Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[NH+:7][C:8]=1[O-:9])(=[O:3])[NH2:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:16]1[O:27][C:26]2[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][C:18]=2[O:17]1>C1(C)C=CC=CC=1>[CH2:16]1[O:27][C:26]2[CH:25]=[CH:24][C:20]([C:21]([O:9][C:8]3[N:7]=[CH:6][NH:5][C:4]=3[C:1](=[O:3])[NH2:2])=[O:22])=[CH:19][C:18]=2[O:17]1
Reactant: NC(=O)c1[nH]c[nH+]c1[O-]
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: NC(=O)c1[nH]cnc1OC(=O)c1ccc2c(c1)OCO2
Reaction time: 4 h

Procedure:
To a mixture of 1.27 g of 4-carbamoylimidazolium-5-olate in 42.4 g of 10% aqueous solution of sodium carbonate was added 7.38 g of 3,4-methylenedioxybenzoylchloride in 20 ml of toluene at room temperature. After addition was over, the mixture was stirred for 4 hours. Then the separated crystals were filtered off, washed with water and toluene, dried in vacuo to give 5-carbamoyl-1H-imidazol-4-yl 3,4-methylenedioxybenzoate, m.p. 206.5°-208° C. (dec.).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:27][CH2:28][OH:29]>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:27][CH2:28][OH:29])[CH2:19][CH2:18]1
Reactant: OCCBr
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCN(CCO)CC3)c2n1

Procedure:
Prepared similarly to Example 1 from 2-(butyloxy)-8-(methyloxy)-9-[2-(4-piperidinyl)ethyl]-9H-purin-6-amine (for example, as prepared for Intermediate 30) and 2-bromoethanol (commercially available, for example, from Aldrich).
Reaction SMILES: [C:1]([S:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl>C1COCC1.CO>[NH2:11][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([S:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:7][CH:8]=1
Reactant: CC(C)(C)Sc1ccc(C#N)cn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)Sc1ccc(CN)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
Use a method similar to the General Procedure 6-5 to react 6-(tert-butylthio)nicotinonitrile (4.4 g, 22.7 mmol) in anhydrous THF (25 mL) with 1M BH3-THF complex in THF (25 mL, 25 mmol). Add 5M aqueous HCl (10 mL) cautiously and stir the mixture overnight at room temperature. Extract into EtOAc, wash with brine, dry over MgSO4 and concentrate in vacuo to give an orange solid. Dissolve the crude mixture in methanol and filter through an SCX column eluting with methanol followed by 3M ammonia in methanol to obtain the title compound (2.74 g, 61%). MS (ES+) m/z: 197 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[N:4][S:5][N:6]=1.[C:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.CO>[C:15]1([N:21]2[CH2:26][CH2:25][N:24]([C:2]3[C:3]([O:7][CH2:8][C:9]4[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=4)=[N:4][S:5][N:6]=3)[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Clc1nsnc1OCc1ccncc1
Solvent: CO
Solvent: CN(C)C=O
Product: c1ccc(N2CCN(c3nsnc3OCc3ccncc3)CC2)cc1
Temperature: 70 °C
Yield: 9 %

