Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH:15]([CH3:17])[CH3:16])([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([NH2:28])=[O:27])=[N:24][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.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]>[C:13]([C@@:10]1([CH:15]([CH3:17])[CH3:16])[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([NH2:28])=[O:27])=[N:24][CH:25]=3)[N:7]=2)[C:9]1=[O:18])#[N:14]
Reactant: NC(=O)c1ccc(N)cn1
Reactant: CC(C)[C@]1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)[C@]1(C#N)CCN(c2ccnc(Nc3ccc(C(N)=O)nc3)n2)C1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 19.6 %

Procedure:
To a solution of (3S)-1-(2-chloropyrimidin-4-yl)-3-isopropyl-2-oxopyrrolidine-3-carbonitrile (200 mg) obtained in Step A of Example 9, 5-aminopyridine-2-carboxamide (120 mg) obtained in Step A of Example 350, cesium carbonate (490 mg) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (71 mg) in tetrahydrofuran (5.0 mL) was added tris(dibenzylideneacetone)dipalladium(0) (69 mg), and the mixture was stirred overnight at 80° C. under argon atmosphere. The insoluble substance was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate), and recrystallized (diisopropyl ether/ethanol) to give the title compound (54 mg).
Reaction SMILES: [CH3:1][CH:2]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([CH3:20])=[N:15]3)[CH2:6][CH2:5]1.[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32]>>[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[C:21]([CH:2]([CH3:1])[CH2:3][N:4]2[CH2:5][CH2:6][N:7]([C:10]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:11]=3[CH:12]=[CH:13][C:14]([CH3:20])=[N:15]4)[CH2:8][CH2:9]2)[CH:22]=1)=[O:32]
Reactant: O=C(O)c1ccccc1F
Reactant: Cc1ccc2c(N3CCN(CC(C)c4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CC(C)c4cccc(NC(=O)c5ccccc5F)c4)CC3)cccc2n1
Yield: 64 %

Procedure:
The title compound was prepared in 64% yield according to the general procedure for the preparation of amides (Method C) starting from 3-{1-methyl-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D21) and 2-fluorobenzoic acid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:10]=1)=O)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28]>O1CCCC1.ClCCl>[Cl:1][CH2:2][C:3]1[S:28][C:7]([C:9]2[C:17]3[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:10]=2)=[N:6][N:5]=1
Reactant: COc1cccc2c(C(=O)NNC(=O)CCl)cn(CC3CCCCC3)c12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cccc2c(-c3nnc(CCl)s3)cn(CC3CCCCC3)c12
Yield: 352.5 %

Procedure:
To a solution of 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid N′-(2-chloroacetyl)hydrazide (prepared as described in Example 37; 50 mg, 0.139 mmol) in tetrahydrofuran (0.5 ml) was added phosphorus pentasulfide (62 mg, 0.139 mmol) and the reaction mixture subjected to microwave irradiation at 150° C. for 5 minutes. The reaction was repeated twice on a 0.7 mmol scale. The combined reaction mixture was poured into a separating funnel and diluted with dichloromethane (60 ml). The organics were washed with 5% aqueous sodium carbonate (2×30 ml), brine (30 ml), dried over sodium sulfate and the solvent removed in vacuo. The resulting residue was purified by flash column chromatography to afford 3-(5-chloromethyl-[1,3,4]thiadiazol-2-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (186 mg, 0.49 mmol).
Reaction SMILES: [CH:1]([C:4]1[C:9]2[C:10](=[O:33])[N:11]([CH2:15][O:16][C:17]3[N:21]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[N:20]=[C:19]([C:29]([F:32])([F:31])[F:30])[CH:18]=3)[S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([O:34][CH2:35][CH2:36][CH2:37][C:38]([O:40]CC2C=CC=CC=2)=[O:39])[CH:5]=1)([CH3:3])[CH3:2].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH:1]([C:4]1[C:9]2[C:10](=[O:33])[N:11]([CH2:15][O:16][C:17]3[N:21]([C:22]4[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=4)[N:20]=[C:19]([C:29]([F:32])([F:31])[F:30])[CH:18]=3)[S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([O:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(OCCCC(=O)OCc2ccccc2)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccc(Cl)cc1)S2(=O)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)c1cc(OCCCC(=O)O)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccc(Cl)cc1)S2(=O)=O
Temperature: 100 °C
Yield: 70.2 %

