Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:40]1[N:41]=[CH:42][N:43]([CH3:45])[CH:44]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)([O-])O.[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:40]5[N:41]=[CH:42][N:43]([CH3:45])[CH:44]=5)=[CH:27][CH:28]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: Cn1cnc(I)c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cn1cnc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)c1
Temperature: 25 °C
Yield: 29 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 4-iodo-1-methyl-1H-imidazole (312 mg, 1.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.05 mmol), tricyclohexylphosphine (34 mg, 0.12 mmol), and tripotassium phosphate (372 mg, 1.7 mmol) in dioxane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (148 mg, 29%) as a brown solid.
Reaction SMILES: [CH3:1][O-].[Na+].[N+:4]([C:7]1[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:10][CH:11]=1)([O-:6])=[O:5].CI>CO>[CH3:1][N:10]1[CH:11]=[C:7]([N+:4]([O-:6])=[O:5])[CH:8]=[C:9]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CCOC(=O)c1cc([N+](=O)[O-])cn1C
Temperature: 35 °C
Reaction time: 0.17 h

Procedure:
A solution of 2.5 g. of sodium methoxide in 25 ml. of methanol is cooled to 10° C. and a mixture of 7.0 g. of ethyl 4-nitro-2-pyrrolecarboxylate in 15 ml. of methanol is added. After 10 minutes, 18.6 g. of methyl iodide is added. The dark-colored solution is warmed to 35° C. for 0.5 hours, then cooled and allowed to stir at room temperature for 16 hours. Chilling and filtration affords a solid which is collected by filtration and recrystallized from ethanol to yield the product.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].C[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>ClC1C=CC=CC=1Cl>[O:4]([C:2]([C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[S:13]([NH2:12])(=[O:15])=[O:14])=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CNS(=O)(=O)c1ccc(C)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(S(N)(=O)=O)c(C(=O)Oc2ccccc2)c1

Procedure:
Phenyl chloroformate (1.57 g, 0.01 mol) and N-methyl-4-methylbenzene sulfonamide (1.85 g, 0.01 mol) were diluted with 1,2-dichlorobenzene (15 ml) and refluxed for 40 hrs. The solvent was evaporated in vacuo and the residue diluted dichloromethane and the dichloromethane washed with water (2×), dried over anhydrous magnesium sulfate. Evaporation of the solvent in vacuo gave N-methyl-N*-phenoxycarbonyl-4-methylbenzene sulfonamide mp 98–100° C. MS m/z 305. (M+ calcd for C15H15NO4S=305). H NMR (300 MHz, CDCl3) d 2.43 (s, 3, CH3), 2.45 (s, 3, NCH3), 6.95 (m, 2, aromatic), 7.18–7.35 (m, 5, aromatic), 7.88 (m, 5, aromatic).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[C:22]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc(-c2c[nH]c3ccccc23)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)n1cc(-c2ccccc2)c2ccccc21
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
In 400 ml of tetrahydrofuran, 42.0 g of 3-phenyl indole was solved. The solution and 25.0 g of potassium tert-butoxide added thereto at -30--20° C. were together heated to normal room temperature and stirred for 30 minutes. The reaction solution was cooled to -20--10° C. and 26 ml of benzoyl chloride added thereto were together heated to normal room temperature and stirred for one hour. The resultant mixture was poured into ice water and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, distilled to expel the chloroform, crystallized by addition of isopropyl ether, separated by filtration, and dried to obtain 60.0 g of 1-benzoyl-3-phenylindole (92.8%) having a melting point of 154-156° C.
Reaction SMILES: [C:1]([SH:3])#N.N.C(Cl)(=O)C1C=CC=CC=1.[F:14][C:15]1[CH:31]=[CH:30][CH:29]=[CH:28][C:16]=1[O:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:21]=2[N:22]=1>CC(C)=O>[F:14][C:15]1[CH:31]=[CH:30][CH:29]=[CH:28][C:16]=1[O:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([N:27]=[C:1]=[S:3])[CH:24]=[CH:23][C:21]=2[N:22]=1
Reactant: Nc1ccc2nc(Oc3ccccc3F)sc2c1
Reactant: N#CS
Agent: N
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Product: Fc1ccccc1Oc1nc2ccc(N=C=S)cc2s1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
An amount of 17 g of ammonium rhodanide is dissolved in 200 ml of absolute acetone; an addition is then made to the solution, with stirring, of 31 g of benzoyl chloride. The reaction mixture is allowed to boil with refluxing for 5 minutes; a solution is then added of 57 g of 2-(2'-fluorophenoxy)-6-aminobenzothiazole (obtained from 2-(2'-fluorophenoxy)-6-nitrobenzothiazole by catalytic hydrogenation, cp. Example 6) in 400 ml of acetone. Stirring is continued for 2 minutes at the boiling temperature, and the mixture then poured, with stirring, into 5000 ml of ice water. Filtration is performed, the filter residue washed with water, and suspended in 350 ml of 10% sodium hydroxide solution. The suspension is quickly brought to boiling temperature and allowed to boil for a further 2 minutes. Cooling is then rapidly carried out in an ice bath; the suspension is neutralised with 2-n hydrochloric acid, and the pH-value adjusted with 2-n ammonia to 8. Filtration is again performed, the filter residue washed wth water until neutral, and dried at 80° in vacuo. The finely powdered material is suspended in 500 ml of anhydrous chlorobenzene and refluxed for 14 hours. After the solvent has been evaporated off, the residue is chromatographed through aluminium oxide with methylene chloride as the eluant. The obtained 2-(2'-fluorophenoxy)-6-isothiocyanobenzothiazole melts at 115° - 117°.
Reaction SMILES: [C:1]([C:4]1[C:14]2[O:13][CH2:12][CH2:11][C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(O)=[O:2].C(N(CC)CC)C.ClC(OCC(C)C)=O>O1CCCC1>[OH:2][CH2:1][C:4]1[C:14]2[O:13][CH2:12][CH2:11][C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1=Cc2cccc(C(=O)O)c2OCC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=Cc2cccc(CO)c2OCC1
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
To a mixture of ethyl 9-carboxy-2,3-dihydro-1-benzoxepin-4-carboxylate (0.52 g) and triethylamine (0.33 ml) in tetrahydrofuran (5.2 ml) was added dropwise isobutyl chloroformate (0.31 ml) below 5° C. under ice-sodium chloride cooling. The reaction mixture was stirred for 30 minutes at the same temperature. The resulting precipitate was filtered off and washed with cold tetrahydrofuran. The filtrate was added to a solution of sodium borohydride (75 mg) in aqueous tetrahydrofuran (10 ml, 90% v/v) at 0° C. The reaction mixture was stirred for 30 minutes at the ambient temperature and evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by medium pressure liquid chromatography (silica gel) using a mixture of ethyl acetate and n-hexane (1:9) to give a solid of ethyl 2,3-dihydro-9-hydroxymethyl-1-benzoxepin-4-carboxylate (0.37 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:19][CH:18]([CH3:20])[CH:17]([CH3:21])[N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)[N:7]=[CH:6]2>C(OCC)(=O)C>[CH3:21][CH:17]1[CH:18]([CH3:20])[CH2:19][N:13]([C:8]2[N:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([F:2])[CH:4]=3)[N:9]=2)[CH2:14][CH2:15][NH:16]1
Reactant: CC1CN(c2ncc3cc(F)ccc3n2)CCN(C(=O)OC(C)(C)C)C1C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1CN(c2ncc3cc(F)ccc3n2)CCNC1C
Reaction time: 0.67 h

