Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14]([Br:19])=[CH:13][C:12]=3[N:11]=[C:10]([NH2:20])[C:9]=2[N:8]=[C:7]1[CH2:21][CH2:22][CH3:23].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)(Cl)Cl>[NH2:20][C:10]1[C:9]2[N:8]=[C:7]([CH2:21][CH2:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[C:18]=2[C:17]2[CH:16]=[CH:15][C:14]([Br:19])=[CH:13][C:12]=2[N:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCN
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCNS(C)(=O)=O
Temperature: 0 °C
Yield: 37.4 %

Procedure:
A suspension of 1-(4-aminobutyl)-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (3.27 g, 8.7 mmol) and triethylamine (3.82 mL, 11.3 mmol) in chloroform (165 mL) was cooled to 0° C. A cold solution of methanesulfonyl chloride (1.37 mL, 9.6 mmol) in chloroform (10 mL) was slowly added. The reaction was allowed to warm to ambient temperature after 15 minutes. Additional triethylamine (3.74 mL) and methanesulfonyl chloride (2.12 mL) were added over the course of several days to drive the reaction to completion. The reaction was concentrated under reduced pressure, and the residue was partitioned between 1% aqueous sodium carbonate and chloroform. The aqueous layer was adjusted to pH 13 with the addition of saturated aqueous sodium bicarbonate and 50% aqueous sodium hydroxide. The precipitate was isolated by filtration, air-dried, and combined with material from another run. The crude product was recrystallized from isopropanol:water (15 mL/g:1.5 mL/g) and dried in a drying oven for several days to provide 1.48 g of N-{4-[4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide as a white solid.
Reaction SMILES: CO.[CH3:3][S:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:21][CH2:20][CH2:19][O:18]2)[CH:12]=1)([CH3:10])[C:6]([O:8]C)=[O:7].[OH-].[Na+]>O>[CH3:3][S:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:21][CH2:20][CH2:19][O:18]2)[CH:12]=1)([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(C)(SC)c1cccc(C2(c3ccccc3)OCCO2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSC(C)(C(=O)O)c1cccc(C2(c3ccccc3)OCCO2)c1
Yield: 97.7 %

Procedure:
Methanol (4 ml) and 1 ml of water were added to 1.277 g of methyl α-methylthio-α-(m-(2-phenyl-1,3-dioxa-2-cyclopentyl)phenyl)propionate. Furthermore, 350 mg of sodium hydroxide was added, and the mixture was heated under reflux for 2 hours. After cooling, 30 ml of water was added, and the mixture was washed twice with 10 ml of diethyl ether. To the aqueous layer was added about 6 ml of 3.5% hydrochloric acid to adjust its pH to 3. It was then extracted four times with 20 ml of diethyl ether. The organic layer was washed twice with 10 ml of water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to afford 1.199 g of α-methylthio-α-(m-(2-phenyl-1,3-dioxa-2-cyclopentyl)phenyl)propionic acid as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH3:18][N:19]([CH3:28])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=[CH2:27])[CH:21]=1>CN1C(=O)CCC1.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:27][CH2:26][C:22]3[CH:21]=[C:20]([N:19]([CH3:28])[CH3:18])[CH:25]=[CH:24][CH:23]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cccc(N(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2cccc(N(C)C)c2)CCN(C)C1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.5 mmol) was in NMP (1 mL) were added powdered KOH (196 mg, 3.5 mmol) and dimethyl-(3-vinyl-phenyl)-amine (147 mg, 1.0 mmol) and the reaction mixture stirred at 100° C. for 16 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3×25 mL). The combined organic layer was washed with water (5×20 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (0-3% MeOH-DCM) to yield {3-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethyl]-phenyl}-dimethyl-amine. 1H NMR (CDCl3, freebase) δ (ppm): 7.21 (m, 2H), 7.18 (dd, 1H), 7.0 (d, 1H), 6.6 (d, 1H), 6.43 (d, 1H), 6.21 (s, 1H), 4.2 (t, 2H), 3.71 (s, 2H), 2.90 (t, 2H), 2.85 (s, 3H), 2.80 (m, 4H), 2.57 (s, 6H), 2.41 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][CH2:12][CH3:13])=[N:8]2)=[C:4]([CH3:14])[N:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[CH3:14][C:4]1[N:3]=[C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:10]=[C:9]2[C:5]=1[NH:6][C:7]([CH2:11][CH2:12][CH3:13])=[N:8]2
Reactant: C1COCCN1
Reactant: CCCc1nc2nc(Cl)nc(C)c2[nH]1
Product: CCCc1nc2nc(N3CCOCC3)nc(C)c2[nH]1
Temperature: 122 °C