Procedure:
4-(4-chloro-[1,2,5]thiadiazol-3-yloxymethyl)-pyridine (50 mg, 0.22 mmol) was dissolved in 200 μL of DMF along with 1-phenylpiperazine (75 μL, 0.49 mmol). The reaction was heated to 70° C. overnight. The reaction mixture was diluted with methanol to a volume of 2 mL and the reaction mixture was purified by reverse phase chromatography, affording 1-phenyl-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine (7 mg). 1H NMR (DMSO-d6) δ 8.62 (d, 2H), 7.46 (d, 2H), 7.23 (t, 2H), 7.01 (d, 2H), 6.82 (t, 1H), 5.58 (s, 2H), 3.64 (m, 4H), 3.23 (m, 4H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.C(N=C=NCCCN(C)C)C.[CH3:25][S:26]([NH2:29])(=[O:28])=[O:27]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:29][S:26]([CH3:25])(=[O:28])=[O:27])=[O:8]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
5-chloro-2,4-difluorobenzoic acid (0.291 g, 1.511 mmol), N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.438 g, 2.285 mmol) and 4-dimethylaminopyridine (0.420 g, 3.438 mmol) were suspended in DCM (5 mL). Methanesulfonamide (0.222 g, 2.334 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM (10 mL) and washed with aqueous HCl solution (2 M, 2×15 mL). The organic layer was dried with a phase separating cartridge and concentrated in vacuo to yield the title compound as a white solid (0.388 g):
Reaction SMILES: [CH2:1]([NH:5][S:6](=[O:9])(=O)[OH:7])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)(Cl)[Cl:11]>C1C=CC=CC=1>[CH2:1]([NH:5][S:6]([Cl:11])(=[O:9])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCCNS(=O)(=O)O
Solvent: c1ccccc1
Product: CCCCNS(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of n-butyl sulfamic acid (1.92 gm, 12.53 mmoles) and phosphorus pentachloride (2.61 gm, 12.53 mmoles) in benzene (20 mL) was warmed gently to initiate gas evolution. The reaction mixture was stirred at room temperature for 0.5 h., during which time a cloudy solution resulted. The cloudy solution was heated to reflux for 0.5 h., then was concentrated. The product n-butyl sulfamoyl chloride was isolated by vacuum distillation (120 C., 300 millitorr), 730 mg (liq.) (34%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:19])/[CH:11]=[CH:12]/C2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Al+3].[Cl-].[Cl-].[Cl-]>>[Cl:8][C:7]1[CH:6]=[C:5]2[C:4](=[CH:3][C:2]=1[Cl:1])[NH:9][C:10](=[O:19])[CH:11]=[CH:12]2
Reactant: O=C(/C=C/c1ccccc1)Nc1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Product: O=c1ccc2cc(Cl)c(Cl)cc2[nH]1
Reaction time: 2 h

Procedure:
A mixture of (2E)-N-(3,4-dichlorophenyl)-3-phenyl-2-propenamide (4.0 g, 13.7 mmol) and AlCl3 (9.1 g, 68.5 mmol) was heated slowly until the mixture became liquefied and then subsequently congealed to form a solid cake. Ice was slowly added to break up the hardened material. The mixture was vigorously stirred for 2 h. The precipitate was collected and washed with 2 N HCl solution, water, and ether to obtain a white mixture of product A and B above (2.8 g, 96%), MS (ES) m/e 215 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:17]=[C:16]([CH:18]=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]3[CH:25]=[C:24]([C:26](=[O:31])[NH:27][CH:28]4[CH2:30][CH2:29]4)[CH:23]=[C:22]([F:32])[C:21]=3[CH3:33])[CH:14]=2)[C:9]1=[O:34])(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[CH:28]1([NH:27][C:26](=[O:31])[C:24]2[CH:25]=[C:20]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[C:9](=[O:34])[N:8]([CH2:7][CH2:6][CH2:5][OH:4])[CH:17]=[C:16]4[CH:18]=[O:19])[C:21]([CH3:33])=[C:22]([F:32])[CH:23]=2)[CH2:30][CH2:29]1
Reactant: CC(=O)OCCCn1cc(C=O)c2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CCCO)cc(C=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
3-(6-(5-(Cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl)-4-formyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (Example 10d, 0.75 g) was treated with methanol (15 mL) and potassium carbonate (0.25 g) and the resulting mixture was stirred at room temperature for 30 min, diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated to afford the subtitle compound (0.67 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([NH2:13])[CH:7]=1.[C:26](O)(=O)[CH3:27].O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[NH:12][C:26]([CH3:27])=[N:13][C:8]=2[CH:7]=1
Reactant: CC(=O)O
Reactant: COC(=O)[C@@H](Cc1ccc(N)c(N)c1)NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)[C@@H](Cc1ccc2[nH]c(C)nc2c1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 95 %

