Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH2:18][CH3:19])=O)=[CH:4][NH:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[CH2:18]([O:17][C:15]([C:5]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:1][CH2:2][NH:3][CH:4]=1)=[S:29])[CH3:19]
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=S)C1=CNCCc2c1[nH]c1ccccc21
Yield: 5 %

Procedure:
To a solution of ethyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (0.51g, 2 mmol) in toluene (20 mL) was added Lawesson's reagent (1.45 g, 3.6 mmol). The resulting suspension was heated to reflux under nitrogen for 24 hours. Solvent was evaporated to give the crude product, which was purified by column chromatography on silica gel eluting with MeOH-DCM (1:19) to give 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carbothioic acid O-ethyl ester (27 mg); MS (ES): 273 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-])=O)[CH:7]=1.[OH-].[Na+].ClCCl>CO.C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH2:13])[C:9]([NH2:10])=[CH:11][CH:12]=1
Reactant: Nc1ccc(OCc2c(Cl)cccc2Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(OCc2c(Cl)cccc2Cl)cc1N
Reaction time: 0.25 h
Yield: 87.7 %

Procedure:
add 1.75 g of iron powder to a solution of 1.4 g of 4-[(2,6-dichlorobenzyl)oxy]-2-nitroaniline in 80 cm3 of methanol and 7 cm3 of glacial acetic acid. The reaction mixture is refluxed for three hours. The mixture is concentrated under reduced pressure (0.2 kPa). The residue is taken up in 30 cm3 of water and the pH of the suspension thus obtained is adjusted to 10-11 by adding 2N aqueous solution of sodium hydroxide; 350 cm3 of dichloromethane is then added. After vigorous stirring for 15 min, the insoluble matter is filtered. The filtrate is decanted, then the organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure (0.2 kPa). We obtain 1.11 g of 4-[(2,6-dichlorobenzyl)oxy]benzene-1,2-diamine in the form of a black resin, which has the following characteristics:
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[NH2:48][CH2:49][CH2:50][OH:51]>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([NH:48][CH2:49][CH2:50][OH:51])=[O:44])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:5])[CH3:3]
Reactant: NCCO
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NCCO)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 2-amino-ethanol (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H47Cl2N6O4 [(M+H)+] 709.3031, observed 709.3029.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([C:13]([OH:15])=O)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:39])[C@@H:28]([NH2:38])[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23][CH2:22]1)=[O:20])[CH3:17].C(Cl)CCl>CN(C=O)C.C(OCC)(=O)C>[CH2:16]([O:18][C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:39])[C@@H:28]([NH:38][C:13]([C:9]2[CH:10]=[C:11]([OH:12])[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[O:15])[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:25][CH2:26]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Reactant: O=C(O)c1cc(=O)n(-c2ccccc2)[nH]1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 7.2 g 1-phenyl-3-carboxy-5-pyrazolone and 12.1 g 4-((S)-2-amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester (prepared as described earlier) in 100 ml DMF 5.4 g HOBT and 6.7 g EDC were added and the reaction mixture was stirred for 12 h at RT. Then the reaction mixture was diluted with ethyl acetate and subsequently extracted with aqueous LiCl (4% w/w), 0.1 M HCl and aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was used in the subsequent reaction.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([CH2:23]Cl)=[CH2:22])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>C(O)C>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([CH2:23][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH2:22])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: C1CCNCC1
Solvent: O
Solvent: CCO
Product: C=C(CN1CCCCC1)CN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 7.0 g of 1-benzhydryl-4-(2-chloromethyl-2-propenyl)-piperazine (0.0205 mole) and 6.98 g of piperidine (0.082 mole) in 150 ml of absolute ethanol is heated until it has dissolved completely, and subjected to reflux for 3 hours. Then, it is conditioned to room temperature and the ethanol is removed by distillation. The resulting crude reaction product is treated with distilled water several times until a solid material is obtained which is then filtered and washed abundantly with water. By recrystallization from ethanol, 7.4 g crystals of 1-benzhydryl-4-(2-(1-piperidinylmethyl)-2-propenyl)-piperazine (I, R1 =benzhydryl, R2 =2-(1-piperidinylmethyl-2-propenyl) are obtained. Yield: 94%; m.p. 99°-102° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:28][CH2:29][OH:30].CCN(C(C)C)C(C)C>CN(C=O)C.C(#N)C.CS(C)=O>[NH2:26][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:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[CH2:28][CH2:29][OH:30]
Reactant: OCCBr
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CS(C)=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCCN3CCO)c2n1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
2-(Butyloxy)-8-(methyloxy)-9-[3-(2-piperidinyl)propyl]-9H-purin-6-amine (for example, as prepared for Intermediate 12) (0.036 g, 0.10 mmol) in DMF (0.5 mL) was added to 2-bromoethanol (commercially available, for example, from Aldrich) (0.0085 mL, 0.12 mmol) (dispensed as 0.12 mL of a stock solution of 1 mmol in acetonitrile (1 mL)). DIPEA (0.040 mL, 0.23 mmol) was added and the reaction mixture heated at 50° C. for 18 hours. An additional aliquot of the 2-bromoethanol solution (0.080 mL, 0.08 mmol) and DIPEA (0.040 mL, 0.23 mmol) were added and heating continued for a further 18 hours. The reaction mixture was diluted with DMSO:MeOH (0.2 mL) and the resultant solution purified by MDAP (Method A). Appropriate fractions were combined and evaporated in vacuo. The residue was dissolved in 4M HCl in dioxane (0.2 mL) and allowed to stand at room temperature for 4 hours. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus. The residue was redissolved in methanol (0.5 mL) and applied to the top of a 0.1 g aminopropyl SPE (preconditioned with methanol, 1.5 mL). The cartridge was washed with methanol (1.5 mL). The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound (0.0053 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11]2)=[CH:2]1.[H-].[Na+].[F:18][C:19]1[CH:38]=[CH:37][C:22]([CH2:23][NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[O:26])=[CH:21][CH:20]=1>CN(C=O)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][NH:24][C:25](=[O:26])[C:27]2[CH:32]=[CH:31][C:30]([S:33]([N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]([CH:10]4[CH2:14][CH2:13][C:12](=[O:15])[CH2:11]4)=[CH:2]3)(=[O:34])=[O:35])=[CH:29][CH:28]=2)=[CH:37][CH:38]=1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCC(c2c[nH]c3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCC(c2cn(S(=O)(=O)c3ccc(C(=O)NCc4ccc(F)cc4)cc3)c3ccccc23)C1
Yield: 29.7 %

