Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([O:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH2:32]([O:34][C:35](=[O:38])[CH:36]=[O:37])[CH3:33]>C1COCC1>[CH2:32]([O:34][C:35](=[O:38])[CH:36]([C:22]1[C:23]([F:25])=[CH:24][C:19]([O:18][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:20][C:21]=1[F:26])[OH:37])[CH3:33]
Reactant: CC(C)(C)[Si](Oc1cc(F)cc(F)c1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1c(F)cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 109.2 %

Procedure:
A well stirred solution under N2 of tert-butyl-(3,5-difluoro-phenoxy)-diphenyl-silane (20.0 g) and N,N,N′,N′-pentamethyldiethylenetriamine (9.9 g) in dry THF (600 ml) was cooled to −75° C. A 1.6 M sol. of BuLi in Hex (35.6 ml) was added via syringe. The reaction mixture was stirred 1 h under cooling (−78° C.). A white precipitate was formed. Glyoxalic acid ethyl ester (50% in Tol, 22.2 g) was added and it was stirred 2 h at −78° C. The cooling bath was removed and the clear solution was left to warm to −10° C. (1 h). After dilution with TBME (500 ml) the mixture was washed with 1 N HCl (2×500 ml) and brine (250 ml), dried over MgSO4 and the solvent was evaporated. The crude product was purified by CC (Hept, then Hept/CH2Cl2 1:4). 27.9 g (60%) of (RS)-[4-(tert-butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-hydroxy-acetic acid ethyl ester were obtained next to 7.3 g (36%) of recovered starting material. Colorless viscous oil. MS 488.4 ([M+NH4]+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:17])([CH3:16])[C:13](O)=[O:14])=[CH:8][CH:7]=1.C[N:19](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:17])([CH3:16])[C:13]([NH2:19])=[O:14])=[CH:8][CH:7]=1
Reactant: CC(C)(C(=O)O)c1ccc(-c2ccco2)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C(N)=O)c1ccc(-c2ccco2)cc1
Reaction time: 2.5 h

Procedure:
To a solution of 2-(4-(furan-2-yl)-phenyl)-2-methyl-propionic Acid (reference example 28) (115 mg, 0.5 mmol) in CH2Cl2 (3 mL) is added DMF (10 mL) followed by oxalyl chloride (0.3 mL, 2M in CH2Cl2). The resulting solution is stirred for 2.5 hours then concentrated. The residue is taken up in methanolic ammonia (7N) and stirred for 14.5 hours, then concentrated to give 124 mg of the title compound as a tan solid. 1H NMR (CDCl3) d 1.58 (s, 6H), 5.2 (bs, 1H), 5.3 (bs, 1H), 6.45 (dd, J=3, 1 Hz, 1H), 6.63 (m, 1H), 7.39 (m, 2H), 7.45 (bs, 1H), 7.65 (m, 2H). MS (EI), m/z 229 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11](N)[CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].[F:17][B-](F)(F)F.N#[O+]>ClC1C=CC=CC=1Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:17])[CH:12]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2cc(N)ccc2c1
Reactant: F[B-](F)(F)F
Agent: N#[O+]
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1ccc2cc(F)ccc2c1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of 6-amino-2-naphthoic acid ethyl ester (500 mg, 2.32 mmol) and nitrosonium tetrafluoroborate (298 mg, 2.56 mmol) in 1,2-dichlorobenzene (10 mL) is stirred at room temperature for 12 hours and at 110° C. for 1 hour. After cooling to room temperature, the reaction mixture is concentrated by rotary evaporator under high vacuum. The residual oil is purified by flash chromatography on silica gel (dichloromethane) to give 6-fluoro-2-naphthoic acid ethyl ester as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]([CH:24]=[O:25])=[C:4](O)[CH:3]=1)=[O:9].[C:27](O)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([C:4]1[CH:3]=[C:2]([CH3:1])[C:7]2[C:8](=[O:9])[O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]=1[CH:24]=[O:25])(=[O:29])[CH3:28]
Reactant: CC(=O)O
Reactant: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=O)c1O2
Solvent: c1ccncc1
Product: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(C(C)=O)c(C=O)c1O2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Psoromic acid (1 mmol) was dissolved in pyridine (2 ml) and glacial acetic acid (1 ml). The reaction was stirred for 14 hours at room temperature. Most of the solvent was removed by rotatory evaporation. The residue was taken up in methylene chloride, washed with water and saturated brine, dried with anhydrous MgSO4, evaporated by a rotatory evaporator and purified by column chromatography.
Reaction SMILES: [S:1]([N:11]1[CH2:13][CH:12]1[CH2:14][C:15]1([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[NH3:22]>CO>[NH2:22][CH2:13][CH:12]([NH:11][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])[CH2:14][C:15]1([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)N2CC2CC2(O)CCCCC2)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(CN)CC2(O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-((1-tosylaziridin-2-yl)methyl)cyclohexanol (107 mg, 0.346 mmol) in MeOH (2 mL) was added satd aq ammonia (2 mL). The resulting solution was stirred at rt for 4 h and concentrated to give 1-(3-amino-2-(tosylamino)propyl)cyclohexanol which was used for the next step without purification. MS m/z 327 (M+H+).
Reaction SMILES: N[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[F:12][B-](F)(F)F.[H+].N([O-])=O.[Na+].[OH-].[Na+]>O>[F:12][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Fc1nc(Cl)c2[nH]cnc2n1
Reaction time: 0.33 h
Yield: 52 %

