Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)([O:3][CH3:4])=[O:2].B(F)(F)F.[CH3:34]COCC>CO>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:34])=[O:26])=[CH:28][CH:29]=1)([O:3][CH3:4])=[O:2]
Reactant: CCOCC
Reactant: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: FB(F)F
Solvent: CO
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cc1
Temperature: 0 °C

Procedure:
A solution of 50.5 g. of 4-(15-carbomethoxypentadecylamino)benzoic acid and 34.4 ml. of boron trifluoride etherate in 200 ml. of methanol is stirred under reflux for 4 hours, allowed to cool, and is poured into 1.20 liters of ice cold 5% aqueous sodium carbonate solution. The white solid is collected by filtration and recrystallized from benzene-ethanol to yield methyl 4-(15-carbomethoxypentadecylamino)benzoate, m.p. 92°-93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10](=O)[CH3:11])[C:5]([C:13]#[N:14])=[CH:4][C:3]=1[NH:15][C:16]1[N:21]=[C:20]([N:22]([CH:32]2[CH2:34][CH2:33]2)CC2C=CC(OC)=CC=2)[C:19]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]2[N:17]=1.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.C(OC)(OC)OC.C([BH3-])#N.[Na+]>C1COCC1.CO.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH3:11])[C:5]([C:13]#[N:14])=[CH:4][C:3]=1[NH:15][C:16]1[N:21]=[C:20]([NH:22][CH:32]2[CH2:34][CH2:33]2)[C:19]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]2[N:17]=1
Reactant: C1COCCN1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)c(CCC(C)=O)cc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(CCc1cc(Cl)c(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)cc1C#N)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
2-((2-chloro-5-cyano-4-(3-oxobutyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (38 mg, 0.070 mmol) and morpholine (9.2 mg, 0.10 mmol) was taken up in THF (0.2 mL) and MeOH (0.2 mL). Trimethyl orthoformate (0.078 mL, 0.070 mmol) and sodium cyanoborohydride (8.8 mg, 0.14 mmol) was then added. The reaction was stirred at room temperature overnight. The reaction was diluted with EtOAc and washed with aq. NaHCO3, then brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was taken up in DCM (0.25 mL) and anisole (0.025 mL) was added, followed by TFA (0.25 mL). The reaction was stirred at room temperature overnight. The reaction was then concentrated in vacuo and purified by preparative HPLC to provide 2-((2-chloro-5-cyano-4-(3-morpholinobutyl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (15.3 mg, 0.030 mmol, 42.5% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]2[N:27]=[CH:28][N:29]([CH3:30])[C:4]=2[CH:3]=1.[C:31](=[NH:44])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:26][O:25][C:18]1[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=1[CH2:16][N:8]([C:6]1[C:5]2[N:27]=[CH:28][N:29]([CH3:30])[C:4]=2[CH:3]=[C:2]([N:44]=[C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:7]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2nc(Cl)cc3c2ncn3C)c(OC)c1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2nc(N=C(c3ccccc3)c3ccccc3)cc3c2ncn3C)c(OC)c1
Temperature: 90 °C
Yield: 88.9 %

Procedure:
Anhydrous dioxane (4 mL) was added to a mixture of tert-butyl 6-chloro-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(2,4-dimethoxybenzyl)carbamate (example 1B, 0.638 g, 1.474 mmol), benzophenone imine (0.297 mL, 1.769 mmol), Pd2(dba)3 (0.270 g, 0.295 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.256 g, 0.442 mmol), and cesium carbonate (0.672 g, 2.063 mmol). The reaction mixture was heated to 90° C. overnight. After cooling to rt, solvent was removed in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed twice with water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography using an Isco 40 g column eluting with 50-100% ethyl acetate/hexane to provide tert-butyl 2,4-dimethoxybenzyl(6-(diphenylmethyleneamino)-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)carbamate (0.757 g, 89% yield) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[C:14](=O)([O-])[O-].[K+].[K+].C(=O)(OC)OC>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(=O)OC
Product: COC(=O)c1cn(C)c2ccccc12
Temperature: 130 °C
Reaction time: 3.5 h
Yield: 151.9 %