Procedure:
A solution of 2-Chloro-6-methyl-8-propylpurine (from Step 1 of Example 32) (0.1 g, 0.47 mmol) in morpholine (2 ml) was placed in a steel-bomb, and the mixture was heated at 122° C. for 18 hours. The reaction was cooled, and the mixture was concentrated in vacuo. The residue was dissolved in CHCl3 (2 ml) and was purified by flash-chromatography on silica-gel using 5% MeOH in CHCl3 giving the titled compound as an amorphous solid (0.1 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@@H:23]2[CH2:25][O:24]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:26][CH2:27][CH2:28][CH2:29][OH:30].CN1CCCC1=O.Cl>[Cl-].[Na+].O.ClCCl>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@@H:23]([OH:24])[CH2:25][NH:26][CH2:27][CH2:28][CH2:29][OH:30])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:9][CH:10]3[CH2:16][CH:14]([CH2:13][CH:12]([CH2:11]3)[CH2:17]1)[CH2:15]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C[C@@H]2CO2)ccc1Cl
Reactant: NCCCO
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C[C@@H](O)CNCCCO)ccc1Cl

Procedure:
2-Chloro-5-[(2R)-2-oxiranylmethyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 5c) (133 mg), 3-amino-1-propanol (3 mL) and 1-methyl-2-pyrrolidinone (5 mL) were heated together at 80° C. in a sealed tube for 22 hours, cooled and poured into brine (50 mL), extracted into ethyl acetate (3×50 mL), washed with brine (3×50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. This was purified by Waters' MCX resin and then by column chromatography eluting with 9:1:0.1 dichloromethane/methanol/ammonia. This was further purified by reverse phase HPLC (gradient 25–95% acetonitrile in 0.2% aqueous trifluoroacetic acid on Xterra™ column). The oil obtained was dissolved in dichloromethane (5 mL) and 1M ethereal hydrogen chloride (4 mL) was added. The mixture was concentrated to give the titled compound as a solid (60 mg).
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([OH:7])[CH:5]=[CH2:6].Br[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:3][CH:4]([O:7][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[CH2:6]
Reactant: C=CC(C)O
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CC(C)OCC(=O)OC(C)(C)C
Temperature: 2.5 °C

Procedure:
A reactor was charged with tetrabutylammonium hydrogen sulfate (0.17 Wt, 0.10 eq) and toluene (2.6 Wt, 3.0 V). The mixture was stirred and cooled to 0-5° C. While maintaining the internal temperature below 10° C., 50 wt % aqueous sodium hydroxide (4.5 wt, 3.0 V, 10.5 eq; 50% wt sodium hydroxide made from 2.25 wt of sodium hydroxide and 2.25 wt of water) was added, followed by 3-buten-2-ol (0.45 Wt, 0.53 V, 1.20 eq). The mixture was stirred at 0-10° C. for 15 minutes. tert-Butyl bromoacetate (1.0 Wt, 1.00 eq) was added while maintaining the internal temperature between 0-10° C. After the addition, the mixture was stirred between 0-5° C. for 1 h and monitored for complete consumption of tert-butyl bromoacetate (target >98% conversion). The reactor was charged with water (3.0 Wt, 3.0 V) and MTBE (4.4 Wt, 6.00 V) and warmed to 20-25° C. The biphasic mixture was stirred vigorously for 15 minutes, and then allowed to partition. The organic layer was washed with water (1.5 Wt, 1.5 V). The organic layer was concentrated under reduced pressure (T<40° C. and not less than 15 torr or 20 mbar). Heptane (1.0 wts, 1.5 V) and MTBE (1.1 wts, 1.5 V) were added. The solution was filtered to remove particulates, and rinsed with additional heptane:MTBE as necessary to clear the product. The solution was returned to the reactor and concentrated under reduced pressure to give 6 (0.91 Wt, 95.0%) as an oil with less than 1 volume of solvent.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl[C:44]1[N:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[F:56])=[CH:46][N:45]=1.[CH3:57][C:58]1[C:66]2[C:61](=[CH:62][C:63]([C:67]([N:69]3[CH2:74][CH2:73][O:72][CH2:71][CH2:70]3)=[O:68])=[CH:64][CH:65]=2)[NH:60][CH:59]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:56][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[C:47]1[CH:46]=[N:45][C:44]([N:60]2[C:61]3[C:66](=[CH:65][CH:64]=[C:63]([C:67]([N:69]4[CH2:74][CH2:73][O:72][CH2:71][CH2:70]4)=[O:68])[CH:62]=3)[C:58]([CH3:57])=[CH:59]2)=[N:49][CH:48]=1
Reactant: Fc1ccccc1-c1cnc(Cl)nc1
Reactant: Cc1c[nH]c2cc(C(=O)N3CCOCC3)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 120 °C

