Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].F[C:9](F)(F)[C:10]([O-:12])=O.C[NH+]1CCCC(C([NH:24][C@H:25]([C:34]2[NH2+:35][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:37][N:38]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]C(=O)C)=O)C1.F[C:46](F)(F)[C:47]([O-:49])=O.F[C:53](F)(F)C([O-])=O.[NH3+][C@H:60]([C:69]1[NH2+:70][C:71]([C:74]2[CH:79]=CC=CC=2)=[CH:72]N=1)[CH2:61]CCCCC(=O)C.CCN(CC)CC.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.COC1C=C2C(=CC=1)NC(C)=C2CC(O)=O>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH3:53][O:49][C:47]1[CH:46]=[C:79]2[C:69](=[CH:60][CH:61]=1)[NH:70][C:71]([CH3:72])=[C:74]2[CH2:9][C:10]([NH:24][C@H:25]([C:34]1[NH2+:35][C:36]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:37][N:38]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:3](=[O:5])[CH3:2])=[O:12]
Reactant: CC(=O)CCCCC[C@H](NC(=O)C1CCC[NH+](C)C1)C1=NC=C(c2ccccc2)[NH2+]1
Reactant: CC(=O)CCCCC[C@H]([NH3+])C1=NC=C(c2ccccc2)[NH2+]1
Agent: CCN=C=NCCCN(C)C
Agent: COc1ccc2[nH]c(C)c(CC(=O)O)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2[nH]c(C)c(CC(=O)N[C@@H](CCCCCC(C)=O)C3=NC=C(c4ccccc4)[NH2+]3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of Example 1, A3 and Et3N (1 eq.) in DCM was added a solution of EDC hydrochloride (1.2 eq.), HOBt (1.2 eq.) and (5-methoxy-2-methyl-1H-indol-3-yl)acetic acid (1.2 eq.) in DCM. The mixture was shaken at RT for 1.5 hr and then the reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified by preparative RP-HPLC, using H2O (0.1% TFA) and MeCN (+0.1% TFA) as eluents (column: C18). The desired fractions were lyophilized to afford the titled compound D1 as a white fluffy powder.
Reaction SMILES: [NH2:1][CH:2]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)[C:3]([N:5]([CH2:14][C:15]1[C:20]2[N:21]=[CH:22][S:23][C:19]=2[CH:18]=[CH:17][CH:16]=1)[CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[O:4].[CH2:36]([NH:43][C:44](=[O:52])[NH:45][C@H:46]([CH3:51])[CH2:47][C:48](O)=[O:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[S:23]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:14][N:5]([CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:3]([CH:2]([NH:1][C:48](=[O:49])[CH2:47][CH:46]([NH:45][C:44]([NH:43][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:52])[CH3:51])[CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[CH:29][CH:30]=3)=[O:4])[C:20]=2[N:21]=[CH:22]1
Reactant: C[C@H](CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(CN(Cc1cccc2scnc12)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(CN(Cc1cccc2scnc12)C(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)CC(C)NC(=O)NCc1ccccc1)OCC
Reaction time: 0.67 h

Procedure:
To a solution of 2-Amino-N-benzothiazol-4-ylmethyl-3-(4-tert-butoxy-phenyl)-N-(2,2-diethoxy-ethyl)-propionamide in CH2Cl2(50 mL) was added a solution of (3R)-3-(3-Benzyl-ureido)-butyric acid (1.44 g, 6.1 mmol), EDC (1.17 g, 7.32 mmol, 1.2 eq), HOBt (0.93 g, 7.32 mmol, 1.2 eq), DIEA (2.13 mL, 12.2 mmol, 2.4 eq) in CH2Cl2(100 mL) stirred for 40 min. The reaction mixture was stirred at room temperature for 14 h, and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The crude compound was used next step without further purification. MS ESI 718 (M+H), 740 (M+Na).