Procedure:
Indole-3-carboxylic acid methyl ester (5.0 g, 28.54 mmol), potassium carbonate (2.5 g), N,N-dimethylformamide (35 mL) and dimethyl carbonate (7.2 mL, 85 mmol) were combined and the stirred mixture was heated to reflux (˜130° C.). Within 3.5 h, the reaction had gone to completion as determined by HPLC analysis. After the reaction mixture was cooled to ˜3° C., ice cold water (100 mL) was slowly added. The resulting slightly off-white solid was recovered by filtration and was washed with water (2×50 mL). The solid was not purified further, but was dried in vacuo at 45° C. for 24 h to provide 5.2 g of 1-methylindole-3-carboxylic acid methyl ester (96.3% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([CH2:19][CH2:20][CH2:21][C:22]([O:24][C:25](C)(C)C)=[O:23])[C:12]([O:14]C(C)(C)C)=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)CCCC(CSc1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)CCCC(CSc1ccc(Cl)c(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.1 %

Procedure:
To a solution of di-tert-butyl 2-(3,4-dichlorophenylthiomethyl)adipate (550 mg) in benzene (7 ml) was added p-toluenesulfonic acid (40 mg), and the mixture was refluxed for 45 minutes. After the reaction mixture was cooled to room temperature, methanol (7 ml) was added, and the solution was stirred at 40° C. for 2.5 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by flash column chromatography on silica by eluting with chloroform/methanol (10:1) to give 340 mg of 3-(3,4-dichlorophenylthio)-2-(3-methoxycarbonylpropyl)propionic acid as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]1=[O:23].Br[CH2:25]/[CH:26]=[CH:27]/[C:28]([O:30][CH3:31])=[O:29].C(=O)(O)[O-].[Na+]>CO>[Cl:9][C:6]1[C:7]2[O:8][CH:26]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:25][NH:1][C:2]=2[C:3]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[C:4]([F:10])[CH:5]=1
Reactant: COC(=O)/C=C/CBr
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2N)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC1CNc2c(c(Cl)cc(F)c2-n2c(=O)cc(C(F)(F)F)n(C)c2=O)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 17.7 %

