Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][I:10])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](C2C=CC(CCO)=CC=2)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][I:10])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: OCCc1ccc(-c2ccc(F)cc2)cc1
Reactant: Brc1ccc(CCI)cc1
Product: Fc1ccc(-c2ccc(CCI)cc2)cc1
Yield: 100 %

Procedure:
The title compound (650 mg, 100%) was prepared following the general procedure of step 1, Preparation 2, outlined for 1-bromo-4-(2-iodoethyl)benzene except that 2-(4′-fluorobiphenyl-4-yl)ethanol (430 mg, 1.99 mmol) was used in place of 2-(4-bromophenyl)ethanol. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.23 (t, J=7.69 Hz, 2H) 3.39 (t, J=7.69 Hz, 2H) 7.13 (t, J=8.72 Hz, 2H) 7.24-7.30 (m, 2H) 7.48-7.58 (m, 4H).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([CH:25]([CH3:31])[CH2:26][C:27]#[C:28][CH2:29][CH3:30])/[CH:5]=[CH:6]/[C@H:7]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][C@H:12]2[C@@H:8]1[CH2:9][C:10](=[O:24])[O:11]2>CO.CCOCC>[OH:3][C@@H:4]([CH:25]([CH3:31])[CH2:26][C:27]#[C:28][CH2:29][CH3:30])/[CH:5]=[CH:6]/[C@H:7]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][C@H:12]2[C@@H:8]1[CH2:9][C:10](=[O:24])[O:11]2
Reactant: CCC#CCC(C)C(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCC#CCC(C)[C@H](O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
3.4 of sodium borohydride is added batchwise to a solution of 6 g of the ketone prepared in example (6e) in 200 ml of methanol, at -40° C., and the mixture is stirred for 1 h at -40° C. under argon. Next it is diluted with ether, washed with water until neutral, dried over magnesium sulfate and vacuum evaporated. By means of column chromatography on silcia gel using ether/hexane (8/2), first 2.6 g of the title compound (3-alpha-hydroxy) is elutriated, next, as the more polar component, 1.9 g of the corresponding isomeric 3 beta-hydroxy compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:16])=O>CN(C=O)C.CO>[F:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=Cc1ccc(C(=O)O)c(F)c1
Solvent: CO
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)Cl)c(F)c1
Reaction time: 2 h

Procedure:
To a slurry of 2-fluoro-4-formylbenzoic acid (0.531 g, 3.16 mmol) 10 mL DCM was added oxalyl chloride (0.168 mL, 1.89 mmol) and catalytic DMF (2 drops). The reaction was allowed to stir under a positive pressure of argon with a needle outlet to air. After 2 h, a quenched aliquot of the reaction (MeOH) was determined to contain no acid. The reaction was concentrated in vacuo and dried on a hood pump for 10 min to give a yellow solid, which was used without further purification.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=1>O1CCCC1>[CH:1]([NH:11][C:12]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=1)=[O:2]
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1N
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2ccccc2)nc1NC=O
Temperature: 55 °C
Reaction time: 2 h

Procedure:
Under ice-cooling, 98% formic acid (12.75 g) was added to acetic anhydride (22.97 g) using an dropping funnel, the obtained mixture was stirred at 50-60° C. for 2 hrs, and cooled to room temperature. Tetrahydrofuran (25 mL) was added to the obtained mixture and a solution of ethyl 3-amino-1-phenyl-1H-pyrazole-4-carboxylate (20.00 g) in tetrahydrofuran (20 mL) was added. The obtained mixture was stirred at room temperature for 3 hrs and concentrated. The residue was recrystallized from ethyl acetate-hexane to give ethyl 3-(formylamino)-1-phenyl-1H-pyrazole-4-carboxylate as colorless needle crystals (20.89 g, yield 93%). melting point: 135-136° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:17][C:18]1[C:19]([CH2:33][NH2:34])=[CH:20][C:21]2[N:25]=[CH:24][N:23]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:22]=2[CH:32]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:14]1([C:11]2[NH:12][N:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:34][CH2:33][C:19]4[C:18]([F:17])=[CH:32][C:22]5[N:23]([CH:26]6[CH2:31][CH2:30][CH2:29][CH2:28][O:27]6)[CH:24]=[N:25][C:21]=5[CH:20]=4)[N:7]=3)[CH:10]=2)[CH2:16][CH2:15]1
Reactant: NCc1cc2ncn(C3CCCCO3)c2cc1F
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc2c(cc1CNc1nccc(Nc3cc(C4CC4)[nH]n3)n1)ncn2C1CCCCO1
Temperature: 120 °C
Yield: 39.9 %

