Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].Br[CH2:14][CH2:15][Cl:16].C(N(CC)CC)C>CN(C=O)C>[Cl:16][CH2:15][CH2:14][O:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1OCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A 1 L round-bottomed flask was charged 2-hydroxyisoindoline-1,3-dione (16.6 g, 98.71 mmol), followed by DMF (100 mL), then 1-bromo-2-chloroethane (25.2 mL, 296.1 mmol), and then triethylamine (42.1 mL, 296.1 mmol). After stirring at ambient temperature overnight, the reaction mixture was filtered (GF/F) and rinsed with DMF. The filtrate (250 mL) was poured into ice-water (2 L) while stirring, and the resulting precipitate was filtered, rinsed with water, and dried, yielding the crude product as a white solid (21 g). The crude product was triturated with heptane (3×400 mL), filtered and air-dried, giving the product as white solid (17.6 g, 79%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:49])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][CH2:16][CH2:17][N:18]2[CH2:48][CH2:47][C:21]3([N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:24][N:23]([CH2:32][C:33]4[CH:34]=[C:35]([CH:43]=[CH:44][CH:45]=4)[C:36]([O:38]C(C)(C)C)=[O:37])[C:22]3=[O:46])[CH2:20][CH2:19]2)[CH:7]=1>Cl.O1CCOCC1>[CH3:1][O:2][C:3](=[O:49])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][CH2:16][CH2:17][N:18]2[CH2:48][CH2:47][C:21]3([N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:24][N:23]([CH2:32][C:33]4[CH:34]=[C:35]([CH:43]=[CH:44][CH:45]=4)[C:36]([OH:38])=[O:37])[C:22]3=[O:46])[CH2:20][CH2:19]2)[CH:7]=1
Reactant: COC(=O)CCc1cn(CCCN2CCC3(CC2)C(=O)N(Cc2cccc(C(=O)OC(C)(C)C)c2)CN3c2ccccc2)c2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CCc1cn(CCCN2CCC3(CC2)C(=O)N(Cc2cccc(C(=O)O)c2)CN3c2ccccc2)c2ccccc12
Yield: 33.5 %

Procedure:
A solution of tert-butyl 3-((8-(3-(3-(3-methoxy-3-oxopropyl)-1H-indol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (400 mg, 0.637 mmol, 1 equiv) in 4M hydrogen chloride solution in dioxane was stirred at ambient temperature for 3 h. The mixture was concentrated in vacuo and the crude residue was purified using preparatory high performance liquid chromatography to afford the acetate salt of the title compound as a white solid (130 mg, 35.7%); 1H NMR (400 MHz, DMSO-d6): δ 1.62 (d, 2H, J=13.2 Hz); 1.89-1.93 (m, 2H); 2.27 (t, 2H, J=6.8 Hz); 2.59-2.72 (m, 8H); 2.95 (t, 2H, J=7.6 and 8 Hz); 3.57 (s, 3H); 4.19 (t, 2H, J=6.8 and 6.4 Hz); 4.59 (s, 2H); 4.61 (s, 2H); 6.76 (t, 1H, J=7.2 Hz); 6.87 (d, 2H, J=8 Hz); 6.97-7.01 (m, 1H); 7.07-7.11 (m, 1H); 7.17 (s, 1H); 7.20-7.24 (m, 2H); 7.46-7.54 (m, 4H); 7.86-7.88 (m, 2H); 13.01 (bs, 1H); MS for C36H40N4O5 m/z 609 (M+H)+.
Reaction SMILES: [C:1]1([C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].[H-].[Na+].Cl>COCCOC.O>[C:1]1([C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH2:14][C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CC(=O)c1cccc2ccccc12
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(=O)CC(=O)CC(=O)c1cccc2ccccc12