Procedure:
Palladium(II) acetate (8 mg, 0.036 mmol) and Xantphos (42 mg, 0.072 mmol) were added under an argon atmosphere to a solution of 2-chloro-5-(2-fluorophenyl)pyrimidine (150 mg, 0.72 mmol), (3-methyl-1H-indol-6-yl)(morpholino)methanone (176 mg, 0.72 mmol; synthesized from morpholine and 3-methyl-1H-indole-6-carboxylic acid) and cesium carbonate (422 mg, 1.29 mmol) in dry THF (5 mL). The reaction mixture was heated in a microwave at 120° C. for 1 h. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate (2×15 mL). Purification by flash chromatography [silica, heptane with 25% to 75% ethyl acetate] afforded the target compound as white solid. Yield: 185 mg (62% of theory). HPLC-MS: m/z [M+H]+=417.1
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[C:4]([F:28])[CH:3]=1.[CH3:29][C:30]1[CH:31]=[C:32](B(O)O)[S:33][CH:34]=1.CC(C)([O-])C.[K+]>COCCOC.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>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:32]4[S:33][CH:34]=[C:30]([CH3:29])[CH:31]=4)=[CH:3][C:4]=3[F:28])(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1F
Reactant: Cc1csc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2cc(C)cs2)cc1F
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-2-fluorobenzenesulfonamide (E103) (100 mg, 0.21 mmol) and (4-methyl-2-thienyl)boronic acid (60 mg, 0.42 mmol) in DME (3 ml) was added potassium tert-butoxide (220 mg, 1.96 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then evaporated in vacuo and purified using an SCX cartridge eluting with methanol followed by ammonia (2M in methanol) The appropriate fractions were combined and evaporated in vacuo and the residue purified further by mass directed autoprep HPLC to afford the title compound (E110). MS (ES+) m/e 490 [M+H]+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[N:11]1([C:17]2[N:18]=[C:19]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[NH:20][C:21](=[O:23])[CH:22]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:11]1([C:17]2[N:18]=[C:19]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:21](=[O:23])[CH:22]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)n1-c1ccccc1
Temperature: 95 °C
Yield: 5.1 %

