Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH:10]([CH2:14]Br)[CH2:11][C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH2:14][CH:10]1[CH2:11][C:12]#[N:13]
Reactant: Oc1ccccc1S
Reactant: N#CCC(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCC1CSc2ccccc2O1
Reaction time: 0.5 h

Procedure:
The starting material is prepared as follows: To the stirred, refluxing solution of 21 g of 2-hydroxy-thiophenol in 290 ml of acetone is added dropwise 12.5 g of 3,4-dibromo-butyronitrile along with small portions of 15.8 g of anhydrous potassium carbonate. After 30 minutes, the double addition procedure with said amounts of dibromo compound and potassium carbonate is repeated, and after a further 30 minutes said procedure is repeated a third time. The mixture is then refluxed for 20 hours, cooled, filtered, the residual salts washed with acetone, and the filtrate evaporated. The residue is distilled (bulb to bulb), and the fraction boiling at 185°/0.5 mm Hg collected, to yield the 2-(1,4-benzoxathian-2-yl)-acetonitrile.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:34])[CH:7]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:8]1[C:9]([CH3:28])=[N:10][C:11]2[S:12][C:13]3[CH2:14][O:15][CH2:16][CH2:17][C:18]=3[C:19]=2[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)C>C(O)C.O1CCCC1>[C:30]([O:29][CH:7]([C:8]1[C:9]([CH3:28])=[N:10][C:11]2[S:12][C:13]3[CH2:14][O:15][CH2:16][CH2:17][C:18]=3[C:19]=2[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:6]([OH:34])=[O:5])([CH3:33])([CH3:32])[CH3:31]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCOC3
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)c(C)nc3sc4c(c23)CCOC4)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Aqueous sodium hydroxide (2N, 2 mL, 4 mmol) was added to a stirred solution of tert-Butoxy-(2-methyl-4-p-tolyl-5,8-dihydro-6H-7-oxa-9-thia-1-aza-fluoren-3-yl)-acetic acid ethyl ester (66 mg, 0.15 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) and the reaction was stirred for 2 hours at 60° C. The reaction was concentrated in vacuo until only the aqueous remained. The pH was adjusted to 2 by the addition of 2N aqueous HCl. The resulting solid was collected by filtration and purified by preparative HPLC to afford the title compound. LCMS 3.63 min, ES+/AP+ 425.1 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH2:19][CH2:20][CH3:21])[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[CH:13]=1)[C:8]([OH:10])=O)=[O:4].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:57][C@@H:58]([CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1>CN(C=O)C>[CH2:72]([C@H:58]([NH:57][C:8](=[O:10])[C:7]1[CH:11]=[C:12]([C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[CH:13]=[C:5]([C:3]([N:2]([CH3:1])[CH2:19][CH2:20][CH3:21])=[O:4])[CH:6]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1)[C:73]1[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=1
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2ccccc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(C)C(=O)c1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 3-{[methyl(propyl)amino]carbonyl}-5-(1,3-oxazol-2-yl)benzoic acid (206 mg, 0.71 mmol) in DMF (5 mL) is added diisopropylethylamine (174 μL, 1.1 mmol), HATU (323 mg, 0.85 mmol), then (2R,3S)-3-amino-1-[(3-ethylbenzyl)amino]-4-phenylbutan-2-ol dihydrochloride prepared by the method of Example SP-272 (292 mg, 0.79 mmol). The reaction is stirred 4 h at room temperature. The reaction is partitioned between chloroform and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/chloroform) gives the title compound. ESI MS m/z 569.3 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[NH:9]1[C:17]2[C:12](=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[CH3:35][CH:33]([CH3:34])[C:32]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([CH2:18][C:13]3[CH:14]=[CH:15][CH:16]=[C:17]4[C:12]=3[CH:11]=[CH:10][N:9]4[C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=3)[CH2:20][CH2:21]2)[CH:26]=1)=[O:36]
Reactant: Cc1cccc(I)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Product: Cc1cccc(-n2ccc3c(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)cccc32)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-3-methylbenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl)-2-methylpropanamide: ESMS m/e: 466.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[N:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[C:6]([Cl:26])[CH:5]=1)([O-])=O.C([O-])(O)=O.[Na+].C(O)(=O)C>C(O)C>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[N:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[C:6]([Cl:26])[CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1Cc2ccnn2Cc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
A mixture of 0.553 g of 5,10-dihydro-5-(4-nitro-2-chlorobenzoyl)-4H-pyrazolo[5,1-c][1,4]benzodiazepine, 1.70 g of stannous chloride dihydrate in 20 ml of ethanol is heated at 70°-80° C. for 1 hour. The mixture is chilled, made basic with 1M NaHCO3 and then stirred at room temperature for 0.5 hour. The mixture is brought to pH 5 with acetic acid and extracted (several times) with ethyl acetate. The combined extracts are dried Na2SO4) and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated and the residue dissolved in dichloromethane and the solution passed through a thin pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to give 0.40 g of a glass, m.p. 98°-117° C.; Anal. Calc'd: C, 62.9; H, 4.7; N, 16.3; Cl, 11.6. Found: C, 62.4; H, 4.3; N, 15.6; Cl, 11.7.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:31])[N:17]3[C:22](=[C:23]([C:25]([OH:27])=O)[CH:24]=2)[C:21]2[S:28][CH:29]=[CH:30][C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([N:34]([CH2:43][CH3:44])[C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1)[CH3:33].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:43]([N:34]([CH2:32][CH3:33])[C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:25]([C:23]2[CH:24]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][CH:11]=3)[C:16](=[O:31])[N:17]3[C:22]=2[C:21]2[S:28][CH:29]=[CH:30][C:20]=2[CH:19]=[CH:18]3)=[O:27])=[CH:37][CH:36]=1)[CH3:44]
Reactant: CCN(CC)c1ccc(CN)cc1
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(CNC(=O)c2cc(-c3ccc(OCc4ccccc4)cc3)c(=O)n3ccc4ccsc4c23)cc1