Procedure:
A solution of 1-(1-naphthalenyl)-1,3-butanedione (5.3 g) and diethyl oxalate (6.75 ml) in 1,2-dimethoxyethane (10 ml) was added dropwise to a stirred suspension of sodium hydride (3.6 g, 50% dispersion in mineral oil, washed with petrol 40°-60° C.) in 1,2-dimethoxyethane (40 ml) under nitrogen. The stirred mixture was heated under reflux for 5 minutes, cooled, acidified with 2 M hydrochloric acid (50 ml), diluted with water (50 ml) and filtered. The filtrate was extracted with ethyl acetate and the extract was dried and evaporated to yield ethyl 6-(1-naphthalenyl)-2,4,6-trioxohexanoate as a dark oil.
Reaction SMILES: ClC(OC(Cl)C)=O.[CH3:8][C:9]12[CH2:23][CH:18]([N:19](C)[CH2:20][CH2:21]1)[CH2:17][CH2:16][C:15]1[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=1.C([O-])(O)=O.[Na+].ClCCl>ClCCCl>[CH3:8][C:9]12[CH2:23][CH:18]([NH:19][CH2:20][CH2:21]1)[CH2:17][CH2:16][C:15]1[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN1CCC2(C)CC1CCc1ccccc12
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC12CCNC(CCc3ccccc31)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Chloroethyl chloroformate (3.8 mL) is added dropwise to a mixture of 1,11-dimethyl-11-aza-tricyclo[8.3.1.0*2,7*]tetradeca-2,4,6-triene (0.75 g) and NaHCO3 (2.9 g) in 1,2-dichloroethane (3.5 mL) chilled in an ice bath. The reaction mixture is warmed to room temperature in the cooling bath and stirred overnight. Then, dichloromethane (20 mL) is added and the precipitate is removed by filtration. The filtrate is concentrated under reduced pressure and the residue is dissolved in methanol (20 mL). The resulting solution is stirred at reflux for 2 h. The solution is concentrated and the residue is purified by HPLC (water/MeCN/NH3) to give the title compound.
Reaction SMILES: BrN1C(=O)CCC1=O.[C:9]([NH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[P:22]([O:27]C)([O:25][CH3:26])[O:23][CH3:24]>C(Cl)(Cl)(Cl)Cl>[C:12]([O:11][C:9]([NH:16][CH:17]([P:22]([O:25][CH3:26])([O:23][CH3:24])=[O:27])[C:18]([O:20][CH3:21])=[O:19])=[O:10])([CH3:14])([CH3:15])[CH3:13]
Reactant: COP(OC)OC
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A quantity of 2.92 g (0.016 mol) of N-bromo succinimide is added to 2.82 g (0.015 mol) of N-Boc glycine, methyl ester in 230 mL of carbon tetrachloride. The mixture is heated at reflux with stirring for 1 hour, cooled to 0° C., and filtered. The filtrate is evaporated to dryness and the residue is dissolved in 30 mL of tetrahydrofuran. A quantity of 2.10 g (0.017 mol) of trimethyl phosphite is added and the solution is maintained at reflux for 18 hours. The solvent is evaporated and the product is purified by silica gel chromatography eluting with ethyl acetate; wt 2.80 g (63%);
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[N:11]=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19].C(N(CC)CC)C>ClCCl>[N+:18]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[NH:1][CH2:2][C:3]([CH3:5])([NH2:6])[CH3:4])=[N:16][CH:15]=[CH:14][CH:13]=2)([O-:20])=[O:19]
Reactant: CC(C)(N)CN
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(N)CNc1c([N+](=O)[O-])cnc2cccnc12
Reaction time: 8 h
Yield: 97.4 %