Procedure:
Add a 3 ml DMF solution of 3-(1H-Indol-3-yl)-cyclopentanone (500 mg, 2.57 mmol, 1 eq) to a 3 ml DMF solution of NaH (155 mg, 60% by weight, 3.86 mmol, 1.1 eq) under N2 atmosphere. Stir reaction for 15 minutes and then add a 5 ml DMF solution of 4-(4-Fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (1.27 g, 3.86 mmol, 1.1 eq). Stir reaction for 48 hours, remove solvent on rotovap, and purify by silica gel chromatography to give N-(4-Fluoro-benzyl)-4-[3-(3-oxo-cyclopentyl)-indole-1-sulfonyl]-benzamide (375 mg, 22% yield). Mass Spectrum (m/e): 490.53 (MH+).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH:15][C:16]([C:18]1[N:19]([CH2:24][C:25](=[O:41])[NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:20]=[C:21]([NH2:23])[CH:22]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCl.C(N(CC)CC)C>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH:15][C:16]([C:18]1[N:19]([CH2:24][C:25](=[O:41])[NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:20]=[C:21]([NH:23][C:42](=[O:49])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:22]=1)=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc(C(=O)NC2CCCCC2OCc2ccccc2)n(CC(=O)NC2CCCCC2OCc2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cn1nc(NC(=O)c2ccccc2)cc1C(=O)NC1CCCCC1OCc1ccccc1)NC1CCCCC1OCc1ccccc1
Reaction time: 2 h

