Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CC(=O)CC>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]2[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH3:29]
Reactant: Oc1ccc(OCc2ccc(F)cc2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(OCc2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A solution of 3 g of 4-(4-fluoro-benzyloxy)-phenol in 40 ml of 2-butanone was treated with 2.5 g potassium carbonate and 1.6 ml of ethyl bromoacetate. The mixture was stirred at 80° C. during 3 h, then, in order to complete the reaction, 1.7 g of potassium carbonate and 1.9 ml of ethyl bromoacetate were added successively in four portions during a period of 24 h. For the working-up, the reaction mixture was cooled to room temperature, then treated with water and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulphate and evaporated under reduced pressure. There were obtained 2.95 g (71% of theory) of [4-(4-fluoro-benzyloxy)-phenoxy]-acetic acid ethyl ester as brownish crystals which were pure enough to be used in the next step without further purification; MS: m/e=304 (M)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:14][CH2:15][CH2:16][NH2:17])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].N1C=CC=CC=1.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([O:14][CH2:15][CH2:16][NH:17][S:24]([CH3:27])(=[O:26])=[O:25])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: NCCOc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NCCOc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
2-((3-Nitro-5-(trifluoromethyl)phenyl)oxy)ethylamine (4.05 g, 16.2 mmols, 1 eq) was dissolved in 100 mL of CH2Cl2. The solution was cooled to 0° C. Pyridine (2.6 mL, 32.4 mmols, 2 eq) was added followed by mesyl chloride (1.25 mL, 16.2 mmols, 1 eq). The reaction was stirred for 18 h during which time it was warmed slowly to RT. The solvent was removed in vacuo, and the residue dissolved in EtOAc. The resulting solution was washed twice with 2 N HCl, once with water, and 3× with brine. After being dried over Na2SO4 the solution was filtered and concentrated. The crude was purified by silica gel chromatography eluting with 50% to 60% EtOAc:hexane to yield the desired compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][C@H:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]([O:7]CCCCC)=[O:6].O.[OH-].[Li+]>C1COCC1.O.Cl>[CH3:1][CH:2]([CH3:19])[CH2:3][C@H:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]([OH:7])=[O:6]
Reactant: CCCCCOC(=O)[C@H](CC(C)C)OCCCCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCO[C@@H](CC(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.2 %

Procedure:
To a solution of (2S)-pentyl 4-methyl-2-pentyloxypentanoate 9 (80 mg, 0.3 mmol) in 20 mL of THF cooled to 0° C. was added dropwise a solution of lithium hydroxide monohydrate (25 mg, 0.6 mmol) in 5 mL of water. The reaction mixture was stirred at rt for 16 h. THF was removed under reduced pressure to give an yellow oil which was diluted with 10 mL of 1 N HCl. The aqueous phase was extracted with CH2Cl2 (8×15 mL), and the extracts were combined, dried over Na2SO4, and concentrated to afford compound 10 (45 mg, 74%). MS [M+H]+ 203.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1>ClCCl>[Cl:16][C:17]1[N:22]=[C:21]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1
Reactant: NC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc(Cl)nc1NC1CCCC1
Yield: 65.13 %

Procedure:
Cyclopentylamine (5.17 ml) and N,N-diisopropylethylamine (12.4 ml) were dissolved into 125 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitropyrimidine (9.7 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for 80 min. Purification was conducted by a column chromatography to obtain a bright-yellow solid (7.9 g) in a yield of 65.13%. 1H NMR (400 MHz, CDCl3): δ 9.03 (s, 1H), 8.38 (s, 1H), 4.59 (m, 1H), 2.13-2.21 (m, 2H), 1.72-1.85 (m, 4H), 1.53-1.71 (m, 2H) ppm.
Reaction SMILES: C(#N)CC#N.[CH2:6]1[N:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1.[Cl-:14].[Li+]>O1CCCC1>[CH2:6]1[N:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1.[ClH:14]
Reactant: [Cl-]
Agent: C1CN2CCN1CC2
Agent: [Li+]
Solvent: N#CCC#N
Solvent: C1CCOC1
Product: Cl
Reaction time: 2 h