Procedure:
To 2-amino-6-chloropurine (5.0 g, 29.5 mmol) in a solution of tetrafluoroboric acid in water (100 mL) at −15° C. was added dropwise sodium nitrite (3.5 g, 50 mmol) in water (160 mL) over a period of 1.5 h. After 20 min at room temperature, the pH of the solution was adjusted to 6 with 50% aqueous sodium hydroxide. The solution was concentrated under reduced pressure. The crude residue was purified on a BIOTAGE™ 40S column (silica, CH2Cl2/MeOH 9:1) to give 2-fluoro-6-chloropurine (2.3 g, 52%). This compound (1.5 g, 8.6 mmol) was suspended in dry tetrahydrofuran (20 mL) at 25° C. The 4-(N-1-tert-butyloxycarbonyl)-aminophenethyl alcohol (3.4 g, 14.5 mmol) and triphenylphosphine (3.8 g, 14.5 mmol) were then added, and the mixture evaporated to dryness. Dry tetrahydrofuran (20 mL) was added and the suspension was cooled to 0° C. before dropwise addition of diethylazodicarboxylate (1.5 mL, 9.8 mmol). After 16 h reaction at room temperature, the solution was concentrated under reduced pressure. The crude residue was purified on a BIOTAGE™ 25M column (silica, hexane/AcOEt 95:5 to 75:25) to yield N-9 alkylated purine as a white solid (2.9 g, 87%). To a solution of alkylated 2-fluoro-6-chloropurine (3.0 g, 7.7 mmol) in n-butanol (15 mL) at 25° C. was added N-1-tert-butyloxycarbonyl-1,3-phenylenediamine (1.8 g, 8.8 mmol) and diisopropylethylamine (2.7 mL, 15.3 mmol). After 48 h reaction at 65° C., the brown solution was concentrated under reduced pressure. The crude residue was purified on a BIOTAGE™ 40M column (silica, hexane/AcOEt 65:45 to 0:1) to yield the fluoropurine derivative as a brown solid (2.8 g, 63%). To a solution of this product (2.8 g, 4.9 mmol) in n-butanol (15 mL) at room temperature was added aminomethylcyclopropane (1.2 g, 17.1 mmol) and diisopropylethylamine (1.7 mL, 9.8 mmol). After 48 h reaction at 110° C., the brown solution was concentrated under reduced pressure. The crude residue was purified on a BIOTAGE™ 40M column (silica, hexane/AcOEt 60:40 to AcOEt/MeOH 98:2) to yield the protected trisubstituted purine as a white solid (2.3 g, 73%). To a solution of this compound (2.08 g, 3.38 mmol) in dichloromethane (10 mL) at room temperature was added 4N HCl in dioxane (10 mL). The reaction was stirred for 5 h at 25° C. and the solution was concentrated under reduced pressure. The solid was then dried for 16 h under vacuum to yield compound 3 as a brown solid. Yield of product: 1.4 g (quantitative); Rf=0.1 (CH2Cl2/MeOH 98:2); 1H NMR (400 MHz, CD3OD): δ 8.24 (s, 1H), 8.20-7.60 (m, 2H), 7.60-7.00 (m, 6H), 4.56 (t, 2H, J=7.0 Hz), 3.40-3.20 (m, 4H), 1.25-1.15 (m, 1H), 0.60-0.50 (m, 2H), 0.40-0.20 (m, 2H); LRMS (ESI): m/z 415 (MH+), 437 (M+Na); HPLC (method 2): 1.6 min.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([NH2:20])[CH:14]=1>>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][C:15]=2[NH2:20])=[O:9])=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(F)cc1N
Product: NCc1ccc(C(=O)Nc2ccc(F)cc2N)cc1
Yield: 35.9 %

