Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH:13]([CH2:16][CH:17]4[CH2:22][CH2:21][N:20]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:19][CH2:18]4)[C:14](=[O:15])[C:7]3=[CH:6][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH:13]([CH2:16][CH:17]4[CH2:22][CH2:21][N:20]([CH2:23][C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:19][CH2:18]4)[C:14](=[O:15])[C:7]3=[CH:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)cc1n2CC(CC2CCN(Cc3ccccc3)CC2)C1=O
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C1c2cc3cc(O)ccc3n2CC1CC1CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 107.1 %

Procedure:
A solution of 2,3-dihydro-7-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-one (1.599 g, 4.12 mmol) in 95 ml of methylene chloride was treated with potassium carbonate (5.696 g, 41.2 mmol) and cooled to -78° C. Boron tribromide (BBr3) was added dropwise to the cooled solution. After addition, the resulting solution was stirred at 0° C. for one hour, then at room temperature overnight. The mixture was treated with 36 g of potassium carbonate and 100 ml of water and stirred for one hour. The organic layer was separated, washed with water, dried and concentrated to give 1.652 g of yellow solid which was purified through silica gel column chromatography to give 0.988 g of the title compound. This material was recrystallized from ethyl acetate to give brown crystals, mp. 186°-188° C. Anal. Calc. for C24H26N2O2.0.1H2O: C, 76.60; H, 7.02; N, 7.45; Found C, 76.45; H, 7.18; N, 7.38.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[N:5]2.[F:13][C:14]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:15]=1[O:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[F:13][C:14]1[CH:27]=[C:26]([O:28][C:7]2[CH:6]=[N:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[N:8]=2)[CH:25]=[CH:24][C:15]=1[O:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Clc1cnc2cc(Br)ccc2n1
Reactant: CCOC(=O)C(C)Oc1ccc(O)cc1F
Product: CCOC(=O)C(C)Oc1ccc(Oc2cnc3cc(Br)ccc3n2)cc1F

Procedure:
Ethyl 2-[2-fluoro-4-(6-bromoquinoxalin-2-yloxy)phenoxy]propionate (10) was prepared from 6-bromo-2-chloro quinoxaline and ethyl 2-(2-fluoro-4-hydroxyphenoxy)propionate following essentially the same procedure as that described in Example 1 part (b). The title compound was obtained as colourless crystals mp 107°-108.6° C. and the assigned structure was characterised by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:15][C:14](=[O:16])[CH:13]([CH3:17])[CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([F:29])[F:28])[N:21]=1>>[F:29][CH:27]([F:28])[O:26][C:22]1[N:21]=[C:20]([CH2:19][N:15]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH:13]([CH3:17])[C:14]2=[O:16])[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(OC)c1C1CC(C)C(=O)N1
Reactant: FC(F)Oc1cccc(CBr)n1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(OC(F)F)n1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 5-(2,6-dimethoxyphenyl)-3-methylpyrrolidin-2-one with 2-(bromomethyl)-6-(difluoromethoxy)pyridine. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 393.19 g/mol.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[C:19]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][N:21]=2)=[CH:11][CH:10]=1.[OH-].[Na+]>ClCCl>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[CH:17][N:18]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:19]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][N:21]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccncn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(-c2ncn(C3CCNCC3)c2-c2ccncn2)cc1
Reaction time: 18 h