Procedure:
From 8-[p-(benzyloxy)phenyl]-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid with 4-diethylamino-benzylamine, N-methylmorpholine, 1-hydroxybenzotriazole and N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride in dimethylformamide.
Reaction SMILES: Br[C:2]1[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][CH2:26][S:27]([NH2:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=[C:6]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:9]2=[O:15])[CH:7]=1.[O:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1>>[O:15]=[C:9]1[NH:10][C:11](=[O:14])[CH:12]=[CH:13][N:8]1[C:6]1[CH:7]=[C:2]([C:35]2[CH:36]=[CH:37][O:33][CH:34]=2)[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][CH2:26][S:27]([NH2:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=1
Reactant: COc1c(Br)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CCS(N)(=O)=O
Reactant: OB(O)c1ccoc1
Product: COc1c(-c2ccoc2)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CCS(N)(=O)=O
Yield: 45 %

Procedure:
The product from Example 63, Part A (25.9 mg, 0.050 mmol) was reacted with furan-3-yl boronic acid (7.2 mg, 0.064 mmol) as described in Example 63, Part B to give the title compound as an off-white solid (10.6 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ 11.46 (s, 1 H) 7.84 (d, J=8.09 Hz, 1 H) 7.80 (t, J=1.84 Hz, 1 H) 7.68-7.75 (m, 2 H) 7.54-7.64 (m, 2 H) 7.50 (t, J=6.07 Hz, 1 H) 7.35 (d, J=2.57 Hz, 1 H) 7.08 (d, J=1.47 Hz, 1 H) 6.57 (s, 1 H) 5.68 (d, J=8.09 Hz, 1 H) 3.47 (s, 2 H) 3.30 (s, 3 H) 2.96 (s, 3 H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:10]([OH:26])[C:11]([N:13]1[CH2:24][C@@H:23]([Cl:25])[CH2:22][C@H:14]1[C:15]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:12].N#N.[C:36]([O:40][C:41]([NH:43][C@H:44]([C:49](O)=[O:50])[CH2:45][C:46](=[O:48])[NH2:47])=[O:42])([CH3:39])([CH3:38])[CH3:37]>CN(C)C=O>[C:36]([O:40][C:41]([NH:43][C@H:44]([C:49]([NH:8][C@@H:9]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:10]([OH:26])[C:11]([N:13]1[CH2:24][C@@H:23]([Cl:25])[CH2:22][C@H:14]1[C:15]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:12])=[O:50])[CH2:45][C:46](=[O:48])[NH2:47])=[O:42])([CH3:38])([CH3:39])[CH3:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@@H](N)Cc1ccccc1
Agent: N#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C
Reaction time: 72 h