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21]C)=[O:20])[CH2:15][CH:14]=2)=[C:5]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH:14]=2)=[C:5]1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)C1CC=C(c2c(-c3ccccc3)n(C)c3ccccc23)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(-c2ccccc2)c(C2=CCC(C(=O)O)CC2)c2ccccc21
Reaction time: 4 h
Yield: 84.5 %

Procedure:
To a solution of 5.6 g (0.085 mol) of potassium hydroxide in 150 mL of ethanol was added 6.9 g (0.020 mol) of methyl 4-(1-methyl-2-phenyl-1H-indol-3-yl)-3-cyclohexene-1-carboxylate (Example 5). This mixture was heated under reflux until solution resulted. Heating was continued 4 h, then the solution was cooled, concentrated in vacuo, dissolved in water, and made acidic with 2N hydrochloric acid to give a precipitate. The solid was collected, washed with water, dissolved in ether, washed with water, dried over sodium sulfate, charcoaled, concentrated in vacuo, and recrystallized twice from ether:hexane to give 5.6 g (85%) of 4-(1-methyl-2-phenyl-1H-indol-3-yl)-3-cyclohexene-1-carboxylic acid, m.p. 171°-172° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:25][CH3:26])[C:10]([N:12]1[C:20]2[C:15](=[C:16]([Cl:21])[CH:17]=[CH:18][CH:19]=2)[CH2:14][C@H:13]1[C:22]([OH:24])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:28][C:29]([F:33])([F:32])[CH2:30][NH2:31].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl.C(OCC)C>[F:28][C:29]([F:33])([F:32])[CH2:30][NH:31][C:22]([CH:13]1[CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[N:12]1[C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:25][CH3:26])=[O:24]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2cccc(Cl)c2C[C@H]1C(=O)O
Reactant: NCC(F)(F)F
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2cccc(Cl)c2CC1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl)-4-chloroindoline-2(S)-carboxylic acid (0.2 g, 0.52 mmol) and 2,2,2-trifluoroethylamine hydrochloride (0.142 g, 1.0 mmol) were dissolved in dried dichloromethane (10 ml) under nitrogen at 0° C., and triethylamine (0.44 ml, 3 mmol) was added followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.265 g, 1.0 mmol). The temperature was allowed to rise to room temperature and the mixture was stirred at room temperature for 24 hours, then filtered. The filtrate was concentrated under vacuum to give a brown solid which was columned on silica gel using 95:5 dichloromethane: diethyl ether as eluent to provide a white solid as the desired product.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH:22]=[CH:21][C:20]([CH3:25])([OH:24])[CH:19]2[C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:27][SiH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[C:29]([SiH2:28][O:27][C:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH:19]1[C:20]([CH3:25])([OH:24])[CH2:21][CH2:22][CH2:23][N:18]1[S:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)(=[O:16])=[O:17])([CH3:30])([CH3:31])[CH3:32]
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)C1N(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)CC=CC1(C)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)C1N(S(=O)(=O)c2ccc(O)cc2)CCCC1(C)O
Yield: 101.3 %

Procedure:
A mixture of 1-(4-benzyloxy-benzenesulfonyl)-2-(tert-butyl-diphenyl-silanyloxymethyl)-3-methyl-1,2,3,6-tetrahydro-pyridin-3-ol (compound of formula VIII, 0.40 g, 0.64 mmol), 10% palladium on charcoal (0.1 g) and 30 ml of methanol was stirred for about 16 hours under about 1 atmosphere of hydrogen gas. The mixture was filtered through a pad of Celite®. Concentration of the filtrate afforded 0.35 g of 2-(tert-butyl-diphenyl-silanyloxymethyl)-1-(4-hydroxy-benzenesulfonyl)-3-methyl-piperidin-3-ol (compound of formula IX) as a colorless solid.
