Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.Br[C:6]1[C:11]([Br:12])=[C:10]([O:13][CH3:14])[C:9]([Br:15])=[CH:8][C:7]=1[NH:16][C:17]([NH:19]C(=O)OCC)=[S:18].C(=O)([O-])[O-].[K+].[K+]>O>[Br:15][C:9]1[C:10]([O:13][CH3:14])=[C:11]([Br:12])[C:6]2[S:18][C:17]([NH2:19])=[N:16][C:7]=2[CH:8]=1
Reactant: CCOC(=O)NC(=S)Nc1cc(Br)c(OC)c(Br)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1c(Br)cc2nc(N)sc2c1Br
Temperature: 90 °C

Procedure:
Anhydrous DMSO (2 mL) was added to a mixture of ethyl N-[(2,3,5-tribromo-4-methoxy-phenyl)carbamothioyl]carbamate (426 mg, 1.02 mmol), CuO (8 mg, 0.10 mmol) and potassium carbonate (211 mg, 1.53 mmol). The mixture was sonicated then heated to 90° C. in a pre-heated heating block under air. The mixture was cooled to rt after 55 minutes and diluted with water. The mixture was extracted into EtOAc (3×50 mL) and the combined organic layers were washed with water then brine. The organic layer was dried over Na2SO4 and the mixture filtered through a PTFE filter to remove copper salts, then the filtrate was concentrated to dryness under reduced pressure. The desired compound was obtained as an off-white solid, 208 mg (60% over 2 steps). m/z: 337.01/339.01/340.97 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.ClC[C:28]1[N:32]=[CH:31][O:30][N:29]=1>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:28]1[N:32]=[CH:31][O:30][N:29]=1
Reactant: ClCc1ncon1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Product: Cl
Product: Clc1ccc2c(c1SCc1ncon1)CCNCC2

Procedure:
Use a method similar to the Preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 3-chloromethyl-1,2,4-oxadiazole to give, after deprotection using a method similar to the General Procedure 1-4, the title compound as a white solid. MS (ES+) m/z 296 (M+H)+.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:28])[NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH:21]([C:18]1[CH:17]=[CH:16][C:15]([CH:12]2[C:11]3[C:24]([CH3:25])=[C:7]([NH:6][C:5]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:28])[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]=3[O:14][CH2:13]2)=[CH:20][CH:19]=1)([CH3:22])[CH3:23]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Reactant: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)N1CCCC1)C(c1ccc(C(C)C)cc1)CO2
Temperature: 50 °C
Yield: 44.2 %