Procedure:
1,2-Diamino-2-methylpropane (8.4 mL, 80.0 mmol) was added to a chilled (0° C.), solution of 4-chloro-3-nitro[1,5]naphthyridine (15.2 g, 72.7 mmol) and triethylamine (20.2 mL, 145 mmol) in dichloromethane (350 mL). The reaction mixture was stirred overnight and then concentrated under reduced pressure. The residue was combined with water (300 mL) and heated at reflux with stirring for 1 hour. The reaction mixture was cooled and filtered. The isolated solid was washed with water and then dried under high vacuum to provide 18.5 g of N1-(3-nitro[1,5]naphthyridin-4-yl)-2-methylpropane-1,2-diamine as a bright yellow powder.
Reaction SMILES: [C:1]([OH:5])(=O)[C:2]#[CH:3].N1(C(N2C=CN=C2)=O)C=CN=C1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26](=[O:38])[CH2:27][C:28]1[NH:32][C:31]2[CH2:33][CH2:34][CH:35]([CH3:37])[CH2:36][C:30]=2[N:29]=1>>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26]([C:27]1[CH:3]=[CH:2][C:1](=[O:5])[N:29]2[C:30]3[CH2:36][CH:35]([CH3:37])[CH2:34][CH2:33][C:31]=3[NH:32][C:28]=12)=[O:38]
Reactant: C#CC(=O)O
Reactant: CC1CCc2[nH]c(CC(=O)c3ccc(F)cc3F)nc2C1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC1CCc2[nH]c3c(C(=O)c4ccc(F)cc4F)ccc(=O)n3c2C1

Procedure:
The compound is prepared as described in example 11 with 138 mg (1.97 mmol) of propiolic acid, 383.6 mg (2.37 mmol) of 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole and 382 mg (1.31 mmol) of 1-(2,4-difluorophenyl)-2-(5-methyl-4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone (example LIV). The isomers are isolated after purification over preparative HPLC (Daicel Chiralpak AD, eluent: iso-hexane-ethanol v/v 60:40):
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[C:30]([NH2:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21]1>>[NH2:31][C:30]1[C:25]([CH:22]2[CH2:23][CH2:24][N:20]([C:11]3[CH:12]=[C:13]4[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:15])[CH2:21]2)=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccnc1C1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: Nc1cccnc1C1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Yield: 91 %

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.81 g, 3.1 mmol) and 2-(3-pyrrolidinyl)-3-pyridinamine, a procedure analogous to that given in Example 1 provided the title compound (1.15 g, 91%) as an off-white solid, mp>270° C.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([O:18][CH3:19])[CH:12]=1)C)(C)(C)C.[ClH:21].C(OCC)(=O)C>C(OCC)(=O)C.C(OCC)C>[ClH:21].[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH:7][CH3:6])=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: COc1cc(CCN(C)C(=O)OC(C)(C)C)ccc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CNCCc1ccc(F)c(OC)c1
Reaction time: 2.5 h

Procedure:
To a solution of [2-(4-fluoro-3-methoxyphenyl)ethyl]methylcarbamic acid t-butyl ester (506 mg) in ethyl acetate (2 mL) was added a solution of 4N hydrochloric acid-ethyl acetate (2 mL) at room temperature and allowed to stand for 2.5 hours. The resulting solid was diluted with diethyl ether, then filtered, and washed with diethyl ether. After drying by aeration, the title compound (338 mg) was obtained as a colorless solid.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][O:6][C:7](=[O:14])[C:8]([CH2:10][C:11](O)=[O:12])=[CH2:9]>C(OCC)C>[C:7]([CH:8]1[CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[C:11](=[O:12])[CH2:10]1)([O:6][CH3:5])=[O:14]
Reactant: CC(C)N
Reactant: C=C(CC(=O)O)C(=O)OC
Solvent: CCOCC
Product: COC(=O)C1CC(=O)N(C(C)C)C1
Reaction time: 24 h