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:28]12[CH2:34][CH:33]1[CH2:32][CH2:31][CH:30]([CH2:35][O:36][C:37]1[C:45]([CH:46]3[CH2:48][CH2:47]3)=[CH:44][C:40]([C:41](O)=[O:42])=[C:39]([F:49])[CH:38]=1)[CH2:29]2.CS(N)(=O)=O.[CH:55]1([S:58]([NH2:61])(=[O:60])=[O:59])[CH2:57][CH2:56]1>>[CH:28]12[CH2:34][CH:33]1[CH2:32][CH2:31][CH:30]([CH2:35][O:36][C:37]1[C:45]([CH:46]3[CH2:48][CH2:47]3)=[CH:44][C:40]([C:41]([NH:61][S:58]([CH:55]3[CH2:57][CH2:56]3)(=[O:60])=[O:59])=[O:42])=[C:39]([F:49])[CH:38]=1)[CH2:29]2
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCC3CC3C2)cc1F
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OCC2CCC3CC3C2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(bicyclo[4.1.0]heptan-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid and making variations as required to replace methanesulfonamide with cyclopropanesulfonamide, the title compound was obtained as a solid (0.043 g, 21%): 1H NMR (300 MHz, CDCl3) δ8.69 (d, J=16.4 Hz, 1H), 7.58 (d, J=9.1 Hz, 1H), 6.59 (d, J=14.5 Hz, 1H), 5.78-5.54 (m, 2H), 3.94-3.84 (m, 2H), 3.15-3.06 (m, 1H), 1.96-1.68 (m, 7H), 1.48-1.40 (m, 2H), 1.26-1.11 (m, 2H), 1.06-0.99 (m, 2H), 0.96-0.90 (m, 2H), 0.69-0.64 (m, 2H); MS (ES+) m/z 408.0 (M+1).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:28])[C:15]([C:23]([O:25]CC)=[O:24])=[C:16]4[S:21][CH:20]([CH3:22])[N:17]43)=[CH:12][C:11]=2[Cl:29])[CH2:6][CH2:5]1)(=O)C.Cl.O.N>C(O)C>[Cl:29][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[N:7]1[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1)[N:17]1[CH:20]([CH3:22])[S:21][C:16]1=[C:15]([C:23]([OH:25])=[O:24])[C:14]2=[O:28]
Reactant: CCOC(=O)c1c2n(c3cc(N4CCN(C(C)=O)CC4)c(Cl)cc3c1=O)C(C)S2
Agent: Cl
Agent: N
Solvent: CCO
Solvent: O
Product: CC1Sc2c(C(=O)O)c(=O)c3cc(Cl)c(N4CCNCC4)cc3n21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 610 mg of ethyl 7-(4-acetyl-1-piperazinyl)-6-chloro-1-methyl-4-oxo-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate, 12 ml of 5% hydrochloric acid and 3 ml of ethanol was heated with stirring on an oil bath of 100°-110° C. for 2 hours. After cooling to about 50° C., this was neutralized with 5% ammonia water. Crystals separated out were collected by filtration, washed with water, dried and recrystallized from N,N-dimethylformamide to give pale yellow crystals, m.p. not lower than 300° C. (decompn).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([O:8][CH2:9][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][NH:27][CH2:26][C:25]1[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC(C=O)COCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CNCc1ccc(F)cc1)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of tert-butyl 2-(benzyloxy)-1-formylethylcarbamate (3.29 g, 11.8 mmol) in anhydrous THF (12 mL) was added 4-fluorobenzylamine (2.03 mL, 17.7 mmol). After 10 min, sodium triacetoxyborohydride (3.99 g, 18.8 mmol) was added, and the reaction was stirred at ambient temperature under inert atmosphere for 30 min. Saturated aqueous NaHCO3 solution was added and the mixture stirred until gas evolution ceased. The aqueous layer was extracted with EtOAc, saturated with NaCl and again extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting cloudy yellow oil was purified by silica gel chromatography (EtOAc to 10% MeOH/EtOAc) to afford the title compound as a pale yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.37-7.23 (m, 7H), 7.03-6.96 (m, 2H), 5.04 (br s, 1H), 4.49 (dd, J=11.5, 18.0 Hz, 2H), 3.86 (br s, 1H), 3.76-3.70 (m, 2H), 3.60 (dd, J=3.0, 9.0 Hz, 1H), 3.53 (d, J=4.5 Hz, 1H), 2.83-2.80 (m, 1H), 2.76-2.72 (m, 1H), 1.44 (s, 9H). ES MS (M+1)=389.5.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].Cl.[CH3:16][N:17]([CH2:19][CH2:20]Cl)[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[CH3:16][N:17]([CH3:18])[CH2:19][CH2:20][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14]
