Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=O)=[O:9].Cl.[CH3:19][O:20][C:21](=[O:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH3:19][O:20][C:21](=[O:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:12](=[O:14])[C@@H:11]1[CH2:15][CH2:16][CH2:17][N:10]1[C:8](=[O:9])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CN1CCCC1=O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CN1CCCC1=O
Temperature: -25 °C
Reaction time: 15 h
Yield: 58.3 %

Procedure:
To a solution of N-[(2-oxo-1-pyrrolidinyl)acetyl]-L-proline (3.01 g) in DMF (25 ml) were added L-proline methyl ester hydrochloride (2.07 g), HOBt (2.54 g) and N-methylmorpholine (1.38 ml). The mixture was cooled to -25° C., added with DCC (2.85 g), and stirred at a temperature of -25°-0° C. for 3 hours and at room temperature for 15 hours. The precipitated dicyclohexylurea was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 2.56 g of N-[(2-oxo-1-pyrrolidinyl)acetyl]-L-prolyl-L-proline methyl ester.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[C:7]2[C:14]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]=3[C:20](=[O:22])[O:21][C:6]=2[CH:5]=1.C(N(CC)CC)C.Cl.[Cl:31][CH2:32][CH2:33][N:34]1[CH2:40][CH:39]2[CH2:41][CH2:42][CH:36]([CH2:37][CH2:38]2)[CH2:35]1>>[ClH:31].[CH:39]12[CH2:41][CH2:42][CH:36]([CH2:37][CH2:38]1)[CH2:35][N:34]([CH2:33][CH2:32][N:17]1[CH2:18][CH2:19][C:14]3[C:7]4[C:8]([O:12][CH3:13])=[C:9]([O:10][CH3:11])[C:4]([O:3][CH3:2])=[CH:5][C:6]=4[O:21][C:20](=[O:22])[C:15]=3[CH2:16]1)[CH2:40]2
Reactant: COc1cc2oc(=O)c3c(c2c(OC)c1OC)CCNC3
Reactant: ClCCN1CC2CCC(CC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cc2oc(=O)c3c(c2c(OC)c1OC)CCN(CCN1CC2CCC(CC2)C1)C3
Yield: 37 %

Procedure:
Prepared by the method described in Example 13 from 1,2,3,4-tetrahydro-8,9,10-trimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one hydrochloride (10.0 g, 0.031 moles), triethylamine (6.8 g, 0.067 moles), and 3-(2-chloroethyl)-3-azabicyclo[3.2.2]nonane hydrochloride (7.5 g, 0.034 moles). The crude product began to precipitate as the monohydrochloride shortly after reflux of the reaction mixture began. The product is filtered and recrystallized several times from 2-methoxyethanol/water to yield the final product (5.5 g) as the monohydrochloride, mp 241°-243° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.C1([Hg][C:23](Br)([Br:25])[F:24])C=CC=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:23]2([Br:25])[F:24])=[CH:4][CH:3]=1
Reactant: FC(Br)(Br)[Hg]c1ccccc1
Reactant: CCOC(=O)C=CSc1ccc(F)cc1
Product: CCOC(=O)C1C(Sc2ccc(F)cc2)C1(F)Br
Reaction time: 0.5 h

Procedure:
Ethyl 3-(4-fluorophenylthio)-2-propenoate can also be combined with phenyl(dibromofluoromethyl)mercury, in 1:1 ratio, and heated at 80°, with stirring for 30 min, to give ethyl 3-(4-fluorophenylthio)-2-bromo-2-fluorocyclopropanecarboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[N:6]=[CH:5]2.[CH3:17][O:18][C:19](=[O:25])[CH2:20][CH2:21][S:22]([O-:24])=[O:23].[Na+]>[Cu]I>[CH3:15][CH:14]([S:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([S:22]([CH2:21][CH2:20][C:19]([O:18][CH3:17])=[O:25])(=[O:24])=[O:23])=[CH:10][CH:9]=2)[CH:5]=[N:6]1)(=[O:13])=[O:12])[CH3:16]
Reactant: CC(C)S(=O)(=O)n1ncc2cc(Br)ccc21
Reactant: COC(=O)CCS(=O)[O-]
Agent: [Cu]I
Agent: [Na+]
Product: COC(=O)CCS(=O)(=O)c1ccc2c(cnn2S(=O)(=O)C(C)C)c1
Temperature: 110 °C