Procedure:
A tube was charged with 53 (235 mg, 1.0 mmol), 106 (237 mg, 0.95 mmol), DIPEA (1.0 mL) and IPA (3 mL), degassed, sealed and heated at 120° C. overnight. The solvent was evaporated in vacuo to afford 170 mg (39%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methyl)pyrimidine-2,4-diamine (108) as white solid: MS (ESI) m/z=449.2 [M+1]+.
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[C:13]1([C:11]2[N:2]=[C:3]3[CH2:8][CH2:7][CH2:6][CH2:5][N:4]3[CH:10]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N=C1CCCCN1
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2cn3c(n2)CCCC3)cc1
Temperature: 25 °C
Yield: 71 %

Procedure:
Combine 2-iminopiperidine hydrochloride (4.9 g, 36.4 mmol, 3 equiv) and 2-bromoacetophenone (2.4 g, 12.1 mmol) with Na2CO3 (5.1 g, 48.4 mmol) in dry DMF (15 mL) and heat the mixture at 80° C. for 16 hours. Then, cool the mixture to room temperature, add water (200 mL), and extract with ether (3×100 mL). Wash the combined organic layers with water (2×50 mL), and re-extract the aqueous layer with ether (2×50 mL). Wash the combined organic layers with saturated aqueous sodium chloride (100 mL), dry (MgSO4), and concentrate in vacuo. Purify the residue by flash chromatography (SiO2; eluent: CH2Cl2 to CH2Cl2:MeOH 50:1) to obtain a brown solid, 1.7 g, 71% yield. MS(ES+): m/z=199.1 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16](Cl)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[CH3:20][O:21][C:22](=[O:30])[C:23]1[C:28]([NH2:29])=[CH:27][CH:26]=[N:25][CH:24]=1.C(N(CC)CC)C>ClC(Cl)C>[CH3:20][O:21][C:22](=[O:30])[C:23]1[C:28]([NH:29][C:16]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=[C:8]([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[F:19])[N:17]=2)=[CH:27][CH:26]=[N:25][CH:24]=1
Reactant: Fc1ccc(Br)cc1-c1nc(Cl)c2nccnc2n1
Reactant: COC(=O)c1cnccc1N
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1cnccc1Nc1nc(-c2cc(Br)ccc2F)nc2nccnc12
Temperature: 70 °C
Yield: 74.6 %

Procedure:
To a solution of 2-(5-bromo-2-fluorophenyl)-4-chloropteridine 106 (200 mg, 0.589 mmol), 4-aminonicotinic acid methyl ester (224 mg, 1.47 mmol) in dichloroethane (5 mL), was added dropwise triethylamine (300 μL, 2.07 mmol). The resulting mixture was heated at 70° C. for 15 min, then quenched with silica and purified by column chromatography (AcOEt/CH2Cl2/triethylamine, 70/19/1). Crystallization from AcOEt/Et2O afforded 200 mg of the title product 107 as yellow prisms (LCMS analysis).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:29])=[C:4]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C:5]([I:23])=[C:6]([C:21]=1[I:22])[C:7]([NH:9][CH2:10][CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][O:13][C:14](=[O:16])[CH3:15])=[O:8].[C:30]([O:33][CH:34]([CH3:38])[C:35](Cl)=[O:36])(=[O:32])[CH3:31]>CC(N(C)C)=O>[C:30]([O:33][CH:34]([CH3:38])[C:35]([NH:1][C:2]1[C:3]([I:29])=[C:4]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C:5]([I:23])=[C:6]([C:21]=1[I:22])[C:7]([NH:9][CH2:10][CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][O:13][C:14](=[O:16])[CH3:15])=[O:8])=[O:36])(=[O:32])[CH3:31]
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Reactant: CC(=O)OC(C)C(=O)Cl
Solvent: CC(=O)N(C)C
Product: CC(=O)OCc1c(I)c(NC(=O)C(C)OC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Yield: 99.2 %

