Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7]1.C([Li])CCC.[I:17]I>O1CCCC1>[I:17][C:5]1[O:1][C:2]([C:6]2([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7]2)=[N:3][CH:4]=1
Reactant: OC1(c2ncco2)CCCC1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ncc(I)o2)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (−78° C.) solution of Example 48A (500 mg, 3.26 mmol) in tetrahydrofuran (50 mL) was added n-butyllithium (4.08 mL, 6.53 mmol, 1.6M in hexane) dropwise. After stirring for 30 min, a solution of iodine (0.829 g, 3.26 mmol) in tetrahydrofuran (5 mL) was added dropwise. After 2 h, the reaction was quenched by the addition of 10% Na2S2O3 solution (10 mL) and ethyl acetate (10 mL) and warmed to room temperature. The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×50 mL). The combined organics were washed with brine (1×50 mL), dried over Na2SO4, concentrated under reduced pressure, and purified by chromatography on SiO2 gel, eluting with 50% ethyl acetate in hexane, to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.65 (s, 2H), 1.79 (s, 2H), 1.89 (s, 2H), 2.02 (s, 2H), 5.50 (s, 1H), 7.22 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]([NH:12]C(=O)OCC)=S)[CH:3]=1.Cl.NO.CC[N:23](C(C)C)C(C)C>CO.CCO>[Cl:8][C:6]1[N:5]2[N:23]=[C:10]([NH2:12])[N:9]=[C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1cc(Cl)cc(Cl)n1
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCO
Product: Nc1nc2cc(Cl)cc(Cl)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
Ethyl [(4,6-dichloropyridin-2-yl)carbamothioyl]carbamate (2.9 g, 9.9 mmol) was added to a stirred suspension of hydroxylamine hydrochloride (1.1 g, 16 mmol) and DIEA (1.9 g, 15 mmol) in MeOH/EtOH (1:1, 40 mL) portion-wise as a solid. This mixture was stirred at rt for 2 h and then heated at 80° C. for 18 h. The reaction mixture was concentrated in vacuo and the resultant reside treated with water yielding a cream solid, which was filtered and dried in a vacuum oven at 40° C. for 18 h to give the desired product (1.2 g, 60%). 1H NMR (DMSO) δ 7.58 (d, J=2.0 Hz, 1H), 7.35 (d, J=2.0 Hz, 1H), 6.44 (s, 2H). m/z [M+H]+=203.15.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]([C:13]#[N:14])[C:11]#[N:12])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]([CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25])([C:11]#[N:12])[C:13]#[N:14])[CH3:9])=[CH:6][CH:7]=1
Reactant: FC(F)(F)CCBr
Reactant: CC(c1ccc(Cl)cc1)C(C#N)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(c1ccc(Cl)cc1)C(C#N)(C#N)CCC(F)(F)F
Yield: 16.3 %

Procedure:
Using 2.05 g of 2-(1-(4-chlorophenyl)ethyl)malononitrile, 10 ml of N,N-dimethylformamide, 1.38 g of potassium carbonate, and 1.77 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.49 g of 2-(1-(4-chlorophenyl)ethyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (42)).
Reaction SMILES: [OH:1][C@H:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Cl:21][C:22]1[CH:23]=[C:24]([C:31]#[N:32])[CH:25]=[N:26][C:27]=1[CH:28]1[CH2:30][O:29]1>>[Cl:21][C:22]1[CH:23]=[C:24]([C:31]#[N:32])[CH:25]=[N:26][C:27]=1[CH:28]([OH:29])[CH2:30][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][C@H:2]([OH:1])[C:10]2[C:11]([CH3:20])=[C:12]3[C:13](=[CH:18][CH:19]=2)[C:14](=[O:17])[O:15][CH2:16]3)[CH2:5][CH2:6]1
Reactant: Cc1c([C@@H](O)CN2CCNCC2)ccc2c1COC2=O
Reactant: N#Cc1cnc(C2CO2)c(Cl)c1
Product: Cc1c([C@@H](O)CN2CCN(CC(O)c3ncc(C#N)cc3Cl)CC2)ccc2c1COC2=O

Procedure:
5-Chloro-6-[1-hydroxy-2-[4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]pyridine-3-carbonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 58 starting from 5-[(1R)-1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one and 5-chloro-6-(oxiran-2-yl)pyridine-3-carbonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[C:8]([C:13]([F:16])([F:15])[F:14])=[N:7]2.O=P(Cl)(Cl)[Cl:19]>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:19])[C:8]([C:13]([F:16])([F:15])[F:14])=[N:7]2
Reactant: O=c1[nH]c2c(Br)cccc2nc1C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1nc2cccc(Br)c2nc1Cl
Reaction time: 60 h
Yield: 52 %