Procedure:
4.4 ml (31.4 mmol) of triethylamine were added, whilst ice-cooling, to a solution of 6.0 g (15.7 mmol) of (4S)-1-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyryl]-4-chloro-N-t-butyl-L-prolinamide [prepared as described in Preparation 21(b)] and 10.6 g (30.0 mmol) of the p-nitrophenyl ester of N2 -t-butoxycarbonyl-L-asparagine in 50 ml of dimethylformamide, and the resulting mixture was stirred for 3 days. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the residue was diluted with methylene chloride. The diluted solution was washed with a 5% w/v aqueous solution of citric acid, with a 1N aqueous solution of sodium hydroxide and with a saturated aqueous solution of sodium chloride, in that order, after which it was concentrated by evaporation under reduced pressure. The residue thus obtained was purified by column chromatography, using a 1:30 by volume mixture of methanol and methylene chloride as the eluent, to give 7.6 g of the title compound as a colorless powder, melting at 126°-132° C.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]([CH:13]=[CH:14][CH:15]([OH:27])[CH2:16][CH:17]([OH:26])[CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[C:11]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].CO.[OH-].[Na+:38]>O>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:27])[CH2:16][CH:17]([OH:26])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:38]
Reactant: CC(C)n1c(C=CC(O)CC(O)CC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 35 °C
Reaction time: 4.5 h
Yield: 31.6 %

Procedure:
A 100 ml round bottom flask was loaded with fluvastatin tert-butyl ester (4.0 g, 8.56 mmole), MeOH (24 ml) and NaOH (0.31 g) in water (2 ml). The mixture was heated to 35° C. and stirred for 4.5 h then water (10 ml) was added and the MeOH was evaporated. The volume of the water was completed to 8 vol. and the mixture was extracted with EtOAc (25 ml). The aqueous solution was evaporated to contain ca. 1 vol. water and ACN (60 ml) was added. The solution was stirred at room temperature over night. The product was isolated by filtration under nitrogen, washed with ACN and dried at 40° C. in a vacuum oven for 24 h to obtain 1.06 g (28.6%) of fluvastatin sodium crystal form XIV, having a peak at 12.4±0.2 degrees two-theta in the XRD pattern
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[C:24]([F:30])[CH:23]=1>>[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:6]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][N:8]([C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=3[Cl:19])[C:7]2=[O:20])=[C:24]([F:30])[CH:23]=1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)[nH]1
Reactant: Fc1cc(Br)ccc1CBr
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(Br)cc1F
Yield: 79 %

Procedure:
By the procedure of Example 76, Step D, 5-n-butyl-2-(2-chloro-5-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 59, Step A) was alkylated with 4-bromo-2-fluorobenzyl bromide to give a 79% yield of the title compound as an off-white foam, homogeneous by TLC in 4:1 hexane-EtOAc; mass spectrum (FAB) m/e 483, 485 (M+1)+.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[CH2:20][CH:19]3[CH:15]([CH2:16][N:17]([C:21](=[O:34])[CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH2:18]3)[C:14]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[F:42])([OH:35])[CH2:13]2)(=O)=O)=CC=1.[C-:44]#[N:45].[K+]>>[C:44]([CH2:11][CH:12]1[CH2:20][CH:19]2[CH:15]([CH2:16][N:17]([C:21](=[O:34])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:18]2)[C:14]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])([OH:35])[CH2:13]1)#[N:45]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC2CC3CN(C(=O)Cc4ccccc4N4CCCC4)CC3C(O)(c3ccccc3F)C2)cc1
Agent: [K+]
Product: N#CCC1CC2CN(C(=O)Cc3ccccc3N3CCCC3)CC2C(O)(c2ccccc2F)C1
Yield: 45.1 %

