Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([O:27]C(=O)C)=[C:8]2[C:16]([Cl:17])=[CH:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+].CO>>[Cl:17][C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:5])[C:7]=2[OH:27])[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH:15]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2ccc(OC)cc2)c1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cn2cc(Cl)c3c(O)c(C(=O)NCC(=O)O)nc(C#N)c32)cc1

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-3-chloro-7-cyano-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 415 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](Br)[CH:17]=2)[CH:12]=[C:11]([Cl:20])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[CH:28]=3)[CH:17]=2)[CH:12]=[C:11]([Cl:20])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Clc1cc2ccc(Br)cc2c(OCc2ccccc2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2ccc3cc(Cl)nc(OCc4ccccc4)c3c2)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a mixture of 1-(benzyloxy)-7-bromo-3-chloroisoquinoline (1.00 g, 2.86 mmol, 1.0 eq), 3-methoxyphenylboronic acid (435 mg, 2.86 mmol, 1.0 eq), K2CO3 (2.13 g, 15.4 mmol, 5.4 eq) in dioxane (10 mL) and H2O (5 mL) was added Pd(PPh3)2Cl2 (100 mg, 0.15 mmol, 0.05 eq) under N2 atmosphere. The resulting mixture was stirred at 110° C. under N2 atmosphere overnight. The solvent was removed in vacuo and the residue was purified with chromatography on silica gel (hexane/ethyl acetate 250:1) to give 550 mg of lxvi-a as white solid (yield 37%). LCMS m/z=376.0 (M+1) (Method B) (retention time=2.43 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][C:6]2=[CH:5][C:4]=1[NH:12][C:13](=[O:21])OC1C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][C:6]2=[CH:5][C:4]=1[NH:12][C:13]([N:35]1[CH2:34][CH2:33][N:32]([C:26]2[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=2)[CH2:37][CH2:36]1)=[O:21]
Reactant: COc1nc2c(cc1NC(=O)Oc1ccccc1)CCC2
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc4c(nc3OC)CCC4)CC2)c1
Yield: 59 %

Procedure:
Phenyl N-(2-methoxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:6])[CH2:4][Br:5].N1C=CN=C1.[C:12]([Si:16](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)C>[Br:1][CH2:2][CH:3]([CH2:4][Br:5])[O:6][Si:16]([C:12]([CH3:15])([CH3:14])[CH3:13])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC(CBr)CBr
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](OC(CBr)CBr)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
To a solution of 1,3-dibromo-2-propanol (20.00 g, 91.79 mmol) in methylene chloride (DCM) (100 mL) cooled to 0° C. was added 1H-imidazole (6.56 g, 96.4 mmol) followed by tert-butylchlorodiphenylsilane (25.1 mL, 96.4 mmol) and 4-dimethylaminopyridine (1.12 g, 9.18 mmol). The reaction was stirred with warming to room temperature overnight. The reaction mixture was diluted with diethyl ether, washed with water, and the aqueous layer was again extracted once with ether. The combined organic extracts were washed with water, followed by brine, dried over sodium sulfate, decanted and concentrated. Flash chromatography (eluting with a gradient from 0-15% ethyl acetate/hexanes) afforded desired product (42 g, 100%). 1H NMR (300 MHz, CDCl3): δ 7.72-7.66 (m, 4H), 7.51-7.37 (m, 6H), 4.00-3.91 (m, 1H), 3.49-3.45 (m, 4H), 1.09 (s, 9H).
Reaction SMILES: [Cl:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([CH:9](O)[CH3:10])=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O>C(Cl)Cl>[Cl:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]([Cl:16])[CH3:10])=[CH:7][N:8]=1
Reactant: CC(O)c1ccc(C(F)(F)Cl)nc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(Cl)c1ccc(C(F)(F)Cl)nc1
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a solution of 1-{6-[chloro(difluoro)methyl]pyridin-3-yl}ethanol (0.78 g, 3.77 mmol) in CH2Cl2 (40 mL) was added thionyl chloride (0.54 mL, 7.54 mmol) dropwise at room temperature. After 1 hr, the reaction was quenched slowly with saturated NaHCO3 aqueous solution and the two phases were separated. The organic layer was dried over Na2SO4, filtered, concentrated, and dried in vacuum to give 0.83 g of the crude 2-[chloro(difluoro)methyl]-5-(1-chloroethyl)pyridine (D) as brown oil in 98% yield, which was directly used for the next step reaction. GC-MS: mass calcd for C8H7Cl2F2N [M]+ 225. Found 225.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][S:10][C:11](=N)N)[N:8]=1.[CH:14]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33]CCl)[CH2:29][CH2:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.[OH-].[Na+]>C(O)C>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][S:10][CH2:11][CH2:33][N:30]2[CH2:31][CH2:32][N:27]([CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)[N:8]=1
Reactant: ClCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: N=C(N)SCc1csc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc(CSCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1
Yield: 71 %