Procedure:
A solution of 8-bromo-3-(trifluoromethyl)quinoxalin-2(1H)-one (432.0 mg, 1.474 mmol) in POCl3 (5.0 mL) was heated at reflux for 10 h then at 100° C. for 2.5 d, then at 140° C. for 10 h. Excess POCl3 was removed in vacuo, and the residue was taken up in DCM (60 mL) and transferred to an Erlenmeyer flask before saturated aq. NaHCO3 (40 mL) was added cautiously (over 5 min) with rapid stirring. The resulting biphasic mixture was stirred rapidly for 5 min (some gas evolution), and the organic layer was separated. The aq. layer was extracted with DCM (3×20 mL), and all organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to provide 5-bromo-3-chloro-2-(trifluoromethyl)quinoxaline (224c, 52%). MS (ESI, pos. ion) m/z: 310.9 (M+1).
Reaction SMILES: [CH3:1][N:2]([N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[C:3](=[O:13])[CH2:4][NH:5]C(OC(C)(C)C)=O.C(O)CC.[BrH:32]>C(OCC)(=O)C>[BrH:32].[CH3:1][N:2]([N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[C:3](=[O:13])[CH2:4][NH2:5]
Reactant: CN(C(=O)CNC(=O)OC(C)(C)C)n1cccc1C(=O)c1ccccc1Cl
Agent: Br
Solvent: CCCO
Solvent: CCOC(C)=O
Product: CN(C(=O)CN)n1cccc1C(=O)c1ccccc1Cl

Procedure:
1-(N-Methyl-(t-butoxycarbonylamino)acetamido]-2-(2-chlorobenzoyl)pyrrole (24 g, 61.2 mmol) was dissolved in 100 ml of ethyl acetate, and 60 ml of n-propanol solution containing 12 ml of 48% HBr was added thereto with stirring. After 1 hour at 35° the solution was evaporated and the residue triturated with ether to give 23.2 g of powder. This powder was recrystallized from isopropanol-ether to give 22 g (96%) of flocculent crystals, m.p. 193°-195°.
Reaction SMILES: [F:1][CH2:2][C:3](=O)[C:4](=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.[NH2:22][C:23]([NH2:30])=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].[Na]>C(O)C>[NH2:22][C:23]1[NH:30][C:3]([CH2:2][F:1])=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:24]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)C=C(N)N
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)CF
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(CF)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
Ethyl 4-fluoro-2-(3-nitrophenylmethylene)-3-oxobutanoate (0.6 g, 2.1 mmoles) and ethyl 3,3-diamino-2-propenoate hydrochloride (0.34 g, 12.0 mmoles) were heated at reflux in ethanol (10 ml) and a solution of sodium (0.05 g) in ethanol (5 ml) was added over one hour. The resulting solution was heated at reflux for a further 10 minutes and then filtered hot. The ethanolic solution was evaporated to dryness in vacuo and the resulting solid triturated with 2-propanol. The resulting solid was chromatographed on silica eluting with ether/petroleum ether (60°-80°) mixtures to give pure title compound, mp 177°-8°.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:23]([F:26])([F:25])[F:24])=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)(=[O:11])=[O:10].CC(O)=O>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]2[C:3]([S:9](=[O:10])(=[O:11])[NH:12][C:13]3[C:14]2=[CH:15][C:16]([C:23]([F:24])([F:26])[F:25])=[C:17]2[C:22]=3[N:21]=[CH:20][CH:19]=[CH:18]2)=[CH:4][CH:5]=1
Reactant: Nc1cc(Cl)ccc1S(=O)(=O)Nc1ccc(C(F)(F)F)c2cccnc12
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=S1(=O)Nc2c(cc(C(F)(F)F)c3cccnc23)-c2cc(Cl)ccc21
Yield: 8.6 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-4-chloro-N-(5-trifluoromethyl-quinolin-8-yl)-benzenesulfonamide (Intermediate 282) (340 mg, 0.85 mmol), t-butyl nitrile (0.15 ml, 1.27 mmol) and AcOH:THF (3.4 ml: 3.4 ml) gave the title compound (28 mg, 9%) after purification by column chromatography with DCM/MeOH (99.5:0.5) as the eluent.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][CH3:21])=[O:19].Cl>O.O1CCOCC1>[CH3:21][O:20][C:18]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:19]
Reactant: COC(=O)Cl
Reactant: CNCCCCCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)N(C)CCCCCC(=O)O
Temperature: 25 °C
Yield: 81.3 %