Procedure:
A mixture of 4-isopropyl-6-[3-(phenylmethyloxycarbonyl)propoxy]-2-[1-(4-chlorophenyl)-3-trifluoromethylpyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (4.19 g; 6.055 mmol) and 50 ml of 20% sulfuric acid in 80 ml of dioxane was heated at 100° C. for 20 hours. The mixture was cooled, poured into ice, neutralized with sodium bicarbonate solution (160 ml, to pH=5), and the resulting solid was filtered and recrystallized (3×, ethyl acetate/hexane; methylene chloride/hexane; and acetonitrile) to afford 2.56 g of 4-isopropyl-6-[3-(carboxy)propoxy]-2-[1-(4-chlorophenyl)-3-trifluoromethylpyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =4-Cl--Ph; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-O(CH2)3CO2H) as a white solid, 162°-164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[C:5]([C:12]#[N:13])=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]([CH:31]2[CH2:33][CH2:32]2)CC2C=CC(OC)=CC=2)[C:18]2=[N:34][CH:35]=[C:36]([C:37]#[N:38])[N:17]2[N:16]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[C:5]([C:12]#[N:13])=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([NH:21][CH:31]2[CH2:33][CH2:32]2)[C:18]2=[N:34][CH:35]=[C:36]([C:37]#[N:38])[N:17]2[N:16]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)c(CCCO)cc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)cc1CCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
2-((2-chloro-5-cyano-4-(3-hydroxypropyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (30 mg, 0.057 mmol) was taken up in DCE (0.6 mL) and anisole (0.031 mL, 0.284 mmol) was added, followed by TFA (0.175 mli, 2.268 mmol). The reaction was stirred at room temperature overnight. LCMS indicates formation of the TFA ester. The solvent was removed in vacuo and the material dissolved in 2N NH3 in MeOH. The solution was stirred at room temperature for 30 min. The solvent was removed in vacuo and the material was triturated with Et2O to remove the anisole. The material was purified by preparative HPLC to provide 2-((2-chloro-5-cyano-4-(3-hydroxypropyl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (6.2 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].[O:31]=[C:32]1[NH:36][C:35](=[O:37])[CH:34]([CH2:38][C:39]2[CH:49]=[CH:48][C:42]([O:43][CH2:44][C:45](O)=[O:46])=[CH:41][CH:40]=2)[S:33]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:31]=[C:32]1[NH:36][C:35](=[O:37])[CH:34]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:43][CH2:44][C:45]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([CH2:15][C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:46])=[CH:48][CH:49]=2)[S:33]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Cc3ccccc3)cc2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Cc3ccccc3)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 90.4 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-benzylphenoxy)phenyl]-N-methylcarbamate (0.61 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.51 g), diethyl cyanophosphonate (0.29 g), triethylamine (0.18 g) and anhydrous tetrahydrofuran (10 ml) and the reaction mixture was purified to give the desired product (0.91 g).
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:3]>[Rh].CO>[ClH:1].[CH2:2]([O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)[CH3:3]
Reactant: CCOc1ccccc1Oc1cccnc1
Agent: [Rh]
Agent: Cl
Solvent: CO
Product: CCOc1ccccc1OC1CCCNC1
Temperature: 50 °C
Reaction time: 9 h

