Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C]=O.[C:10](OC=C)(=O)[CH3:11]>[Ru]>[C:1]([O:7][CH:10]=[CH2:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: C=COC(C)=O
Reactant: CC(C)(C)C(=O)O
Agent: [Ru]
Agent: [C]=O
Product: C=COC(=O)C(C)(C)C
Yield: 96 %

Procedure:
Vinyl pivalate (91 pounds) was prepared in two, 20 gallon-batch runs in a 30 gallon stainless steel reactor. In two batches, pivalic acid (75.5 lbs, 10 gallons) and vinyl acetate (77.9 lbs, 10 gallons) were transvinylated in the presence of 300 ppm ruthenium catalyst, described in the preceeding paragraph, at 145° C. using a 50 psig carbon monoxide reaction atmosphere for 5 hours. Reaction product was removed from the reactor by vacuum distillation (60°-130° C., 240 mm Hg) from the ruthenium catalyst without difficulty. Based on gas chromatographic analysis, 90.4% and 94.7% of the vinyl pivalate respectively formed in the two reaction batches, could be accounted for after distillation. This demonstrates that reequilibration of vinyl pivalate (and acetic acid) to vinyl acetate (and pivalic acid) was successfully controlled during distillation within 9.6% (batch 1) and 5.3% (batch 2), respectively. Mass balances for all components were better than 98%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([OH:25])[C@@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2].[C:26](C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.O(C)S(C(F)(F)F)(=O)=O.Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([O:25][CH3:26])[C@@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)n1
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@@H](O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Agent: COS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)[C@H]1[C@@H]2C[C@@H](OC)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Yield: 62.9 %