Procedure:
To a solution of 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate (353 mg, 0.75 mmol) obtained in Example 138 and pyrrolidine (0.076 mL, 0.9 mmol) in dimethylsulfoxide (5 mL) was added diisopropylethylamine (0.13 mL, 0.75 mmol) at room temperature, and the resulting mixture was heated at 50° C. and reacted for 16 hours. The reaction solution was cooled to room temperature and poured into water, and the product was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 130 mg (yield: 44%) of the title compound. Melting point: 186-188° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:44]=[CH:45][CH:46]=1)[CH2:12][C@@H:13]1[C@@H:17](/[CH:18]=[CH:19]/[C@@H:20]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:16]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:15][C@@H:14]1[CH2:42][OH:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:54]1([CH3:64])[CH:59]=[CH:58][C:57]([S:60](Cl)(=[O:62])=[O:61])=[CH:56][CH:55]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:64][C:54]1[CH:59]=[CH:58][C:57]([S:60]([O:43][CH2:42][C@H:14]2[CH2:15][C@@H:16]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C@H:17](/[CH:18]=[CH:19]/[C@@H:20]([O:26][Si:27]([C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:28])[CH3:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:13]2[CH2:12][C:11]2[CH:44]=[CH:45][CH:46]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)(=[O:62])=[O:61])=[CH:56][CH:55]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](Cc2cccc(OCc3ccccc3)c2)[C@@H](CO)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](Cc2cccc(OCc3ccccc3)c2)[C@@H](COS(=O)(=O)c2ccc(C)cc2)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution of ((1S,2S,3R,4R)-2-(3-(benzyloxy)benzyl)-4-(ter-butyldimethylsilyoxy)-3-((S,E)-3-(tert-butyldimethylsilyoxy)oct-1-enyl)cyclopentyl)methanol (15 g, 0.023 mol) in dry CH2Cl2 (500 ml) was cooled to 0° C. under nitrogen and treated with triethylamine (9.6 ml, 0.068 mol), then with p-Toluenesulfonic chloride (8.77 g, 0.046 mol). The mixture was poured to saturated sodium bicarbonate aqueous and stirred for 30 minutes. The reaction mixture was phase separated and the aqueous layer was extracted with 500 ml ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. Yield: 85%.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[NH:23][N:22]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[N:20]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([C:21]2[N:20]=[C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][O:11][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[NH:23][N:22]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: COc1cccc(-c2n[nH]c(-c3ccccc3CO)n2)c1
Reactant: CCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCC(=O)OCc1ccccc1-c1nc(-c2cccc(OC)c2)n[nH]1
Temperature: 50 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
A solution of octanoyl chloride (4.25 ml, 25 mmole) in dioxane (10 ml) is added dropwise during ten minutes into a stirred suspension of 5-(2-hydroxymethylphenyl)-3-(3-methoxyphenyl)-1H-1,2,4-triazole (2.81 g, 10 mmole) and triethylamine (4.2 ml, 30 mmole) in dioxane (50 ml). After 1 hour, 8% NaHCO3 (50 ml) is added and the reaction mixture is heated to 50° C. for two hours, cooled to room temperature, diluted with water (60 ml) and extracted with methylene chloride. The organic extracts are washed with water, dried over Na2SO4 and concentrated to dryness yielding a raw residue which is purified by silica-gel column chromatography eluting with a mixture 0% to 10% ethyl acetate in toluene and crystallized from isopropyl ether/petroleum ether. Yield: 56.5%. M.p. 61° C. and 87° C. (as a mixture of crystal forms).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.C(O[C:26]1([CH:38]=[CH:37][CH:36]=[CH:35][CH2:34]1)[CH:27]=[N:28][C:29](=O)[CH2:30][CH2:31][CH3:32])C>C(Cl)(Cl)Cl>[CH3:10][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:29]([CH2:30][CH2:31][CH3:32])=[N:28][C:27]([C:26]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[N:9]1
Reactant: CCCC(=O)N=CC1(OCC)C=CC=CC1
Reactant: Cc1ccccc1NN
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCc1nc(-c2ccccc2)nn1-c1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
Next, 8.1 g of o-tolyl hydrazine hydrochloride and 100 mL of carbon tetrachloride were put into a 500-mL three-neck flask, 7.8 g of triethylamine (Et3N) was added dropwise to this mixture little by little, and the mixture was stirred at room temperature for 1 hour. After a predetermined time elapsed, 11 g of N-(1-ethoxybenzylidene)butyramide obtained in Step 1 was added to the mixture, and the mixture was stirred at room temperature for 24 hours. After the stirring, the mixture was dissolved in chloroform and washed with water and saturated saline. After the washing, anhydrous magnesium sulfate was added to the organic layer for drying. This mixture was gravity-filtered, and the obtained filtrate was concentrated to give an oily substance. This oily substance was purified by silica gel column chromatography. As the developing solvent, a mixed solvent of dichloromethane and ethyl acetate in a ratio of 24:1 (v/v) was used. The obtained fraction was concentrated, so that 1-(2-methylphenyl)-3-phenyl-5-propyl-1H-1,2,4-triazole (abbreviation: HPrp3tz1-mp) was obtained (a red oily substance, 45% yield). The synthesis scheme of Step 2 is shown in (A-2) below.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][CH3:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)cc2)on1
Product: COc1ccccc1-c1ccc(S(=O)(=O)Nc2cc(C)no2)cc1
Yield: 81 %