Reactant: CN(C)CCCl
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of 6-nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 2.60 mmol), (N,N-dimethylamino)ethyl chloride hydrochloride (412 mg, 2.86 mmol) and potassium carbonate (1.07 g, 7.74 mmol) in 8 mL DMF was stirred at room temperature for 48 hours. Additional (N,N-dimethylamino)ethyl chloride hydrochloride (187 mg, 1.30 mmol) and potassium carbonate (359 mg, 2.60 mmol). Reaction was stirred for an additional 16 hours. After this time, the reaction was transferred to a separatory funnel and diluted with cold water and ethyl acetate. The aqueous was extracted twice more with ethyl acetate and the combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/CH2Cl2 to give a yellow solid. Yield: 370 mg (54%). 1H NMR (CDCl3) δ: 8.15 (dd, J=2.7, 9.0 Hz, 1H), 8.06 (d, J=2.7 Hz, 1H), 7.17 (d, J=9 Hz, 1H), 4.09 (t, J=7.2 Hz, 2H), 3.00 (t, J=6.6 Hz, 2H), 2.71 (t, J=7.5 Hz, 2H), 2.52 (t, J=7.5 Hz, 2H), 2.32 (s, 6H). MS (ESI): 264.1 (M+1).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:13][C:14]1[CH:15]=[N+:16]([O-:51])[CH:17]=[C:18]([Cl:50])[C:19]=1[CH2:20][C@@H:21]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[CH:36]=1)[O:22][C:23](OC1C=CC([N+]([O-])=O)=CC=1)=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:50][C:18]1[CH:17]=[N+:16]([O-:51])[CH:15]=[C:14]([Cl:13])[C:19]=1[CH2:20][C@@H:21]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[CH:36]=1)[O:22][C:23]([S:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])[CH:3]=1)=[O:24]
Reactant: CS(=O)(=O)Nc1cccc(S)c1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(SC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
To a suspension of N-(3-mercaptophenyl)methanesulfonamide (97 mg, 0.478 mmol) in DCM (15 ml), under nitrogen atmosphere, (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-nitrophenoxy)-carbonyloxy)ethyl)pyridine 1-oxide (prepared with an analogous procedure to that described in Scheme 3, Step 1) (200 mg, 0.342 mmol), and DMAP (20.87 mg, 0.171 mmol) were added, and the reaction mixture was stirred at RT for 3 hours. The organic solution was washed with K2CO3 dil. aq., dried over Na2SO4, filtered and evaporated. The crude was triturated with EtOH affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3-(methylsulfonamido) phenylthio)carbonyloxy)ethyl)pyridine 1-oxide (162.9 mg, 0.251 mmol, 73.4% yield, MS/ESI+ 649.04 [MH]+, [αD]=−93.81, c=0.53 in DCM).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCC1CCCN1Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: ClCC1CCCN1Cc1ccccc1
Temperature: 25 °C

Procedure:
Into a 5,000 ml 3-necked roundbottom flask, was placed a solution of (1-benzylpyrrolidin-2-yl)methanol (250. g, 1.30 mol) in chloroform (2,500 ml). This was followed by the dropwise addition of a solution of thionyl chloride (232. g, 1.95 mol) in chloroform (500 ml), while maintaining the internal temperature at room temperature (60 minute addition time). The resulting solution was heated to reflux for 2 hours. After cooling to ambient temperature, the mixture was concentrated, and the resulting residue was dissolved in 3,000 ml of ethyl acetate. Adjustment of the pH to 7 was accomplished by the addition of triethylamine. The resulting mixture was filtered and the filtrate was concentrated and the residue was purified by flash column chromatography (ethylacetate/petroleum ether gradient) to afford 1-benzyl-2-(chloromethyl)pyrrolidine.