Procedure:
In the course of 30 minutes, 59.1 g (1 mol) of isopropyl amine were added dropwise to 158 g (1 mol) of itaconic acid methyl ester in 120 ml of diethyl ether. When the slightly exothermic reaction had finished, the reaction mixture was allowed to stand for 24 hours at room temperature. Then the solvent was removed in vacuo and the residue was subjected to fractionated vacuum distillation. boiling point: 95-98° C/0.05 mm Hg; nD20 : 1.4680
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH:7]2[CH2:16][C:15]3[N:14]=[C:13]([CH3:17])[CH:12]=[CH:11][C:10]=3[CH2:9][CH2:8]2)[N:3]=[CH:2]1.C([O-])(O)=O.[Na+].C1C=CC(OC(Cl)=[S:31])=CC=1>C1COCC1.O>[CH3:17][C:13]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][CH:7]([CH2:6][C:4]3[NH:3][C:2](=[S:31])[NH:1][CH:5]=3)[CH2:16][C:15]=2[N:14]=1
Reactant: Cc1ccc2c(n1)CC(Cc1c[nH]cn1)CC2
Reactant: S=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(n1)CC(Cc1c[nH]c(=S)[nH]1)CC2
Reaction time: 5 h

Procedure:
A solution of 7-(1H-imidazol-4-ylmethyl)-2-methyl-5,6,7,8-tetrahydro-quinoline (Intermediate 200A5) (5.16 g, 22.7 mmol) in THF (20 mL) and water (20 mL) was treated with NaHCO3 (11.5 g, 136 mmol) and phenyl chlorothionoformate (7.9 mL, 57 mmol). Stirring was continued for 5 h at rt. The mixture was diluted with water and extracted with ethyl acetate (2×). The organic portions were combined, dried over MgSO4, filtered and freed of solvent. The residue was dissolved in MeOH (10 mL) and treated with NEt3 (140 mL) for 18 h. The mixture was evaporated to dryness, diluted with water and extracted with chloroform:isopropanol (3:1). The organic portions were combined, dried over MgSO4, filtered and concentrated onto SiO2. The solvent was removed under vacuum and the product was purified on a column of SiO2 with a gradient elution of 60% acetone:hexanes to 100% acetone to give enantiomeric 4-(2-methyl-5,6,7,8-tetrahydro-quinolin-7-ylmethyl)-1,3-dihydro-imidazole-2-thione (Compound 201, racemic mixture) as a white solid, 3.0 g (51%). Individual enantiomers can be obtained from the racemic mixture as described below.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH:18]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]1.[H-].[Na+].CCOC(C)=O>O1CCOCC1>[NH:18]1[CH2:22][CH2:21][CH:20]([O:23][C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:19]1
Reactant: Clc1nccnc1OCCOc1ccccc1
Reactant: OC1CCNC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1ccc(OCCOc2nccnc2OC2CCNC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
2-Chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.60 mmol; from Example 1, Step 1) was added to a stirred mixture of 3-pyrrolidinol (260 mg, 2.99 mmol) and NaH (55% dispersion in mineral oil; 110 mg, 2.50 mmol) in dioxane (2 mL), and the reaction was stirred at room temperature for 2 h. EtOAc was added and the mixture was washed with water, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel using EtOAc/MeOH/HOAc/H2O (50:40:9:1) as eluent to give 38 mg (22%) of the title compound. Anal. (C16H19N3O3) H; C: calcd, 63.77; found, 62.20; N: calcd, 13.94; found, 13.0.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([F:23])[CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[N:31]=[C:32]([NH2:35])[S:33][CH:34]=1>>[N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:35][C:32]3[S:33][CH:34]=[C:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[N:31]=3)=[O:19])=[C:16]([F:23])[CH:15]=2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nc(-c2ccccn2)cs1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1F
Product: O=C(Nc1nc(-c2ccccn2)cs1)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1F