Procedure:
5-Amino-2-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-2H-pyrazole-3-carboxylic acid (2-benzyloxy-cyclohexyl)-amide (0.05 gm, 0.008 mmol) was dissolved in 1 ml of dichloromethane and 0.033 ml of triethylamine. Benzoyl chloride (0.014 ml) was added and the reaction mixture stirred for 2 hours. ESI M+1=664.
Reaction SMILES: [H-].[Na+].[Cl:3][CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][OH:7].[Cl:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:10][C:11]1[CH:16]=[C:15]([O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][Cl:3])[N:14]=[CH:13][N:12]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(CO)CCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(CCl)COc1cc(Cl)ncn1
Reaction time: 0.17 h

Procedure:
In 5 ml of tetrahydrofuran was suspended 0.14 g of sodium hydride (60% in oil), to which 0.5 ml of a solution containing 0.36 g of 3-chloro-2,2-dimethyl-1-propanol was added dropwise at 0° C., followed by stirring for 10 minutes. To this was added dropwise 0.5 ml of tetrahydrofuran containing 0.4 g of 4,6-dichloropyrimidine dissolved therein, followed by stirring at the same temperature for 2 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.62 g of 4-chloro-6-(3-chloro-2,2-dimethylpropyloxy)pyrimidine.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1.C([O-])(O)=O.[Na+]>C(OCC)C>[Br:11][C:12]1[CH:13]=[C:14]([S:18]([O:5][C:4]2[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.8 %

Procedure:
To a solution of 534 mg (4.30 mmol) of orcinol monohydrate and 1.00 g (3.91 mmol) of 3-bromobenzenesulfonyl chloride in 25 mL of diethyl ether was added 25 mL of saturated aqueous NaHCO3 and the biphasic mixture was stirred vigorously at ambient temperature for 3 days. The layers were separated and the aqueous layer extracted with 2×30 mL of ethyl acetate. The combined organic layers were washed with 50 mL of brine, dried (Na2SO4) and concentrated to 1.4 g of an amber-colored resin. Chromatography on 65 g of silica gel with 3% ethyl acetate-dichloromethane afforded 870 mg (65%) of the desired product as a colorless syrup: 1H-NMR (300 MHz; CDCl3) δ 8.02 (t, 1H, J=1.8 Hz), 7.79 (m, 2H), 7.41 (t, 1H, J=7.9 Hz), 6.57 (m, 1H), 6.40 (m, 1H), 6.33 (t, 1H, J=2.2 Hz) and 2.24 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[I:10]N1C(=O)CCC1=O.FC(F)(F)C(O)=O.N>C(O)(=O)C>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([I:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Cc1cc(N)ncc1Br
Reactant: O=C1CCC(=O)N1I
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1c(Br)cnc(N)c1I
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.5 %

Procedure:
5-Bromo-4-methylpyridine-2-amine (3.1 g) was dissolved in acetic acid (20 ml). N-Iodosuccinimide (3.8 g) and trifluoroacetic acid (0.2 ml) were added and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was poured into ice water and neutralized with 28% aqueous ammonia. Then, the precipitated solid was collected by filtration, washed with water and dried to give the title compound (4.9 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].CCOC(C)=O>CC1OCCC1>[CH2:27]([O:26][C:24](=[O:25])[NH:11][C:6]1[CH:5]=[C:4]([C:12]([F:13])([F:14])[F:15])[N:3]=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9])[CH3:28]
Reactant: Nc1cc(C(F)(F)F)nc(Cl)c1[N+](=O)[O-]
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1cc(C(F)(F)F)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
2-Chloro-3-nitro-6-trifluoromethyl-pyridin-4-ylamine (2.2 g, 9.1 mmol) was stirred in 2-MeTHF (20 ml) and triethylamine added (1.52 ml, 10.9 mmol). The solution was cooled in an ice bath to ˜5° C. before the dropwise addition of ethyl chloroformate (1.04 ml, 10.9 mmol), the solution warmed to ambient temperature and left to stir under a nitrogen atmosphere for 16 h. 20 ml EtOAc and 10 ml H20 were added and the phases separated, washed with a additional 2×10 ml sat'd brine solution. The organic extract was dried over MgSO4, concentrated in vacuo and preabsorbed onto a silica column. Elution with Hept:EtOAc, 9:1 gave 2.1 g of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:16]([O:17][CH3:18])=[CH:15][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.CS([C:22]1[N:27]=[CH:26][C:25]2=[CH:28][CH:29]=[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])[N:24]2[N:23]=1)=O.C(O)(C(F)(F)F)=O>>[CH3:18][O:17][C:16]1[C:2]([NH:1][C:22]2[N:27]=[CH:26][C:25]3=[CH:28][CH:29]=[C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH3:38])[N:24]3[N:23]=2)=[CH:3][C:4]2[CH2:10][CH2:9][N:8]([CH2:11][C@H:12]([OH:14])[CH3:13])[CH2:7][CH2:6][C:5]=2[CH:15]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: COc1cc2c(cc1N)CCN(C[C@@H](C)O)CC2
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1Nc1ncc3ccc(-c4ccccc4OC)n3n1)CCN(C[C@@H](C)O)CC2