Procedure:
A solution of (1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (VII-1) (345 mg, 1.0 mmol), 2,6-di-tert.-butylpyridine (1.35 mL, 6.0 mmol) and methyl triflate (0.55 mL, 5.0 mmol) in DCM (2 mL) was stirred at 23° C. for 4 d. The reaction mixture was poured on ice, acidified with 1 N HCl and extracted with ether. After washing with sat. NaHCO3 -sol., brine and drying over MgSO4 the crude product was purified by silica gel column chromatography with hexane/EtOAc 4:1 to give (1S,2R,3R,5R,6S)-2-azido-3-methoxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXIII-1) (226 mg, 63%) as a yellow oil. 1H-NMR (250 MHz, CDC13) □1.26 (3H, t, J=7.1 Hz), 1.77 (1H, t, J=3.5 Hz), 2.05-2.18 (2H, m), 2.25 (1H, dd, J=7, 3.5 Hz), 2.34 (1H, dd, J=12, 7 Hz), 3.28 (3H, s), 3.42 (1H, bt,J=8 Hz), 4.12 (2H, q, J=7.1 Hz), 5.25 (1H, d,J=12 Hz), 5.34 (1H, d, J=12 Hz), 7.30-7.40 (5H, m); MS [EI] 258 [ (M--CO2Et-N2)+ ]; □D20 -48.02° (c=1.11, CHCl3).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]1([CH2:9][C:10]#[C:11][C:12]#[N:13])[CH2:8][CH2:7][CH2:6][CH2:5]1.CCO>[OH-].[Na+].CCOCC>[CH:4]1([CH2:9][C:10]2[O:3][N:2]=[C:12]([NH2:13])[CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: NO
Reactant: N#CC#CCC1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: Nc1cc(CC2CCCC2)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydroxylamine HCl (20.3 mmol) was dissolved in 14.9 mL of 2.5 M aqueous NaOH solution at rt and 4-Cyclopentyl-but-2-ynenitrile (16.9 mmol) was added in solution with 50 mL EtOH. The cloudy suspension was stirred at rt for 2 hours. The reaction material was then diluted with 200 mL of Et2O and washed with two 50 mL portions of water, followed by 50 mL of aqueous saturated sodium chloride solution. The organics were then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude products were then purified through flash chromatography to give 5-Cyclopentylmethyl-isoxazol-3-ylamine.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[C:28]([F:34])[C:27]=1[O:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1.[Cl:46][C:47]1[CH:51]=[CH:50][NH:49][C:48]=1[C:52](O)=[O:53].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:46][C:47]1[CH:51]=[CH:50][NH:49][C:48]=1[C:52]([NH:33][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([Cl:25])=[C:27]([O:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38][CH:37]=2)[C:28]=1[F:34])=[O:53]
Reactant: NCc1ccc(Cl)c(Oc2cccc3ccccc23)c1F
Reactant: O=C(O)c1[nH]ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)c(Oc2cccc3ccccc23)c1F)c1[nH]ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
HATU (0.113 g, 0.298 mmol) was added to a solution of {[4-chloro-2-fluoro-3-(1-naphthalenyloxy)phenyl]methyl}amine (0.060 g, 0.199 mmol) and 3-chloro-1H-pyrrole-2-carboxylic acid (0.0289 g, 0.199 mmol) nd diisopropylethylamine (0.052 mL, 0.298 mmol) and diisopropylethylamine (0.052 mL, 0.298 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% TFA) to give the title compound (0.018 g, 21%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.80 (br. s., 1H), 8.29-8.40 (m, 1H), 7.91-8.04 (m, 2H), 7.57-7.69 (m, 3H), 7.51 (dd, 1H), 7.35 (t, 2H), 6.93 (t, 1H), 6.52 (d, 1H), 6.19 (t, 1H), 4.54 (d, 2H). ES MS: m/z 429 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17]O)[N:7]=1)[CH3:2].CS([Cl:24])(=O)=O.N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][Cl:24])[N:7]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1nn(CO)c(=O)c2ccccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Cc1nn(CCl)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl-3-hydroxymethyl-4-oxo-3-H-phthalazin-1-ylacetate (1.31 g) and methanesulfonyl chloride (0.69 g) in methylene chloride (10 ml) containing pyridine (0.8 ml) was stirred at room temperature overnight. Upon evaporation of methylene chloride and purification of the residue by chromatography on silica gel, eluting with a mixture of a chloroform and ethyl acetate (9:1), the title product was obtained (yield: 0.51 g; m.p. 99°-100° C.).
Reaction SMILES: [CH:1]([OH:3])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.Cl.[NH2:34][CH2:35][C:36]1[CH:37]=[C:38]([CH2:42][N:43]2[C:51]3[C:46](=[C:47]([O:52][CH3:53])[CH:48]=[CH:49][CH:50]=3)[C:45]([NH:54][S:55]([C:58]3[S:59][C:60]([Cl:63])=[CH:61][CH:62]=3)(=[O:57])=[O:56])=[N:44]2)[CH:39]=[CH:40][CH:41]=1>CN(C=O)C>[Cl:63][C:60]1[S:59][C:58]([S:55]([NH:54][C:45]2[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][C:47]=3[O:52][CH3:53])[N:43]([CH2:42][C:38]3[CH:39]=[CH:40][CH:41]=[C:36]([CH2:35][NH:34][CH:1]=[O:3])[CH:37]=3)[N:44]=2)(=[O:56])=[O:57])=[CH:62][CH:61]=1
Reactant: O=CO
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
To a solution of formic acid (5 μL, 0.13 mmol) in dry DMF (0.3 mL) was added TBTU (34.7 mg, 0.108 mmol) followed with triethylamine (50.2 μl, 0.360 mmol). This mixture was stirred at room temperature for about 10 min before adding N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see Intermediate 4) (45 mg, 0.09 mmol). The resultant pale yellow mixture was stirred at room temperature overnight. LCMS showed very little reaction, so more acid (˜0.25 mL), followed with TBTU (˜30 mg) were added. This addition was repeated 3 more times over 20 h until by LCMS analysis, there was more product than SM. The reaction mixture was partitioned between ethylacetate (2 mL) and saturated sodium bicarbonate solution (2 mL). The aqueous was extracted with ethyl acetate (×2). The combined organic solutions were washed with water, brine, dried (Na2SO4) and concentrated in vacuo to leave a pale oil which crystalised on standing. This was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by Mass Directed AutoPrep on supelcosil ABZ+Plus column eluting with a gradient of MeCN-Water (95:5+0.05% Formic acid)−Water (+0.1% Formic acid). The solvent was evaporated in vacuo to give the title compound (15.9 mg, 36%) as a pale yellow powder: LCMS (System A) RT=1.02 min, ES+ve m/z 491/493 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C@H:13]([CH2:17][OH:18])[CH:14]([CH3:16])[CH3:15].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:5]([O:4][C:2]([NH:12][C@H:13]([CH2:17][OH:18])[CH:14]([CH3:16])[CH3:15])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)[C@H](N)CO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
Benzyl chloroformate (91.0 g, 95% purity) was added dropwise over a period of 1 h to a precooled (0° C.) solution of L-valinol (50.0 g) and triethylamine (60.0 g) in chloroform (1500 ml). The reaction mixture was stirred for 1 h at 0° C. and then allowed to warm to,room temperature over 2 h. After the reaction mixture was evaporated, ethyl acetate (1500 ml) was added to the residue and the organic solution was washed (1N NaOH, brine), dried (MgSO4), and evaporated. The residue was purified by flash chromatography, using a stepwise gradient elution of ether:hexane (1:5) followed by ether, to give the alcohol (91.4 g) as a white waxy solid; TLC, Rf =0.23, hexane:ethanol (50:50).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[Na+].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Nc1c(F)ccc(O)c1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(F)c(N)c1F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 75 %