Procedure:
The procedure is as described for Example 13, starting from 0.07 g of (3aRS,4RS,6SR,7aSR)-6-p-toluenesulphonyloxymethyl-4-(2-fluorophenyl)-2-[2-(1-pyrrolidinyl)phenylacetyl]perhydroisoindol-4-ol and 0.015 g of potassium cyanide, and gives 0.024 g of (3aRS,4RS,6SR,7aSR)-6-cyanomethyl-4-(2-fluorophenyl)-2-[2-(1-pyrrolidinyl)phenylacetyl]perhydroisoindol-4-ol in the form of a thick white foam.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH3:15])=[C:9]([N+:16]([O-])=O)[CH:8]=1)=[O:5].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:31]([N:38]1[C:42](=[O:43])[C:41](=[C:44]2[N:48]([CH3:49])[C:47]3[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=3[S:45]2)[S:40][CH2+:39]1SC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:38]1[C:42](=[O:43])[C:41](=[C:44]2[N:48]([CH3:49])[C:47]3[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=3[S:45]2)[S:40][C:39]1=[N:16][C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][N:2]([CH3:19])[CH3:1])[CH:12]=[CH:11][C:10]=1[NH:13][CH2:14][CH3:15])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNc1ccc(NC(=O)CN(C)C)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 2-dimethylamino-4′-ethylamino-3′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 8.85 (1H, s), 7.43 (3H, t), 7.18–7.28 (5H, m), 7.10 (2H, t), 6.95 (1H, d), 6.48 (1H, d), 5.10 (2H, s), 3.71 (3H, s), 3.03 (2H, s), 2.93 (2H, q), 2.33 (6H, s), 0.97 (3H, t); MS(ESI): 584(MH+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH2:16](O)C.N1(CO)C2C=CC=CC=2N=N1.[BH4-].[Na+]>C(OCC)(=O)C>[CH3:16][NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: CCO
Agent: OCn1nnc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN[C@@H]1CCCC[C@@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a mixture of tert-butyl [(1S,2R)-2-aminocyclohexyl]carbamate (500 mg) and ethanol (10 mL) was added 1H-benzotriazol-1-yl methanol (350 mg), followed by stirring at room temperature for 7 hours. Sodium borohydride (180 mg) was added thereto under ice-cooling, followed by stirring at room temperature for 15 hours. To the reactant were added ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution, followed by liquid separation. The organic phase was dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-190:9:1) to obtain tert-butyl [(1S,2R)-2-(methylamino)cyclohexyl]carbamate (174 mg) as a pale yellow oily material.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][C:10]=1[CH:21]1[CH2:30][C:29]([CH3:32])([CH3:31])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:33](O)=[O:34])[CH:27]=2)[NH:22]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][C:10]=1[CH:21]1[CH2:30][C:29]([CH3:31])([CH3:32])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:33]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:34])[CH:27]=2)[NH:22]1
Reactant: CC1(C)CC(c2cc(N3CCOCC3)ccc2Cl)Nc2ccc(C(=O)O)cc21
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cc(N3CCOCC3)ccc2Cl)Nc2ccc(C(=O)NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
To a suspension of 60% sodium hydride (650 mg, 16 mmol) in N,N-dimethylformamide (5 mL) was added methanesulfonamide (1.53 g, 16 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A23. A solution of 2-(2-chloro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (900 mg, 2.3 mmol) and 1,1′-carbonyldiimidazole (730 mg, 4.5 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B23. Solution B23 was added to Solution A23 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[2-(2-chloro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (190 mg, 17%) as a white solid: MS (ESI) M+1=478.0.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH:19]([CH:21]1[CH2:23][CH2:22]1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:32])=O>C(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH:19]([Cl:32])[CH:21]1[CH2:23][CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1c2ccc(Cl)n2nc(C(O)C2CC2)n1Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=c1c2ccc(Cl)n2nc(C(Cl)C2CC2)n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 65 %