Procedure:
S-(2-Aminothiazol-4-ylmethyl)isothiourea dihydrochloride (2.6 g) and 4-benzhydryl-1-(2-chloroethyl)piperazine (3.87 g) were suspended in ethanol (50 ml) in a stream of nitrogen, and thereto was added at a time water (30 ml) containing sodium hydroxide (2.8 g) at ambient temperature with stirring, and the stirring was continued at 50° C. for half an hour. The precipitated crystals were collected by filtration, washed with ethanol and then recrystallized from methanol to give pale yellow crystals (3.0 g) of 2-amino-4-[2-(4-benzhydrylpiperazin-1-yl)ethylthiomethyl]thiazole, mp 159°-161° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][N:4]=1.[Li]C(CC)C.CNN(NC)[C:20](=[O:22])[CH3:21].O>CCOCC>[F:1][C:2]([F:11])([F:10])[C:3]1[N:4]=[CH:5][C:6]([C:20](=[O:22])[CH3:21])=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: CNN(NC)C(C)=O
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: O
Product: CC(=O)c1ccc(C(F)(F)F)nc1
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
To a solution of 2-trifluoromethyl-5-bromopyridine (5.0 g, 22 mmol) in Et2O (50 mL) was added sec-BuLi (0.91 M in cyclohexane, 24 mL, 22 mmol) at −78° C. After 10 minutes of stirring, N,N-dimethylaminoacetamide (2.3 mL, 24 mmol) dissolved in Et2O (10 mL) was added drop wise. Stirring was continued at −78° C. for 1 h and then at rt over night. The reaction mixture was poured into water (100 mL) and the water phase was extracted with Et2O (3×100 mL). Combined organics were washed with water and brine and dried (MgSO4). After careful evaporation of the solvent, the crude was purified by column chromotography (SiO2, pentane/ether 9/1) to give the title compound (2.3 g, 12 mmol, 54%) as a light yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:5]([C:6]3[C:11]2=[CH:10][C:9]([NH2:16])=[CH:8][CH:7]=3)[CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([NH:34][CH3:35])(=[O:33])=[O:32])[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([NH:34][CH3:35])(=[O:33])=[O:32])=[N:23][C:18]([NH:16][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[CH:5]2[CH2:15][CH2:14][CH:12]3[CH2:13][N:3]([CH2:1][CH3:2])[CH2:4]2)=[N:19][CH:20]=1
Reactant: CCN1CC2CCC(C1)c1cc(N)ccc12
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCN1CC2CCC(C1)c1cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)NC)n3)ccc12

Procedure:
2-[5-Chloro-2-(10-ethyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide was prepared from 10-ethyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide in an analogous manner to Example 271. Product isolated as a clear thin film (13 mg, 18%). LCMS (m/e) 513 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.13 (s, 1H), 8.48 (d, 1H, J=8.4 Hz), 8.01 (s, 1H), 7.95 (d, 1H, J=7.9 Hz), 7.55 (t, 1H, J=7.7 Hz), 7.27-7.20 (m, 2H), 7.06 (s, 1H), 6.99 (d, 1H, J=8.5 Hz), 5.11 (bs, 1H), 3.00-2.80 (m, 4H), 2.63 (s, 3H), 2.44 (q, 2H, J=6.7 Hz), 2.30-2.10 (m, 4H), 1.62-1.58 (m, 2H), 1.01 (t, 3H, J=7.0 Hz).
Reaction SMILES: C(OC(N1CCC([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[C:23]#[N:24])CC1)=O)(C)(C)C.[ClH:25].O1[CH2:31][CH2:30]OCC1>>[ClH:25].[F:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH2:14][N:24]2[CH2:31][CH2:30][CH2:16][CH2:17][CH2:23]2)[C:17]=1[C:23]#[N:24]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cccc(F)c2C#N)CC1
Agent: Cl
Product: N#Cc1c(F)cccc1OCN1CCCCC1
Reaction time: 5 h
Yield: 66 %