Reaction SMILES: [C:1]1([S:7]([OH:10])(=[O:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Ca+2].[F:14][C:15]1[CH:40]=[CH:39][C:18]([O:19][CH2:20][CH:21]2[CH2:25][CH2:24][CH:23](C#CCCOC(C3CCCCO3)=O)[O:22]2)=[CH:17][CH:16]=1>C(Cl)Cl>[C:1]1([S:7]([CH:23]2[O:22][CH:21]([CH2:20][O:19][C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:40][CH:39]=3)[CH2:25][CH2:24]2)(=[O:9])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCCC#CC1CCC(COc2ccc(F)cc2)O1)C1CCCCO1
Reactant: O=S(=O)(O)c1ccccc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)C1CCC(COc2ccc(F)cc2)O1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To benzenesulfonic acid sodium salt (10.0 g, 0.061 mol), 25% HCl was added dropwise with stirring until the solid dissolved. The reaction mixture was extracted (100 mL each, 3 times) with EtOAc, dried over Na2SO4 and concentrated to give benzenesulfonic acid (7.8 g, 90%). To a 100 mL round bottom with a magnetic stir bar, benzenesulfonic acid (4.61 g, 0.0324 mol), CaCl2(3.6 g, 0.0324 mol) and dry dichloromethane (30 mL) were added. The reaction mixture was cooled to 0° C. and (2S) (5RS)-2-(4-fluorophenoxymethyl)-5-hydroxy-tetrahydrofuran (4.6 g, 0.0216 mol) in dry CH2Cl2 (20 mL) was added. The reaction mixture was stirred for 3 h and monitored by TLC (EtOAc-light petroleum ether 1:4, Rf=0.25). The reaction mixture was filtered through celite and washed with CH2Cl2 (3 times). The combined organic layer was washed with saturated aqueous Na2CO3, water brine and dried over Na2SO4. Solvent was removed under reduced pressure to afford the crude (2S) (5RS)-5-benzenesulfonyl-2-(4-fluorophenoxymethyl)tetrahydrofuran 14 which was crystallized from chloroform-hexane to give pure white solid, yield 6.8 g (93%), m.p. 102° C.-104° C. 1H NMR (200 MHz, CDCl3): δ 1.90-3.0 (m, 4 H), 3.85-5.0 (m, 4 H), 6.70-7.05 (m, 4 H), 7.45-7.72 (m, 3 H), 7.77-8.0 (m, 2 H).