Procedure:
N-(3-methyl-5-isoxazolyl)-4-(2-methoxyphenyl)benzenesulfonamide was prepared in the same manner as described in Example 14 using N-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide and 2-methoxybenzeneboronic acid resulting in an 81% yield of the final product.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.Cl[CH2:9][CH2:10][CH:11]1[CH2:17][N:16]([CH3:18])[C:15](=[O:19])[C:14]2[CH:20]=[CH:21][CH:22]=[N:23][C:13]=2[O:12]1>CN(C)C=O>[CH3:18][N:16]1[C:15](=[O:19])[C:14]2[CH:20]=[CH:21][CH:22]=[N:23][C:13]=2[O:12][CH:11]([CH2:10][CH2:9][N:3]2[CH:7]=[CH:6][CH:5]=[N:4]2)[CH2:17]1
Reactant: c1cn[nH]c1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC(CCn2cccn2)Oc2ncccc2C1=O
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (1.2 g active, 0.05 mole) in dimethylformamide (15 ml) was added dropwise a solution of pyrazole (3.10 g, 0.045 mole) in dimethylformamide (15 ml). The resulting solution was then added to a solution of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-one (9.12 g, 0.038 mole) in 30 ml of dimethylformamide. The flask was sealed and stirred overnight. Because the reaction had not yet gone to completion at this point, pyrazole (3.12 g, 0.045 mole) was added to the reaction solution and stirred overnight. The reaction was still not complete and another suspension of sodium hydride (0.5 g active, 0.021 mole) and pyrazole (1.5 g, 0.022 mole) in dimethylformamide (10 ml) was added and the reaction stirred overnight. The reaction appeared to be complete. Dimethylformamide was removed by rotary evaporation (80° C., vacuum pump), and the residue taken up in chloroform (100 ml) which was washed with dilute aqueous sodium hydroxide (1×50 ml), dried over anhydrous sodium sulfate and concentrated by rotary evaporation (70° C., water aspirator). The material was purified by high pressure liquid chromatography, 95:5 by volume ethanol:methanol on a silica gel column. The fractions containing the desired product were concentrated by rotary evaporation (70° C., water aspirator). Crystallization ensued upon cooling. The crystals were collected and recrystallized from ethanol. The yield was 1.5 (14.5%), m.p. 132°-134° C.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>CN(C)C=O>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:39][CH:36]3[CH2:38][CH2:37]3)[C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCCC2)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC1CC1)N1CCC(N2CCCCC2)CC1
Yield: 91 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 168), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a colorless solid (91%).
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:15])NC2C([C:13]=1[OH:14])=CC=CC=2)([O-:3])=[O:2].[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[NH2:20].C(OCC)(=O)CC(OCC)=O>>[Cl:16][C:17]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:19]2[C:18]=1[C:5]([OH:15])=[CH:4][C:13]([OH:14])=[N:20]2.[Cl:16][C:17]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:19]2[C:18]=1[C:5]([OH:15])=[C:4]([N+:1]([O-:3])=[O:2])[C:13](=[O:14])[NH:20]2
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=c1[nH]c2ccccc2c(O)c1[N+](=O)[O-]
Solvent: CCOC(=O)CC(=O)OCC
Product: O=c1[nH]c2cc(Cl)cc(Cl)c2c(O)c1[N+](=O)[O-]
Product: Oc1cc(O)c2c(Cl)cc(Cl)cc2n1

Procedure:
3-Nitro-4-hydroxy-1,2-dihydroquinolin-2-one 16a (Buckle, D. R., et al., J. Med. Chem. 18:726-732 (1975)) was prepared by nitration of 2,4-dihydroxyquinolin 15a (Scheme I, eq 6). Compound 16a was found to have a Ki value of 18 μM with a potency of 1.4% of 5,7-dichlorokynurenic acid (DCK). Further nitration of 16a gave mono-nitro subtituted compound 16b, which was found to be about as active as 16a. 5,7-Dichloro-2,4-dihydroxyquinoline 15c was prepared by reaction of 3,5-dichloroaniline with diethyl malonate followed by basic hydrolysis and cyclization in polyphosphoric acid (PPA) (eq 7). Patel, G. H., et al., J. Sci. Industr. Res. 19B:436-438 (1960). Nitration of 15c gave 5,7-dichloro-3-nitro-4-hydroxy-1,2-dihydroquinolin-2-one 16c which was found to have a Ki value of 1.4 μM with a potency of 19% of DCK. The binding ability of these nitro compounds to glycine/NMDA receptor is very similar to quinoxalinedione (QX) compounds (QX 2% of DCK, 5,7-dichloro-QX, 20% of QX). Thus, the series of 3-nitro-4-hydroxy-1,2-dihydroquinolin-2-ones provides some promising antagonists which bind to the glycine/NMDA receptor. ##STR15##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][CH:17]([OH:26])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(C)C>C(O)CCC>[O:19]([CH2:18][CH:17]([OH:26])[CH2:16][CH2:15][N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: OC(CCCl)COc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCCCO
Product: OC(CCN1CCN(c2ccc(F)cc2)CC1)COc1ccccc1