Procedure:
4-(2-Cyano-3-fluorophenoxymethyl)piperidine-1-carboxylic acid tert-butyl ester (920 mg, 2.8 mmol) was dissolved in 5 mL of dioxane, and 3 mL of 4M HCl in dioxane was added over 1 minute at room temperature. Reaction stirred for 5 hrs and white precipitate was collected by filtration. Solids rinsed once with cold ether and dried to afford 2-fluoro-6-(piperidin-1-ylmethoxy)benzonitrile hydrochloride. (500 mg; 66% yield).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:13](=[O:25])[CH2:12]1)=O)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:22][Si:21]([CH3:24])([CH3:23])[CH2:20][CH2:19][O:18][CH2:17][N:14]1[CH2:15][CH2:16][NH:11][CH2:12][C:13]1=[O:25]
Reactant: C[Si](C)(C)CCOCN1CCN(C(=O)OCc2ccccc2)CC1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[Si](C)(C)CCOCN1CCNCC1=O

Procedure:
3-Oxo-4-(2-trimethylsilanyl-ethoxymethyl)-piperazine-1-carboxylic acid benzyl ester (3.00 g, 8.22 mmol) was dissolved in TIF (30 ml) and MeOH (30 ml), and vigorously stirred on 20% Pd(OH)2/C under a hydrogen atmosphere (1 atm) for 14 h. After N2 was purged, Pd(OH)2/C was removed through filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3/MeOH=95/5 to 90/10) to obtain the intended compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[N:7]([CH2:20][CH:21]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:22]1[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=1)[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([O:5][C:6](=[O:37])[N:7]([CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[CH2:20][CH:21]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CCOc1ccc([N+](=O)[O-])cc1)CC(O[Si](C)(C)C(C)(C)C)c1ccc(Cl)nc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCOc1ccc(N)cc1)CC(O[Si](C)(C)C(C)(C)C)c1cccnc1
Reaction time: 1.5 h
Yield: 61.9 %

Procedure:
To a stirred slurry of [2-(tert-butyl-dimethyl-silanyloxy)-2-(6-chloro-pyridin-3-yl)-ethyl]-[2-(4-nitro-phenoxy)-ethyl]-carbamic acid tert-butyl ester (530 mg) and 10% palladium-on-carbon (530 mg) in MeOH (20 mL) was added ammonium formate (1.2 g). After 1.5 h, the reaction mixture was filtered through Celite® washing with methanol and concentrated in vacuo. The residue was suspended in half-saturated aqueous sodium bicarbonate, washed with ethyl acetate (3×), the combined organic phases were dried (Na2SO4) and concentrated in vacuo. The resulting oil was chromatographed on a Biotage® F40S column (40% ethyl acetate/hexanes) to afford 290 mg of the title compound (I-3d) as a colorless oil.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]([F:23])([F:22])[C:14]1[N:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][CH:15]=1>C1COCC1>[F:23][C:13]([F:22])([F:12])[C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[CH2:8][O:21]2)=[CH:18][N:19]=1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: FC(F)(F)c1ccc(C2CO2)cn1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 6-(trifluoromethyl)pyridine-3-carbaldehyde (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[N:5]([CH:12]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:23]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[CH2:6][CH:7](OC)OC)[CH3:2].Cl>CC(C)=O.O>[CH2:1]([O:3][C:4]([N:5]1[CH:6]=[CH:7][C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[C:25]([O:28][CH3:29])[CH:26]=2)[CH:12]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)=[O:38])[CH3:2]
Reactant: CCOC(=O)N(CC(OC)OC)C(Cc1cccc(OC)c1)c1ccc(OC)c(OCc2ccccc2)c1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)N1C=Cc2cc(OC)c(OCc3ccccc3)cc2C1Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
[1-(3-Benzyloxy-4-methoxy-phenyl)-2-(3-methoxy-phenyl)-ethyl]-(2,2-dimethoxy-ethyl)-carbamic acid ethyl ester (3.15 g, 6.01 mmol) was dissolved in acetone (125 mL) at 0° C., and 6M aqueous hydrochloric acid (25 mL) was added dropwise. After the addition was complete, the mixture was stored at 0° C. overnight (14 hours). The mixture was warmed to room temperature and stirred×4 hours. The mixture was cooled in an ice bath and diluted with water (150 mL). The mixture was extracted with ethyl acetate (3×60 mL). The combined organic extracts were washed with water (60 mL), saturated aqueous sodium chloride solution (60 mL) and dried over anhydrous magnesium sulfate. Concentration of the solvent gave an oily solid that was crystallized from ethyl acetate/hexanes to give 7-benzyloxy-6-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (1.32 g, 2.87 mmol, 48%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:9])[CH2:7][SH:8])[CH3:4].Cl[C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:12]=1[C:13]#[N:14]>CN(C)C=O>[NH2:14][C:13]1[C:12]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]=2[S:8][C:7]=1[C:6]([O:5][CH2:3][CH3:4])=[O:9]
Reactant: Cc1cccc(Cl)c1C#N
Reactant: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cccc(C)c2c1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.5 %