Procedure:
The title compound (186 mg, 72% yield) was prepared as a brown solid from 4-cyano-benzoic acid (294 mg, 2 mmol) and 4-fluoro-o-phenylenediamine (302 mg, 2.4 mmol) by an analogous procedure to that described in example 8. LC-MS (m/z) 260 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].[F:13][C:14]1[CH:33]=[CH:32][C:17]([O:18][C:19]2[C:20]([C:29](O)=[O:30])=[N:21][C:22]3[C:27]([N:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:16]([O:34][CH3:35])[CH:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[OH-].[Li+]>CN(C=O)C>[F:13][C:14]1[CH:33]=[CH:32][C:17]([O:18][C:19]2[C:20]([C:29]([NH:1][C:2]3[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=3)[C:5]([OH:7])=[O:6])=[O:30])=[N:21][C:22]3[C:27]([N:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:16]([O:34][CH3:35])[CH:15]=1
Reactant: COc1cc(F)ccc1Oc1nc2ccccc2nc1C(=O)O
Reactant: CCOC(=O)c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1Oc1nc2ccccc2nc1C(=O)Nc1cccc(C(=O)O)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
To ethyl 3-aminobenzoate (18.9 mg, 0.11 mmol) in DMF (0.3 mL) was added 3-(4-fluoro-2-methoxy-phenoxy)quinoxaline-2-carboxylic acid (30 mg, 0.09 mmol), HATU (54.4 mg, 0.14 mmol) and Et3N (39.9 μL, 0.29 mmol). The reaction is stirred at 50° C. for 2 hours. Lithium hydroxide (45 μL of 4M, 0.18 mmol) was added and the reaction was stirred at 25° C. overnight. The reaction was filtered and purified by reverse phase HPLC using a gradient of methanol in water (1-99%) and ammonium formate as a modifier to yield 3-(3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamido)benzoic acid (36) (16.4 mg, 42%). ESI-MS m/z calc. 433.11, found 434.0 (M+1)+; Retention time: 1.56 minutes (2.5 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.39 (t, J=1.9 Hz, 1H), 8.18 (dd, J=8.0, 1.6 Hz, 1H), 7.99-7.92 (m, 1H), 7.87-7.68 (m, 4H), 7.48 (t, J=7.9 Hz, 1H), 7.35 (dd, J=8.8, 5.9 Hz, 1H), 7.16 (dd, J=10.7, 2.9 Hz, 1H), 6.88 (td, J=8.5, 2.9 Hz, 1H), 3.71 (s, 3H) ppm.
Reaction SMILES: Br[C:2]1[C:3]([F:24])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:19]([F:22])([F:21])[F:20])=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:23]=1.[CH3:25][C:26]1[O:30][N:29]=[C:28]([C@:31]([OH:35])([C:33]#[CH:34])[CH3:32])[CH:27]=1>>[F:24][C:3]1[C:2]([C:34]#[C:33][C@@:31]([OH:35])([C:28]2[CH:27]=[C:26]([CH3:25])[O:30][N:29]=2)[CH3:32])=[CH:23][C:6]2[C:7]3[N:8]([C:13]([C:19]([F:20])([F:22])[F:21])=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=3)[CH:9]3[CH2:12][CH:11]([C:5]=2[CH:4]=1)[CH2:10]3
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: NC(=O)c1nc2n(c1C(F)(F)F)C1CC(C1)c1cc(F)c(Br)cc1-2
Product: Cc1cc([C@](C)(O)C#Cc2cc3c(cc2F)C2CC(C2)n2c-3nc(C(N)=O)c2C(F)(F)F)no1
Yield: 46 %

Procedure:
10-bromo-9-fluoro-3-(trifluoromethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol via General Procedure E to afford 38 mg (46%) of (R)-9-fluoro-10-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-3-(trifluoromethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:9][C:8]([CH3:10])=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])[NH:5]1)#[N:2].C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C)C=O.O1CCCC1>[C:1]([N:3]=[C:4]1[NH:9][C:8]([CH3:10])=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])[N:5]1[C:31]([O:33][CH2:34][CH3:35])=[O:32])#[N:2]
Reactant: COC(=O)C1=C(C)NC(=NC#N)NC1c1cccc(Cl)c1Cl
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1C(=NC#N)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.8 %