Procedure:
This compound was prepared according to the procedure of Example 6. A mixture of 3.6 g (0.02 mole) of 1-(4-fluorophenyl)piperazine, 4.0 g (0.02 mole) of 4-chloro-1-phenoxy 2-butanol and 5.3 g (0.05 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 5.1 g (74%) of offwhite powder, m.p. 97°-99° C. Recrystallizing solvent used was isopropyl alcohol.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:10](=O)([O-])[O-].[K+].[K+].N1[C:21]2[CH:22]=[CH:23][CH:24]=[N:25][C:20]=2[CH2:19]NC1>CN(C=O)C>[N:4]1([C:3]2[C:22]3[C:23](=[CH:10][CH:19]=[CH:20][CH:21]=3)[CH:24]=[N:25][CH:2]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: ClCCN1CCNCC1
Reactant: c1cnc2c(c1)NCNC2
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2c(N3CCNCC3)cncc2c1
Yield: 187.5 %

Procedure:
2.9 g (10 mmol) of chloroethylpiperazine and 2.8 g (20 mmol) of potassium carbonate were added to a solution of 2.4 g (10 mmol) of tetrahydropyridopyrimidine in 40 ml of DMF. After reaction at 90° C. for two hours, and then poured onto ice-water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over sodium sulfate, and the solvent was removed under reduced pressure. The oil that remained was taken up in acetone, and the hydrochloride was precipitated out using isopropanol/HCI. This gave 4 g (75%) of the product were obtained (melting point 205° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18](Cl)=[N:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:10].[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:29][CH2:28][C:25]2[CH:26]=[N:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[N:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(CO)cn1
Reactant: O=S(=O)(Nc1nccnc1Cl)c1cccc(Cl)c1Cl
Product: COc1ccc(COc2nccnc2NS(=O)(=O)c2cccc(Cl)c2Cl)cn1

Procedure:
Prepared by the method of Example 28b using 2,3-dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (Example 28a) (0.338 g) and (6-methoxy-3-pyridinyl)methanol (0.21 g). Yield 0.23 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[N:15]2[CH3:18])=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:10]=1.[C:36](O)(=O)[CH3:37]>>[CH3:18][N:15]1[C:14]([CH2:19][N:20]2[CH2:21][CH2:22][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:24][CH2:25]2)=[N:13][C:12]2[C:16]1=[N:17][C:9]([N:8]1[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=[C:36]1[CH3:37])=[N:10][C:11]=2[N:30]1[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1
Reactant: CC(=O)O
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Yield: 21.1 %

Procedure:
A mixture of 2-(1-((2-(2-aminophenylamino)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (177 mg, 0.368 mmol) in acetic acid (1.5 mL) was stirred at reflux for 5 hours. The reaction mixture was then concentrated and then purified first by flash chromatography (10% MeOH in DCM containing 1% 2 M ammonia in MeOH), followed by RP-HPLC to give 157 (0.0373 g, 21.1%). LCMS: M+H+=505.3. 1H-NMR (400 MHz, DMSO-d6): δ 8.09 (m, 1H), 7.60 (m, 1H), 7.25 (m, 2H), 4.26 (s, br, 4H), 4.02 (s, 1H), 3.83 (s, 3H), 3.78 (m, 4H), 3.73 (s, 2H), 2.90 (m, 2H), 2.84 (s, 3H), 1.99 (m, 2H), 1.66 (m, 2H), 1.21 (m, 3H), 1.02 (s, 6H).
Reaction SMILES: C(=O)(OCC(Cl)(Cl)Cl)N.C(=O)([O-])OCC(Cl)(Cl)Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:32][CH:31]3[N:33](C(OCC(Cl)(Cl)Cl)=O)[CH:28]([CH2:29][CH2:30]3)[CH:27]2[O:42]C(OCC(Cl)(Cl)Cl)=O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]2[CH2:32][CH:31]3[NH:33][CH:28]([CH2:29][CH2:30]3)[CH:27]2[OH:42])=[CH:24][CH:25]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)OC1C(c2ccc(F)cc2)CC2CCC1N2C(=O)OCC(Cl)(Cl)Cl
Agent: NC(=O)OCC(Cl)(Cl)Cl
Agent: O=C([O-])OCC(Cl)(Cl)Cl
Product: OC1C2CCC(CC1c1ccc(F)cc1)N2