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-2-fluorobenzoic acid (9) (160 mg, 0.48 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (70 mg, 0.40 mmol) using method C. The residue was purified using flash chromatography eluting with EtOAc. The resulting solid was triturated with diethyl ether to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-2-fluoro-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as an off white solid. Yield: 38 mg (19%). 1H-NMR: 8.63-8.60 (m, 1H), 7.98-7.85 (m, 4H), 7.61 (d, J=8.5 Hz, 2H), 7.52 (dd, J=8.5, 2.0 Hz, 1H), 7.35 (ddd, J=7.5, 5.0, 1.0 Hz, 1H), 7.26-7.20 (m, 1H), 7.15-7.12 (m, 2H), 3.87-3.82 (m, 2H), 2.51-2.47 (m, 2H), 1.71-1.63 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:4]=1.Cl[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:20]1[CH2:19][CH2:18][N:17]([C:5]2[N:4]=[C:3]([N:2]([CH3:1])[CH3:23])[CH:8]=[C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)[N:6]=2)[CH2:22][CH2:21]1
Reactant: COc1ccccc1CCl
Reactant: Cc1ccc(Nc2cc(N(C)C)nc(N3CCNCC3)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccccc1CN1CCN(c2nc(Nc3ccc(C)cc3)cc(N(C)C)n2)CC1
Temperature: 200 °C
Yield: 26.9 %

Procedure:
A mixture of N4,N4-dimethyl-N6-(4-methylphenyl)-2-(1-piperazinyl)-4,6-pyrimidinediamine (30 mg, 0.086 mmol), 1-(chloromethyl)-2-methoxybenzene (17 mg, 0.1 mmol) and triethylamine (200 mg, 2 mmol) in 1 DMF (1 mL) heated by microwave at 200° C. for 12 minutes. The crude product was treated with saturated NaHCO3 (50 mL) and extracted with EtOAC (3×50 mL). The organic layer was washed with brine (2×100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (10 mg, 27%).
Reaction SMILES: O[CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH2:4][CH2:3]1.S(Cl)([Cl:17])=O>>[Cl:17][CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH2:4][CH2:3]1
Reactant: COC(=O)c1cccc2c1CCC2O
Reactant: O=S(Cl)Cl
Product: COC(=O)c1cccc2c1CCC2Cl

Procedure:
In 6 ml. of chllroform is dissolved 5.7 g. of methyl 1-hydroxyindan-4-carboxylate and, under cooling with ice, the solution is stirred. Then, 3 ml. of thionyl chloride is added dropwise and, after the dropwise addition has been completed, the mixture is further stirred under cooling with ice for one hour. Then, the solvent and the excess thionyl chloride are distilled off under reduced pressure. The residue obtained is purified by column chromatography on silica gel (500 g. silica gel; eluant: chloroform). The procedure gives methyl 1-chloroindan-4-carboxylate as an oily product.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:5]=1[C:6](OC)=[O:7])(=O)[CH3:2].O.[NH2:17][NH2:18]>CO.O>[CH3:15][O:14][C:11]1[CH:10]=[C:5]2[C:4]([C:1]([CH3:2])=[N:17][NH:18][C:6]2=[O:7])=[CH:13][CH:12]=1
Reactant: NN
Reactant: COC(=O)c1cc(OC)ccc1C(C)=O
Solvent: O
Solvent: CO
Product: COc1ccc2c(C)n[nH]c(=O)c2c1
Temperature: 95 °C
Reaction time: 5 h
Yield: 95.2 %