Procedure:
TFA (242 mL) was added to a solution of tert-butyl 4-[4-(4-fluorophenyl)-5-pyrimidin-4-yl-1H-imidazol-1-yl]piperidine-1-carboxylate (C14) (30.70 g, 72.49 mmol) in dichloromethane (242 mL). After 18 hours, the reaction was treated with aqueous sodium hydroxide solution (2 N) until the pH of the mixture reached 12.0. {Caution: potential exotherm!} The aqueous layer was extracted with dichloromethane (2×500 mL), and the combined organic layers were concentrated in vacuo to provide the product as a yellowish solid. Yield: 23.90 g, 73.91 mmol, quantitative. 1H NMR (400 MHz, CDCl3) δ 1.82-1.92 (m, 2H), 2.14 (br d, J=12 Hz, 2H), 2.71 (ddd, J=12.3, 12.3, 2.2 Hz, 2H), 3.22 (br d, J=12 Hz, 2H), 4.82 (tt, J=12.0, 3.9 Hz, 1H), 7.03 (dd, J=8.8, 8.8 Hz, 2H), 7.16 (dd, J=5.3, 1.4 Hz, 1H), 7.41 (dd, J=8.9, 5.4 Hz, 2H), 7.83 (s, 1H), 8.57 (d, J=5.3 Hz, 1H), 9.30 (d, J=1.4 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:31][N:32]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:20]=[C:2]([C:35]2[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: Cn1cc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2cnn(C)c2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 49.9 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (0.2 g, 0.42 mmol) and (1-methyl-1H-pyrazol-4-yl)boronic acid (0.105 g, 0.505 mmol) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (0.16 g, 1.51 mmol) was added and solution purged with argon for 15 min. Pd (PPh3)4 (0.048 g, 0.042 mmol) was then added and the reaction mixture again purged with argon for 10 min. The reaction mixture was heated at 100° C. for 2 h. The reaction mixture was then diluted with water and extracted with 10% MeOH/DCM. The combined extracts were dried over Na2SO4 and the solvent removed under reduced pressure to afford the crude product which was purified by column chromatography to afford the title compound (0.100 g, 50%). LCMS: 478.20 (M+1)+; HPLC: 95.82% (@254 nm) (Rt; 4.322; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.12 (s, 1H), 8.10 (t, 1H), 7.81 (s, 1H), 7.33 (s, 1H), 7.13 (s, 1H), 5.86 (s, 1H), 4.27 (d, 2H, J=4.8 Hz), 3.81-3.83 (m, 5H), 3.21-3.26 (m, 2H), 2.98-3.08 (m, 3H), 2.20 (s, 3H), 2.17 (s, 3H), 2.10 (s, 3H), 1.63-1.66 (m, 2H), 1.48-1.52 (m, 2H), 0.86 (t, 3H, J=7.2 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Br:19])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:18]=1.Cl.N1C=CC=CC=1>O>[Br:1][C:2]1[CH:3]=[C:4]([Br:19])[C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)=[CH:7][C:6]=2[CH:18]=1
Reactant: COc1ccc(-c2cc3cc(Br)cc(Br)c3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc(-c2cc3cc(Br)cc(Br)c3o2)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
Compound 87 was treated with Pyridine HCl (5 g) and heated to 200° C. After 1 hr, the reaction was cooled and diluted with water. The aqueous layer was extracted with EtOAc, dried over MgSO4, and the product was purified by column chromatography (eluant 25% EtOAc/hexanes) to give a solid (0.12 g, 18%); Mp=203-205° C.; 1H NMR (DMSO-d6) δ 10.04 (br s, 1 H), 7.83 (d, 1 H, J=1.5 Hz), 7.75 (d, 2 H, J=8.3 Hz), 7.68 (d, 1 H, J=2.0 Hz), 7.28 (s, 1 H), 6.91 (d, 2 H, J=8.3 Hz); MS 365/367/369 [M−H]−
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[C:23](#[N:25])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:23]#[N:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1
Reactant: CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [C-]#N
Product: N#C[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 65 °C