Procedure:
A suspension of 2-(cyanoimino)-6-(2,3-dichlorophenyl)-3,6-dihydro-4-methyl-5-pyrimidinecarboxylic acid, methyl ester (444 mg, 1.31 mmoles) in dry dimethylformamide (2 ml) and tetrahydrofuran (2 ml) was cooled to 0° C. and was treated with triethylamine (0.5 ml) followed by ethyl chloroformate (284 mg, 2.62 mmoles). After the addition of ethyl chloroformate, the reaction turned yellow. The cooling bath was removed and stirring was continued at room temperature for 3 hours. The reaction was then diluted with ethyl acetate and washed with water, 5% citric acid, sodium bicarbonate and brine. After drying over magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography (12% ethyl acetate in dichloromethane). The resulting product was crystallized from dichloromethane-isopropyl ether to provide 317 mg of the title compound as a colorless solid, melting point 176°-178° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[NH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH3:22][O:21][C:19]([C:18]1[CH:23]=[CH:24][C:15]([NH:14][S:2]([C:5]2[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=2)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])=[CH:16][CH:17]=1)=[O:20]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(=O)(=O)c2cccc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
A mixture of 2.00 g of 3-(chlorosulfonyl)benzoic acid, 1.37 g of methyl 4-aminobenzoate, and 20 mL of pyridine was stirred at room temperature overnight, and then the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 665 mg of 3-{[4-(methoxycarbonyl)phenyl]sulfamoyl}benzoic acid as a pink solid.
Reaction SMILES: [CH2:1]([N:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:20][CH2:21][CH2:22]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CS(Cl)(=O)=O.[CH2:47]([CH2:49][NH2:50])[OH:48]>C(Cl)(Cl)Cl>[OH:48][CH2:47][CH2:49][NH:50][CH2:22][CH2:21][CH2:20][N:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCO)CCCCCCCCCCCCCCCCCC
Reactant: NCCO
Agent: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)CCCNCCO

Procedure:
To a stirred solution of N,N-dioctadecyl-3-aminopropanol (1.16 g., 2 mM.) in chloroform (30 ml.) is added methanesulfonyl chloride (0.285 g., 2.5 mM.) and the mixture stirred for seventy-five minutes. Ethanolamine (1.22 g., 20 mM.) is added and the mixture refluxed for forty-five minutes, then cooled and diluted with chloroform (200 ml.). The chloroform solution is washed successively with aqueous sodium hydroxide (5 percent), water and saturated aqueous sodium chloride. It is then dried (Na2SO4) and concentrated to a waxy solid.
Reaction SMILES: [ClH:1].Cl.[Br:3][C:4]1[CH:5]=[C:6]([CH:12]([C:21]([CH2:25][CH3:26])([OH:24])[CH2:22][CH3:23])[CH2:13][N:14]2[CH2:19][CH2:18][N:17](C)[CH2:16][CH2:15]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].BrC1C=C(C(C(CC)(O)CC)C(N2CCN(C(OC(C)(C)C)=O)CC2)=O)C=CC=1OC.Cl>>[ClH:1].[ClH:1].[Br:3][C:4]1[CH:5]=[C:6]([CH:12]([C:21]([CH2:22][CH3:23])([OH:24])[CH2:25][CH3:26])[CH2:13][N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CCC(O)(CC)C(CN1CCN(C)CC1)c1ccc(OC)c(Br)c1
Agent: CCC(O)(CC)C(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c1ccc(OC)c(Br)c1
Agent: Cl
Product: CCC(O)(CC)C(CN1CCNCC1)c1ccc(OC)c(Br)c1

Procedure:
In an analogous manner to Example 1, step 2 2-(3-bromo-4-methoxyphenyl)-3-ethyl-1-(4-methylpiperazin-1-yl)pentan-3-ol dihydrochloride was prepared from tert-butyl 4-[2-(3-bromo-4-methoxyphenyl)-3-ethyl-3-hydroxypentanoyl]piperazine-1-carboxylate. MS m/z 385/387 ([M+H]+); HRMS: calcd for C18H29BrN2O.2.00 HCl, 456.0946; found (ESI), 385.1494.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:10].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+]>CN(C=O)C>[Cl:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:1]([CH2:6][C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]#[N:7]
Reactant: N#Cc1ccc(N)c(Cl)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 191.4 %