Procedure:
5-bromo-1-(propan-2-ylsulfonyl)-1H-indazole (0.85 g, 2.79 mmol), sodium 3-methoxy-3-oxopropane-1-sulfinate (2.42 g, 13.9 mmol) and CuI (2.66 g, 13.9 mmol) were charged in a sealable microwave flask. The flask was closed and degassed twice, after which dry DMSO (3.0 mL) was added and the reaction mixture degassed before being heated at 110° C. in an oil bath overnight. The reaction mixture was cooled and diluted with ethyl acetate (40 mL), and then filtered on a silica gel pad and eluted with ethyl acetate. The organic phases were concentrated under reduced pressure. The crude was purified on silica gel eluting with hexanes and ethyl acetate, then with DCM and methanol to afford the title compound.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([CH2:22][CH2:23][OH:24])[CH:13]=3)[CH2:7][CH2:6]2)[O:4]CC1.CC(C)=O.Cl.O.C(=O)(O)[O-]>>[OH:24][CH2:23][CH2:22][C:14]1[N:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[N:17]=[C:12]([O:11][CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)[CH:13]=1
Reactant: OCCc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC(Oc2cc(CCO)nc(C(F)(F)F)n2)CC1
Reaction time: 17 h

Procedure:
2-[6-(1,4-Dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidin-4-yl]ethanol was dissolved in acetone (60 mL, 900 mmol), and 5.0 M hydrogen chloride in water (20 mL, 98 mmol) was added and stirred for 17 hours. LCMS and HPLC analysis showed nearly complete conversion to M+H 305. Aqueous bicarbonate was added and the reaction mixture was stirred, then concentrated. This mixture was extracted with EtOAc. The EtOAc was dried (Na2SO4), and evaporated in vacuo to give 1.3 g light yellow viscous oil (used in the next reaction without purification). 1H NMR (300 MHz, CDCl3): δ6.80 (s, 1H); 5.60 (m, 1H, OCH); 4.06 (t, 2H, OCH2); 3.04 (t, 2H, CH2); 2.61 (m, 2H); 2.45 (m, 2H); 2.25 (m, 2H).
Reaction SMILES: [CH3:1][Si:2]([CH:5]=[N+:6]=[N-:7])([CH3:4])[CH3:3].C([Li])CCC.C1(S([CH:22]=[CH:23][C:24]2[CH:25]=[CH:26][C:27]3[S:32][C:31]4[N:33]=[CH:34][CH:35]=[N:36][C:30]=4[N:29]([CH2:37][O:38][CH3:39])[C:28]=3[CH:40]=2)(=O)=O)C=CC=CC=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]1[C:23]([C:24]2[CH:25]=[CH:26][C:27]3[S:32][C:31]4[N:33]=[CH:34][CH:35]=[N:36][C:30]=4[N:29]([CH2:37][O:38][CH3:39])[C:28]=3[CH:40]=2)=[CH:22][NH:7][N:6]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COCN1c2cc(C=CS(=O)(=O)c3ccccc3)ccc2Sc2nccnc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCN1c2cc(-c3c[nH]nc3[Si](C)(C)C)ccc2Sc2nccnc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1.5 ml of a 2.0 M solution of (trimethylsilyl)-diazomethane in hexane was added to dry tetrahydrofuran (7 ml) in a nitrogen atmosphere and cooled to −78° C. After dropping 1.0 ml of a 1.6 M n-butyllithium solution in n-hexane thereinto, the resulting mixture was stirred for 30 minutes. Into the reaction mixture was dropped a solution of 410 mg of 8-(2-benzenesulfonylvinyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine obtained in Example 1080-1 in dry tetrahydrofuran (5 ml). Then the reaction mixture was gradually heated to room temperature and an aqueous solution of ammonium chloride was added thereto followed by extraction with ethyl acetate. Then the mixture was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane) to thereby give 130 mg of the title compound as yellow crystals.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][CH3:15])=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([OH:30])=O)[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([N:14]([C:10]4[CH:11]=[C:12]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:13]5)[CH3:15])=[O:30])[CH2:26][CH2:27]3)=[CH:24][C:19]=2[O:18][CH2:17]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CNc1ccc2[nH]c(C(C)(C)C)cc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C(=O)C1(c2ccc3c(c2)OCO3)CC1)c1ccc2[nH]c(C(C)(C)C)cc2c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
2-tert-Butyl-N-methyl-1H-indol-5-amine (20.2 mg, 0.100 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (42.1 μL, 0.300 mmol) and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 16 h at 80° C. The crude product was then purified by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)-N-methylcyclopropanecarboxamide. ESI-MS m/z calc. 390.2, found 3913(M+1)+. Retention time of 3.41 minutes.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]#[N:12])=[CH:4][C:5]([S:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].CC([O-])(C)C.[K+]>C1COCC1.CS(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:21][C:2]1[C:3]([C:11]#[N:12])=[CH:4][C:5]([S:8][CH2:9][CH3:10])=[N:6][CH:7]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CCSc1cc(C#N)c(Cl)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCSc1cc(C#N)c(Oc2ccc(Cl)c(Cl)c2)cn1
Yield: 36.2 %