Procedure:
To a stirred solution of 3-benzyl-7-chloro-2-(cyclopropyl-hydroxy-methyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (1.40 g, 4.24 mmol) and pyridine (1.5 mL, 18.5 mmol) in CH2Cl2 (20 mL) was added thionyl chloride (2 M, 4.5 mL, 9.0 mmol) at 0° C. under nitrogen and stirred for 20 min. The reaction mixture was then stirred at rt overnight, poured into ice water, and extracted with CH2Cl2 (3×40 mL). The organic layers were washed with brine and dried over MgSO4. Concentration and purification of the crude product by flash column chromatography (SiO2, EtOAc/hexane 1:9) gave the title compound as a white solid (0.96 g, 65%): 1H NMR (CDCl3) δ 7.22 (m, 3H), 7.04 (m, 3H), 6.48 (d, 1H, J=4.4 Hz), 6.05 (d, 1H, J=16.5 Hz), 4.68 (d, 1H, J=16.5 Hz), 3.81 (d, 1H, J=10.45 Hz), 1.96 (m, 1H), 1.19 (m, 1H), 0.72 (m, 1H), 0.57 (m, 1H), 0.22 (m, 1H), −0.35 (m, 1H); 3C NMR (CDCl3) δ 154.2, 148.2, 136.4, 129.2, 128.0, 125.8, 118.0, 117.6, 110.6, 109.0, 62.5, 44.1, 15.3, 7.22, 6.19; MS (ESI+) 348.02 (M++H), 370.01 (M++Na).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[F:13][C:14]1[CH:39]=[CH:38][C:17]([NH:18][C:19]2[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:20]=2[C:21]([NH:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:22])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([N:18]2[C:19]3[C:20](=[CH:32][C:33]([F:37])=[C:34]([F:36])[CH:35]=3)[C:21](=[O:22])[N:23]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:1]2=[O:2])=[CH:38][CH:39]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1ccc(F)cc1
Product: O=c1c2cc(F)c(F)cc2n(-c2ccc(F)cc2)c(=O)n1OCc1ccccc1
Yield: 49.1 %

Procedure:
Using General Method 3, the reaction of carbonyldiimidazole (3.0 g, 18.4 mmol) and crude 2-(4-fluoro-anilino)-N-benzyloxy-4,5-difluoro-benzamide (Example U, 3.43 g, 9.2 mmol) provided 1.8 g of the title compound as a solid, mp 201-202° C.
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][C:26](=O)[CH2:25]1)=[O:23].[OH:31][C:32]1[C:37]([C:38]([NH:40][NH2:41])=O)=[CH:36][CH:35]=[CH:34][N:33]=1>ClCCl>[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]2[C:38]([C:37]3[C:32]([OH:31])=[N:33][CH:34]=[CH:35][CH:36]=3)=[N:40][N:41]=[C:26]2[CH2:25]1)=[O:23]
Reactant: NNC(=O)c1cccnc1O
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCn2c(nnc2-c2cccnc2O)C1
Temperature: 25 °C
Reaction time: 0.92 h

Procedure:
Triethyloxonium tetrafluoroborate (215 mg, 1.134 mmol) was added under argon to a solution of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (300 mg, 1.031 mmol) in Dichloromethane (DCM) (2.5 mL). The mixture was stirred at room temperature for 1 h 15 min—after 55 min, the mixture became clear. 2-Hydroxy-3-pyridinecarbohydrazide (I92) (189 mg, 1.237 mmol) was added to the solution and the mixture was stirred at room temperature for one day. The solvent was evaporated under reduced pressure and the residue was dissolved in tert-butanol (2.500 mL).