Procedure:
In 100 ml of anhydrous tetrahydrofurane under argon at 0° C., 20.27 g (100 mmoles) of 4-styrenesulfonyl chloride CH2═CHC6H4SO2Cl (commercially available from Monomer-Polymer & Dajac Laboratories), 10.42 g (100 mmoles) of malononitrile and 22.44 g (200 mmoles) of DABCO were reacted. After 2 hours at 0° C. and 48 hours at room temperature, the solution was filtered to remove the DABCO hydrochloride formed, and it was treated with 4.24 g of anhydrous lithium chloride (100 mmoles), stored and weighed in a glove box. There is immediately formed a precipitate of DABCO hydrochloride and the reaction mixture was then again filtered after stirring for 6 hours. After evaporation and drying under vacuum during 24 hours at room temperature, 31.16 g of the lithium salt of 4-styrenesulfonylmalononitrile were recovered, with a purity characterized by a proton and carbon RMN higher than 97%.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:16])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=2)[O:4]1.[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH3:9][C:7]1([CH3:8])[C:3]([CH3:16])([CH3:2])[O:4][B:5]([C:10]2[CH2:11][CH2:12][N:13]([CH2:19][CH2:18][C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH:15]=2)[O:6]1
Reactant: CC1(C)OB(C2=CCNCC2)OC1(C)C
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)CCN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reaction time: 8 h

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (100 mg), tert-butyl acrylate (0.089 mL), potassium carbonate (169 mg), and acetonitrile (2 mL) was stirred overnight at 70 C. In another reaction vessel, a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (1.00 g), tert-butyl acrylate (0.895 mL), potassium carbonate (1.688 g), and acetonitrile (10 mL) was stirred overnight at 70 C. These two reaction mixtures were combined, and water was added thereto, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to obtain the title compound (1.11 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:10]([NH2:12])[CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([C@@H:10]([NH:12][C:42]([C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:33]([CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:21]4[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:31][CH:30]=2)[C:34]([CH3:46])=[C:35]3[CH3:45])=[O:43])[CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(F)cc([C@H](C)N)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: COc1cc(F)cc([C@H](C)NC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3-fluoro-5-methoxyphenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 551 [M+H]+.
Reaction SMILES: [Cl-].[C:2]([CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]([NH3+:17])[CH2:7]1)(O)=[O:3].COS(C1C=CC(C)=CC=1)(=O)=O.C1(N=C=NCCN2CCOCC2)CCCCC1>N1C=CC=CC=1>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[CH:8]1[CH2:7][CH:6]2[CH2:5][C:2](=[O:3])[NH:17]1
Reactant: COc1ccc2c(c1)C(CC(=O)O)CC2[NH3+]
Agent: C(=NCCN1CCOCC1)=NC1CCCCC1
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [Cl-]
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C1CC(=O)NC2C1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
3-Carboxymethyl-5-methoxy-indan-1-yl-ammonium chloride (13.2 g) and 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide methyl-p-toluenesulfonate (21.7 g) dissolved in pyridine (500 mL) is stirred at room temperature for 7 d. Then, the pyridine is removed under reduced pressure and the residue is taken up in water (200 mL) and dichloromethane (200 mL). The organic phase is separated and the aqueous phase is extracted twice with dichloromethane. The combined organic phases are washed with 1 M hydrochloric acid, 1 M NaOH solution, and water. After drying (MgSO4), the solvent is evaporated under reduced pressure to yield the product as a beige solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:7]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[CH:8]=[C:9]2[C:14]([CH2:15][CH:16]([CH3:18])[CH3:17])=[N:13][N:12]([CH3:19])[C:11](=[O:20])[C:10]=12.ClC1C=C(C=CC=1)C(OO)=[O:37].C(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>ClCCl>[OH:1][CH2:2][CH2:3][CH2:4][S:5]([C:6]1[N:7]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[CH:8]=[C:9]2[C:14]([CH2:15][CH:16]([CH3:18])[CH3:17])=[N:13][N:12]([CH3:19])[C:11](=[O:20])[C:10]=12)=[O:37]
Reactant: CC(C)Cc1nn(C)c(=O)c2c(SCCCO)n(Cc3cccc4ccccc34)cc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Cc1nn(C)c(=O)c2c(S(=O)CCCO)n(Cc3cccc4ccccc34)cc12
Yield: 13.6 %