Procedure:
5-Chloro-2-ethylthio-4-pyridinecarbonitrile (5.4 g) was mixed with 5.4 g of 3,4-dichlorophenol in the presence of 3.7 g of t-BuOK in 30 ml of THF and 30 ml of DMSO. The mixture was heated at boiling temperature for about 70 hours to give 3.2 g (36%) of the desired 5-(3,4-dichlorophenoxy)-2-ethylthio-4-pyridinecarbonitrile, m.p. 79°-81° C.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][CH3:7])[C:3](Cl)=[O:4].[NH2:8][C:9]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12]>C1(C)C=CC=CC=1>[Cl:1][CH:2]([C:3]1[O:4][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([F:19])([F:20])[F:21])[C:9]=2[N:8]=1)[CH2:6][CH3:7]
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Reactant: CCC(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: CCC(Cl)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
A suspension of 20.3 g of 2-chloro-butyryl chloride and 12.3 g of 2-amino-3-trifluoromethyl-benzoic acid in toluene was refluxed under reduced pressure for one hour and was then evaporated to dryness under reduced pressure. The oil residue was added to 100 ml of iced water and the mixture was stirred for one hour and was vacuum filtered. The product was washed with water and dried under reduced pressure at 50° C. to obtain 17 g of 2-(1-chloropropyl)-8-trifluoromethyl-4H-3,1-benzoxazine-4-one melting at 65°-70° C.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].C(N(CC)CC)C.[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:29]([C:21]1[S:20][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=1)(=[O:30])=[O:31])[CH3:4]
Reactant: O=S(=O)(Cl)c1nc2ccccc2s1
Reactant: CCOC(=O)CNCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of N-(2-aminoethyl)-glycine ethyl ester 2HCl (1.10 g, 5.0 mmol), prepared as described by Will (D. W. Will et al., Tetrahedron, 1995, 51, 12069.), in dichloromethane (50 mL) was slowly added triethylamine (2.02 g, 20 mmol) at room temperature. Then benzothiazole-2-sulfonyl chloride (1.19 g 5.0 mmol) in dichloromethane (10 mL) was added to the reaction mixture at room temperature for 5 min. The resulting reaction mixture was stirred for additional 2 h. at room temperature and washed with water (30 mL). The organic layer was dried over MgSO4 and filtered. The filtrate was evaporated to remove solvent to give desired product (1.60 g, 92%) as a solid. 1H NMR (500 MHz; DMSO-d6) δ 8.28 (d, 1H), 8.19 (d, 1H), 7.69˜7.63 (m, 2H), 4.03 (q, 2H), 3.24 (s, 2H), 3.13 (t, 2H), 2.62 (t, 2H), 1.15 (t, 3H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:12]([Mg]Cl)([CH3:14])[CH3:13]>C1COCC1>[CH:12]([C:8]1([OH:11])[CH2:7][CH2:6][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:10][CH2:9]1)([CH3:14])[CH3:13]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)C1(O)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a solution of commercially available 1,4-dioxaspiro[4.5]decan-8-one (3.00 g, 19.2 mmol, in THF (20 mL) cooled to −78° C. under argon was added a isopropylmagnesium chloride (10 mL, 20 mmol, 2 M in THF) dropwise. After the complete addition, the reaction mixture was allowed to reach room temperature overnight. It was then re-cooled to −78° C. and quenched with saturated NaHCO3 solution and warmed to room temperature. After extraction with ether, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0-100% ether/hexanes) to afford the product.
Reaction SMILES: Br[C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Li]C.[Li]CCCC.[Cl:38]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O>[Cl:38][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Agent: [Li]C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 36.8 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.300 g, 0.624 mmol; Example 15, Step B) was placed in THF (10 mL) and cooled to −78° C. MeLi (1.17 mL, 1.87 mmol) was then added, and the reaction was stirred for 10 minutes. Excess THF (10 mL) was added to aid solubility. n-BuLi (0.525 mL, 1.31 mmol) was then added and stirred for an additional 10 minutes, followed by the addition of a hexachloroethane (0.296 g, 1.25 mmol) solution in THF (3 mL). The reaction was then stirred for an additional 10 minutes at 0° C., poured into water, and extracted into DCM. The organic fractions were dried, filtered, and concentrated to give a crude oil that was purified by reverse phase HPLC (50-75% ACN in water) to give the product (R)-tert-butyl 1-(5-chloro-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.100 g, 36.7% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2].[N+:15]([O-])([O-:17])=[O:16].[NH4+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1ccccc1
Reactant: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: N#Cc1cc([N+](=O)[O-])ccc1-c1ccccc1
Temperature: 0 °C
Yield: 94.4 %