Procedure:
A mixture of 3-(2-amino-4-chloro-6-fluoro-3-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (0.43 g), methyl 4-bromocrotonate (0.22 g ) and sodium bicarbonate (0.3 g ) in methanol was stirred at 25° C. for 12 hours . The solvent was removed under reduced pressure and ethyl acetate (200 ml) was added. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to an oil. The crude product was purified by column chromatography on silica gel using ethyl acetate-hexane (1:2) as eluent to give title compounds (0.097 g)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][C:17]([F:20])([F:19])[F:18])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[S:26]([NH:1][C:2]1[CH:3]=[C:4]([O:16][C:17]([F:20])([F:18])[F:19])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2)(=[O:28])=[O:27]
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(N)c2[nH]1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
To a mixture of ethyl 7-amino-5-(trifluoromethoxy)-1H-indole-2-carboxylate (2.53 g) and pyridine (50 mL) was added thiophene-2-sulfonyl chloride (1.94 g) at 0° C., and the mixture was stirred at room temperature for 4 hr, and concentrated. 1N Hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained crystals were washed with diisopropyl ether to give the title compound (3.40 g, yield 89%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give colorless prism crystals. melting point 196-197° C.
Reaction SMILES: [C:1]([OH:11])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:30]([N:34]([C:45]([O:47][CH2:48]Cl)=[O:46])[CH2:35][C:36]([O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])=[O:37])([CH3:33])([CH3:32])[CH3:31]>CO>[C:4]1(/[CH:3]=[CH:2]/[C:1]([O:11][CH2:48][O:47][C:45](=[O:46])[N:34]([C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:35][C:36](=[O:37])[O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:43])[CH3:44])=[O:10])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)N(CC(=O)OCC[Si](C)(C)C)C(=O)OCCl
Reactant: O=C(O)/C=C/c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)N(CC(=O)OCC[Si](C)(C)C)C(=O)OCOC(=O)/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Trans-cinnamic acid (23.1 mmol) and 1.0 M tetrabutylammonium hydroxide (22.2 mmol) in methanol are stirred for one hour, and the methanol is removed. THF is added. To this solution is added 2-(trimethylsilyl)ethyl 2-(tert-butyl((chloromethoxy)carbonyl)amino)-acetate (18.5 mmol) and the mixture is stirred at room temperature for 24 hr. The solvent is removed and the residue is diluted with ether. The resulting solution is washed with water and brine. The organic layer is dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 5.01 g (61%) MS (ESI) m/z 436.3.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:24]1[CH:30]=[C:29]([CH3:31])[C:27]([NH2:28])=[C:26]([Cl:32])[CH:25]=1.[C:33]([NH:36][C:37](=[CH2:42])[C:38]([O:40][CH3:41])=[O:39])(=[O:35])[CH3:34].C(N(CC)CC)C>C(#N)C>[C:33]([NH:36]/[C:37](=[CH:42]/[C:24]1[CH:30]=[C:29]([CH3:31])[C:27]([NH2:28])=[C:26]([Cl:32])[CH:25]=1)/[C:38]([O:40][CH3:41])=[O:39])(=[O:35])[CH3:34]
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: Cc1cc(Br)cc(Cl)c1N
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)/C(=C\c1cc(C)c(N)c(Cl)c1)NC(C)=O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Under protective nitrogen gas 2.02 g (9.0 mmol) palladium(II)acetate and 2.82 g (9.0 mmol) tri-o-tolylphosphine were added to a mixture of 25.0 g (113 mmol) 4-bromo-2-chloro-6-methyl-aniline, 19.9 g (136 mmol) methyl 2-acetamidoacrylate, 350 ml triethylamine and 150 ml acetonitrile at ambient temperature. The reaction mixture was stirred for 18 hours at 80° C., evaporated down under reduced pressure, the residue was combined with 600 ml dichloromethane and water and filtered off from the insoluble precipitate. The organic phase was dried over sodium sulphate, evaporated down under reduced pressure and then combined with 200 ml of ethyl acetate/cyclohexane (3/1). The insoluble fraction was suction filtered and the mother liquor was purified by column chromatography through silica gel. The corresponding fractions were evaporated down under reduced pressure and combined with the insolublen fraction suction filtered previously.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[S:15][C:14]3[CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][N:17]1CCCNC[CH2:18]1>>[CH3:16][N:17]1[CH2:4][CH2:3][CH2:2][N:1]([CH2:6][C:7]2[S:15][C:14]3[CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[CH:8]=2)[CH2:5][CH2:18]1
Reactant: CN1CCCNCC1
Reactant: c1c(CN2CCCC2)sc2c1CNCC2
Product: CN1CCCN(Cc2cc3c(s2)CCNC3)CC1