Procedure:
To a stirred solution of 3-amino-2,4-difluorophenol (intermediate X(a)) (713 mg, 4.9 mmol, 1.0 eq) in DMF (30 mL) was added Na2CO3 (1.56 g, 14.7 mmol, 3.0 eq). The resulting mixture was stirred for 40 min at room temperature. Ethyl bromoacetate (1 g, 5.90 mmol 1.2 eq) was added and the reaction stirred overnight. The reaction was diluted with water then extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by chromatography (petroleum ether: EtOAc, 25:1) to give the title compound (intermediate IV(a)) as an oil (850 mg, 71%).
Reaction SMILES: Br[C:2]([CH3:8])([CH3:7])[C:3]([NH:5][CH3:6])=[O:4].[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C1(C)C=CC=CC=1.[Ag]=O>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][N:19]([C:2]([CH3:8])([C:3](=[O:4])[NH:5][CH3:6])[CH3:7])[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CNC(=O)C(C)(C)Br
Agent: O=[Ag]
Solvent: Cc1ccccc1
Product: CNC(=O)C(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 93.2 %

Procedure:
A mixture of 2-bromo-2,N-dimethyl-propionamide (312 mg), 1-BOC-piperazine (323 mg) and silver oxide (800 mg) was stirred in toluene (5 mL) at reflux. After 24 h the reaction mixture was cooled, filtered through celite, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent was removed in vacuo to yield 4-(1-methyl-1-methylcarbamoyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (461 mg). Removal of the BOC group with HCl yielded the desired compound, which was isolated as the hydrochloride salt.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:24]3[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc([N+](=O)[O-])sc3n2)cc1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: COC(=O)c1ccc(-c2nc(NCc3cccc([N+](=O)[O-])c3)c3cc([N+](=O)[O-])sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3-nitrobenzylamine is reacted with 4-(4-chloro-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3-nitrobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:13]([OH:15])=[O:14])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.O[C:23]1[CH:38]=[CH:37][C:26]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[CH:25][CH:24]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl.CN(C1C=CN=CC=1)C>[CH2:30]([O:29][C:27](=[O:28])[C:26]1[CH:37]=[CH:38][C:23]([O:14][C:13](=[O:15])[CH:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([CH3:21])([CH3:1])[CH2:3][CH2:4][O:5]3)=[CH:10][CH:9]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:24][CH:25]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: CCCCCC(C(=O)O)c1ccc2c(c1)OCCC2(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCC(C(=O)Oc1ccc(C(=O)OCc2ccccc2)cc1)c1ccc2c(c1)OCCC2(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
A solution of 2-(4,4-dimethyl-chroman-7-yl)-heptanoic acid (105 mg, 0.36 mmol) in 5 mL of dichloromethane with 91.6 mg, 0.4 mmol of benzyl 4-hydroxybenzoate and 44 mg, 0.36 mmol of DMAP was cooled to 0° C. and treated with 83 mg, 0.4 mmol of DCC. The mixture was kept at 0° C. for 15 minutes, then warmed to room temperature. After 2 h, the mixture was filtered and the resulting solution was washed with water and brine. The solution was dried and concentrated, then purified by flash chromatography (8% ethyl acetate/hexane) to give 152 mg (84%) of 4-[2-(4,4-dimethyl-chroman-7-yl)-heptanoyloxy]-benzoic acid benzyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([C:15]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([C:24]([NH2:26])=[NH:25])=[CH:23][C:17]=4[N:16]=3)[C:9]=2[OH:27])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C1COCC1.O>[Cl:14][C:12]1[CH:11]=[C:10]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([C:24]([NH2:26])=[NH:25])=[CH:23][C:17]=3[N:16]=2)[C:9]([OH:27])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[CH:3]=2)[CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: N=C(N)c1ccc2[nH]c(-c3cc(Cl)cc(-c4cccc(N)c4)c3O)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cccc(-c2cc(Cl)cc(-c3nc4cc(C(=N)N)ccc4[nH]3)c2O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(3′-Amino-5-chloro-2-hydroxy-biphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine 73 (0.070 g, 0.15 mmol) and THF/water (1:1, 0.5 mL) is chilled (0° C.) and treated with 2 N NaOH (0.16 mL, 0.32 mmol) and methane sulfonyl chloride (0.013 mL, 0.16 mmol) in alternating portions. The mixture is kept at 0° C. for 1 h and then treated with another portion of 2 N NaOH (0.016 mL, 0.032 mmol) and methane sulfonyl chloride (0.001 mL, 0.013 mmol). After another 1 h, the solvents were reduced in volume under reduced pressure, and the crude material is purified by C18 reversed-phase HPLC (2-65% MeCN/H2O containing 20 mM HCl, over 50 min.). The appropriate fractions were pooled and the solvent is removed under reduced pressure. 2-(5-chloro-2-hydroxy-3′-methanesulfonylamino-biphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine 74 is obtained as a tan powder (0.012 g, 16% yield) (Example 288, Table 2a):
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][N:22]4[CH:26]=[CH:25][N:24]=[CH:23]4)=[CH:15][CH:14]=3)[N:10]=2)[CH:7]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[N:22]1([CH2:21][CH2:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:9]3[N:10]=[C:5]4[CH:4]=[CH:3][C:2]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:7][N:6]4[CH:8]=3)=[CH:14][CH:15]=2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: Brc1ccc2nc(COc3ccc(CCCn4ccnc4)cc3)cn2c1
Reactant: OB(O)c1ccccc1
Product: c1ccc(-c2ccc3nc(COc4ccc(CCCn5ccnc5)cc4)cn3c2)cc1
Yield: 78 %