Procedure:
2-Cyanobiphenyl (0.111 moles, 20.0 g) and ammonium nitrate (10.0 grams) were added to 250 ml chloroform. Trifluoroacetic anhydride (80 ml) was added. The reaction mixture was stirred until the ammonium nitrate was dissolved. The reaction mixture was added to 300 ml of ice water. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to yield 23.5 g of 2-Cyano-4-nitrobiphenyl. (MS)
Reaction SMILES: C([O:8][C:9](=[O:24])[CH:10]([O:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1.[H][H]>[Pd]>[C:16]([O:15][CH:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9]([OH:24])=[O:8])(=[O:23])[C:17]1[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=1
Reactant: CC(C)CC(OC(=O)c1ccncc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Product: CC(C)CC(OC(=O)c1ccncc1)C(=O)O

Procedure:
8.2 g of benzyl-(RS)-2-(isonicotinoyloxy)-isocaproate were hydrogenated in 50 ml of alcohol after the addition of 800 mg. of palladium-on-charcoal (5%) until the theoretical amount of hydrogen had been taken up. The catalyst was then filtered off and the filtrate evaporated under reduced pressure at 45°. The resulting oil was dissolved in excess sodium bicarbonate solution and extracted twice with 20 ml portions of ether and the bicarbonate solution adjusted to pH 2.5 with 3-N hydrochloric acid. The acidic solution was extracted twice with 70 ml portions of ethyl acetate. After being washed twice with 20 ml portions of 5% sodium chloride solution, the ethyl acetate solution was dried with magnesium sulphate and evaporated under reduced pressure at 45°. The resulting oil was crystallized from ether/petroleum ether to yield (RS)-2-(isonicotinoyloxy)-isocaproic acid; mp 98°-100°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Cl:14])[C:5]2[NH:9][C:8]([CH:10]([F:12])[F:11])=[N:7][C:6]=2[CH:13]=1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[N:19]=[C:18]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[CH:3]=[C:4]([Cl:14])[C:5]2[N:9]=[C:8]([CH:10]([F:11])[F:12])[N:7]([C:20]3[N:21]=[C:16]([Cl:15])[N:17]=[C:18]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)[N:19]=3)[C:6]=2[CH:13]=1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Reactant: Nc1cc(Cl)c2[nH]c(C(F)F)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Nc1cc(Cl)c2nc(C(F)F)n(-c3nc(Cl)nc(N4CCOCC4)n3)c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 28.4 %