Procedure:
5-Amino-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide (3.20 g, 4.3 mmol) was dissolved in dry dimethylacetamide (4 ml). 2-Acetoxypropionyl chloride (2.17 ml, 17.2 mmol) was then added dropwise with efficient stirring. Stirring was continued over night. After work up according to the procedure in Example 24i, 3.66 g (100%) of product was isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:12]C(C)([O-])C.[K+].CI>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][N:8]2[CH3:12])=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(I)n[nH]c2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 66 %

Procedure:
In a round-bottomed flask, 6-chloro-3-iodo-1H-indazole (167 mg, 0.57 mmol) was dissolved in THF (2 ml) and the solution was cooled to 0° C. Potassium tert-butoxide (90 mg, 0.80 mmol) was added and the reaction mixture was stirred at 0° C. for 1.25 h. Methyl iodide (0.045 ml, 0.72 mmol) was added dropwise then the ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over silica gel with EtOAc/Hexanes (gradient 0-5% EtOAc) to afford 110 mg (63%) of 6-chloro-3-iodo-1-methyl-1H-indazole as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[CH:18]([C:19]3[C:20]([C:25]([F:28])([F:27])[F:26])=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:17](O)[O:16][N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10].FC(F)(F)C(O)=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[C:18]([C:19]3[C:20]([C:25]([F:27])([F:28])[F:26])=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][O:16][N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C2=NOC(O)C2c2cccnc2C(F)(F)F)cc([N+](=O)[O-])c1OC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1cc(-c2nocc2-c2cccnc2C(F)(F)F)cc([N+](=O)[O-])c1OC
Reaction time: 0.17 h

Procedure:
3-(3,4-dimethoxy-5-nitrophenyl)-4-(2-(trifluoromethyl)pyridin-3-yl)-4,5-dihydroisoxazol-5-ol (2.06 g, 5 mmol) was heated in 20 mL of ethyl acetate to 70° C. To the resulting slurry was added trifluoroacetic acid (0.74 g, 6.5 mmol) dropwise. After 10 minutes, the reaction was evaporated to dryness and the residue was recrystallised from isopropanol to give 3-(3,4-dimethoxy-5-nitrophenyl)-4-(2-(trifluoromethyl)pyridin-3-yl)isoxazole, 1.224 g (62%).
Reaction SMILES: [C:1](C=P(CCCC)(CCCC)CCCC)#N.C1(C)C=CC=CC=1.[CH2:24]([C:26]1[C:34]([OH:35])=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[N:29][NH:30]2)[CH3:25]>C1(C)C=CC=CC=1>[CH:24]([C:26]1[C:34]([OH:35])=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[N:29][NH:30]2)([CH3:1])[CH3:25]
Reactant: CCc1c(O)ccc2[nH]ncc12
Reactant: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)c1c(O)ccc2[nH]ncc12

Procedure:
A cyanomethylenetributylphosphorane/toluene solution (1.2 g, 4.53 mmol) was added to a solution prepared by dissolving the 4-ethyl-1H-indazol-5-ol (359 mg, 1.46 mmol) obtained in Example 682 and the cis-2-(4-hydroxycyclohexyl)-1H-isoinzole-1,3(2H)-dione (854 mg, 3.48 mmol) obtained in Example 323, (c) in toluene (15 ml), and the resulting mixture was stirred at 120° C. for 3 hours. The reaction solution was concentrated, and to the resulting residue were added chloroform and a 1N-aqueous sodium hydroxide solution to effect partition, followed by extraction with chloroform (twice). The extract solution was dried over anhydrous magnesium sulfate. The residue was purified by a silica gel chromatography (hexane/ethyl acetate=2/1) to obtain trans-2-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione (681.1 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH2:15][C:16]([CH3:22])([C:18]([O:20]C)=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[K+]>O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH2:15][C:16]([CH3:22])([C:18]([OH:20])=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1(C)CCCc2c(-c3ccc(Cl)cc3)noc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C(=O)O)CCCc2c(-c3ccc(Cl)cc3)noc2C1
Yield: 47.1 %

Procedure:
2 g of methyl 3-(4-chlorophenyl)-7-methyl-5,6,7,8-tetrahydro-4H-cyclohept[d]isoxazole-7-carboxylate were treated with 0.5 g of potassium hydroxide in 2 ml of water and 20 ml of methanol at 20° C. for 16 hours. After working-up as described in Example 5 and crystallization from glacial acetic acid, there was obtained 0.9 g of 3-(4-chlorophenyl)-7-methyl-5,6,7,8-tetrahydro-4H-cyclohept[d]isoxazole-7-carboxylic acid of melting point 232°-235° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4]/[N:5]=[CH:6]/[C:7]1[C:8]([F:30])=[C:9]([F:29])[C:10]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:11]([CH:19]=1)[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13].CN(C)C=O.CON(C(C)=O)[C:39](=[O:41])[CH3:40]>CO>[C:39]([NH:1][CH2:2][CH2:3][O:4]/[N:5]=[CH:6]/[C:7]1[C:8]([F:30])=[C:9]([F:29])[C:10]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:11]([CH:19]=1)[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13])(=[O:41])[CH3:40]
Reactant: NCCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: CON(C(C)=O)C(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)NCCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.8 %

Procedure:
To a solution of (E)-5-[(2-amino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (8.14 mg, 0.02 mmol) described in Step C in a mixed solvent of dimethylformamide (1 ml) and methanol (5 ml) was added N-methoxydiacetamide (100 mg, 0.76 mmol), and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the resultant residue was purified with Mega Bond Elut silica gel (Varian, 5 g). (E)-5-[(2-Acetylamino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (8.10 mg, 92% yield) was obtained as a pale yellow solid from fractions eluted with 6% methanol/methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[Cl:1])[N:8]=1)(=[O:24])=[O:23]
Reactant: Nc1nc(-c2sccc2Cl)cs1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1nc(-c2sccc2Cl)cs1

Procedure:
The title compound was prepared from 4-(3-chloro-2-thienyl)-1,3-thiazol-2-amine and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (9.4 mg) with purity >90%: MS (pos) m/z 439.1, 441.1; HRS m/z 437.8875 (calc. of monoisotopic mass for C14H9Cl3N2O2S3 gives 437.8892).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:16])=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19].[Na].O.[CH2:23](I)[CH3:24]>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:16])=[CH:4][C:3]=1[CH2:17][C:18]([O:20][CH2:23][CH3:24])=[O:19]
Reactant: CCI
Reactant: Nc1c(CC(=O)O)cc(Cl)cc1C(=O)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cc(Cl)cc(C(=O)c2ccccc2)c1N
Reaction time: 2 h
Yield: 4.7 %

Procedure:
A solution of 3.12 g (0.1 mole) of 2-amino-3-benzoyl-5-chlorobenzeneacetic acid, sodium salt.1/2 H2O in 250 ml of dry dimethylformamide was treated with 44 g of ethyl iodide (0.3 mole) under nitrogen and stirred for 2 hours. The resulting solution was then added to one liter of water and extracted several times with ethyl ether. The combined ether layers were washed with water, dried over sodium sulfate, filtered and stripped to yield a solid yellow residue. This residue was recrystallized from ethyl alcohol, yielding 1.5 g of the title compound as yellow needles, m.p. 80°-82° C.
Reaction SMILES: [CH:1]1([C:4](=[O:25])[CH:5]([C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])C(OC(C)(C)C)=O)[CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1]1([C:4](=[O:25])[CH2:5][C:13]([C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])=[O:24])[CH2:3][CH2:2]1
Reactant: COc1cc(SC)ccc1C(=O)C(C(=O)OC(C)(C)C)C(=O)C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cc(SC)ccc1C(=O)CC(=O)C1CC1
Yield: 101.3 %

Procedure:
A solution of t-butyl 3-cyclopropyl-2-(2-methoxy4-methylsulphenylbenzoyl)-3-oxopropionate (35.1 g) and 4-toluenesulphonic acid (1.2 g) in toluene was stirred and heated at reflux for 8 hours. After cooling, it was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 3-cyclopropyl-1-(2-methoxy-4-methylsulphenylphenyl)-propan-1,3-dione (25.8 g) as a red solid, NMR (CDCl3); 0.7-1.2 (m,4H), 1.4-2.0 (m, 1H), 2.4(s,3H), 3.75 (s,3H), 6.4(s, 1H), 6.6(s, 1H), 6.65 (d, 1H) and 7.65 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3([C:36]([O:38][CH3:39])=[O:37])[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12](=[O:25])[NH:13][C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([CH3:24])=[CH2:23])[CH:17]=1)[CH3:15])=[CH:6][CH:5]=2>CCO.[Pd]>[CH:22]([C:18]1[CH:17]=[C:16]([C@@H:14]([NH:13][C:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]4([C:36]([O:38][CH3:39])=[O:37])[CH2:35][CH2:34]4)=[CH:31][CH:32]=2)[C:2]([CH3:1])=[C:10]3[CH3:11])=[O:25])[CH3:15])[CH:21]=[CH:20][CH:19]=1)([CH3:24])[CH3:23]
Reactant: C=C(C)c1cccc([C@H](C)NC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(C3(C(=O)OC)CC3)cc2)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C1(c2ccc(Cn3c(C)c(C)c4cc(C(=O)N[C@@H](C)c5cccc(C(C)C)c5)ccc43)cc2)CC1
Reaction time: 5 h

Procedure:
To a solution of (S)-methyl 1-(4-((2,3-dimethyl-5-((1-(3-(prop-1-en-2-yl)phenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)phenyl)cyclopropanecarboxylate in EtOH (5 mL) was added Pd/C 10%. The resulting mixture was stirred for 5 h under hydrogen atmosphere. The solution was then filtered and concentrated to afford a yellow oil which was directly used without further purification. ESI-MS (m/z): 523 [MH]+
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)(C)(C)C.Cl>O1CCOCC1>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([S:29]([N:16]([CH2:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][C:6]([OH:39])=[O:5])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)(=[O:31])=[O:30])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccc(Cl)cc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccc(Cl)cc2)c1
Yield: 73.7 %

Procedure:
To (3-{[(4-chloro-benzenesulfonyl)-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenoxy)-acetic acid tert-butyl ester (48 mg), of Step B, was added HCl in dioxane (4M, 3 mL) at room temperature for 24 h. The reaction was concentrated in vacuo, azeotroping with CH2Cl2 to provide the title compound (32 mg). 1H NMR (400 MHz, CDCl3) δ 8.20-6.80 (m, 11H), 6.75 (s, 1H), 6.65 (s, 1H), 6.38 (s, 1H), 4.50 (s, 2H), 4.23 (s, 2H), 4.16 (s, 2H); MS 526 (M−1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]=[CH:27][CH3:28])[CH2:23][CH2:22][C:21]([C:29](O)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[CH3:37][N:38]([CH:40]=O)[CH3:39]>>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]=[CH:27][CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:24][C:18]4[CH:19]=[CH:32][C:15]([CH2:40][N:38]([CH3:37])[CH:39]5[CH2:7][CH2:6][O:5][CH2:1][CH2:2]5)=[CH:16][CH:17]=4)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC=CCN1CCC(C(=O)O)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC=CCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In DMF (3.9 ml) was dissolved 7-[4-(2-butoxyethoxy)phenyl)-1-crotyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.20 g). To the solution was added thionyl chloride (82 μl), and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and a solution of the resulting residue in THF was added dropwise to a solution of 4-[methyl(tetrahydropyranyl-4-yl)aminomethyl]aniline (111 mg) and triethylamine (0.31 ml) in THF (3.3 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (ethyl acetate/ethanol=4/1), which was recrystallized from isopropyl ether/ethyl acetate to give 7-[4-(2-butoxyethoxy)phenyl]-1-crotyl-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 83) (9 mg).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[NH:3][CH:2]=1.Br[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CC(=O)OCC>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:3]1[C:4]2=[N:9][CH:8]=[CH:7][CH:6]=[C:5]2[N:1]=[CH:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1cnc2[nH]cnc2c1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cn1cnc2cccnc21)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a brown solution of 4-azabenzimidazole (4.75 g) in DMF (80 mL) was added benzyl bromoacetate (6.58 mL) followed by Cs2CO3 (25.9 g). The resulting light brown suspension was stirred overnight. The reaction mixture was diluted with EA and washed twice with water and aq. sat. NH4Cl. The aq. layers were extracted twice with EA. The combined org. layers were dried over MgSO4, filtrated off and evaporated in reduced pressure. The crude was purified by CC (Biotage, SNAP 100 g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8:2; gradient in % B: 0 to 5 over 3CV, 5 for 5CV, 5 to 15 over 5CV, 15% B for 3CV) to afford 4.99 g of the desired compound as yellow solid. LC-MS (C): tR=0.59 min; [M+H]+: 267.86.