Procedure:
Hydrogen chloride gas was bubbled through a 0° C. solution of compound 1-10 (338 mg, 0.9 mmol) in ethyl acetate (5 mL) for 1 minute. The reaction was sealed and stirred for 40 minutes. Concentration in vacuo gave the titled compound as a white solid. Data for 1-11: LC/MS: m/z (M+CH3CN)=315.2 found; 315.3 calculated.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:56][CH2:57][CH2:58][C:59]([CH3:64])([N+:61]([O-:63])=[O:62])[CH3:60]>CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:56][CH2:57][CH2:58][C:59]([CH3:64])([N+:61]([O-:63])=[O:62])[CH3:60])[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Reactant: CC(C)(CCCCl)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCCC(C)(C)[N+](=O)[O-])c4ccc(OC(F)F)cc34)nc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
To a solution of N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (208 mg, 0.35 mmol) in DMF (15 mL) was added K2CO3 (193 mg, 1.4 mmol) and 1-chloro-4-methyl-4-nitropentane (100 mg, 0.59 mmol), after the addition, the reaction mixture was heated to 100° C. with stirring for 4 hours. Then, the mixture was quenched with H2O (25 mL) and product extracted with EtOAc (50 mL). The organic layer was washed with H2O (100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(4-methyl-4-nitropentyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (200 mg, 69%) as yellow solid, material used in the next step without further purification. LCMS: (M+H)+=772; (M+Na)+=794.0.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:17][C:18]1[C:19](=[O:24])[NH:20][CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:17][C:18]1[C:19]([O:24][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=3)=[CH:5][CH:4]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Reactant: Cc1ccc[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccnc1OCc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 90 °C
Yield: 60.4 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 3-methyl-2-pyridone (20 mg, 0.18 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(3-methyl-pyridin-2-yloxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (20 mg, 60%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (br. s., 1H), 7.99 (br. s., 1H), 7.86 (d, J=8.5 Hz, 2H), 7.68 (d, J=6.9 Hz, 1H), 7.56 (d, J=1.2 Hz, 1H), 7.41 (d, J=8.2 Hz, 2H), 7.29 (dd, J=14.0, 6.2 Hz, 2H), 7.18 (d, J=6.6 Hz, 1H), 5.98-6.24 (m, 2H), 5.15 (s, 2H), 1.99 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[ClH:18]>>[ClH:18].[CH3:16][N:13]1[CH2:14][CH2:15][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:17])=[O:2])=[CH:5][CH:6]=2)[CH2:11][CH2:12]1
Reactant: COC(=O)c1ccc(C2CCN(C)CC2)cc1
Agent: Cl
Product: CN1CCC(c2ccc(C(=O)O)cc2)CC1