Procedure:
6-Amino-4-chloro-2-difluoromethylbenzimidazole (500 mg, 2.3 mmol) was dissolved in acetone (50 ml), 2,4-dichloro-6-morpholino-1,3,5-triazine (542 mg, 2.3 mmol) was added at −15° C., and potassium carbonate (500 mg) was further added. After having elevated the temperature gradually to room temperature, the mixture was stirred at room temperature for 5 hours. The solvent was evaporated under vacuum, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:4) to afford 2-(6-amino-4-chloro-2-difluoromethylbenzimidazol-1-yl)-4-chloro-6-morpholino-1,3,5-triazine (272 mg, yield 28%).
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)(C)=O.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[C:28](=[O:30])[CH3:29])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[C:28]1([CH3:8])[CH2:29][O:30]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[S+](C)(C)=O
Reactant: CC(=O)c1cc(Cl)ccc1OCc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(c2cc(Cl)ccc2OCc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 60% sodium hydride (1.2 g,30 mmol) in tetrahydrofuran (30 mL)-dimethyl sulfoxide (30 mL) was heated at external temperature of 60° C., and trimethylsulfoxonium iodide (6.5 g, 30 mmol) was added portionwise to the mixture. The resultant mixture was stirred for 1 hour and then cooled to room temperature. A solution of 1-(2-(benzyloxy)-5-chlorophenyl)-1-ethanone [compound (9-1)] (5.0 g, 19 mmol) in tetrahydrofuran (10 mL) was added dropwise to the mixture, and the mixture was stirred for 3 hours at external temperature of 60° C. After the mixture was cooled to room temperature, the mixture was added to ice-water, followed by extraction with diethyl ether. The extracted substance was washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure, to thereby yield 2-(2-(benzyloxy)-5-chlorophenyl)-2-methyloxirane as a colorless oily product (yield: 4.4 g). The obtained product was used in the subsequent reaction step without purification.
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)=O.[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]3[NH:26][CH2:25][CH2:24][C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:22][C:21]=3[CH:31]=2)=[CH:13][C:12]=1[F:32])[CH3:9].C(OC=O)=O>C1COCC1>[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]3[N:26]([CH:1]=[O:3])[CH2:25][CH2:24][C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:22][C:21]=3[CH:31]=2)=[CH:13][C:12]=1[F:32])[CH3:9]
Reactant: CC(=O)O
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1F
Agent: O=COC=O
Solvent: C1CCOC1
Solvent: O=CO
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To anhydrous acetic acid (0.63 ml) was added formic acid (0.31 ml) at 0° C., and the mixture was stirred at 60° C. for 2 hours, cooled and diluted with THF (10 ml). In THF (10 ml) was dissolved methyl 7-(4-ethoxy-3-fluorophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (510 mg), and the solution was added dropwise to the previously prepared solution of formic anhydride in THF, at 0° C. The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give methyl 7-(4-ethoxy-3-fluoropheny)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (490 mg, 89%) as white crystals.
Reaction SMILES: Br.FC1C=CC(C2[S:13][C:12]([NH:14]C(=O)C)=[N:11]C=2C)=CC=1OC.Br[CH:22]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([S:33]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)(=[O:35])=[O:34])[CH:27]=1)[C:23](=O)[CH3:24].C(NC(N)=S)(=O)C.NC(N)=S>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:22]2[S:13][C:12]([NH2:14])=[N:11][C:23]=2[CH3:24])=[CH:27][C:28]=1[S:33]([N:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1)(=[O:35])=[O:34]
Reactant: COc1cc(-c2sc(NC(C)=O)nc2C)ccc1F
Reactant: CC(=O)C(Br)c1ccc(Cl)c(S(=O)(=O)N2CCN(C)CC2)c1
Agent: Br
Agent: CC(=O)NC(N)=S
Agent: NC(N)=S
Product: Cc1nc(N)sc1-c1ccc(Cl)c(S(=O)(=O)N2CCN(C)CC2)c1

Procedure:
The title compound is prepared as an HBr salt by the same procedure as N-[5-(4-fluoro-3-methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide (161c) by replacing 1-bromo-1-(4-fluoro-3-methoxy-phenyl)-propan-2-one (161b) with 1-bromo-1-[4-chloro-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propan-2-one (171c) and N-acetylthiourea with thiourea.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.C(OC([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33]O)[CH2:29][CH2:28]1)=O)(C)(C)C>>[F:19][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=2)[C:8]([O:10][CH2:33][CH:30]2[CH2:31][CH2:32][NH:27][CH2:28][CH2:29]2)=[O:9])[CH2:3]1
Reactant: O=C(O)[C@](O)(c1ccc(Br)cc1)[C@@H]1CCC(F)(F)C1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Product: O=C(OCC1CCNCC1)[C@](O)(c1ccc(Br)cc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)acetic acid and N-t-butoxycarbonyl-4-piperidine-methanol, the title compound was prepared by a method similar to Steps 2 and 3 of Referential Example 12.