCc1sc(COC2CCCCO2)nc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1sc(CO)nc1-c1cccc(C2=Nc3cc(N(C)C)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (79 mg) (Example J6) and 3-oxo-3-{3-[-5-propyl-2-(tetrahydro-pyran-2-yloxymethyl)-thiazol-4-yl]-phenyl}-propionic acid tert-butyl ester (138 mg) (Example K41) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as yellow solid (45 mg).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([NH:15][C:16](=[O:18])[CH3:17])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:19])C.[O:21]1[C:25]([C:26]2[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][CH:27]=2)=[CH:24][N:23]=[CH:22]1>>[C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:8]([S:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]3[O:21][CH:22]=[N:23][CH:24]=3)=[CH:31][CH:30]=1)=[C:7]([CH3:19])[N:6]2[CH2:5][C:4]([OH:3])=[O:20])(=[O:18])[CH3:17]
Reactant: Sc1ccc(-c2cnco2)cc1
Reactant: CCOC(=O)Cn1c(C)cc2c(NC(C)=O)cccc21
Product: CC(=O)Nc1cccc2c1c(Sc1ccc(-c3cnco3)cc1)c(C)n2CC(=O)O

Procedure:
The title compound was prepared by the method of example 3 using (4-acetylamino-2-methyl-indol-1-yl)-acetic acid ethyl ester and the product of example 2 step (i).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].ClOC(C)(C)C.[CH3:15][S:16][CH2:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[N:19]=1.CO.C[O-].[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:17]([C:18]2[N:19]=[C:20]([O:26][CH3:27])[CH:21]=[C:22]([O:24][CH3:25])[N:23]=2)[S:16][CH3:15])[C:3]=1[NH2:4]
Reactant: COc1cc(OC)nc(CSC)n1
Reactant: Nc1ccccc1Cl
Agent: CC(C)(C)OCl
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COc1cc(OC)nc(C(SC)c2cccc(Cl)c2N)n1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 82.6 %

Procedure:
2-Chloroaniline 5.2 g (26.0 mmol) was dissolved in dichloromethane (200 ml) and the solution was cooled to −70° C. To the cooled solution a dichloromethane (10 ml) solution of tert-butyl hypochlorite 2.82 g (26.0 mmol) was added dropwise and the solution was stirred at −70° C. for 10 minutes. To the obtained reaction solution a dichloromethane (20 ml) solution of 2-methylthiomethyl-4,6-dimethoxypyrimidine 3.38 g (26.0 mmol) was added dropwise and the solution was stirred at −70° C. for 40 minutes. To the obtained reaction solution 28% sodium methoxide methanol solution (9 ml) was added and the solution was stirred until it came to room temperature. Water was added to the reaction solution and the organic layer was separated. The water layer was further extracted twice with dichloromethane. After the organic layer had been washed with water and dried, dichloromethane was distilled off under reduced pressure and the objective 2-chloro-6-[1-(4,6-dimethoxypyrimidin-2-yl)-1-methylthiomethyl]aniline 7.00 g (yield 83%) was obtained as oily substance from the obtained oily substance by column chromatography using 1:8 mixed solvent of ethyl acetate and hexane as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:14]([O:16]C)=[O:15])[C:10]([O:12]C)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].Cl.ClCCl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:10]([OH:12])=[O:11])[C:14]([OH:16])=[O:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)C(C(=O)OC)c1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=C(O)C(C(=O)O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The crude 1,3-dimethyl 2-(3,5-dichlorophenyl)propanedioate form Step A was taken up in methanol (150 mL) and water (300 mL). To this mixture was added 50% aqueous sodium hydroxide (120 g, 1.5 mol) over 30 min at room temperature. The reaction mixture was stirred at room temperature for 18 hours and then cooled to 10° C. in an ice bath. The mixture was acidified with concentrated hydrochloric acid (135 mL of 37%) over 30 min while maintaining the temperature of the reaction mixture at less than 17° C. The reaction mixture was extracted with ethyl acetate (600 mL) and the organic phase was concentrated under vacuum to give a viscous oil. The crude oil was treated with dichloromethane (200 mL) and stirred till a thick slurry formed. The slurry was filtered and dried via suction filtration under a nitrogen blanket for 48 hours at room temperature to give a solid (76.0 g, 84% over 2 steps).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:27]=[C:28]([SH:33])[CH:29]=[CH:30][C:31]=1[CH3:32]>CCCCO.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>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([S:33][C:28]4[CH:29]=[CH:30][C:31]([CH3:32])=[C:26]([CH3:25])[CH:27]=4)[CH:11]=3)[CH:6]=[CH:7][N:8]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(Br)cc23)CC1
Reactant: Cc1ccc(S)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCO
Product: Cc1ccc(Sc2ccc3ccnc(N4CCN(C(=O)OC(C)(C)C)CC4)c3c2)cc1C
Temperature: 110 °C
Yield: 44.5 %