Procedure:
4-(1-Methyl-piperidin-4-yl)-benzoic acid methyl ester (4.55 mmol) is dissolved in 4N HCl (10 ml) and heated under reflux for 8 hours. After cooling the solvent is evaporated and the residue is suspended in acetone and the solid filtered of, washed with acetone and dried (vacuum). A pale-brown powder with mp. >270° C. is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>CN(C)C=O>[CH2:23]([O:22][C:20]([CH2:19][CH2:18][CH2:17][CH2:16][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2)=[O:21])[CH3:24]
Reactant: CCOC(=O)CCCCBr
Reactant: O=c1ccc2cc(O)ccc2o1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCOc1ccc2oc(=O)ccc2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
6-Hydroxycoumarin (405 mg; prepared in reference example 25) was dissolved in dry dimethylformamide (6 ml). Sodium hydride (60 mg) was added to the solution. The mixture was reacted for 15 min. Ethyl 5-bromopentanoate (0.48 ml) was added dropwise to the reaction solution. The mixture was stirred for 1 hr at 60° C. Ice-water was added to the reaction solution. The mixture was acidified with 1N hydrochloric acid. The mixture was extracted with ether. The extract was washed with water, dried anhydrous magnesium sulfate and then evaporated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1→2:1) to give the title compound (398 mg) having the following physical data.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Br:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])(=[O:3])[CH3:2].[BH4-].[Na+]>O>[Br:13][C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=1
Reactant: CC(=O)c1cc(Br)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(O)c1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
10 mmol of 3-acetyl-4-nitro-bromobenzene was placed in a 100 mL two-neck round-bottomed flask and dissolved in 30 mL of a solvent (ether), and then sodium borohydride was slowly added dropwise thereto in an ice bath. The reaction mixture was stirred at room temperature for 2 hours. After the completion of the reaction was confirmed by TLC, 5 mL of water was added to terminate the reaction and the precipitate was filtered off. The filtrate was washed twice with 30 mL of a sodium chloride solution, dried over anhydrous sodium sulfate, distilled under reduced pressure and purified by silica gel column chromatography (hexane/EtOAc=2/1) to obtain the desired 1-(5-bromo-2-nitrophenyl)ethanol as a yellow oil (71%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:12]3[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([N:23]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:20]2[N:19]=[CH:18][C:17]([C:16]3[C:11]4[CH2:10][CH2:9][N:8]([C:5]5[CH:6]=[N:7][C:2]([N:52]6[CH2:53][CH2:54][N:49]([CH3:48])[CH2:50][CH2:51]6)=[CH:3][CH:4]=5)[C:12]=4[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=3)=[CH:22][N:21]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(Cl)nc3)cn2)cc1
Reactant: CN1CCNCC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(N4CCN(C)CC4)nc3)cn2)cc1
Yield: 99.3 %

Procedure:
Using {5-[7-(6-chloro-pyridin-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (200 mg, 0.31 mmol) obtained in Step A in Example 1-D-48 and N-methylpiperazine (46 mg, 0.46 mmol) instead of N,N,N′-trimethyl ethylenediamine, in the same manner as Example 1-D-48, amination was carried out, to obtain a crude product of bis-(4-methoxy-benzyl)-(5-{7-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl)-amine as a colorless solid (220 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-71) as a yellow solid (35 mg, 24%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].S(Cl)(Cl)=O.Cl.CN.[CH:19]([N:22](C(C)C)CC)(C)C>C1(C)C=CC=CC=1.ClCCl.O>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:22][CH3:19])=[O:7]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cccc(CCl)c1
Agent: CN
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 80 %