Procedure:
(S)-Methanesulfonic acid 1-benzyl-pyrrolidin-3-yl ester (28 g, 110 mmol) was dissolved in anhydrous acetonitrile (60 mL) and solid tetrabutylammonium cyanide (59 g, 220 mmol) was added at once at room temperature. The resulting mixture was heated at 65° C. for 16 h and cooled to room temperature. Saturated NaHCO3 (100 mL) solution was added. The organic layer was separated and the aqueous layer extracted with toluene (3×100 mL). The combined organic layers were washed with water (3×100 mL), brine, and dried over Na2SO4 and concentrated under reduced pressure to give (R)-1-benzyl-3-cyanopyrrolidine as brown oil (21 g), which was vacuum distilled at 150° C./5 mmHg to give a colorless liquid (19 g, 85%): [α]23−22.0° (c=2.5, MeOH); 1H NMR (400 MHz, CDCl3) δ 7.36-7.17 (m, 5H), 3.66 (app s, 2H), 3.05-2.99 (m, 1H), 2.93 (app t, J=8.8 Hz, 1H), 2.72-2.60 (m, 3H), 2.31-2.22 (m, 1H), 2.17-2.11 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:20](O)=[O:21])[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=1.Cl.[NH2:24][C@@H:25]([CH2:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[C:46]([F:51])[CH:45]=1)[C@H:26]([OH:42])[CH2:27][NH:28][C:29]1([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)[CH2:31][CH2:30]1.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C.O.C(N(CC)CC)C>[F:51][C:46]1[CH:45]=[C:44]([CH:49]=[C:48]([F:50])[CH:47]=1)[CH2:43][C@H:25]([NH:24][C:20]([C:4]1[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=[C:2]([Cl:1])[CH:3]=1)=[O:21])[C@H:26]([OH:42])[CH2:27][NH:28][C:29]1([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:40])[F:41])[CH:33]=2)[CH2:31][CH2:30]1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Reactant: CCCC(CCC)N1CCc2c(C(=O)O)cc(Cl)cc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC(CCC)N1CCc2c(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNC3(c4cccc(C(F)(F)F)c4)CC3)cc(Cl)cc2C1=O
Reaction time: 15 h

Procedure:
Added, under an argon atmosphere and at a temperature close to 20° C., to a solution of 180 mg of 7-chloro-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid in 2.2 cm3 of anhydrous dimethylformamide are 0.25 cm3 of triethylamine and 263 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), then 90 mg of 1-hydroxy-7-azabenzotriazole and 127 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The solution is kept stirring, under argon, for 15 h at a temperature close to 20° C. The reaction medium is then added to 10 cm3 of water and 20 cm3 of ethyl acetate. After decanting, the organic phase is washed with 10 cm3 of a saturated aqueous solution of ammonium chloride, five lots of 10 cm3 of water, then 10 cm3 of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa). The residual solution (around 2 cm3) is purified by flash chromatography over silica (column: 15 g; spherical silica of BP-SUP type, particle size: 20-40 μm; eluent: 50% heptane/50% ethyl acetate). After concentrating the fractions under reduced pressure, 274 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-7-chloro-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained in the form of a beige foam.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:22]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2-c1ccccc1
Reactant: OB(O)c1ccccc1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1ccc2c(c1)c1cc(-c3ccccc3-c3ccccc3)ccc1n2-c1ccccc1
Temperature: 100 °C
Yield: 42 %

Procedure:
A mixture of 40.1 g (100 mmol) of 3,6-dibromo-9-phenyl-9H-carbazole, 21.8 g (110 mmol) of biphenyl-2-ylboronic acid, 2.31 g (2 mmol) of Pd(PPh3)4, 75 ml of 2M Na2CO3, 150 ml of EtOH and 300 ml toluene was degassed and placed under nitrogen, and then heated at 100° C. for 12 h. After finishing the reaction, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica to give product (19.9 g, 42.0 mmol, 42%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:11]2([CH2:33]O)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:22][C:23]3[O:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)[C:12]2=[O:32])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[CH3:21][O:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[C:11]1([C:3]3=[CH:4][C:5]4[O:9][CH2:8][O:7][C:6]=4[CH:10]=[C:2]3[O:1][CH2:33]1)[C:12](=[O:32])[N:13]2[CH2:22][C:23]1[O:24][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:26][CH:27]=1
Reactant: COc1cccc2c1C(CO)(c1cc3c(cc1O)OCO3)C(=O)N2Cc1ccc(C(F)(F)F)o1
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: COc1cccc2c1C1(COc3cc4c(cc31)OCO4)C(=O)N2Cc1ccc(C(F)(F)F)o1