Procedure:
A solution of (R)-2-benzyloxycarbonylamino-3-(3,4-diamino-phenyl)-propionic acid methyl ester-acetic acid (640 mg) in acetic acid (8 mL) was heated at 130° C. for 4 h. The mixture was then poured into water and cooled to 0° C. The pH was adjusted to 8 by gradual addition of solid sodium bicarbonate. The mixture was then extracted with ethyl acetate (3×100 mL), and the combined organic layers were washed with water, brine and dried over sodium sulfate. After filtration, solvents were removed to afford the title compound as a brownish foamy solid (95%). 1H-NMR (CDCl3, 500 MHz) δ 7.39 (d, J=8.5 Hz, 1H), 7.35 (s, 1H), 7.26-7.22 (m, 5H), 7.06 (d, J=8.0 Hz, 1H), 5.03 (d, J=12.5 Hz, 1H), 4.99 (d, J=13.0 hz, 1H), 4.51 (dd, J=8.5, 5.5 Hz, 1H), 3.70 (s, 3H), 3.27 (dd, J=13.5, 5.0 Hz, 1H), 3.03 (dd, J=14.0, 9.0 Hz, 1H), 2.55 (s, 3H). Mass spec.: 368.19 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: C1=COCCC1
Reactant: Clc1ncnc2nc[nH]c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: Clc1ncnc2c1ncn2C1CCCCO1
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of 6-chloropurine (2.70 g, 17.5 mmol) and p-toluenesulfonic acid monohydrate (0.14 g, 0.71 mmol) in methylene chloride (30 mL) was added dihydropyran (2.39 mL, 26.2 mmol). The suspension was stirred for 3 h. The reaction mixture was washed with 2.5% Na2CO3 solution (100 mL×2), and brine (50 mL). The organic layer was dried over sodium sulfate and concentrated. The oil was treated with hexanes (100 mL) and stirred. The hexanes layer was decanted. The oil solidified upon standing to give the desired product (4.17 g, 98%).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[C:17]([CH:18](O)[CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:15]=[CH:14][C:6]=2[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH2:1]([C:3]1[O:4][C:5]2[C:17]([CH2:18][CH2:19][N:20]([CH2:21][CH3:22])[CH2:23][CH3:24])=[CH:16][CH:15]=[CH:14][C:6]=2[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCc1oc2c(C(O)CN(CC)CC)cccc2c1-c1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCc1oc2c(CCN(CC)CC)cccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
180 mg (0.53 mmol) of 2-ethyl-3-phenyl-7-(2-diethylamino-1-hydroxyethyl)benzofuran, 1 ml of triethylsilane and 1 ml of trifluoroacetic acid are introduced into a 25 ml three-necked flask equipped with a reflux condenser. The mixture is stirred for 2 hours at room temperature and then 2 ml of triethylsilane and 1 ml of trifluoroacetic acid are added. The mixture is heated at 70° C. for 48 hours. Potassium carbonate and ethyl ether (30 ml) are added and the mixture is filtered. The filtrate is concentrated under vacuum and the residue is purified by silica column chromatography (elution solvent: 5% methanol in dichloromethane). 80 mg of 2-ethyl-3-phenyl-7-(2-(diethylamino)ethyl)benzofuran are obtained in the form of a wax.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>>[OH:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:12][NH:14][C:4]2=[O:5]
Reactant: Nc1ccc(O)cc1C(=O)O
Reactant: NC=O
Product: O=c1[nH]cnc2ccc(O)cc12
Temperature: 190 °C

Procedure:
To a solution of 2-amino-5-hydroxybenzoic acid 0201 (30.6 g, 0.2 mol) in formamide was stirred and heated to 190° C. for 0.5 h. The mixture was allowed to cool to room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=O.C(N)CCC.[N+:23]([CH2:26][CH3:27])([O-:25])=[O:24]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:26]([N+:23]([O-:25])=[O:24])[CH3:27])[CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC[N+](=O)[O-]
Reactant: COc1cc(C=O)ccc1Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCCCN
Product: COc1cc(C=C(C)[N+](=O)[O-])ccc1Oc1ccccc1
Temperature: 25 °C
Yield: 69 %

Procedure:
1.15 g of 3-methoxy-4-phenoxybenzaldehyde, 96 μl of n-butylamine, 10 ml of nitroethane and 5 ml of toluene were mixed and refluxed under heating for 2 hours. The reaction solution was left to cool to room temperature and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain 953 mg (yield: 69%) of the above identified compound as a colorless oily substance.
Reaction SMILES: [CH2:1]([CH:8]([C:12]([NH:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=[O:30].C(Cl)CCl>CC#N>[O:30]=[C:25]1[CH2:26][CH2:27][C:28](=[O:29])[N:24]1[O:10][C:9](=[O:11])[CH:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:12]([NH:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)C(Cc1ccccc1)C(=O)NOCc1ccccc1
Solvent: CC#N
Solvent: ClCCCl
Product: O=C(NOCc1ccccc1)C(Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.6 %