Procedure:
A mixture of 4-(7-bromo-isoquinoline-1-yl)-piperazine-1-carboxylic acid, tert-butyl ester (0.5 g, 1.3 mmol), 3,4-dimethyl-thiophenol (175 uL, 1.3 mmol), NatBuO (0.44 g, 4.5 mmol), Pd(PPh3)4 (74 mg, 0.065 mmol) in n-BuOH (10 mL) was heated at 110° C., 3 h. The reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with water (50 mL×3), separated and dried (MgSO4), filtered. The volatiles were evaporated and the residue was purified by flash column chromatography (SiO2, n-pentane:ethyl acetate 9.5:0.5→8:2) to give 260 mg of the title compound as colorless oil (yield 44%). 1H NMR (CDCl3) δ 8.00-8.10 (m, 2H), 7.55-7.65 (m, 3H), 7.40-7.50 (m, 1H), 7.10-7.30 (m, 2H), 3.30-3.40 (m, 4H), 3.10-3.20 (m, 4H), 2.30 (s, 3H), 2.25 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[NH:10][NH2:11].CN([CH:15]=[C:16]1[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:21]=2[NH:20][C:19]2[N:27]=[CH:28][CH:29]=[CH:30][C:18]=2[C:17]1=O)C>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[N:10]1[CH:15]=[C:16]2[C:17]([C:18]3[CH:30]=[CH:29][CH:28]=[N:27][C:19]=3[NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=32)=[N:11]1
Reactant: CN(C)C=C1C(=O)c2cccnc2Nc2ccncc21
Reactant: NNc1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCO
Product: Clc1cccc(Cl)c1-n1cc2c(n1)-c1cccnc1Nc1ccncc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2,6-Dichlorophenyl)hydrazine hydrochloride (168 mg, 0.788 mmol) was added to a solution of 6-[(dimethylamino)methylene]-6,11-dihydro-5H-dipyrido[2,3-b:3′,4′-f]azepin-5-one (105 mg, 0.394 mmol, Intermediate E-1) in ethanol (4 mL) and stirred at room temperature. After 30 minutes, the mixture was heated to 60° C. overnight. The reaction was then cooled to room temperature and the major product from the reaction mixture was isolated using preparative LC/MS to provide the desired product as a white powder. 1H NMR (DMSO-d6) δ 8.77 (bs, 1H), 8.45 (bs, 1H), 8.40 (bs, 1H), 8.04 (m, 2H), 7.94 (d, 1H), 7.75 (m, 2H), 7.62 (m, 1H), 6.95 (m, 1H), 6.87 (m, 1H). LC/MS: 380 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]([F:20])([F:19])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C@@H:16]([NH2:18])[CH3:17])[CH:11]=2)=[CH:6][CH:5]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH2:35][CH2:34][CH2:33][C@H:32]2[C:36](O)=[O:37])(=[O:30])=[O:29])=[CH:24][CH:23]=1.ON1C2C=CC=CC=2N=N1.CCN(CC)CC>CO.CN(C=O)C>[F:2][C:3]([F:19])([F:20])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C@@H:16]([NH:18][C:36]([C@@H:32]3[CH2:33][CH2:34][CH2:35][N:31]3[S:28]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)(=[O:30])=[O:29])=[O:37])[CH3:17])[CH:11]=2)=[CH:8][CH:9]=1
Reactant: C[C@H](N)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccc(F)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(F)cc1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reaction time: 12 h
Yield: 53.8 %

Procedure:
A mixture of (5)-1-(4′-trifluoromethyl-biphenyl-3-yl)ethylamine hydrochloride (75 mg, 0.25 mmol), (S)-1-(4-fluoro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (68 mg, 0.25 mmol), N-(3-dimethylamniopropyl)-N′-ethylcarbodiimide hydrochloride (71 mg, 0.37 mmol), 1-hydroxybenzotriazole (50 mg, 0.37 mmol) and DMF (2 mL) was added Et3N (0.10 mL, 0.75 mmol). After 12 h, MeOH (0.5 mL) was added to the reaction mixture and resulting solution was purified by preparative reverse-phase HPLC to afford (70 mg, 54%) of a white solid. MS (ESI): mass calcd. for C26H24F4N2O3S, 520.1; m/z found, 521.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 7.93-7.87 (m, 2H), 7.79 (d, J=8.0, 2H), 7.73-7.66 (m, 3H), 7.54 (d, J=7.6, 1H), 7.49 (t, J=7.6, 1H), 7.44 (d, J=7.6, 1H), 7.35 (d, J=8.0, 1H), 7.30-7.23 (m, J=8.7, 1H), 5.27-5.11 (m, 1H), 4.11 (dd, J=8.9, 3.1, 1H), 3.71-3.60 (m, 1H), 3.26-3.15 (m, 1H), 2.28-2.17 (m, 1H), 1.91-1.75 (m, 1H), 1.74-1.64 (m, 2H), 1.60 (d, J=7.0, 3H).