Procedure:
Following a procedure analogous to 251c, (R)-1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol (0.139 g, 0.557 mmol) and 2-methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (64 mg, 0.22 mol) were converted to the title compounds (22.66 mgs) as a TFA salt. H-NMR (CDCl3) δ 9.30 (broad s, 1H, TFA), 8.96 (s, 1H), 7.97 (s, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.61 (s, 1H), 7.50-7.45 (m, 1H), 7.26-7.21 (m, 1H), 7.14-7.09 (m, 1H), 6.99-6.93 (m, 2H), 6.93 (s, 1H), 4.22-4.12 (m, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 3.69-3.60 (m, 2H), 3.29-2.93 (complex series of m, 8H), 1.16 (d, J=6.0 Hz, 3H); LC/MS (ESI+): 474.6 (M+H).
Reaction SMILES: [CH:1]1([N:7]([CH:28]2[CH2:33][CH2:32][NH2+:31][CH2:30][CH2:29]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])[CH2:19][CH2:18]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[CH:35]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH:1]1([N:7]([CH:28]2[CH2:33][CH2:32][N:31]([C:40]([CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[O:41])[CH2:30][CH2:29]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])[CH2:19][CH2:18]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCC1
Reactant: CCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CC[NH2+]CC3)s2)CC1
Agent: [Cl-]
Product: CCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCN(C(=O)C4CCCC4)CC3)s2)CC1

Procedure:
Prepared in 65% (193 mg) yield as described in general procedure (N) from 4-{1-cyclohexyl-3-[5-(4-ethanesulfonyl-piperazin-1-ylmethyl)-thiazol-2-yl]-ureido}-piperidinium; chloride (268 mg, 0.5 mmol) and cyclopentanecarbonyl chloride (80 mg, 0.6 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].I[CH2:37][CH3:38]>CN(C=O)C>[CH2:37]([O:1][C:2]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1)=[O:5])[CH3:38]
Reactant: CCI
Reactant: CC(C)Oc1ccc(NC(=O)c2cc(S(=O)(=O)N3CCCCC3)ccc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(S(=O)(=O)N2CCCCC2)cc1C(=O)Nc1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
The compound (30 mg) obtained in Example 151 was dissolved in DMF (0.50 mL), then potassium carbonate (30 mg) and iodoethane (0.030 mL) were added thereto in that order, and stirred at room temperature for 18 hours. This was purified through reversed-phase HPLC (0.1% TFA acetonitrile/H2O=from 10% to 95%, gradient) to give the entitled compound (25 mg, 78%) as a colorless solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[N:19]=3)[N:14]=[CH:13][CH:12]=2)[OH:10])[CH2:4][CH2:3]1.[O:23]=[C:24]1[NH:33][C:32]2[N:31]=[CH:30][C:29]([CH:34]=O)=[CH:28][C:27]=2[CH2:26][CH2:25]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>ClC(Cl)C.C(O)C>[OH:10][C@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[N:19]=2)[N:14]=[CH:13][CH:12]=1)[CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH2:34][C:29]2[CH:28]=[C:27]3[C:32](=[N:31][CH:30]=2)[NH:33][C:24](=[O:23])[CH2:25][CH2:26]3)[CH2:3][CH2:4]1
Reactant: O=Cc1cnc2c(c1)CCC(=O)N2
Reactant: COc1ccc2nccc([C@@H](O)CN3CCC(N)CC3)c2n1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCO
Product: COc1ccc2nccc([C@@H](O)CN3CCC(NCc4cnc5c(c4)CCC(=O)N5)CC3)c2n1
Reaction time: 72 h
Yield: 21 %