Procedure:
2,6-Dihydro-7-[(3-hydroxypropyl)thio]-2-methyl-4-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyridazin-1-one (0.34 g) prepared as described in Example 3 above was dissolved in dichloromethane (7 ml) and 3-chloroperoxybenzoic acid (229 mg) was added. After 4 hours sodium bicarbonate (aqueous) and sodium metabisulfite (aqueous) were added and the mixture was extracted thrice with dichloromethane. The combined organic extracts were washed with brine, dried, filtered and evaporated. The residue was chromatographed eluting with ethyl acetate and then ethyl acetate:ethanol (19:1-9:1) to give 2 products. The more polar product was triturated with ether to give 2,6-Dihydro-7-[(3-hydroxypropyl)sulfinyl]-2-methyl-4(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyridazin-1-one (A) (48 mg) whilst the less polar product was recrystallised from isohexane-ethyl acetate to give 2,6-dihydro-7-[(3-hydroxypropyl)sulfonyl]-2-methyl-4-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyridazin-1-one (B) (94 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:35][C:36]1([F:41])[CH2:40][CH2:39][NH:38][CH2:37]1>>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33][N:38]5[CH2:39][CH2:40][C:36]([F:41])([F:35])[CH2:37]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(-c3ccc(CBr)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: FC1(F)CCNC1
Product: Nc1ncnn2c(-c3ccc(CN4CCC(F)(F)C4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 2.4 %

Procedure:
Using a procedure similar to that of Example 282, step 2, with 5-(2-benzyl-2H-indazol-6-yl)-7-(4-bromomethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and 3,3-difluoro-pyrrolidine as starting materials, 6.3 mg (2.4%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 725 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.70 (s, 2 H), 3.2 (m, 2 H), 2.70 (m, 2 H), 2.20 (s, 2 H); ES-MS m/z 536.22 [M+H]+, HPLC RT (min) 2.52.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH2:11][CH2:12][O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)=[CH:17][C:15]=3[CH:16]=2)=[O:9])[CH2:3][CH2:2]1.[CH:28]1([CH:34]=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[CH:28]1([CH2:34][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]3[CH2:11][CH2:12][O:13][C:14]4[CH:20]=[CH:19][C:18]([C:21]5[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=5)=[CH:17][C:15]=4[CH:16]=3)=[O:9])[CH2:5][CH2:6]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=CC1CCCCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCNCC2)CCO3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCN(CC4CCCCC4)CC2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
To N-(4-piperidinyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (0.15 g) and cyclohexane carbaldehyde (0.056 g) dissolved in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (0.13 g) under ice cooling, and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was neutralized with a 1 N aqueous solution of sodium hydroxide, was then concentrated and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate/hexane to obtain N-(1-cyclohexylmethylpiperidin-4-yl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 55) (0.13 g) as colorless prisms.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(OCC)=O)C.[OH:19][C:20]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:21]=1[CH:22]=O.C(O)(=O)C>O1CCCC1>[OH:19][C:20]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:21]=1/[CH:22]=[CH:11]/[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)/C=C/c1cc([N+](=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.5 %

Procedure:
Sodium hydride (content: 62%, 3.3g) was suspended in tetrahydrofuran (30 ml). The suspension was ice-cooled in an atmosphere of argon gas. A solution of t-butyl diethylphosphonoacetate (20.9 g) in tetrahydrofuran (20 ml) was added to the suspension. The mixture was stirred for 15 min. at room temperature. A solution of 2-hydroxy-5-nitrobenzaldehyde (6.6 g) in tetrahydrofuran (20 ml) was gradually added to the mixture often with ice-cooling. The mixture was stirred for 10 min. at room temperature. Acetic acid was gradually added to the mixture until pH of the mixture was down to 5.0. The reaction mixture was gel-filtered with using YMC gel. Moreover the gel was washed with ethyl acetate. A mixture of the filtrate and washings was evaporated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1→3:2) to give the title compound (10.0 g) having the following physical data.
Reaction SMILES: P(I)(I)P(I)I.[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH:22]3O[CH:23]3[CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH3:8].N1C=CC=CC=1.Cl>C(Cl)Cl>[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][C@H:19](/[CH:22]=[CH:23]/[CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH3:8]
Reactant: CCCC1OC1[C@H]1CC[C@H](c2ccc(OCC)cc2)CC1
Agent: Cl
Agent: IP(I)P(I)I
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC/C=C/[C@H]1CC[C@H](c2ccc(OCC)cc2)CC1

Procedure:
A suspension of 404.4 mg of diphosphorus tetraiodide in 5 ml of methylene chloride was treated dropwise while gassing with argon at room temperature within 5 minutes with a solution of 205 mg of 4-ethoxy-1-[trans-4-(1,2-epoxypentyl)cyclohexyl]benzene and 0.703 ml of pyridine in 8 ml of methylene chloride. The suspension was heated to reflux while stirring, a further 404.4 mg of diphosphorus tetraiodide being added after 2 hours. After stirring under reflux for a total of 19 hours, the reaction was interrupted and the mixture was treated with 1N hydrochloric acid and extracted three times with diethyl ether. The organic extracts were washed successively with 1N hydrochloric acid, sodium thiosulphate solution and water, dried over magnesium sulphate, filtered and evaporated. Chromatographic separation of the residue (0.2 g) on silica gel with ethyl acetate/petroleum ether (vol. 3:97) as the eluent gave 120 mg of 4-ethoxy-1-[trans-4-(trans-1-pentenyl)cyclohexyl]benzene. After recrystallization from 10 ml of methanol, the product was obtained as white crystals of melting point (C-N) 32.2° C. and clearing point (N-I) 54.9° C.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[F:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].N1C=CC=CC=1>CCOC(C)=O>[F:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
EtSO2Cl (21.5 mL, 0.22 mol) was added drop wise to a mixture of 4-fluoro-3-nitroaniline (29.6 g, 0.19 mol) and pyridine (100 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc (1 L). The resulting solution was washed with HCl 2N (4×200 mL), NaHCO3 saturated solution (4×200 mL) and water (4×200 mL). The organic phase was dried over anhydrous Na2SO4 and the solvent was removed to provide the title product as beige solid (46.3 g)
Reaction SMILES: Br[C:2]1[C:3]2C=C3[C@@H](CC(O)=O)CCN3C=2C=C(F)[CH:10]=1.[CH3:19][O:20][C:21](=[O:37])[CH2:22][C@@H:23]1[C:27]2=[CH:28][C:29]3[C:30](Br)=[CH:31][C:32]([F:35])=[CH:33][C:34]=3[N:26]2[CH2:25][CH2:24]1>>[CH3:19][O:20][C:21](=[O:37])[CH2:22][C@@H:23]1[C:27]2=[CH:28][C:29]3[C:30]([CH:2]([CH3:3])[CH3:10])=[CH:31][C:32]([F:35])=[CH:33][C:34]=3[N:26]2[CH2:25][CH2:24]1
Reactant: O=C(O)C[C@H]1CCn2c1cc1c(Br)cc(F)cc12
Reactant: COC(=O)C[C@H]1CCn2c1cc1c(Br)cc(F)cc12
Product: COC(=O)C[C@H]1CCn2c1cc1c(C(C)C)cc(F)cc12