Procedure:
At 0° C., sodium hydride, 60% dispersion in mineral oil, (280 mg, 7 mmol) was added to a solution of ethyl-2-mercaptoacetate (750 μL, 6.8 mmol) in N,N-dimethylformamide (20 mL). After 15 minutes, 2-chloro-6-methylbenzonitrile (1 g, 6.60 mmol) was also added to the mixture which was stirred at room temperature for 2 hours more. The mixture was then concentrated and the residue was diluted with ethyl acetate. The organic layer was washed with water (30 mL), brine (30 mL), dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (cyclohexane/dichloromethane 50/50) to afford the desired benzothiophene (23a) as a white solid (800 mg, 3.40 mmol, 52%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][P:13]([OH:16])(=[O:15])[OH:14])[C:7](=[O:17])[C:6](=[O:18])[NH:5]2.C(=O)([O-])[O-].[Na+].[Na+].[C:25](OC(=O)C)(=[O:27])[CH3:26]>O>[C:25]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][P:13]([OH:16])(=[O:14])[OH:15])[C:7](=[O:17])[C:6](=[O:18])[NH:5]2)(=[O:27])[CH3:26]
Reactant: Nc1ccc2c(c1)[nH]c(=O)c(=O)n2CP(=O)(O)O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)[nH]c(=O)c(=O)n2CP(=O)(O)O
Reaction time: 1 h

Procedure:
100 mg of 1-(6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-l-yl)methanephosphonic acid is adjusted in 20 ml of water to a pH of 9.5 with a saturated sodium carbonate solution and combined with 0.2 ml of acetic anhydride. After one hour of stirring, the mixture is concentrated, dissolved in a minimum amount of water, introduced into an ion exchanger (IR 120, strongly acidic), and eluted with water: The corresponding fractions are combined, concentrated, and dried, thus obtaining 110 mg of 1-(6-acetylamino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)methanephosphonic acid, mp: 120° C.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13]Cl)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.F[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[CH2:25][CH2:26][CH2:27][NH2:28]>>[NH:21]1[C:22]2[C:18](=[CH:17][CH:16]=[CH:24][CH:23]=2)[C:19]([CH2:25][CH2:26][CH2:27][NH:28][CH2:13][CH2:12][O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[CH:20]1
Reactant: NCCCc1c[nH]c2ccc(F)cc12
Reactant: ClCCOc1cccc2ccccc12
Product: c1ccc2c(OCCNCCCc3c[nH]c4ccccc34)cccc2c1
Yield: 85 %