Procedure:
Following the procedure described in EXAMPLE 1, and making non-critical variations using 3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-4-methoxy-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (33%) as a white solid: mp 149-153° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.32-7.24 (m, 1H), 6.82-6.62 (m, 3H), 6.46 (s, 1H), 6.40 (d, 1H), 6.08 (s, 1H), 5.87 (ABq, 2H), 4.92 (ABq, 2H), 4.82 (ABq, 2H), 3.70 (s, 3H); MS (ES+) m/z 460.3 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[CH:19]=[CH:18][O:17][CH:16]=2)=[O:8])[CH2:3][CH2:2]1.Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:22]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[O:17]1[CH:18]=[CH:19][C:15]([C:10]2[N:11]=[C:12]([NH:14][C:28](=[O:29])[CH2:27][C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[S:13][C:9]=2[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:8])=[CH:16]1
Reactant: Nc1nc(-c2ccoc2)c(C(=O)C2CCOCC2)s1
Reactant: O=C(O)Cc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Cc1cccnc1)Nc1nc(-c2ccoc2)c(C(=O)C2CCOCC2)s1
Temperature: 80 °C
Reaction time: 10 h
Yield: 51.3 %

Procedure:
Compound 610 (102 mg, 0.366 mmol) was dissolved in DMF (3 mL), and 3-pyridylacetic acid hydrochloride (635 mg, 3.66 mmol), EDC hydrochloride (702 mg, 3.66 mmol), 1-hydroxybenzotriazole monohydrate (561 mg, 3.66 mmol) and triethylamine (0.510 mL, 3.66 mmol) were added thereto, followed by stirring at 80° C. for 10 hours. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The resulting solid was purified through silica gel column chromatography (hexane:ethyl acetate=2:1), followed by recrystallizing from a mixed solvent of ethanol and water to afford the entitled Compound 618 (74.6 mg, 52%) as a white solid.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:16]3[CH:17]=[C:18]([CH:21]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)[C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[CH:19]=[CH:20][C:15]=3[NH:14][C:13](=S)[CH2:12][S:11]2)[CH:7]=[CH:8][CH:9]=1.[Na+].[Cl-]>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:16]3[CH:17]=[C:18]([CH:21]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)[C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]([NH:1][NH2:2])[CH2:12][S:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: NN
Reactant: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCC(=S)N2
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCC(NN)=N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
Hydrazine (3.2 ml) was added at room temperature to a mixture of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-4,1-benzothiazepine-2(3H)-thione (described in Example B16a) (0.0063 mol) in THF (35 ml). The mixture was stirred at room temperature for 30 min, poured out into ice water, saturated with NaCl and extracted with DCM and a small amount of methanol. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 2.3 g (71.9%) of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-2-hydrazino-3,5-dihydro-4,1-benzothiazepine.
Reaction SMILES: C(OC([NH:11][C@:12]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][C:16](=[O:18])[NH:15][C:13]1=[O:14])=O)C1C=CC=CC=1.O.[H][H]>C(O)C.[Pd]>[NH2:11][C@:12]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][C:16](=[O:18])[NH:15][C:13]1=[O:14]
Reactant: CCOC(=O)[C@@]1(NC(=O)OCc2ccccc2)CC(=O)NC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@@]1(N)CC(=O)NC1=O
Temperature: 35 °C
Reaction time: 33 h
Yield: 86.7 %