Procedure:
N-methyl-caprolactam (15 g, 118 mmol) was combined with barium hydroxide (10.1 g, 72 mmol) and water (150 ml). The suspension was warmed to 110° C. for 18 hours then cooled over an ice bath. Gaseous carbon dioxide was bubbled through the solution for 20 minutes. The suspension was filtered through a celite pad and the filtrate was concentrated to dryness. The residue was triturated with acetonitrile, collected, rinsed with ether and dried in vacuo to yield 6-(methylamino)hexanoic acid as a white solid (10.7 g). 6-(Methylamino)hexanoic acid (5 g, 34.5 mmol), and potassium carbonate (18 g, 130 mmol) were suspended in water (50 ml) and dioxane (25 ml) then cooled to 0° C. Methyl chloroformate (13 ml, 168 mmol) was added over 1 minute, then the mixture was stirred and allowed to warm slowly to room temperature for 16 hours. Conc. HCl (20 ml) was added then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated and dried in vacuo to give 6-[(methoxycarbonyl)(methyl)amino]hexanoic acid as a thick clear oil (5.7 g).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)=[N:10][S:11][C:7]=2[CH:6]=1.[NH:21]1[CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:2][CH2:3][O:4][C:5]2[CH:20]=[CH:19][C:8]3[C:9]([C:12]4[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=4)=[N:10][S:11][C:7]=3[CH:6]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: C1CNC1
Reactant: BrCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: Brc1ccc(-c2nsc3cc(OCCN4CCC4)ccc23)cc1

Procedure:
According to the method in example 4, 6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and azetidine were converted to yield 6-(2-Azetidin-1-yl-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole, MS: 390 (MH+, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5](=[CH:9][C:10]=1[Cl:11])[C:6]([OH:8])=O.C(OC(=O)C)(=O)C>>[Cl:11][C:10]1[CH:9]=[C:5]2[C:6](=[O:8])[O:14][C:12](=[O:13])[C:4]2=[CH:3][C:2]=1[Cl:1]
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc(Cl)c(Cl)cc21

Procedure:
4,5-Dichlorophthalic acid (30 g., 0.127 mole) is refluxed in 150 ml. of acetic anhydride for 3 hours. The acetic anhydride is evaporated and the residue is triturated with diethyl ether and filtered to give a quantitative yield of 4,5-dichlorophthalic anhydride. The crude product is recrystallized from ethyl acetate and hexane.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]([C@H:43]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[N:46]([C:53](=[O:61])[C:54]3[CH:59]=[CH:58][C:57]([OH:60])=[CH:56][CH:55]=3)[C@@H:45]([CH3:62])[CH2:44]2)[C:40](=[O:42])[CH3:41])=[CH:35][CH:34]=1.[CH2:63]([O:65][C:66]([CH:68]1[CH2:73][CH2:72][CH:71](O)[CH2:70][CH2:69]1)=[O:67])[CH3:64]>C1COCC1>[CH2:63]([O:65][C:66]([CH:68]1[CH2:73][CH2:72][CH:71]([O:60][C:57]2[CH:56]=[CH:55][C:54]([C:53]([N:46]3[C:47]4[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=4)[C@H:43]([N:39]([C:40](=[O:42])[CH3:41])[C:36]4[CH:35]=[CH:34][C:33]([Cl:32])=[CH:38][CH:37]=4)[CH2:44][C@@H:45]3[CH3:62])=[O:61])=[CH:59][CH:58]=2)[CH2:70][CH2:69]1)=[O:67])[CH3:64]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(Oc2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 36.9 %