Procedure:
Starting from [(1R)-8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetic acid (from Step 1 of Example 62A) which was converted to methyl[(1R)-8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate by addition of CH2N2, the title compound was synthesized following the procedures described in Steps 1 and 2 of Example 44.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].ClS([N:24]=[C:25]=[O:26])(=O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[N:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:25]([NH2:24])=[O:26])=[O:5])[CH3:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOC(=O)c1sc(C)nc1NCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1sc(C)nc1N(Cc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-benzylamino-2-methyl-thiazole-5-carboxylic acid ethyl ester (0.40 g, 1.45 mmol) in DCM (10 mL) was added chlorosulfonyl isocyanate (140 μL, 1.59 mmol) dropwise at −78° C. The mixture was allowed to warm to RT and stirred for 30 minutes. The resulting solution was concentrated in vacuo then dissolved in acetone (5 mL), before H2O (2 mL) was added dropwise. The mixture was stirred at RT for 30 minutes, then concentrated in vacuo. The resultant oil was partitioned between EtOAc and H2O. The organic layer was isolated, washed with brine, dried (MgSO4) and concentrated in vacuo to give 4-(1-benzyl-ureido)-2-methyl-thiazole-5-carboxylic acid ethyl ester as a pale brown oil. To a solution of 4-(1-benzyl-ureido)-2-methyl-thiazole-5-carboxylic acid ethyl ester in MeOH (10 mL) was added a solution of sodium methoxide in MeOH (25% w/w, 1.33 mL, 5.80 mmol) and the mixture was stirred at RT for 18 h. The crude reaction mixture was concentrated in vacuo and partitioned between EtOAc and an aqueous solution of HCl (1 M). The organic layer was isolated, washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was triturated with EtOAc to give the title compound as a pale yellow solid (0.25 g, 63%).
Reaction SMILES: [N+:1]([C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[C:5]=1[NH2:18])([O-])=O.Cl[Sn]Cl.O>CO.Cl>[F:11][C:10]([F:12])([F:13])[C:9]1[CH:8]=[CH:7][C:6]([C:14]([F:17])([F:16])[F:15])=[C:5]([NH2:18])[C:4]=1[NH2:1]
Reactant: Nc1c(C(F)(F)F)ccc(C(F)(F)F)c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Nc1c(C(F)(F)F)ccc(C(F)(F)F)c1N
Temperature: 50 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of 2-nitro-3,6-bis(trifluoromethyl)benzenamine (2.3 g, 8.4 mmol) in methanol (10 mL) was added a solution of SnCl2.H2O (7.56 g, 33.6 mmol) in concentrated HCl (15 mL). The mixture was heated to 50° C. and stirred for 2 hours. Methanol was removed in vacuum and the aqueous solution was basified with sodium hydroxide solution. The suspension was diluted with EtOAc (150 mL), and the mixture was stirred at room temperature for 30 minutes and filtered. The filtrate was washed with brine (100 mL), dried over sodium sulfate, and filtered. The solution was concentrated to give a crude product of 3,6-bis(trifluoromethyl)benzene-1,2-diamine (1.5 g). MS (ESI): m/z 245 [M+H]+
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:23][N:24]3C(=O)C4C(=CC=CC=4)C3=O)[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][OH:22])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>C(O)C>[NH2:24][CH2:23][C:9]1[CH:10]=[C:11]2[C:15](=[C:7]([NH:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=1)[NH:14][C:13]([C:16]1[S:17][CH2:18][C@@H:19]([CH2:21][OH:22])[N:20]=1)=[CH:12]2
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CO)CS3)cc2c1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CO)CS3)cc2c1
Reaction time: 3 h
Yield: 29 %

Procedure:
2-[7-Cyclopentylamino-2-((R)-4-hydroxymethyl-4,5-dihydro-thiazol-2-yl)-1H-indol-5-ylmethyl]-isoindol-1,3-dione (27 mg, 0.07 mmol) prepared in Example 64 was dissolved in ethanol (3 mL). Hydrazine hydrate (0.6 mL, 0.11 mmol) was added thereto, and the mixture was stirred for 3 h at 80°. After completion of the reaction, the reaction mixture was distilled under reduced pressure, and purified by column chromatography to give the title compound (7 mg, Yield 37%).