Procedure:
To a solution of 4-amino-3-chlorobenzonitrile (1.0 g, 6.56 mmol, 1 eq) and benzyl bromide (3.12 mL, 26.2 mmol, 4.0 eq) in dry DMF (10 mL) was added at rt NaH (1.31 g, 32.8 mmol, 5 eq) portionwise under Ar(g). The reaction mixture was stirred at rt overnight, and was subsequently partitioned with H2O (30 mL) and extracted with EtOAc (5×20 mL) and CH2Cl2 (20 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (1:0-9:1) to furnish 2 as a white solid (2.09 g, 96%).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([CH3:14])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)#[N:4].[C:15]([C:19]1[N:20]=[C:21]([C:24]2[O:25][C:26]3[CH:32]=[CH:31][C:30]([CH2:33]Cl)=[CH:29][C:27]=3[CH:28]=2)[S:22][CH:23]=1)([CH3:18])([CH3:17])[CH3:16].[I-].[K+].Cl>CN(C)C=O>[C:15]([C:19]1[N:20]=[C:21]([C:24]2[O:25][C:26]3[CH:32]=[CH:31][C:30]([CH2:33][N:7]4[C:8]5[C:13](=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=5)[C:5]([C:3]#[N:4])=[CH:6]4)=[CH:29][C:27]=3[CH:28]=2)[S:22][CH:23]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1csc(-c2cc3cc(CCl)ccc3o2)n1
Reactant: Cc1ccc2c(C#N)c[nH]c2c1
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ccc2c(C#N)cn(Cc3ccc4oc(-c5nc(C(C)(C)C)cs5)cc4c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.6 %

Procedure:
Sodium hydride (60% in mineral oil, 30 mg) was added into a solution of 3-cyano-6-methylindole (73 mg) in N,N-dimethylformamide (2 ml) at room temperature. After 30 minutes, 4-tert-butyl-2-[5-(chloromethyl)benzofuran-2-yl]thiazole (150 mg) and small amount of potassium iodide were added to the solution. After being stirred continuously for 3 hours, the resulting mixture was poured into ice-water and the mixture was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with a mixture of toluene and ethyl acetate. The fractions containing the objective compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-{5-[(3-cyano-6-methylindol-1-yl)methyl]benzofuran-2-yl}thiazole (0.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19]Br)[NH:12][C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1.Cl.[NH:27]1[CH2:32][CH2:31][O:30][CH:29]([C:33]([OH:35])=[O:34])[CH2:28]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[NH:12][C:13]([CH2:19][N:27]2[CH2:32][CH2:31][O:30][CH:29]([C:33]([OH:35])=[O:34])[CH2:28]2)=[C:14]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: O=C(O)C1CNCCO1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: COC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 40 %

Procedure:
Methyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.22 g, 2.5 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.5 g, 3 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.54 g, 40%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:13]1([C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)O)[OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]2([O:14][C:13]3[CH:15]=[CH:17][CH:18]=[CH:19][C:20]=3[O:12]2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: Oc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC2(CC1)Oc1ccccc1O2

Procedure:
A mixture of 1-ethoxycarbonyl-4-piperidinone (17 g), pyrocatechol (13 g) and p-toluenesulfonic acid (2.5 g) in 250 ml of dry toluene was refluxed with continuous removal of water. After 3 h the reaction mixture was concentrated in vacuo, 2% NaOH (200 ml) was added followed by extraction with dichloromethane. After drying over magnesium sulfate and removal of solvent in vacuo, the remaining red oil was applied to a silica gel column (eluent:ethyl acetate/heptane=1:1) giving 22 g of a slightly yellow oil, 1'-ethoxycarbonyl-spiro[1,3-benzodioxole-2,4'-piperidine]. The oil was dissolved in ethanol (250 ml), NaOH (10 g) and water (20 ml) were added and the mixture refluxed for 20 h. Removal of the solvents in vacuo addition of salt water followed by extraction with dichloromethane gave, after drying the organic phase over magnesium sulfate and removal of the solvent in vacuo, a red oil which was applied to a silica gel column (eluent:ethyl acetate/methanol/triethylamine =4:5:1 ) yielding 10 g of colorless crystals, spiro[1,3-benzodioxole-2,4'-piperidine], mp: 108°-10° C. The title compound, 25a, prepared from 4-phenyl-1-butyl methanesulfonate (2.3 g) and spiro[1,3-benzodioxole-2,4'-piperidine] (1.9 g) according to the method described in EXAMPLE 2, crystallized as the maleate salt from acetone by addition of maleic acid. Yield: 1.6 g, mp: 156°-57° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6](=[O:26])[N:7]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc([N+](=O)[O-])cc1)Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCc1ccc(N)cc1)Cc1ccccc1

Procedure:
Benzyl-[2-(4-nitro-phenyl)-ethyl]-carbamic acid tert-butyl ester (100 mmol) was dissolved in THF (20 ml) and hydrogenated under a pressure of one atmosphere overnight. The reaction mixture was filtered and washed with THF. The filtrate was concentrated to dryness and was used directly in the procedure for Example 1D.