Procedure:
6.24 ml of 0.6 M sodium bis(trimethylsilyl)amide in toluene are added to a suspension of 1 g of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (obtained in step 1d of example 1d), 912 mg of phenylboronic acid, 680 mg of copper(11) acetate and 1.37 g of 4-dimethylaminopyridine in 12 ml of toluene. The reaction mixture is heated at 95° C. for 16 hours under a stream of dry air, and then filtered through celite. The filtrate is concentrated under reduced pressure and the residue is purified twice by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol (90/10, V/V) and then with a mixture of diisopropyl ether and methanol (90/10, V/V), so as to give 65 mg of ethyl (4-morpholin-4-yl-6-oxo-1-phenyl-1,6-dihydropyrimidin-2-yl)acetate in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([O:14]CC)(=O)[CH2:7][C:8]([O:10]CC)=O.Cl.[C:18]([NH2:21])(=[NH:20])[CH3:19]>C(O)C>[OH:14][C:6]1[CH:7]=[C:8]([OH:10])[N:21]=[C:18]([CH3:19])[N:20]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(O)cc(O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
To a solution of sodium ethoxide, prepared from sodium (36.2 g) and ethanol (1000 ml), diethyl malonate (114 ml) and acetamidine hydrochloride (71 g) were added at room temperature, and the mixture was stirred for 5 hours under reflux. After cooling to room temperature, the resulting solid was collected by filtration and washed with ethanol and then dissolved in water. The aqueous solution was acidified to pH Ca.2 with concentrated hydrochloric acid (Ca. 170 ml) under ice-cooling. The formed precipitate was separated by filtration and washed with water, ethanol and ether to give 153 g (81%) of the objective compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C@@:10]3([C@@H:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=O)([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][C@H:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:52]([S:54]([NH2:57])(=[O:56])=[O:55])[CH3:53].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([O:23][C:24]([CH3:25])([CH3:26])[C:27]([NH:57][S:54]([CH2:52][CH3:53])(=[O:56])=[O:55])=[O:29])=[C:16]([C@H:15]2[CH2:14][C:13](=[O:30])[NH:12][C@@H:11]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C@:10]32[C:5]2[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:9]3=[O:39])[CH:21]=1
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(F)cc1[C@@H]1NC(=O)C[C@H](c2cc(Cl)ccc2OC(C)(C)C(=O)O)[C@@]12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NC(=O)C(C)(C)Oc1ccc(Cl)cc1[C@H]1CC(=O)N[C@@H](c2cc(F)ccc2C)[C@]12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.1 %

Procedure:
A solution of chiral (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (57 mg, 0.1 mmol) prepared in Example 12a and CDI (32 mg, 0.2 mmol) in DMF (1 mL) was heated at 60° C. for 2 h. Then to this solution was added a mixture of ethanesulfonamide (66 mg, 0.6 mmol) and NaH (24 mg, 60%, 0.6 mmol) in DMF (1 mL), which had been stirred for 2 h at room temperature. After the resulting mixture was stirred at room temperature for 1 h, it was poured into water and the aqueous solution was acidified to “pH” 1-2 by addition of concentrated HCl. After the aqueous phase was extracted with EtOAc twice, the combined organic layers were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (10 mg).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=O.[C:17](N1C=CN=C1)([N:19]1C=CN=C1)=O.Cl.CN.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:19][CH3:17])=[O:16]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cnn(-c2cccc(Cl)c2)c1Cl
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(-c2cccc(Cl)c2)c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.8 %

Procedure:
A solution of 5.7 g of 5-chloro-1-(3-chlorophenyl)-1H-pyrazole-4-carboxylic acid and 5.4 g of carbonyldiimidazole in 150 ml DMF was stirred at room temperature for 20 minutes. Next, 3.0 g of methylamine hydrochloride and 4.4 g of triethylamine were added and the mixture was stirred at room temperature for 20 hours. The mixture was poured into ice water and the precipitated solid was collected by filtration and dried. The solid was recrystallized from toluene to provide 3.1 g of 5-chloro-1-(3-chlorophenyl)-N-methyl-1H-pyrazole-4-carboxamide. Yield 50%. mp=163°-165° C.
Reaction SMILES: [OH-].[Na+].COP([CH2:9][C:10](=[O:18])[C:11]([F:17])([F:16])[CH2:12][CH2:13][CH2:14][CH3:15])(=O)OC.[CH2:19]([O:26][C@@H:27]1[CH2:31][C:30](=[O:32])[C@H:29]([CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[C@H:28]1[CH:49]=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>O.O1CCCC1.[Cl-].[Zn+2].[Cl-].ClCCl>[CH2:19]([O:26][C@@H:27]1[CH2:31][C:30](=[O:32])[C@H:29]([CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:40])[C@H:28]1/[CH:49]=[CH:9]/[C:10](=[O:18])[C:11]([F:16])([F:17])[CH2:12][CH2:13][CH2:14][CH3:15])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Reactant: O=C[C@H]1[C@H](OCc2ccccc2)CC(=O)[C@@H]1C/C=C\CCCC(=O)OCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(F)(F)C(=O)/C=C/[C@H]1[C@H](OCc2ccccc2)CC(=O)[C@@H]1C/C=C\CCCC(=O)OCc1ccccc1