Procedure:
To a solution of methyl 2-acetyl-5-methoxybenzoate (2) (2.21 g, 10.60 mmol) in methanol (13 mL) is added hydrazine monohydrate (1.59 g, 31.80 mmol). The mixture is stirred at 95° C. under argon for 5 h, then cooled to room temperature, diluted with H2O (50 mL), and extracted with ethyl acetate (2×100 mL, 2×50 mL, and 2×30 mL). The extract is washed (brine), dried, and concentrated at reduced pressure. The residue is suspended in ethyl acetate (20 mL), heated, then cooled, and filtered to give 1.92 g (95%) of 3 as a white solid, mp 203-205° C. IR 3314, 2918, 1652, 1241 cm−1; 1H NMR (CDCl3) δ 2.60 (s, 3H, CH3), 4.01 (s, 3H, CH3O), 7.42 (dd, J=9.0, 2.7 Hz, 1H, 6-PhthH), 7.75 (d, J=9.0 Hz, 1H, 5-PhthH), 7.88 (d, J=2.7 Hz, 1H, 8-PhthH), 10.75 ppm (s, 1H, NH).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C@H:8]2[NH2:11])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24]([Cl:31])[N:23]=1>>[Cl:31][C:24]1[N:23]=[C:22]([NH:11][C@H:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=3)[CH2:6][CH2:7]2)[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=1
Reactant: N[C@@H]1CCc2ccc(F)cc21
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Cl)nc1N[C@@H]1CCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
Purge a 12 L 3-necked flask with nitrogen, and then assemble thermocouple, heating mantle and condenser. Charge (1R)-6-fluoro-2,3-dihydro-1H-inden-1-amine (386 g, 2.55 mol) to the flask, add 3A-EtOH (3.9 L), diisopropylethylamine (1.34 L, 7.68 mol), and 2,6-dichloro-3-nitropyridine (643 g, 3.07 moles). Stir the reaction mixture at ambient temperature for eight hours followed by heating to 70° C. for 12 hours. Cool the reaction mixture to 8° C. over 1.25 h, then filter onto a polypropylene pad. Wash the solids with 3A-EtOH (760 mL), transfer to a tared dish and further dry in a vacuum oven (45° C.) to afford the title compound as an orange solid (786 g, 71%, 98.0% ee). GC/MS (m/z): 307 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[OH:43][CH2:44][CH:45]([CH2:48]O)[CH2:46][OH:47].[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH2:48][CH:45]([CH2:46][OH:47])[CH2:44][OH:43])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: OCC(CO)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C(=O)OCC(CO)CO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 50.1 %

Procedure:
In a manner similar to the method described in Example 7, chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (100.2 mg, 0.163 mmol) was reacted with N,N′-carbonyldiimidazole (Aldrich, 69.5 mg, 0.416 mmol) and then, a mixture of 2-(hydroxymethyl)-1,3-propanediol (Aldrich, 91.8 mg, 0.839 mmol) and sodium hydride (41.6 mg, 1.65 mmol) in tetrahydrofuran to give chiral 3-hydroxy-2-(hydroxymethyl)propyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white lyophilized solid (57.5 mg, 50% yield). MS (ES+) m/z calcd. for C35H38Cl2F2N3O6: [(M+H)+]: 704. found: 704.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]2[CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[C:12](=[O:13])[C:3]=12.[NH:26]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27]1>>[CH3:9][N:6]1[C:7](=[O:8])[C:2]([C:29]2[CH:30]=[N:26][NH:27][CH:28]=2)=[C:3]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH2:10][C:4]2=[CH:5]1
Reactant: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Reactant: OB(O)c1cn[nH]c1
Product: Cn1cc2c(c(-c3cn[nH]c3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2

Procedure:
The title compound was prepared in analogy to the process of Example 13 starting from 7-chloro-5-methyl-2-(2-quinolin-2-yl-ethyl)-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (see Example c4)) and 1H-pyrazol-4-ylboronic acid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1([C:12]([O:14]C)=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=1>O1CCCC1.C1OCCOCCOCCOCCOCCOC1>[CH:7]1([C:12](=[O:14])[CH2:25][C:24]([C:21]2[CH:22]=[CH:23][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:19][CH:20]=2)=[O:26])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COC(=O)C1CCCC1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C1CCCC1)c1ccc(C(F)(F)F)cc1
Yield: 66.3 %

Procedure:
1.97 kg of potassium tert-butoxide, 2.26 kg of methyl cyclopentanecarboxylate, 1.66 kg of p-trifluoromethylacetophenone and 36 g of 18-crown-6 ether were refluxed in 18 litres of tetrahydrofuran for 4 hours. Quenching of the reaction was carried out using 16 litres of 10% strength hydrochloric acid at room temperature. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with saturated sodium chloride solution. After distilling off the solvent, the residue was distilled in an oil-pump vacuum at 1.5 mbar. 1.664 kg of 1-cyclopentyl-3-(4-trifluoromethylphenyl)propane-1,3-dione resulted as an oil, which crystallized completely on allowing to stand.