Procedure:
This compound was prepared in the manner described above for Example 13 by replacing 2-(indan-4-yloxy)-ethylchloride with 2-(napthalen-1 -yloxy)-ethylchloride (0.6 g, 2.8 mmol), and 3-(5-fluoro-1H-indol-3-yl)-propylamine with 3-(1H-indol-3-yl)-propylarmine (1.35 g, 7.2 mmol) in 85% yield (1.42 g) as a yellow solid: mp 119-120° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)[CH3:2].O.NN>C(O)C.[Ni]>[CH2:17]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1)[CH3:18]
Reactant: CCN(CC)CCCOc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CCN(CC)CCCOc1ccc(N)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of diethyl-[3-(4-nitro-phenoxy)-propyl]-amine (15.2 g, 60.4 mmol) is dissolved in absolute ethanol (350 mL) and to this solution is added hydrazine monohydrate (18 mL, 6 equiv.) followed by the addition of a small portion of Raney nickel. The reaction mixture is heated to 50° C. with stirring for 3 h until all gas evolution has ceased. The reaction mixture is filtered through celite to remove the Raney nickel. The filtrate is concentrated under reduced pressure to give the named compound as a greenish brown oil (quantitative). This material is carried on in subsequent steps without purification.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN.[ClH:26]>C(O)C>[ClH:26].[C:1]1([S:7]([CH2:10][CH2:11][NH2:12])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)c1ccccc1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 40.5 %

Procedure:
A solution of 32.3 g (0.102 mole) of 2-[2-(phenylsulfonyl)ethyl]-1H-isoindole-1,3-(2H)-dione and 11.8 g (0.2 mole) of 85% hydrazine hydrate in 500 ml of absolute ethanol was refluxed for 6 hr. The reaction mixture was cooled to room temperature, filtered and concentrated. The concentrate was dissolved in chloroform and extracted with 5% sodium hydroxide. The chloroform layer was dried and evaporated to give a clear oil. The oil, the free base of the title compound, was reacted with ethereal hydrogen chloride. Recrystallization of the precipitated salt from methanol-diethyl ether gave white crystalline product, m.p. 151°-154° C. in 40.5% yield.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CC(O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1COCCN1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1
Yield: 103.4 %

Procedure:
1-Fluoro-4-nitrobenzene (3.00 mL, 28.3 mmol) was combined in a flask with anhydrous 2-propanol (28 mL), triethylamine (4.34 mL, 311 mmol), and morpholine (2.47 mL, 28.3 mmol). The mixture was refluxed for 3.5 h before adding additional morpholine (2.47 mL, 28.3 mmol) and refluxing for 20 h. The mixture was then cooled and concentrated under reduced pressure. Purification by silica gel flash chromatography provided 161-a (6.09 g, 98%) as a 95% pure solid. MS: APCI (AP−): 207.1 (M)−.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][OH:5].CS(O[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=3)[N:26]=2)[CH2:17][CH2:16]1)(=O)=O>>[F:33][C:30]([F:31])([F:32])[C:27]1[N:25]2[N:26]=[C:21]([N:18]3[CH2:17][CH2:16][CH:15]([CH2:14][O:5][CH2:4][C:3]([O:7][CH3:8])=[O:6])[CH2:20][CH2:19]3)[CH:22]=[CH:23][C:24]2=[N:29][N:28]=1
Reactant: CS(=O)(=O)OCC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Product: COC(=O)COCC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 100 °C
Yield: 17.4 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.120 g, 3.0 mmol) was added to neat methyl glycolate (1.544 mL, 20.0 mmol). When the effervescence had subsided 6-[4-(methanesulfonyloxymethyl)piperidin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.759 g, 2.0 mmol) was added and the mixture was heated at 100° C. for 40 minutes. The reaction mixture was partitioned between DCM and water. The organic phase was washed with water and brine, dried over MgSO4 and evaporated. The product was isolated by MPLC silica chromatography, eluting with ethyl acetate. The product containing fractions were evaporated to an oil which crystallised from ether, giving methyl 2-[[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]methoxy]acetate (0.130 g, 17%).
Reaction SMILES: Cl.O[CH:3]([CH2:18]OC1C=CC(C(C)(C)C)=CC=1)[CH2:4]NC(C)(C)CC1C=CC(OC)=CC=1.Cl.[OH:31][CH:32]([CH2:47][O:48][C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=1)[CH2:33][NH:34][C:35]([CH3:46])([CH3:45])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1>>[ClH:55].[OH:31][CH:32]([CH2:47][O:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH:3]([CH3:18])[CH3:4])[CH:50]=1)[CH2:33][NH:34][C:35]([CH3:46])([CH3:45])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2cccc(C(C)C)c2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 356 (M−15,0.1), 251 (18), 250 (100), 163 (6), 121 (21), 117 (5), 114 (10), 91 (9).