Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][OH:2].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8]([CH:12]=1)[C:9](Cl)=[O:10]>ClCCl>[CH3:1][O:2][C:9](=[O:10])[C:8]1[CH:12]=[C:4]([Cl:3])[CH:5]=[CH:6][C:7]=1[F:13]
Reactant: CO
Reactant: O=C(Cl)c1cc(Cl)ccc1F
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Methanol (20 ml) was added to a solution 5-chloro-2-fluoro-benzoyl chloride (1.2 g, 6.2 mmol) in dichloromethane (10 ml) in an ice-bath. The reaction mixture was warmed to room temperature, stirred for 3 h and then concentrated to afford 5-chloro-2-fluoro-benzoic acid methyl ester (1.17 g, 100%). 1H NMR (CDCl3), δ (ppm): 7.93 (m, 1H), 7.48 (m, 1H), 7.12 (m, 1H), 3.96 (s, 3H). Step 2: 5-Chloro-2-fluoro-benzoic acid hydrazide: A mixture of 5-chloro-2-fluoro-benzoic acid methyl ester (1.17 g, 6.2 mmol) and hydrazine monohydrate (0.451 ml, 9.3 mmol) in ethanol (20 ml) was stirred at room temperature overnight. The reaction mixture was concentrated and then the residue was triturated with diethyl ether to afford 5-chloro-2-fluoro-benzoic acid hydrazide (497 mg, 42%, white solid). 1H NMR (DMSO), δ (ppm): 9.66 (bs, 1H), 7.58 (m, 2H), 7.36 (m, 1H), 4.58 (bs, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8]([Cl:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CCOCC.[CH2:17]1[CH2:22][O:21][CH:20]=[CH:19][CH2:18]1>C(Cl)Cl>[O:21]1[CH2:22][CH2:17][CH2:18][CH2:19][CH:20]1[O:1][C:2]1[CH:3]=[C:4]([S:8]([Cl:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(O)c1
Reactant: C1=COCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: O=S(=O)(Cl)c1cccc(OC2CCCCO2)c1

Procedure:
The synthesis of HIV protease inhibitor UIC-98-056 with hydroxyethylene and hydroxyethylamine isosteres is outlined in FIG. 3. The known lactone 1 was converted to acid 2 by lithium hydroxide mediated hydrolysis followed by protection of the alcohol functionality as tert-butyldimethylsilyl ether (Ghosh et al., 1998, Synthesis, 937 (Review); Ghosh et al., 1991, J. Org. Chem. 56:6500; Evens et al., 1985). The previously described (Ghosh et al., 1992, J. Chem. Soc., Chem. Co., 273; Ghosh et al., 1998, Synthesis, 937 (Review)) azido epoxide 3 was reacted with isobutylamine in 2-propanol at 80° C. for 4 h and the resulting azidoalcohol was treated with m-tetrahydropyranyloxybenzenesulfonyl chloride 4 (Metanilic acid was diazotized at 0° C. and the resulting salt was boiled with water to obtain 3-hydroxybenzene sulfonic acid which was then treated with thionyl chloride/catalytic DMF/reflux to obtain sulfonyl chloride. The hydroxy group of the resulting 3-hydroxybenzene sulfonyl chloride was protected as THP ether by treating with DHP/catalytic PPTS in methylene chloride to get 4 as an oil.) in the presence of aqueous NaHCO3 to provide the sulfonamide derivative 5. The azide functionality of 5 was hydrogenated over 10% Pd—C in methanol to afford the corresponding amine which was coupled with the acid 2 in the presence of 1-[3-dimethylaminopropyl]-3-ethylcarodiimide (EDC) and 1-hydroxybenzotriazole (HOBt) to afford the amide 6. Removal of the BOC group by treatment with aqueous hydrochloric acid and alkoxycarbonylation of the resulting amine with the known (Ghosh et al., 1993a) mixed active carbonate 7 in methylene chloride in the presence of 3 equivalents of triethylamine (Et3N) 23° C. for 12 h afforded the inhibitor 8 (UIC-98-056).
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][C:7]1[CH:8]=[CH:9][C:10]([F:14])=[C:11]([OH:13])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[Si:17](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CN=C1>CN(C=O)C>[C:1]([Si:5]([CH3:16])([CH3:15])[O:6][C:7]1[CH:8]=[CH:9][C:10]([F:14])=[C:11]([O:13][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reaction time: 8 h