Procedure:
To a solution of diethyl azodicarboxylate (120 mg) in 5 ml THF at 0° C., was added PPh3 (181 mg). The mixture was stirred for 10 min at 0° C. Then (2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (200 mg) was added. The mixture was stirred for 20 min at 0° C. 4-Hydroxy-cyclohexanecarboxylic acid ethyl ester (80 mg) was added. The final reaction mixture was stirred for overnight at RT. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30/70 hexanes/ethyl acetate gradient) to afford pure (2S,4R)-4-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-cyclohexanecarboxylic acid ethyl ester (100 mg, 37%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:20](CC)CC)C.ClC(OCC)=O.N>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15](=[O:17])[NH2:20])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(N)=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a solution cooled at 0° C. of cis-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (68.0 g, 280 mmol) and triethylamine (31.1 g, 307 mmol) in THF (300 mL) was added ethyl chloroformate (29.3 mL, 308 mmol) dropwise. After stirring at 0° C. for 30 min, 25% aqueous ammonia (168 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hr and concentrated. The residue was extracted with EtOAc (three times). The combined organic layer was washed with saturated aqueous NaHCO3, 1 M HCl, brine, and water, dried over Na2SO4, filtered, and concentrated to give cis-(4-carbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (62.0 g, 88%) as a white solid.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[C:15]=1O)[C:11]#[N:12]>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[C:15]=1[Cl:4])[C:11]#[N:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)c(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
(I1C): DMF (2 mL) was cooled to −20° C. and treated gradually in dropwise manner with oxalyl chloride (0.216 mL, 2.469 mmol). After 10 min, a solution of 3-bromo-4-hydroxy-5-nitrobenzonitrile (200 mg, 0.823 mmol) in DMF (2 mL) was added slowly via syringe while maintaining internal temperature below −10° C. After addition, the mixture was allowed to warm to room temperature and then heated at 100° C. for 1.5 h. The reaction mixture was cooled and poured into ice-water; the solid was collected by filtration, rinsed with water and dried to give 172 mg of 3-bromo-4-chloro-5-nitrobenzonitrile as tan solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 8.13 (1H, d, J=1.76 Hz), 8.02 (1H, d, J=1.98 Hz)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[CH:12][C:13]2[C:19](=[O:20])[C:18]3[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH2:26][C@H:27]4[CH2:31][O:30]C(C)(C)[O:28]4)[C:17]=3[CH2:16][CH2:15][C:14]=2[CH:34]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[CH:12][C:13]2[C:19](=[O:20])[C:18]3[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH2:26][C@H:27]([OH:28])[CH2:31][OH:30])[C:17]=3[CH2:16][CH2:15][C:14]=2[CH:34]=1
Reactant: CC1(C)OC[C@H](COc2cccc3c2CCc2cc(Nc4ccc(F)cc4F)ccc2C3=O)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: O=C1c2ccc(Nc3ccc(F)cc3F)cc2CCc2c(OC[C@H](O)CO)cccc21
Yield: 88 %

Procedure:
For the synthesis of the title compound, 0.10 g (0.215 mmol) of (S)-8-(2,4-difluorophenylamino)-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one and 0.0054 g (0.0284 mmol) of p-toluenesulfonic acid monohydrate in 6 ml of methanol and 1.5 ml of water are reacted by method N. Yield: 88%;
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[NH:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([NH:20][NH2:21])=[O:19])=[CH:17][C:12]=2[N:11]=[CH:10]1.C1(C)C=CC=CC=1>CO>[CH3:6][N:4]([CH:3]=[N:21][NH:20][C:18]([C:16]1[CH:15]=[CH:14][C:13]2[NH:9][CH:10]=[N:11][C:12]=2[CH:17]=1)=[O:19])[CH3:5]
Reactant: NNC(=O)c1ccc2[nH]cnc2c1
Reactant: COC(OC)N(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: CN(C)C=NNC(=O)c1ccc2[nH]cnc2c1
Yield: 87 %