Procedure:
By cleavage of the 2,2,2-trichloroethyl carbamate and 2,2,2-trichloroethyl carbonate from 2,2,2-trichloro-ethyl (1RS,2RS,3RS,5RS)-3-(4-fluoro-phenyl)-2-(2,2,2-trichloro-ethoxy-carbonyloxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate in an analogous manner to that described in Example 12(d) there was obtained (1RS,2RS,3RS,5RS)-3-(4-fluoro-phenyl)-8-aza-bicyclo[3.2.1]octan-2-ol as a colourless solid; MS: 221 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N+:12]([O-:15])([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:10]=[C:9]([N+:12]([O-:14])=[O:13])[C:8]2[C:4](=[CH:5][C:6](=[O:11])[N:7]=2)[CH:3]=1.[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:12]([O-:15])=[O:13])[CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2
Reactant: O=[N+]([O-])O
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: O=S(=O)(O)O
Product: O=C1C=c2cc(F)cc([N+](=O)[O-])c2=N1
Product: O=C1Cc2cc(F)cc([N+](=O)[O-])c2N1
Temperature: -5 °C
Yield: 62.5 %

Procedure:
5-Fluoro-1,3-dihydro-indol-2-one 4a (5.0 g, 33 mmol) was dissolved in sulfuric acid (17.6 ml, 98%) under stirring at −5° C., and nitric acid (2.1 ml, 65%-68%) was added to the solution while maintaining the temperature below 0° C. Upon completion of the addition, the mixture was stirred at room temperature for 1 hour. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was poured into ice water and filtered after ice-out. The filter cake was washed with water for three times, and the resulting solid was recrystallized to obtain the title compound 5-fluoro-7-nitro-1,3-dihydro-indol-2-one 20a (4.0 g, yield 62.5%) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11](I)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH2:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][C:35]#[CH:36])[CH2:28][CH2:27]1)[CH3:25]>>[Cl:1][C:2]1[C:3]2[C:11]([C:36]#[C:35][CH2:34][CH2:33][CH2:32][N:29]3[CH2:28][CH2:27][N:26]([CH2:24][CH3:25])[CH2:31][CH2:30]3)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(N)nc32)c1C
Reactant: C#CCCCN1CCN(CC)CC1
Product: CCN1CCN(CCCC#Cc2cn(Cc3ncc(C)c(OC)c3C)c3nc(N)nc(Cl)c23)CC1

Procedure:
Sonogashira coupling of 4-chloro-5-iodo-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine with 1-ethyl-4-(pent-4-ynyl)piperazine, according to the general procedure A gave the title compound, as a solid. Mp=142.3-144.1° C. HPLC Rt=4.11 min.
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:9])=[CH:6][CH:5]=1)(=O)[CH3:2].[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[CH2:11]([NH:10][C:8](=[O:9])[C:7]1[CH:23]=[CH:24][C:4]([CH:1]([NH:32][CH2:31][C:30]2[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:35])[F:36])=[CH:34][CH:33]=2)[CH3:2])=[CH:5][CH:6]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(C(C)=O)cc1
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: CCCCCCCCCCCCNC(=O)c1ccc(C(C)NCc2ccc(C(F)(F)F)cc2)cc1
Yield: 71 %

Procedure:
The same procedure as employed in the preparation of Example 223 (step b) but using 4-acetyl-N-dodecylbenzamide and 4-(trifluoromethyl)benzylamine gave the title compound as a colorless oil (71%). M−(LC/MS(ESI)): 489.1; M+(LC/MS(ESI)): 491.5. HPLC (Condition A), Rt: 5.51 min (HPLC purity: 50.0%).