Procedure:
Aqueous 12.2M hydrochloric acid solution (80.0 mL, 0.976 mol) was added slowly to a mixture of 3-(2-ethoxyphenoxy)pyridine (210 g, 0.976 mol), rhodium (5% on alumina, 21 g, 0.010 mol), and methanol (2.1 L) in a Parr reactor. The reactor was purged sequentially with nitrogen and hydrogen (4 times each), and then was heated to 50° C. and pressurized to 50 psi with hydrogen. After 9 hours, the reactor was cooled to 25° C. and was purged with nitrogen. The catalyst was removed by filtration, rinsing with methanol. The resulting methanol solution was distilled to a low volume under reduced pressure at 50-55° C.; ethyl acetate (2.3 L) was added and the distillation was continued at ambient pressure and at constant volume with the addition of further ethyl acetate (1.5 L). The distillation was stopped when the solution became turbid. The mixture was cooled to 20° C. and the resulting crystals were collected by filtration, rinsing with ethyl acetate (0.70 L), to afford after drying 3-(2-ethoxyphenoxy)piperidine hydrochloride (201 g). 1H NMR (400 MHz, DMSO-d6) δ 9.20 (br s, 2H), 7.12 (d, 1H), 7.03 (m, 2H), 6.89 (m, 1H), 4.45 (m, 1H), 4.04 (q, 2H), 3.27 (app dd, 1H), 3.05 (m, 3H), 1.94 (m, 2H), 1.72 (m, 2H), 1.35 (t, 3H). MS (ES+) 222.1 (M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:11]1[CH:16]=[C:15]([NH:17][C:18]2[CH:23]=[N:22][C:21]([C:24](OC)=[O:25])=[CH:20][N:19]=2)[CH:14]=[C:13]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:12]=1[OH:32])([CH3:10])([CH3:9])[CH3:8].O.S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)C.O1CCCC1>[C:7]([C:11]1[CH:16]=[C:15]([NH:17][C:18]2[CH:23]=[N:22][C:21]([CH2:24][OH:25])=[CH:20][N:19]=2)[CH:14]=[C:13]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:12]=1[OH:32])([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)c1cnc(Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cn1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)c1cc(Nc2cnc(CO)cn2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.1 %

Procedure:
Lithium aluminum hydride (0.14 g) was suspended in 26 ml of diethyl ether. While the suspension was stirred at room temperature, 13 ml of a solution of 0.50 g of 2,6-di-tert-butyl-4-[(5-methoxycarbonyl-2-pyrazinyl)amino]phenol (Compound20) in tetrahydrofuran was added thereto. The resulting mixture was furtherstirred at room temperature for 4 hours. With cooling on an ice bath 0.5 mlof water was added thereto, followed by addition of 1.4 g of magnesium sulfate, and the mixture was stirred for 15 minutes. Insoluble materials were filtered off, and the filtrate was concentrated. The resulting crude product was purified by silica gel column chromatography (eluent: methanol-chloroform=1:19), giving 0.30 g of the title compound (Compound 32) as a pale yellow solid.
Reaction SMILES: B.[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[C:11]=1[CH3:12])=[O:6])[CH3:3].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:13]2[CH:14]=[CH:15][C:16]([CH2:17][OH:18])=[CH:20][CH:21]=2)[C:11]=1[CH3:12])=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cnn(-c2ccc(C(=O)O)cc2)c1C
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2ccc(CO)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.8 %