Reaction SMILES: CN(/[CH:4]=[C:5]1/[C:6](=O)[C:7]2[C:12]([C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[CH2:14]/1)=[CH:11][CH:10]=[CH:9][CH:8]=2)C.[OH:23][CH2:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH2:34])=[NH:33])[CH:28]=[CH:29][CH:30]=1>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C@H:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[N:34]=[C:32]([NH:31][C:27]3[CH:26]=[C:25]([CH2:24][OH:23])[CH:30]=[CH:29][CH:28]=3)[N:33]=[CH:4][C:5]=2[CH2:14]1
Reactant: CN(C)/C=C1\C[C@@H](c2ccccc2F)c2ccccc2C1=O
Reactant: N=C(N)Nc1cccc(CO)c1
Product: OCc1cccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccccc2F)C3)c1

Procedure:
This was synthesized by using general procedure 6 except that (R,E)-2-((dimethylamino)methylene)-4-(2-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one reacted with 1-(3-(hydroxymethyl)phenyl)guanidine to give (R)-(3-(6-(2-fluorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenyl)methanol M.p.=158-159° C. 1H NMR 400 MHz (DMSO-d6) δ 9.57 (s, 1 H), 8.41-8.39 (m, 1 H), 8.32 (s, 1 H), 7.92 (s, 1 H), 7.70-7.68 (m, 1 H), 7.53-7.45 (m, 2 H), 7.29-7.21 (m, 3 H), 7.08-7.02 (m, 2 H), 6.91-6.89 (d, 1 H), 6.81-6.77 (m, 1 H), 5.19 (t, J=6.0 Hz, 1 H), 4.67 (t, J=6.8 Hz, 1 H), 4.52 (d, J=5.2 Hz, 2H), 3.22-3.02 (m, 2 H). LCMS m/e 398 (M+H).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8]C2C=CC(Cl)=C(NC(=O)C3C=CC=C(F)C=3)C=2)=[O:7])=[CH:4][N:3]=1.C(N1CCNCC1)(=O)C>>[C:6]([NH2:8])(=[O:7])[C:5]1[CH:26]=[CH:27][CH:2]=[N:3][CH:4]=1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2cccc(F)c2)c1)c1ccc(Cl)nc1
Agent: CC(=O)N1CCNCC1
Product: NC(=O)c1cccnc1

Procedure:
6-chloro-N-(4-chloro-3-(3-fluorobenzamido)phenyl)nicotinamide (0.117 mmol) was used in general procedure 3 with 1-acetylpiperazine (0.35 mmol). The product was purified by RP-HPLC to give 6-(4-acetylpiperazin-1-yl)-N-(3-fluoro-3-(3-chlorobenzamido)phenyl))phenyl)nicotinamide. MS (Q1) 496.1 (M)+
Reaction SMILES: [C:1]([C:3]1[CH:44]=[CH:43][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:16]3[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]4[C:17]=3[CH:18]=[CH:19][N:20]4[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(O)[C:11]([F:14])([F:13])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2].[C:45](C1C=CC2N=C(C(C3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)(O)C(F)(F)F)N(COCC[Si](C)(C)C)C=2C=1)#[N:46].Cl.CO.S(Cl)(Cl)=O.CCO>CN.CN(C=O)C>[C:1]([C:3]1[CH:44]=[CH:43][C:6]2[NH:7][C:8]([C:10]([C:16]3[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]4[C:17]=3[CH:18]=[CH:19][N:20]4[C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])([NH:46][CH3:45])[C:11]([F:14])([F:12])[F:13])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)(c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C)C(F)(F)F
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)(c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: CN
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CNC(c1nc2cc(C#N)ccc2[nH]1)(c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C)C(F)(F)F
Temperature: 60 °C

Procedure:
To a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 33-A) (1.27 g, 2.014 mmol) was added 1.25 M HCl in MeOH (16.11 mL, 20.14 mmol) and the mixture was stirred at 60° C. After 40 minutes the reaction was cooled to room temperature and concentrated. The mixture was dissolved in CHCl3 (40 mL), then was added thionyl chloride (1.47 mL, 20.14 mmol) and DMF (0.5 mL) and the mixture was heated at 70° C. After 10 minutes the reaction was cooled to room temperature and concentrated. At this point the reaction was dissolved in 33% methylamine in EtOH (25 mL, 201 mmol) and stirred at room temperature. After 5 minutes the mixture was concentrated and the resulting residue was purified directly by flash chromatography (0-100% EtOAc in heptanes) to provide (±)-tert-butyl 4-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(methylamino)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate. MS (ESI+) m/z 514.3 (M+H). In addition, (±)-tert-butyl 4-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-1-(dimethylamino)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate was also isolated. MS (ESI−) m/z 526.3 (M−H).