Procedure:
Intermediate (12a) (0.5 g, 1.7 mmol) was added to N-hydroxysuccinimide (290 mg, 2.6 mmol) and EDC (320 mg, 1.7 mmol) and dissolved in MeCN (6 mL). The mixture was stirred overnight at room temperature and then partitioned between EtOAc and 10% aqueous citric acid. The organic layer was separated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to provide intermediate (12b) as a foam (0.8 g, 2 mmol).
Reaction SMILES: Br[CH:2]([C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:12])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C([O-])=[O:21].[Na+].CO>C(OCC)(=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:11](=[O:12])[CH:2]([OH:21])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:14][CH:15]=1
Reactant: O=C[O-]
Reactant: CCOC(=O)CCCC(Br)C(=O)c1ccc(F)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)CCCC(O)C(=O)c1ccc(F)cc1

Procedure:
A mixture of ethyl 5-bromo-6-(4-fluorophenyl)-6-oxohexanoate (17.6 g), sodium formate (16.9 g) and methanol (150 ml) was stirred with heating under reflux for 16 hours. The reaction mixture was diluted with ethyl acetate (500 ml), and washed with water (200 ml×2). The organic layer was dried over anhydrous magnesium sulfate and then concentrated, the residue was subjected to silica gel column chromatography, and ethyl 6-(4-fluorophenyl)-5-hydroxy-6-oxohexanoate was obtained as a yellow oil (13.8 g, 96%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH2:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1>CN(C)C=O>[CH2:19]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][C:3]=2[N+:16]([O-:18])=[O:17])[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC1CC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1CC(=O)NN=C1c1ccc(N2CCN(Cc3ccccc3)CC2)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 95.7 %

Procedure:
16.1 g (60 mmol) of 6-(4-chloro-3-nitro-phenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone, 15.9 g (90 mmol) of 1-benzyl-piperazine and 7.3 ml (90 mmol) of pyridine are stirred into 60 ml of dimethyl formamide at 100° C. A further 5.8 g (33 mmol) of 1-benzyl-piperazine is added after 7 hours and stirring of the reaction mixture is continued for 12 hours at 100° C. When the reaction mixture is cold it is poured out on 300 ml of ice water and the solid which precipitates is suction filtered. The aqueous phase is extracted twice with 200 ml of dichloromethane. The combined organic phases are washed with water and saturated sodium chloride solution, dried, filtered and concentrated by evaporation in vacuo. The solid residue obtained is recrystallized from 500 ml of ethanol together with the solid initially obtained. 23.4 g (95%) of orange red crystals melting at 220° to 221° C. are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([O:12][CH2:13][CH3:14])=[CH:10][C:9]([O:15][CH2:16][CH3:17])=[CH:8][N:7]=1)=O)C.CC(C[AlH]CC(C)C)C>C(Cl)Cl.C1COCC1>[CH2:13]([O:12][C:11]1[C:6]([CH2:4][OH:3])=[N:7][CH:8]=[C:9]([O:15][CH2:16][CH3:17])[CH:10]=1)[CH3:14]
Reactant: CCOC(=O)c1ncc(OCC)cc1OCC
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOc1cnc(CO)c(OCC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.9 %

Procedure:
To the 3,5-diethoxy-pyridine-2-carboxylic acid ethyl ester solution (250 mg, 1.04 mmol) in CH2Cl2 (10 ml), a solution of DIBAL in THF (1N, 3 mL) is added, and stirred at room temperature for 20 minutes. Excess reagent is quenched with Glauber's salt (Na2H2SO4·10H2O), filtered and concentrated to afford (3,5-diethoxy-pyridin-2-yl)-methanol (166 mg, 80% yield); 1H NMR (300 MHz, CDCl3): 7.77 (s, 1H), 6.69 (s, 1H), 4.65 (s, 2H), 4.15 (q, J=6.9 Hz, 2H), 3.65 (q, J=6.9 Hz, 2H), 1.45 (t, J=6.9 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1.[CH:34](=O)[CH3:35].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:34][CH3:35])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: CC=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccccc1