Procedure:
To a stirred solution of (R)-2-(4-aminopiperidin-1-yl)-1-(6-methoxy-[1,5]naphthyridin-4-yl)ethanol (2f) (0.34 g, 1.13 mmole) in dichloroethane (10 mL) and dry ethanol (5 mL) at RT was added 7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridine-3-carboxaldehyde (113 g) (0.20 g, 1.13 mmole) and granular Na2SO4 (approximately 100 mg). After 72 h, the reaction was concentrated. The remaining residue was dissolved in dry ethanol and reacted with NaBH4 (0.043 g, 1.13 mmole). After 12 h at RT, the reaction was concentrated under vacuum and the residue was dissolved in a mixture of H2O (10 mL) and saturated aqueous NaHCO3 (50 mL). The aqueous solution was extracted with EtOAc (2×75 mL) and the combined organic phases were washed with brine then were dried over Na2SO4. Flash chromatography on silica gel (9:1 CHCl3/MeOH containing 5% NH4OH) afforded the title compound (0.11 g, 21%) as a white solid: 1H NMR (400 MHz, d6-DMSO) δ 10.43 (br s, 1H), 8.77 (d, J=4.5 Hz, 1H), 8.23 (d, J=9.0 Hz, 1H), 8.01 (s, 1H), 7.75 (d, J=4.5 Hz, 1H), 7.58 (s, 1H), 7.24 (d, J=9.0 Hz, 1H), 5.77 (m, 1H), 5.23 (br s, 1H), 4.02 (s, 3H), 3.63 (s, 2H), 3.38 (m, 2H), 3.11 (m, 1H), 2.83 (m, 2H), 2.65 (m, 1H), 2.47 (m, 2H), 2.32 (m, 1H), 2.17 (m, 1H), 1.79 (m, 2H), 1.27 (m, 2H); MS (ES) m/e 463 M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[S-:13][C:14]#[N:15].[K+].O>C(O)C>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:13][C:14]#[N:15]
Reactant: N#C[S-]
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CSCC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A solution of 2-bromo-1-(2,4-dichlorophenyl)ethanone (7.09 g, 26.5 mmol) and potassium thiocyanate (2.57 g, 26.5 mmol) in ethanol (70 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (70 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 5.97 g (91.7%) of the desired product as a solid.
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[C:8]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:9]=[CH:10][C:11]=2[O:15][CH2:16][CH3:17])[S:4]1(=[O:6])=[O:5].[Na].[C:28]1([N:34]2[C:38]([SH:39])=[N:37][N:36]=[N:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([N:34]2[C:38]([S:39][CH2:2][N:3]3[C:13](=[O:14])[C:12]4[C:7](=[C:8]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:9]=[CH:10][C:11]=4[O:15][CH2:16][CH3:17])[S:4]3(=[O:6])=[O:5])=[N:37][N:36]=[N:35]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOc1ccc(OCC(=O)OC(C)(C)C)c2c1C(=O)N(CCl)S2(=O)=O
Reactant: Sc1nnnn1-c1ccccc1
Agent: [Na]
Product: CCOc1ccc(OCC(=O)OC(C)(C)C)c2c1C(=O)N(CSc1nnnn1-c1ccccc1)S2(=O)=O
Yield: 71 %

Procedure:
By the method of part F of Example 45 condensation of 2-chloromethyl-4-ethoxy-7-(t-butoxycarbonylmethoxy)saccharin (1.42 g) and 1-phenyltetrazol-5-thiol sodium salt (0.70 g initially and a small amount more after 6 hours reaction time, total reaction time 8 hours) and isolation of the product (1.20 g) by extraction with dichloromethane and purification of part (0.42 g) thereof by column chromatography on silica gel using dichloromethane-acetone (up to 98:2) as eluant afforded 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-7-(t-butoxycarbonylmethoxy)saccharin, 300 mg, 71% yield, mp 110°-112° C.