Procedure:
0.93M Tetrahydrofuran solution of borane (18 ml) was added dropwise to a solution of 4-[4-(ethoxycarbonyl)-5-methyl-1H-pyrazol-1-yl]benzoic acid (3.0 g) in tetrahydrofuran (50 ml) at 0° C. and stirred at room temperature for three hours. After completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added therein and extracted with ethyl acetate three times. The organic layer was washed with saturated brine, dried oner anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified with NH silica gel column chromatography (n-hexene/ethyl acetate) to give 1-[4-(hydroxymethyl)phenyl]-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.93 g) as a white solid.
Reaction SMILES: [O-]CC.[Li+].[C:5]([C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][C:21]2[CH:22]=[C:23]([CH:26]=[C:27]([CH:29]=[CH:30][C:31]3[CH:36]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:34]=[C:33]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:32]=3)[CH:28]=2)[CH:24]=O)[CH:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:14]=1)([CH3:8])([CH3:7])[CH3:6].[Cl-].[CH3:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][PH3+])=[CH:49][CH:48]=1.II>C(OCC)C.C1(C)C=CC=CC=1>[C:5]([C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][C:21]2[CH:22]=[C:23]([CH:24]=[CH:46][C:47]3[CH:54]=[CH:53][C:50]([CH3:51])=[CH:49][CH:48]=3)[CH:26]=[C:27]([CH:29]=[CH:30][C:31]3[CH:36]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:34]=[C:33]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:32]=3)[CH:28]=2)[CH:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:14]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: Cc1ccc(C[PH3+])cc1
Reactant: CC(C)(C)c1cc(C=Cc2cc(C=O)cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)c2)cc(C(C)(C)C)c1
Agent: CC[O-]
Agent: II
Agent: [Cl-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1ccc(C=Cc2cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
Lithium ethoxide (1.0 M in ethanol, 15.0.mL, 15 mmol) was added to a stirred suspension of 3,5-bis[(3,5-di-tert-butylphenyl)vinyl]benzaldehyde (A) (WO99/9921935) (4.00 g, 7.48 mmol) and 4-methylbenzylphosphoniumchloride (8) (3.62 g, 8.98 mmol) in diethyl ether (40 mL), giving a clear orange solution which was stirred at room temperature for 2 h. The solution was washed with water (3×40 mL) and brine (40 mL), dried over anhydrous magnesium sulphate, filtered and the solvent removed, This residue was passed through a plug of silica with dichloromethane—light petroleum (1:4) as eluent to give a white solid, which was found by 1H NMR to be mainly cis isomer. The solid was heated with iodine (210 mg) and toluene (100 mL) at 100° C. under argon for 6 h and allowed to cool. The solution was washed with saturated aqueous sodium metabisulphite (50 mL) and brine (50 mL) and the solvent removed. The residue was recrystallised from a dichloromethane—hexanes mixture to leave 4-({3,5-bis[(3,5-di-tert-butylphenyl)vinyl]phenyl}vinyl)toluene (9) (3.00 g, 64%) as a white solid. δH(400 MHz, CDCl3) 1.40 (36 H, s, t-butyl), 2.39 (3 H, s, CH3), 7.13 and 7.22 (2 H, d, J 16, core vinyl H), 7.17 and 7.28 (4 H, d, J 16, branch vinyl H), 7.21 and 7.48 (4 H, AA′BB′, core phenyl H), 7.39 (2 H, dd, J 1.5, sp H), 7.43 (4 H, d, J 1.5, sp H), 7.59 (2 H, d, J 1, bp H) and 7.62 (1 H s, bp H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)[CH3:2].[Cl-].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:18]=[N+:19]([CH3:21])[CH3:20].COC1C=C(C=CC=1OC)C=O.CNC>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]([N:19]([CH3:21])[CH3:20])[C:8]2[C:7]3[C:11](=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][CH:6]=3)[NH:10][CH:9]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: CCc1cccc2cc[nH]c12
Reactant: COc1ccc(C=[N+](C)C)cc1OC
Agent: CNC
Agent: COc1ccc(C=O)cc1OC
Agent: [Cl-]
Product: CCc1cccc2c(C(c3ccc(OC)c(OC)c3)N(C)C)c[nH]c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 7-ethyl-1H-indole and (3,4-dimethoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3,4-dimethoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:11]([C@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:11]([C@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH2:1]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C[C@H]1CCCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 77.4 %