Procedure:
In substantially the same manner as in Working Example 135, 6-bromo-2-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]imidazo[1,2-a]pyridine was allowed to react with phenylboronic acid to give 2-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-6-phenylimidazo[1,2-a]pyridine. The yield was 78%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 106-107° C.
Reaction SMILES: [C:1]([C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([O:32][CH2:33][CH3:34])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:38][O:39][NH2:40].N1C=CC=CC=1>CO>[CH2:33]([O:32][CH:27]([CH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][CH2:17][N:13]2[C:12]3[CH:35]=[CH:36][C:9]([C:1](=[N:40][O:39][CH3:38])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11]=3[S:15][C:14]2=[O:16])=[CH:21][CH:22]=1)[C:28]([O:30][CH3:31])=[O:29])[CH3:34]
Reactant: CCOC(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)C(=O)OC
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CCOC(Cc1ccc(OCCn2c(=O)sc3cc(C(=NOC)c4ccccc4)ccc32)cc1)C(=O)OC

Procedure:
To 30 ml of methanol add the compound obtained in Step C (0.00198 mol), O-methyl-hydroxylamine hydrochloride (0.00594 mol) and pyridine (0.00594 mol). Heat at reflux for 3 hours. Evaporate to dryness. Add 100 ml of hydrochloric acid (1N) and then extract with 50 ml of dichloromethane twice. The organic phase is dried over MgSO4 and then evaporated to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11]3[C:10](=[CH:12][CH:13]=1)[S:9](=[O:15])(=[O:14])[NH:8][C:7]=3[CH:6]=[CH:5][CH:4]=2.Cl[CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1.[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:3]2[C:11]3[C:10](=[CH:12][CH:13]=1)[S:9](=[O:15])(=[O:14])[N:8]([CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[CH2:22][CH2:21]1)[C:7]=3[CH:6]=[CH:5][CH:4]=2
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Reactant: O=S1(=O)Nc2cccc3c(Cl)ccc1c23
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2ccc(Cl)c3cccc(c23)N1CCCN1CCN(c2ccc(F)cc2)CC1
Temperature: 90 °C