Procedure:
A solution of 53.0 g 5-(tert-butyl-dimethyl-silanyloxy)-2-fluoro-phenol (M. Kawase, A. K. Sinhababu, R. T. Borchardt, Chem. Pharm. Bull. (1990),38, 2939) in 120 ml DMF was cooled to 0° C. Within 15 min 61.6 ml tert-butyldiphenylsilyl chloride were added. Then 16.4 g imidazole were added portionwise. The suspension was stirred overnight, then quenched with 150 ml H2O at 0° C. The crude product was isolated by extraction with hexanes and purified by chromatography on silica gel (hexanes) to yield 88.9 g of 4-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-diphenyl-silanyloxy)-fluorobenzene as colorless liquid.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[NH2:25][CH2:26][CH2:27][C:28]1[N:32]=[CH:31][NH:30][CH:29]=1>C(O)CCC>[NH:30]1[CH:29]=[C:28]([CH2:27][CH2:26][NH:25][C:2]2[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[CH:10]=3)=[O:7])=[C:4]([CH3:24])[N:3]=2)[N:32]=[CH:31]1
Reactant: NCCc1c[nH]cn1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: CCCCO
Product: Cc1nc(NCCc2c[nH]cn2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 60 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 93 mg of histamine in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield 6-(2-(1H-imidazol-4-yl)ethylamino)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide. MS (Q1) 433.0 (M)
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N+:13]=1[O-].P(Br)(Br)([Br:22])=O.C([O-])([O-])=O.[Na+].[Na+]>ClC(Cl)C>[Br:22][C:14]1[N:13]=[C:12]([N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])[CH:17]=[CH:16][C:15]=1[CH3:18]
Reactant: Cc1ccc(N2C(=O)c3ccccc3C2=O)[n+]([O-])c1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Cc1ccc(N2C(=O)c3ccccc3C2=O)nc1Br
Temperature: 40 °C

Procedure:
To a solution of 2-(1,3-dioxoisoindolin-2-yl)-5-methylpyridine 1-oxide (501 mg, 1.97 mmol) in 1,1-dichloroethane (5 ml) is added POBr3 (679 mg, 2.36 mmol) in small portions at 0° C., and the solution is then heated at 40° C. for 2 hours. The solution is cooled to room temperature, poured into crushed ice, neutralized with Na2CO3 and extracted with dichloromethane. The separated organic layer is further washed with water, brine and dried over Na2SO4. After concentration, the crude product is purified by silica gel flash chromatography, eluted with 3% ethyl acetate in dichloromethane to afford 2-(6-bromo-5-methylpyridin-2-yl)isoindoline-1,3-dione as an off-white solid. LC-MS m/z: 317.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]([F:26])([F:25])[F:24])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH:19](O)[CH3:20])=[CH:14][CH:13]=3)[C:6]=2[CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:60]=[N+:61]=[N-:62])(C2C=CC=CC=2)=O)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[N:60]([CH:19]([CH3:20])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:7]2[C:6]3[CH:22]=[C:2]([Cl:1])[C:3]([C:23]([F:26])([F:25])[F:24])=[CH:4][C:5]=3[N:9]=[C:8]2[CH2:10][CH3:11])=[CH:13][CH:14]=1)=[N+:61]=[N-:62]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CC(C)O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CC(C)N=[N+]=[N-])cc1
Reaction time: 3 h
Yield: 36.8 %

Procedure:
To a stirred solution of 1-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-2-propanol (step 8 of Example 247, 1.96 g, 5.12 mmol), triphenylphosphine (1.75 g, 6.66 mmol) and diphenylphosphoryl azide (1.83 mg, 6.66 mmol) in tetrahydrofuran (15 ml) was added diethyl azodicarboxylate (1.16 mg, 6.66 mmol) at room temperature. The resulting mixture was stirred at temperature for 3 h, then under reflux temperature. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (Na2SO4), and concentrated. Purification by flash column chromatography eluting with hexane/ethyl acetate (2:1) and TLC developing with hexane/ethyl acetate (1:1) afforded 769 mg (37%) of the title compound as a slight yellow syrup.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][C:13]([NH2:16])=[CH:12][N:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:15]=[CH:14][C:13]([NH:16][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=3)(=[O:28])=[O:27])=[CH:12][N:11]=2)[CH2:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(c2ncc(N)cn2)CC1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN1CCN(c2ncc(NS(=O)(=O)c3ccc(C(C)C)cc3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
216 mg (0.98 mmol) of 2-(4-Allylpiperazin-1-yl)pyrimidin-5-ylamine from Example 16.2 and 215 mg (0.98 mmol) of 4-isopropylbenzenesulfonyl chloride were dissolved in 20 ml of tetrahydrofuran at room temperature, after which 0.4 ml (3.0 mmol) of triethylamine was added dropwise and the mixture was stirred at room temperature overnight. After the solvent had been evaporated down to dryness, water was added to the resulting residue. The aqueous reaction mixture was made acid using 1N aqueous hydrochloric acid and extracted twice with diethyl ether. The aqueous phase was made alkaline to pH 9-10, using a 1N solution of sodium hydroxide and then extracted three times with diethyl ether. The combined organic phases were dried over sodium sulfate. The residue which was obtained after filtering off the drying agent and evaporating the solvent down to dryness was thoroughly stirred with a mixture composed of heptane and diethyl ether, filtered off with suction and dried, with 71 mg (18% of theory) of the title compound being obtained.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([OH:3])=O.[NH2:14][C:15]([CH3:19])([CH3:18])[CH2:16]O.ClC1C=CC=CC=1Cl>C(OCC)(=O)C>[CH3:16][C:15]1([CH3:19])[N:14]2[C:7](=[O:9])[C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[CH:4]=[C:1]2[O:3][CH2:18]1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Reactant: CC(C)(N)CO
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1Cl
Product: CC1(C)COc2cc3ccccc3c(=O)n21

Procedure:
A mixture of 1 g. of 2-carboxymethylbenzoic acid, 0.5 g. of 2-amino-2-methylpropanol, and 5 ml. of o-dichlorobenzene was heated to 150°-160° C. for 4 hours. After cooling, the solvent was distilled off from the reaction mixture under reduced pressure and the residue obtained was dissolved in 30 ml. of ethyl acetate. Then, the solution was successively washed with diluted hydrochloric acid, a diluted sodium carbonate solution, and water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. By recrystallizing the residue obtained from cyclohexane, 700 mg. of 3,3-dimethyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-b]isoquinoline was obtained.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]2OCC[O:17]2)=[CH:11][C:10]=1[CH3:21])C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CCO.CCOC(C)=O.[Pd]>[NH2:8][C:9]1[C:10]([CH3:21])=[CH:11][C:12]([CH2:16][OH:17])=[C:13]([CH3:15])[CH:14]=1
Reactant: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(C)cc1C1OCCO1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(CO)c(C)cc1N
Reaction time: 3 h

Procedure:
A stirred solution of dibenzyl-[4-(1,3-dioxolan-2-yl)-2,5-dimethylphenyl)amine (2.00 g, 5.35 mmol) in EtOH (14.0 mL) and EtOAc (7.00 mL) was flushed with nitrogen for 3 min and then sodium bicarbonate (0.200 g, 2.38 mmol) and palladium on activated carbon (10 wt. %, ˜50% water; 0.800 g, 0.360 mmol) were added. The reaction mixture was flushed with hydrogen gas for 3 min and then stirred under a hydrogen atmosphere (balloon) for 3 h. The mixture was then filtered through a pad of Celite and the pad washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure to give the title compound, which was used without any further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[CH2:12]([OH:15])[C:13]#[CH:14].C(N(CC)CC)C>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH:12]([OH:15])[C:13]#[CH:14])[CH:7]=[CH:8][N:9]=1
Reactant: Brc1cccc2ccncc12
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC(O)c1cccc2ccncc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In an inert atmosphere. 0.068 g of bis(triphenylphosphine)palladium dichloride and 0.013 g of cuprous iodide was added with stirring to a deoxygenated solution of 1 g of 8-bromoisoquinoline, 0.56 mL of propargyl alcohol and 2 mL of triethylamine in 25 mL of dichloromethane. The mixture was stirred at room temperature for 2 hours and then at reflux for 20 hours. The cooled reaction was filtered and the filtrate was concentrated in vacuo. The residual oil was purified by HPLC (ethyl acetate-toluene; 2:3) to yield 0.4 g of -(8-isoquinolinyl)-2-propyne-1-ol, mp 138°-139° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=O.Cl.Cl.[NH2:21][O:22][CH2:23][CH2:24][NH2:25].N1C=CC=CC=1.[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]\[C:35]([OH:37])=[O:36]>C(O)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]\[C:35]([OH:37])=[O:36].[NH2:25][CH2:24][CH2:23][O:22][N:21]=[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCCCC(=O)c1ccc(C(F)(F)F)cc1
Reactant: NCCON
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: c1ccncc1
Solvent: CCO
Product: COCCCCC(=NOCCN)c1ccc(C(F)(F)F)cc1

Procedure:
20.4 Mmol (5.3 g) of 5-methoxy-4'-trifluoromethylvalerophenone (melting point 43°-44° C), 20.5 mmol (3.1 g) of 2-aminooxyethylaminedihydrochloride and 10 ml of pyridine were refluxed for 15 hours in 20 ml of absolute ethanol. After evaporating the pyridine and the ethanol in vacuo, the residue was dissolved in water. This solution was washed with petroleum ether and 10 ml of 50% sodium hydroxide solution were then added. Then three extractions with 40 ml of ether were carried out. The ether extract was washed successively with 20 ml of 5% sodium bicarbonate solution and 20 ml of water. After drying on sodium sulphate, the ether layer was evaporated in vacuo. Toluene was then evaporated another three times (to remove the pyridine) and the oil thus obtained was dissolved in 15 ml of absolute ethanol. An equimolar quantity of maleic acid was added to said solution and the solution was then heated until a clear solution was obtained. The ethanol was then removed in vacuo and the residue was crystallized from 10 ml of acetonitrile at +5° C. After sucking off and washing with cold acetonitrile, it was dried in air. The melting point of the resulting title compound was 120°-121.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:14]3[CH:24]=[CH:25][CH:26]=[CH:27][C:13]=3[N:12]=2)[CH2:6][CH2:5]1.[N:28]([C:31]1[CH:40]=[CH:39][CH:38]=[CH:37][C:32]=1[C:33](OC)=[O:34])=[C:29]=[S:30]>O1CCCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]2[C:14]3[CH:24]=[CH:25][CH:26]=[CH:27][C:13]=3[N:12]=[C:11]2[NH:10][CH:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][N:1]3[C:33](=[O:34])[C:32]4[C:31](=[CH:40][CH:39]=[CH:38][CH:37]=4)[NH:28][C:29]3=[S:30])[CH2:5][CH2:6]2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccccc1N=C=S
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: C1CCOC1
Product: O=c1c2ccccc2[nH]c(=S)n1CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 10.9 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine in 150 parts of tetrahydrofuran was added dropwise a solution of 6 parts of methyl 2-isothiocyanatobenzoate in 30 parts of tetrahydrofuran at room temperature: slightly exothermic reaction, the temperature rose to 30° C. Upon completion, stirring at room temperature was continued for one hour. The reaction mixture was evaporated. The residue was stirred in trichloromethane. The formed precipitate was filtered off and crystallized from 2-propanone. The product was filtered off and dried, yielding 5.2 parts of 3-[2-[4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl]ethyl]-1,2-dihydro-2-thioxo-4(3H)-quinazolinone; mp. 198.5° C. (compound 131).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]4[CH2:24][CH2:25][CH2:26][C:22]=4[N:21]=[C:20]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[N:19]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8]1)=[O:6]>O.CO>[N:27]1([C:20]2[N:19]=[C:18]([NH:17][C:14]3[CH:13]=[CH:12][C:11]([C:7]4([C:5]([OH:6])=[O:4])[CH2:10][CH2:9][CH2:8]4)=[CH:16][CH:15]=3)[C:23]3[CH2:24][CH2:25][CH2:26][C:22]=3[N:21]=2)[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: COC(=O)C1(c2ccc(Nc3nc(N4CCOCC4)nc4c3CCC4)cc2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1(c2ccc(Nc3nc(N4CCOCC4)nc4c3CCC4)cc2)CCC1
Reaction time: 3 h
Yield: 93.1 %