Procedure:
The preparation of this amine was carried out in analogy to that described for 2-(pyrrolidin-1-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (TP1 1) employing 1-methyl-1,4-diazepane in step-8.
Reaction SMILES: ClC1C(F)=C(N[C:9]([CH3:19])=[C:10]([N+:16]([O-:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])C=CC=1.[N+]([CH2:24][C:25](OCC)=[O:26])([O-])=O.C(C(CC)(CC)C([O-])([O-])[O-])C.C(O)C>C1(C)C=CC=CC=1>[CH2:25]([O:26][C:9]([CH3:19])=[C:10]([N+:16]([O-:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:24]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: CCOC(=O)C(=C(C)Nc1cccc(Cl)c1F)[N+](=O)[O-]
Agent: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=C(C)OCC)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Intermediate 24A1. Ethyl 3-((3-chloro-2-fluorophenyl)amino)-2-nitrobut-2-enoate: Using a modified procedure described by Gomez-Sanchez. (Reference: Gomez-Sanchez, A. et al., Anales De Quimica, 81(2):139 (1985).) A clear, faint yellow solution of ethyl nitroacetate (4.17 ml, 37.6 mmol) and triethylorthoacetate (6.93 mL, 37.6 mmol) in toluene (9.39 mL) was heated to 110° C. A Dean-Stark trap was used to azeotrope the ethanol. Approximately every 30 min, the solvent was removed from the Dean-Stark and additional toluene (6 mL) was added to the reaction flask. Over the course of the reaction the color became a clear, dull yellow color. After 7.5 h, the reaction was stopped and it was cooled to rt. Excess solvent and starting materials were removed by distillation (5 mm Hg at 100° C.) leaving ethyl 3-ethoxy-2-nitrobut-2-enoate (5.46 g) as an orange liquid. An orange solution of 3-chloro-2-fluoroaniline (5.86 g, 40.2 mmol) and ethyl 3-ethoxy-2-nitrobut-2-enoate (5.45 g, 26.8 mmol) in ethanol (13.41 mL) was stirred at rt. After 7 h, the reaction was stopped and concentrated to give an orange oil. The orange oil was diluted with EtOAc and washed with 1.0 N HCl (2×), saturated NaHCO3, brine, dried over sodium sulfate, filtered and concentrated to give an orange oil. Purification by normal phase chromatography gave Intermediate 24A1 (2.90 g, 36%) as a viscous orange-yellow oil. 1H NMR indicated a 1:1 E:Z mixture. MS(ESI) m/z: 325.0 (M+H)+. 1H NMR (500 MHz, CDCl3) δ 11.54 (br. s., 1H), 10.77 (br. s., 1H), 7.50-7.45 (m, 1H), 7.44-7.38 (m, 1H), 7.24-7.12 (m, 4H), 4.39 (q, J=7.2 Hz, 2H), 4.34 (q, J=7.2 Hz, 2H), 2.15 (d, J=1.4 Hz, 3H), 2.12 (d, J=1.4 Hz, 3H), 1.39 (t, J=7.2 Hz, 3H), 1.36 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH:9]=[C:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:13]([N:16]1[C:24]2[C:19](=[CH:20][C:21](O)=[C:22]([Br:25])[CH:23]=2)[CH2:18][CH2:17]1)(=[O:15])[CH3:14]>>[C:13]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([O:12][CH2:11][C:8]3[CH2:9][CH2:10][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH:7]=3)=[C:22]([Br:25])[CH:23]=2)[CH2:18][CH2:17]1)(=[O:15])[CH3:14]
Reactant: CC(C)(C)N1CC=C(CO)CC1
Reactant: CC(=O)N1CCc2cc(O)c(Br)cc21
Product: CC(=O)N1CCc2cc(OCC3=CCN(C(C)(C)C)CC3)c(Br)cc21

Procedure:
The title compound was prepared from 1-tert-butyl-1,2,3,6-tetrahydropyridine-4-methanol (D58) and 1-acetyl-6-bromo-2,3-dihydroindol-5-ol (Tetrahedron, 1973, 29 (8), 1115) using the method outlined in Description 8a in WO 96/19477 (68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:15][C:16]#[N:17])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:4][CH:3]=1.C(O[CH:23](N(C)C)[N:24]([CH3:26])[CH3:25])(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:15][C:16]#[N:17])[CH2:13][CH2:12][CH2:11][C:10](=[CH:23][N:24]([CH3:26])[CH3:25])[C:9]2=[O:14])=[CH:6][CH:7]=1
Reactant: N#CCC1(c2ccc(Cl)cc2)CCCCC1=O
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C1CCCC(CC#N)(c2ccc(Cl)cc2)C1=O

Procedure:
[1-(4-Chlorophenyl)-2-oxo-cyclohexyl]-acetonitrile (101 mg, 0.43 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (149 mg) as a red oil which was used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[CH:6][CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])[CH3:2]
Reactant: CCOC(=O)C=CCc1cc(F)ccc1OC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCc1cc(F)ccc1OC
Reaction time: 15 h
Yield: 93.6 %

Procedure:
To a solution of ethyl-3-(5′-fluoro-2′-methoxybenzyl)acrylate (2.36 g, 10.0 mmol) in ethanol (100%, 40 mL) under Ar(g) was added Pd/C (10%, 200 mg) very carefully and the flask containing the mixture was evacuated and purged with H2 three time each. Then a balloon was attached to the flask and the reaction was allowed to go for 15 h at room temperature. The reaction mixture was filtered through a pad of silica eluted with mixed solvent of EtOAc and Hexane (1:1). The crude product that obtained by removal of the solvent in vacuo was purified by a flash column chromatography (10% EtOAc in hexane, Rf=0.20) to give the product (2.25 g, 95%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([CH3:14])=[CH:8][C:9]([CH:12]=O)=[N:10][CH:11]=2)[CH2:3][CH2:2]1.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([CH3:14])=[CH:8][C:9](/[CH:12]=[N:21]/[S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])=[N:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)[S@](N)=O
Reactant: Cc1cc(C=O)ncc1OCC1CC1
Product: Cc1cc(/C=N/[S@](=O)C(C)(C)C)ncc1OCC1CC1
Yield: 90 %