Procedure:
Dimethylformamide dimethyl acetal (19 g, 15.90 mmol) was added to a suspension of 1H-benzo[d]imidazole-5-carbohydrazide (3.50 g, 19.88 mmol) in 1:1 toluene; methanol (60 mL) and refluxed overnight. The volatiles were evaporated in vacuo to afford crude compound which was triturated with 6% methanol in chloroform (10 mL), precipitated solid was filtered and dried under reduced pressure to afford 3.20 g (69.56%%) 1H-benzimidazole-5-carboxylic acid dimethylaminomethylene-hydrazide as brown solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][CH3:8])=[CH:5][C:4]([CH3:9])=[N:3]1.S(Cl)(Cl)=O.[Cl:14][S:15](O)(=[O:17])=[O:16]>>[CH3:1][N:2]1[C:6]([O:7][CH3:8])=[C:5]([S:15]([Cl:14])(=[O:17])=[O:16])[C:4]([CH3:9])=[N:3]1
Reactant: COc1cc(C)nn1C
Reactant: O=S(=O)(O)Cl
Solvent: O=S(Cl)Cl
Product: COc1c(S(=O)(=O)Cl)c(C)nn1C
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Into 70 ml of chlorosulfonic acid was added dropwise under cooling at 5° C. or lower 12.6 g (0.1 mol) of 1,3-dimethyl-5-methoxypyrazole. After the addition, the mixture was stirred at 100° C. for 8 hours. Then, the reaction mixture was cooled to 80° C., followed by dropwise addition of 11.9 g (0.1 mol) of thionyl chloride over 30 minutes. After the dropwise addition, the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled and poured carefully into ice-water, whereby crude 1,3-dimethyl-5-methoxy-pyrazole-4-sulfonylchloride was formed as crystals The crystals were separated by filtration, dissolved in 20 ml of tetrahydrofuran and the resultant solution was added dropwise into 100 ml of aqueous ammonia (28%) at 10° C. or lower. After the addition, the mixture was stirred at room temperature for 30 minutes. The reaction mixture was evaporated under reduced pressure to remove low boiling components, whereby crystals were precipitated. The crystals were filtered, washed with water and dried to give 11.5 g of 1,3-dimethyl-5-methoxypyrazole-4-sulfonamide melting at 144°-146° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:10]=3[N:11]([CH3:27])[C:12](=[O:26])[CH:13]([CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[N:14]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl>[Cl:32][C:30]1[CH:29]=[CH:28][C:10]2[N:11]([CH3:27])[C:12](=[O:26])[CH:13]([CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[N:14]=[C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:40](=[O:47])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH2:7][CH2:6]3)[C:9]=2[CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(N2CCC(N)CC2)c2cc(Cl)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(N2CCC(NC(=O)c3ccccc3)CC2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
5-(4-Aminopiperidin-1-yl)-7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (50 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL) and triethylamine (31 μL, 0.22 mmol), a solution of benzoyl chloride (10 μL, 0.11 mmol) in dichloromethane (0.2 mL) was added dropwise, and stirred at ambient temperature for 30 minutes. To the solution was added silica gel and the mixture was concentrated. Column chromatography eluting with a gradient of 50-100% ethyl acetate in hexanes provided N-(1-(7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)piperidin-4-yl)benzamide (35 mg, 57% yield). ESI m/z measured 551.2224 [M+H]+. calculated 551.2214.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>C1COCC1.CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[O:1][C:2]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[N:3][CH:4]=1
Reactant: CCCC(=O)Cl
Reactant: c1ccc(-c2cnco2)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)c1ncc(-c2ccccn2)o1
Reaction time: 0.33 h
Yield: 46.3 %

Procedure:
(193) A solution of 2-(oxazol-5-yl)pyridine (98 mg, 0.67 mmol) in anhydrous THF (5 mL) cooled to −75° C. under N2 was treated with n-BuLi (2.5 M in hexanes, 1.1 equiv, 0.74 mmol, 0.3 mL), and stirred for 20 min. ZnCl2 (0.5 M in THF, 2.0 equiv, 1.34 mmol, 2.7 mL) was added at −75° C., and stirred for 45 min at 0° C. Cul (1.0 equiv, 0.67 mmol, 128 mg) was added, and the solution was stirred for 10 min at 0° C. Butyryl chloride (2.0 equiv, 1.34 mmol, 143 mg, 0.14 mL) was added and the solution was stirred for 1 h at 0° C. The reaction was diluted with EtOAc (10 mL), and washed with 15% aqueous NH4OH (1×10 mL), H2O (1×10 mL), and saturated aqueous NaCl (1×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5 cm×17.5 cm, 20% EtOAc-hexanes) afforded 1-(5-(pyridin-2-yl)oxazol-2-yl)butan-1-one (193) (68 mg, 0.31 mmol, 46% yield) as a light brown powder: mp 54-55° C; 1H NMR (CDCl3, 250 MHz) d 8.65-8.62 (m, 1H), 7.85-7.78 (m, 3H), 7.31-7.26 (m, 1H), 3.07 (t, J=7.3 Hz, 2H), 1.87-1.72 (m, 2H), 1.00 (t, J=7.7 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz)d 188.4, 162.0, 157.3, 150.1, 146.3, 136.9, 126.8, 124.1, 120.3, 40.9, 17.5, 13.5; IR (KBr) umax 2963, 2933, 2872, 1675, 1469, 1426, 1387, 1227 cm−1; MALDI-FTMS (DHB) m/z 217.0968 (C12H12N2O2+H+ requires 217.0971).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N+:16](/[CH:19]=[CH:12]/[C:11]1[CH:14]=[CH:15][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:9][CH:10]=1)([O-:18])=[O:17]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Nc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(Nc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 87.6 %

Procedure:
A mixture of 4-phenylamino-benzaldehyde (3 g, 15.2 mmol) described in Manufacturing Example 69-1-1, nitromethane (1.63 mL, 30.4 mmol), ammonium acetate (1.76 g, 22.8 mmol) and acetic acid (30 mL) was stirred for 6 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.2 g). This compound was used in the following reaction without being purified.