Procedure:
A solution of sodium hydroxide (0.588 g, 14.7 mmol) in water (15 mL) was added to a solution of 1-[4-(2-morpholin-4-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid methyl ester (1.0 g, 2.45 mmol) in MeOH (15 mL) and stirred at a temperature in the range of 15° C. to 40° C. for 3 hours. Thereafter, MeOH was evaporated under reduced pressure and pH of the solution was adjusted to ˜4 by adding concentrated hydrochloric acid. The precipitated solid was filtered, washed with water and dried in vacuo to afford the title compound as a white solid (0.9 g, 93.2% yield).
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([Cl:18])=[C:16]([CH:19](Cl)[CH3:20])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][S-:23].[Na+]>CO>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([Cl:18])=[C:16]([CH:19]([S:23][CH3:22])[CH3:20])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(Cl)c1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSC(C)c1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl

Procedure:
19.8 g (60 mmol) of 4-(cis-4-tert-butylcyclohexylamino)-5-chloro-6-(1-chloroethyl)pyrimidine and 4.2 g (60 mmol) of sodium methanethiolate were heated at reflux in 100 ml of methanol for 6 hours. The mixture was concentrated and the residue was taken up in water/toluene. The organic phase was dried and concentrated, to give 17.7 g (85% of theory) of a colorless resin which was subsequently reacted without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:11]([NH2:20])[N:10]([CH3:21])[N:9]=1)(=[O:3])[CH3:2].[H-].[Na+].[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>CC(N(C)C)=O.O>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[C:11]([NH:20][S:34]([C:31]2[CH:32]=[CH:33][C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[N:10]([CH3:21])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOc1nn(C)c(N)c1-c1ccc(C)cc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)OCCOc1nn(C)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc(C)cc1
Reaction time: 0.08 h
Yield: 24.3 %

Procedure:
To 2-{[5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-yl]oxy}ethyl acetate (Preparation 5) (250 mg) in dimethyl acetamide (2 ml) at room temperature was added sodium hydride (41 mg, 60% dispersion in oil), the mixture was stirred for 5 minutes. To the mixture was added 4-tert-butylbenzenesulphonyl chloride (79 mg), the mixture was stirred for a further 1 hour. The reaction was diluted with water (20 ml) and extracted with diethyl ether (20 ml). The organic fraction was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 10 g) eluted with dichloromethane:ether (1:1) to yield the title compound as a pale orange solid (40 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].Cl>C(#N)C>[C:17]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[N:3]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1n[nH]c2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(=O)n1nc(C)c2ccccc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
290 g (2.20 mol) of 3-methylindazole and an acetonitrile solution (400 ml) of pyridine (4.34 mol) were stirred as the mixture was cooled on a water bath, and 310 ml (3.30 mol) of acetic anhydride was added dropwise thereto. Upon addition, the reaction temperature rose from 15° C. to 43° C. After the conclusion of the dropwise addition, the reaction solution was warmed to from 55° to 60° C., and stirred at this temperature for one hour. After cooling to 20° C., the reaction solution was poured into 1.5 kg of ice-cold water containing 500 ml of aqueous hydrochloric acid. The crystals deposited were filtered off, and washed with water. Thus, 328 g (1.89 mol) of 1-acetyl-3-methylindazole was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[N:7][NH:6][C:5]=1[C:9]([OH:11])=O)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.C[N:19](C)C=O>ClCCl>[N+:1]([C:4]1[CH:8]=[N:7][NH:6][C:5]=1[C:9]([NH2:19])=[O:11])([O-:3])=[O:2]
Reactant: O=C(O)c1[nH]ncc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1[nH]ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Nitro-2H-pyrazole-3-carboxylic acid (2.72 g, 17.4 mmol) was added to a solution of oxalyl chloride (2.42 mL, 27.7 mmol) and N,N-dimethylformamide (80 μL) in dichloromethane (45 mL) and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and azeotroped from dichloromethane (3×100 mL). The crude product was dissolved in tetrahydrofuran, cooled in an ice bath, and treated with 0.880 ammonia solution (20 mL). The reaction mixture was stirred at room temperature for 18 hours then concentrated in vacuo and the residue partitioned between dichloromethane (300 mL) and water (100 mL). The organic layer was separated, dried over magnesium sulphate and concentrated in vacuo to yield the title product. LRMS ES+m/z 157 [MH]+