Procedure:
NaHMDS (1.0 M in THF, 18.6 mL, 18.6 mmol) was slowly added over 15 min to a 0° C. solution of methyltriphenylphosphonium bromide (7.19 gm, 20.1 mmol) in THF (65 mL). The yellow mixture was stirred at 0° C. for 45 min and then cooled to −78° C. A solution of (R)-tert-butyl 2-formylpiperidine-1-carboxylate (3.30 gm, 15.5 mmol) in THF (10 mL) was added dropwise. The reaction mixture was then stirred at 0° C. for 1 hr. The reaction was quenched by the addition of saturated aqueous NH4Cl. The solution was partitioned between EtOAc and water. The aqueous phase was isolated and extracted with EtOAc. All organic phases were combined, dried over MgSO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (R)-tert-butyl 2-vinylpiperidine-1-carboxylate (2.53 gm, 12.0 mmol, 77% yield) as an orange oil. Anal. Calcd. for C12H21N0 m/z 211.3. found: 212.0 (M+H)+.
Reaction SMILES: O1CCCC1.[N:6]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10][NH:9][CH:8]([C:12]([O:14][CH3:15])=[O:13])[CH2:7]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:30]1[N:35]=[CH:34][N:33]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[C:32](=[O:44])[N:31]=1>O>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][N:33]2[CH:34]=[N:35][C:30]([N:9]3[CH2:10][CH2:11][N:6]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][CH:8]3[C:12]([O:14][CH3:15])=[O:13])=[N:31][C:32]2=[O:44])=[CH:38][CH:39]=1
Reactant: O=c1nc(Cl)ncn1Cc1ccc(Cl)cc1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1c1ncn(Cc2ccc(Cl)cc2)c(=O)n1
Yield: 43.1 %

Procedure:
To tetrahydrofuran solution (2.3 mL) of 1-tert-butyl 3-methyl piperazine-1,3-dicarboxylate (43 mg, 0.17 mmol), sodium carbonate (37 mg, 0.35 mmol) and 4-chloro-1-(4-chlorobenzyl)-1,3,5-triazin-2(1H)-one (45 mg, 0.17 mmol) synthesized in Reference Synthesis Example 11 were added and the resultant solution was stirred at room temperature for 1 day. After completion of the reaction, water was added thereto and extraction with chloroform from the resultant mixture was performed three times. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure and ethyl acetate was added to the obtained residue. The obtained solid was collected by filtration and dried under reduced pressure to obtain the title compound (34 mg, yield 42%).
Reaction SMILES: [CH3:1][C@@H:2]1[C:6]2[N:7](S(C3C=CC(C)=CC=3)(=O)=O)[CH:8]=[CH:9][C:5]=2[C:4](=[O:20])[NH:3]1.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][C@@H:2]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4](=[O:20])[NH:3]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2[C@@H](C)NC3=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@H]1NC(=O)c2cc[nH]c21
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a stirring solution of (R)-6-methyl-1-tosyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (702e; 15.6 g, 53.7 mmol) in 250 mL MeOH under nitrogen in an ice/water bath was added K2CO3 (14.85 g, 107 mmol). The slurry was stirred and the bath was allowed to slowly expire overnight. The stir bar was removed; 100 g silica gel was added; and the reaction was concentrated in vacuo. A DCM-wetted pad of silica gel (4 cm) was poured in a 15 cm diameter flitted funnel and the dried silica gel/reaction mixture was placed on the silica gel pad and covered with 4 cm sand. 1 L fractions collected: #1—1 L DCM; #2—1 L 10% MeOH/DCM; #3—1 L 10% MeOH/DCM; #4—750 mL 10% MeOH/DCM #5—1 L 10% MeOH/DCM. Fractions 3-5 were combined and concentrated in vacuo to give 7.7 g (74% ee) as a tan solid. The material was further purified by chiral SFC (mobile phase CO2/15% MeOH (20 mM NH3), chiral column ASH (250×30 mm), wave length 256 nm, flow rate 120 mL/min). The second eluting peak was collected and concentrated in vacuo to give (R)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (702) (5.3 g, 39.0 mmol, 73% yield) as an off-white solid. 1H NMR (400 MHz, MeOH-d4) δ ppm 6.84 (1H, d, J=2.9 Hz), 6.23 (1H, d, J=2.9 Hz), 4.53 (1H, q, J=6.7 Hz), 1.41 (3H, d, J=6.8 Hz). m/z (ESI, +ve) 137.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:6](=[O:18])[NH:7][C:8]2[C:13]([C:14]=1[CH3:15])=[C:12]([OH:16])[CH:11]=[CH:10][C:9]=2[F:17].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:35][O:36][C:37](=[O:41])[C@H:38](Cl)[CH3:39]>O>[CH3:35][O:36][C:37](=[O:41])[C@@H:38]([O:16][C:12]1[CH:11]=[CH:10][C:9]([F:17])=[C:8]2[C:13]=1[C:14]([CH3:15])=[C:5]([CH2:4][C:3]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:2]=1[Cl:1])[C:6](=[O:18])[NH:7]2)[CH3:39]
Reactant: COC(=O)[C@@H](C)Cl
Reactant: Cc1c(Cc2ccc(Cl)cc2Cl)c(=O)[nH]c2c(F)ccc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](C)Oc1ccc(F)c2[nH]c(=O)c(Cc3ccc(Cl)cc3Cl)c(C)c12
Temperature: 40 °C
Reaction time: 24 h