Procedure:
To a solution of 3-(chloromethyl)-benzoic acid (34.1 g, 200 mmol) in toluene (125 mL) was added thionyl chloride (21.9 mL, 300 mmol) at room temperature. The resulting solution was heated at reflux for 15 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting oily residue was azeotroped with toluene and dried under high vacuum to obtain the crude acid chloride. To a suspension of the above crude acid chloride (200 mmol) in dichloromethane (400 mL) was added methylamine hydrochloride (14.9 g, 220 mmol) at −5° C. to 0° C. Diisopropylethylamine (69.6 mL, 400 mmol) was added drop-wise over 15-20 minutes at 0° C. After completion of the addition, the mixture was stirred for 45 minutes at 0° C., then warmed to room temperature. After stirring at room temperature for 15 minutes, the reaction mixture was diluted with water (300 mL) and the aqueous layer was extracted with dichloromethane (100 mL). The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. Filtration and concentration gave the crude solid which was dissolved in toluene at ˜60-70° C. The resulting solution was stored in the refrigerator overnight and the precipitated solids were collected by filtration and then washed with hexanes. After drying in air, 3-(chloromethyl)-N-methyl-benzamide (80%) was isolated as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C@H:11]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:27](Cl)(Cl)Cl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@@H:11]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])[N:12]2[S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:15])=[O:14])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2[C@H](CCCO)CC[C@H]2c2ccc(F)cc2)cc1
Reactant: ClC(Cl)Cl
Product: COCCC[C@@H]1CC[C@H](c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound, colorless oil, MS: m/e=392.1 (M+H+) and [α]D20=−82.7° (c=0.2682 in chloroform), was prepared in accordance with the general method of example 8 from (2S,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propan-1-ol.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1.C(N(CC)C(C)C)(C)C.[C:27]1([S:37]([Cl:40])(=[O:39])=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[ClH:40].[CH2:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][N:8]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3][S:37]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)(=[O:39])=[O:38]
Reactant: NCCCCN1CCc2ccccc2C1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NCCCCN1CCc2ccccc2C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
A solution of 2-(4-aminobutyl)-1,2,3,4-tetrahydroisoquinoline dihydrochloride (272 mg, 1 mmol), N,N-diisopropylethylamine (517 mg, 4 mmol) in CH2Cl2 (10 mL), was added naphtalene-1-sulfonyl chloride (238 mg, 1.05 mmol) and was stirred overnight at room temperature. The resulting solution was washed with water (3×15 mL) and dried over Na2SO4, and evaporated to dryness. The free base was dissolved in 2-propanol (5 mL). A 2.8 M solution of hydrogen chloride in ethanol (0.40 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (310 mg, 72%).
Reaction SMILES: Cl.NO.[OH-].[Na+].CC1[N:8]([C@H:13]2[CH2:20][C@@:19]3([C:21]([O:23][CH3:24])=[O:22])[C@H:15]([CH2:16][CH2:17][CH2:18]3)[CH2:14]2)C(C)=CC=1>O.CO>[NH2:8][C@H:13]1[CH2:20][C@@:19]2([C:21]([O:23][CH3:24])=[O:22])[C@H:15]([CH2:16][CH2:17][CH2:18]2)[CH2:14]1
Reactant: COC(=O)[C@@]12CCC[C@@H]1C[C@@H](n1c(C)ccc1C)C2
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)[C@@]12CCC[C@@H]1C[C@@H](N)C2
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To an aqueous solution of hydroxylamine hydrochloride (458 g, 6.59 mol) and sodium hydroxide (120 g, 3 mol) in water (350 mL) was added a solution of Example 1D (119 g, 0.454 mol) in methanol (2 L) and the mixture was stirred at 65° C. for 8 hours. The mixture was cooled to room temperature, sufficient water was added and the methanol was removed under reduced pressure. The resulting slurry was adjusted to pH 10 with an aqueous sodium hydroxide solution (2.5 N) and the reaction mixture was extracted with dichloromethane. The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=[CH:18][C:3]=1[C:4]([CH:6]([C:14](=[O:17])[CH2:15][CH3:16])C(OC(C)(C)C)=O)=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=[CH:18][C:3]=1[C:4](=[O:5])[CH2:6][C:14](=[O:17])[CH2:15][CH3:16]
Reactant: CCC(=O)C(C(=O)OC(C)(C)C)C(=O)c1ccc(S(C)(=O)=O)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCC(=O)CC(=O)c1ccc(S(C)(=O)=O)cc1Cl
Yield: 78.8 %

Procedure:
A mixture of crude t-butyl 2-[2-chloro-4-(methylsulphonyl)benzoyl]-3-oxopentanoate (12.0 g) and 4-toluenesulphonic acid (0.1 g) in toluene was stirred and heated at reflux for 3.5 hours. After cooling, the mixture was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with ether and filtered to give 1-[2-chloro-4-(methylsulphonyl)phenyl]pentan-1,3-dione (7.02 g) as a white solid NMR(CDCl3): 1.2(t,3H) 2.45 (q,2H) 3.0(s,3H) 5.9(s,1H) 7.5-8.0(m,3H).