Procedure:
(2R)-2-Benzyloxycarbonylamino-2-ethoxycarbonylsuccinimide (24.4 g, 76.2 mmol) in ethanol (73.2 ml) was heated at 60° C. to be dissolved and 5% Pd—C (2.71 g) and water (2.17 g) were added at 30-40° C. of inner temperature. After the atmosphere was substituted with nitrogen gas, hydrogen gas was introduced and the mixture was stirred at 30-40° C. for about 33 hours. When completion of the reaction was confirmed by HPLC, the reaction solution was filtered, the insoluble materials were washed with sprayed ethanol (20 ml×2) and the filtrate was concentrated. The resulting crystals were recrystallized from ethanol (24.4 ml) and the precipitated crystals were filtered, washed with sprayed ethanol (15 ml) and dried in vacuo at room temperature to give (2R)-2-amino-2-ethoxycarbonylsuccinimide (12.3 g). Yield 86.7%, HPLC 99.7%, Optical purity 100% e.e.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[CH2:5][C:6]=1C.[Li]CCCC>CCOCC>[CH3:13][C:10]1[O:9][C:8]([C:4]2[CH:3]=[C:2]([CH3:1])[CH2:6][CH:5]=2)=[CH:12][CH:11]=1
Reactant: CC1=C(C)CC(c2ccc(C)o2)=C1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC1=CC(c2ccc(C)o2)=CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.7 %

Procedure:
The solution of 2-(3,4-dimethyl-1,3-cyclopentadien-1-yl)-5-methylfuran (3.2 g, 20 mmol) in Et2O (40 mL) was cooled to −20° C. and BuLi (8 mL 2.5N in hexane, 20 mmol) was added dropwise. Suspension obtained was stirred 1 h at room temperature, cooled again to −20° C., and ZrCl4(THF)2 (3.77 g, 10 mmol) was added. After 16 h of stirring, the precipitate was filtered off, dissolved in dichloromethane, solution was filtered and solvent was evaporated. Residue was washed with Et2O, pentane and dried in vacuo giving 0.6 g of product as pure form. Filtrate was concentrated and 1.3 g of complex was obtained as mixture of isomers (1:1 ratio). (total yield 38%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C=O)C>[Si:15]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Yield: 74.7 %

Procedure:
A solution of 3.66 g of 3-hydroxybenzaldehyde, 3.1 g of imidazole, and 4.39 g of tert-butyldimethylsilyl chloride in 10 ml of DMF is stirred at room temperature for 18 h, then partitioned between ether and water. The organic phase is washed with water, dried (MgSO4), and concentrated under reduced pressure. Flash chromatography of the residue on silica gel using 5% ether-hexane provides 5.14 g of the title compound as a pale yellow liquid.
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].Cl.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.Cl.N>CO.O>[NH2:6][C:5]1[N:19]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)[N:20]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: NNc1ccc(Cl)cc1
Reactant: COC(OC)C(C#N)=NO
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Product: Nc1c(N=O)cnn1-c1ccc(Cl)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 96.9% by weight synthesized in the same manner as in Example 1, 3.96 g (21 mmol) of 4-chlorophenylhydrazine hydrochloride with a purity of 95% by weight, 1.4 ml of water, 10 ml of methanol and 1.3 ml (15 mmol) of conc. hydrochloric acid, and the mixture was reacted at 50 to 52° C. for 2 hours. After completion of the reaction, 25 ml of water and 5 ml of methanol were added to the mixture to cool the same up to 10° C., and 2.3 ml (37.9 mmol) of 28% by weight aqueous ammonia was gradually added dropwise to the mixture and the resulting mixture was stirred for 30 minutes while maintaining the liquid temperature to 5° C. or lower. Precipitated crystals were collected by filtration, and then, the crystals were washed with 10 ml of cold water and dried under reduced pressure to obtain 3.73 g of 5-amino-1-(4-chlorophenyl)-4-nitrosopyrazole (Isolation yield: 74.3%) as a yellowish solid with a purity of 88.7% by weight (absolute calibration curve method by high performance liquid chromatography).