Procedure:
The title compound is prepared in 90% yield (688 mg, yellow oil) from 5-(cyclopropylmethoxy)-4-methylpicolinaldehyde (495 mg, 2.59 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (471 mg, 3.88 mmol) in a similar manner to Step-6 of Amine-49.
Reaction SMILES: [NH:1]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][C:13]=3[O:23][CH3:24])[NH:11][C:7]=2[CH:6]=1)C(C)=O>Cl>[NH2:1][C:5]1[CH:26]=[CH:25][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][C:13]=3[O:23][CH3:24])[NH:11][C:7]=2[CH:6]=1
Reactant: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(NC(C)=O)cc2[nH]1
Agent: Cl
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(N)cc2[nH]1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Five grams (13.3 mmol) of 5-acetamino-2-(2'-methoxy-4'-methanesulfonyloxy-phenyl)-benzimidazole were suspended in 150 ml of concentrated hydrochloric acid and stirred at 80° C. for two hours. After cooling, the crude product precipitated was subjected to suction filtration and chromatographed on 500 gm of aluminium oxide (neutral) (eluant: methylene chloride with 2.5% ethanol).
Reaction SMILES: S([O-])(O)(=O)=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([N:20]=1)=[C:18]1[C:13]([CH:14]=[CH:15][CH:16]=[N+:17]1[CH3:21])=[CH:12][CH:11]=2.[OH-:22].[Na+]>[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([N:20]=1)=[C:18]1[C:13]([CH:14]=[CH:15][C:16](=[O:22])[N:17]1[CH3:21])=[CH:12][CH:11]=2
Reactant: C[n+]1cccc2ccc3ccc(Br)nc3c21
Reactant: [OH-]
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: Cn1c(=O)ccc2ccc3ccc(Br)nc3c21
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a stirred aqueous solution of potassium ferricyanide (100 g; 303 mmol) (1.1 L), compound (8) (42.7 g; 115 mmol) and an aqueous sodium hydroxide (76 g; 1.9 mol) (110 mL) were alternately added over 25 minutes in an ice bath (inner temperature of 4 to 6° C.). The resulting mixture was stirred in an ice bath for 1 hour, and further stirred at room temperature for 3.5 hours. Crude crystals which precipitated out were separated by filtration and washed with water, and then dried. The resulting crude crystals were separated and purified by silica gel column chromatography (SiO2 800 g) (chloroform/methanol=50/1 to 30/1 to 20/1) and dried to give 27.4 g (yield: 82%) of the title compound (9).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[S:41](=[O:43])(=[O:42])[NH:40][C:39](=[O:44])[CH2:38]2)=[C:33]([F:45])[CH:32]=1)[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[C:20]=1[C:21]([O:23][CH3:24])=[O:22])=[O:11])=O)(C)(C)C.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>C(Cl)Cl>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[NH2:8][C@@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[S:41](=[O:42])(=[O:43])[NH:40][C:39](=[O:44])[CH2:38]2)=[C:33]([F:45])[CH:32]=1)[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[C:20]=1[C:21]([O:23][CH3:24])=[O:22])=[O:11]
Reactant: COC(=O)c1c(O)cccc1OCCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(F)c1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(O)cccc1OCCCCCNC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Methyl 2-[5-((2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)-3-fluorophenyl]propanoylamino)pentyl]oxy-6-hydroxybenzoate (66.5 mg, 0.100 mmol) was dissolved in methylene chloride (5.0 mL) and treated with trifluoroacetic acid (1.0 mL). After 1 h of stirring at rt, the solution was concentrated in vacuo to afford a slightly tan oil (20.2 mg, 99%). The material was used in subsequent steps without purification. LCMS found for C25H31FN3O8S (M+H)+: m/z=652.