Procedure:
A mixture of 3-(2,4-dichlorobenzyl)-8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one (0.40 g), N,N-dimethylformamide (5.0 mL), potassium carbonate (0.17 g) and (R)-2-chloropropionic acid methyl ester (0.15 g) was stirred at 40° C. for 24 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of toluene, dichloromethane and ethyl acetate (1:1:0 to 0:1:0 to 0:10:1 by volume) to afford title compound as a cream solid, 0.21 g.
Reaction SMILES: [C:1]([CH:4]([CH2:15][CH2:16][CH2:17][SH:18])[CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])(O)=[O:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[O:2]=[C:1]1[CH:4]([CH2:5][C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=[O:10])[CH2:15][CH2:16][CH2:17][S:18]1
Reactant: O=C(O)c1cccc(CC(CCCS)C(=O)O)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: O=C(O)c1cccc(CC2CCCSC2=O)c1
Yield: 63.9 %

Procedure:
A solution of 3-(2-carboxy-5-mercaptopentyl)benzoic acid (5.12 g, 20 mmol) and 10-camphorsulfonic acid (500 mg) in toluene (30 mL) was refluxed for 6 hours. The liberated water was removed using a Dean-Stork azeotropic adapter. Toluene was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (EtOAc/hexanes, 1:4). Fractions containing the product were collected, evaporated and recrystallized from EtOAc/hexanes to afford 3.2 g of 3-[(2-oxotetrahydro-2H-thiopyran-3-yl)methyl]benzoic acid as a white solid (67% yield): 1H NMR (CDCl3) δ 1.58–1.68 (m, 1 H), 1.90–2.02 (m, 2 H), 2.04–2.13 (m, 1 H), 2.68 (m, 1 H), 2.78–2.86 (m, 1 H), 3.08–3.19 (m, 2 H), 3.37–3.44 (m, 1 H), 7.38–7.48 (m, 2 H), 7.93 (brs, 1 H), 7.94–8.02 (m, 1 H); 13C NMR (CDCl3) δ 22.6, 27.8, 31.1, 36.8, 52.0, 128.8, 129.2, 129.8, 131.3, 135.3, 140.1, 172.6, 203.7. Analysis calculated for C13H14O3S: C, 62.38; H, 5.64; S, 12.81. Found: C, 62.19; H, 5.65; S, 12.59.