Procedure:
To a mixture of zinc chloride (25.0 mmoL) in water (15 mL) at about 10° C. was added 50% sodium hydroxide (49.0 mmoL) followed by water (5 mL). The mixture was stirred vigorously with a mechanical stirred at room temperature. To the mixture was added dimethyl(3,3-difluoro-2-oxoheptyl)phosphonate (17.0 mmoL) in tetrahydrofuran (15 mL). The mixture was stirred at room temperature for about an hour. To the mixture was added (5Z)-benzyl 7-[(1R,2R,3R)-3-benzyloxy-2-formyl-5-oxocyclopentyl]hept-5-enoate (17, R1 is phenyl, R2 and R3 are H and R7 is benzyl, 15.0 mmoL) in tetrahydrofuran (15 mL). The mixture was stirred at room temperature overnight. To the mixture was added dichloromethane (60 mL) and water (50 mL). The pH was adjusted to approximately 4 with 5 wt % hydrochloric acid. The layers were separated; the organic layer was dried over sodium sulfate, filtered through Celite® and concentrated to dryness. The residue was purified by column chromatography (40% ethyl acetate in heptanes) to yield (5Z)-benzyl 7-[(1R,2R,3R)-3-benzyloxy-2-[(E)-4,4-difluoro-3-oxooct-1-enyl]-5-oxocyclopentyl]hept-5-enoate (18, R1 is phenyl and R2, R3 are H and R7 is benzyl) as an oil (4.1 g).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.C(N(CC)CC)C.[C:21]1([C:26](Cl)=[O:27])[S:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:21]1([C:26]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:27])[S:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCCSc1ccccn1
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCSc1ccccn1)c1cccs1
Yield: 85.5 %

Procedure:
To a solution of 1.50 g (6.22 mmol) of 2-(3-aminopropylthio)pyridine dihydrochloride and 3.19 ml (22.9 mmol) of triethylamine in 60 ml of methylene chloride, 1.09 ml (7.46 mmol) of 2-thenoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder was washed with ether and dried to obtain 1.48 g of the desired compound (yield: 85.5%, colorless powder). mp: 81.0°-82.0° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([N:15]=[CH:16][N:17]([CH3:19])[CH3:18])(=[O:14])=[O:13])[CH:6]=1)([CH3:4])[CH3:3].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:32](O)=[O:33]>>[CH:32]([C:9]1[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:6]=[C:7]([S:12]([N:15]=[CH:16][N:17]([CH3:19])[CH3:18])(=[O:13])=[O:14])[C:8]=1[OH:11])=[O:33]
Reactant: CN(C)C=NS(=O)(=O)c1cc(C(C)(C)C)ccc1O
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: CN(C)C=NS(=O)(=O)c1cc(C(C)(C)C)cc(C=O)c1O

Procedure:
2.84 g (0.01 mol) of 4-(1,1-dimethylethyl)-2-dimethylaminomethyleneaminosulfonylphenol are boiled under reflux with 1.4 g of urotropine in 10 ml of trifluoroacetic acid for 6 h. The mixture is poured onto ice-water, and the rubber-like mass which has separated out is taken up in ether, the solution is washed to neutrality and the solvent is removed in vacuo. The residue is chromatographed on silica gel using ethyl acetate/toluene 4:1 as the eluting agent. 2-formyl-4-(1,1-dimethylethyl)-6-dimethylaminomethyleneaminosulfonylphenol of melting point 182°-183° C. is obtained, and this is immediately dissolved in 2N sodium hydroxide solution. The solution is left on a steam bath for 30 minutes, and then the solution is acidified to pH 2-3 with 2N hydrochloric acid, and filtered with suction.