Procedure:
4-Amino-N-((1-(5-benzylaminopentyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide (1.46 g) as starting compound, acetaldehyde (0.19 ml) and sodium cyanoborohydride (0.43 g) were reacted and treated in the same manner as in Example 136 to give 0.8 g of 4-amino-5-chloro-N-((1-(5-(N-ethyl-N-benzylamino)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:12](=[O:28])[C:13]2[C:18]([C:19]=1[O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:17][C:16]([C:25]([NH2:27])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[N:11]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:12](=[O:28])[C:13]2[C:18]([C:19]=1[O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:17][C:16]([C:25]([NH2:27])=[S:42])=[CH:15][CH:14]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(N)=O)cc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(N)=S)cc12
Yield: 65 %

Procedure:
To a suspension of 3-[[(tert-butoxycarbonyl)amino]methyl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide (0.44 g, 1 mmol) in toluene (20 ml) was added Lawesson's reagent (0.24 g, 0.6 mmol), and the mixture was refluxed under heating for 1 h. The reaction mixture was purified by silica gel column chromatography to give tert-butyl[6-(aminothiocarbonyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.18 g, 39.1%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:21]([O:23]CC3C=CC=CC=3)=[O:22])[N:11]([CH3:20])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:21]([OH:23])=[O:22])[N:11]([CH3:20])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: Cn1c(C(=O)OCc2ccccc2)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(C(=O)O)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 102.9 %

Procedure:
To a suspension of benzyl 4,5-di-(4-chlorophenyl)-1-methylimidazole-2-carboxylate (185 mg, 0.42 mmol) from Example 19, Step C in methanol (20 mL) was added aq. 5N sodium hydroxide (0.25 mL, 1.27 mmol). The reaction was stirred at rt for 20 hr, concentrated in vacuo, acidified with 2N hydrochloric acid (0.50 mL), and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated to dryness to afford the crude title acid (150 mg) as a mixture with decarboxylated material. This material was used directly in Step B.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[NH:8][CH:7]=1.[OH-].[K+]>CO>[C:15]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:5][CH2:4][C:3]([OH:17])=[O:2])#[N:16]
Reactant: COC(=O)CCc1c[nH]c2ccc(C#N)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc2[nH]cc(CCC(=O)O)c2c1
Yield: 100.2 %

Procedure:
Methy-5-cyanoindole-3-propionate (200 mg) was saponified in MeOH (10 mL)/KOH (150 mg, 0.88 mmol) at rt for 18 h. The solution was concentrated in vacuo, dissolved in water and washed with chloroform. The acidic layer was acidified and extracted with ethyl acetate, dried with Na2SO4, filtered and concentrated in vacuo to afford 188 mg of product. 1H NMR (CD3OD) δ ppm 2.83 (t, 2H, J=6.6 Hz), 4.43 (t, 2H, J=6.6 Hz), 6.6 (nd,1H, J3.2 Hz), 7.42 (d, 2H, J=7.3 Hz), 7.43 (s, 1H), 7.61 (d, 1H, J=7.3 Hz), 7.99 (s, 1H); LRMS ESI (M+H)+ 215.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[NH:6]2.[Si:18]([O:25][C@@H:26]1[C@H:30]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:29][C@@H:28]([NH2:40])[CH2:27]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(N(CC)C(C)C)(C)C>C(O)C>[Si:18]([O:25][C@@H:26]1[C@H:30]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH2:29][C@@H:28]([NH:40][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[NH:6]3)[CH2:27]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: Clc1cccc(-c2nc3c(Cl)ncnc3[nH]2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2ncnc3[nH]c(-c4cccc(Cl)c4)nc23)C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 83.5 %

Procedure:
A solution of 6-chloro-8-(3-chlorophenyl)-9H-purine (155 mg, 0.58 mmol), (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanamine (200 mg, 0.56 mmol) (Example 128, steps a-c), and N,N-diisopropylethylamine (0.20 mL, 1.17 mmol) in ethanol (2.00 mL) was microwaved at 160° C. for 30 minutes. The reaction mixture was concentrated under vacuum, and the residue was purified by flash chromatography (0 to 5% Methanol/DCM) to afford the title compound (275 mg, 76%) as a light yellow solid.