Procedure:
The experiment is carried out as in Example 18, starting with 6-chloronaphtho[l,8-cd]isothiazole 1,1-dioxide (1.4 g), 1-(3-chloropropyl)-4-(4-fluorophenyl)piperazine (1.5 g), sodium hydride (0.18 g) in an 80% dispersion in vaseline oil and dimethylformamide (15 cc). The reaction mixture is heated for 1 hour 30 minutes at 90° C., cooled to a temperature of about 20° C. and then concentrated to dryness at 60° C. under reduced pressure (0.5 mm Hg; 0.07 kPa). The residue is redissolved in dichloromethane (50 cc) and the solution is washed with distilled water (20 cc), dried over magnesium sulphate and concentrated to dryness at 20° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is purified by chromatography on a silica column with mixture of dichloromethane and ethyl acetate (95-5 vol) as eluant, then recrystallized from boiling acetonitrile (10 cc). 6-Chloro-2-{3-[4-(4-fluorophenyl)-l-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1.2 is obtained, m.p. 125° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[CH3:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1.C1CCN2C(=NCCC2)CC1>C(O)(C)C>[CH3:17][C:18]1[N:19]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]3)[CH:20]=[CH:21][N:22]=1
Reactant: O=C1CCc2cc(OCCCBr)ccc2N1
Reactant: Cc1ncc[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)O
Product: Cc1nccn1CCCOc1ccc2c(c1)CCC(=O)N2

Procedure:
2.0 Grams (7.0 mM) of 6-(3-bromopropoxy)-3,4-dihydrocarbostyril, 2.2 g (7.7 mM) of 2-methylimidazol and 1.3 ml (8.4 mM) of DBU were dissolved in 80 ml of isopropanol, and the resulting solution was refluxed by heating for 20 hours. The reaction mixture was concentrated, and to the resulting residue was added water, then extracted with chloroform. The chloroform extract was washed with water, dried with anhydrous sodium sulfate, then concentrated. The resulting residue was purified by means of a silica gel column chromatography (eluent: dichloromethane: methanol=20:1), and recrystallized from ethanol-n-hexane to yield 1.0 g of 6- [3-(2-methyl-1-imidazolyl)propoxy]-3,4-dihydrocarbostyril. White powdery substance. Melting point: 141.5°-142.5° C.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[C:2]#[C:3][CH2:4][CH3:5].[C:9](=[N:14]O)([NH2:13])[CH2:10][CH2:11][CH3:12]>C1(C)C(C)=CC=CC=1>[CH2:4]([C:3]1[N:13]=[C:9]([CH2:10][CH2:11][CH3:12])[NH:14][C:2]=1[C:1]([O:7][CH3:8])=[O:6])[CH3:5]
Reactant: CCCC(N)=NO
Reactant: CCC#CC(=O)OC
Solvent: Cc1ccccc1C
Product: CCCc1nc(CC)c(C(=O)OC)[nH]1
Temperature: 50 °C
Yield: 27.9 %

Procedure:
93 g of methyl pentynoate and 82 g butyramidoxime are mixed together without solvent and heated to 50° C for 24 hours. 400 mL xylene was added and water was azaeotropically removed for 6 hours. The reaction was then distilled (140° C. at 0.2 torr) to give 44 g product.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=O.COC1C=CC(/C=[C:35]2/[C:36]([NH:38][C:39]([S:41]/2)=[NH:40])=[O:37])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:40][C:39]1[S:41]/[C:35](=[CH:1]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])/[C:36](=[O:37])[N:38]=1
Reactant: CC(C)COc1c(C#N)cnc2ccc(C=O)cc12
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)COc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 6-formyl-4-isobutoxy-quinoline-3-carbonitrile (example 66b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-isobutoxy-quinoline-3-carbonitrile. LC-MS m/e 353 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CC[C@H](OS(C2C=CC(C)=CC=2)(=O)=O)C1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CCCN1[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cc1ccc(S(=O)(=O)O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Product: C[C@@H]1CCCN1[C@@H]1CCN(C(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared in a manner substantially the same as intermediate (2R,3′S)-2-Methyl-[1,3′]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester by condensing 3-(3S)-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester and R-(−)-2-methylpiperindine (obtained from Advanced Asymmetrics). LCMS: