Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8](C(OC(C)(C)C)=O)[C@H:9]([C:19]([NH:21][C@H:22]([C:39]([NH:41][C@H:42]([C:58]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:59])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])=[O:40])[CH2:23][C:24]1[N:28]=[CH:27][N:26]([S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:25]=1)=[O:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[NH2:8][C@H:9]([C:19]([NH:21][C@H:22]([C:39]([NH:41][C@H:42]([C:58]([O:60][CH2:61][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)=[O:59])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[O:49])=[O:40])[CH2:23][C:24]1[N:28]=[CH:27][N:26]([S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:30])=[O:31])[CH:25]=1)=[O:20])[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)[C@H](COCc3ccccc3)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)[C@@H](N)COCc3ccccc3)C(=O)N[C@@H](CCCCNC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)c2)cc1
Yield: 96.4 %

Procedure:
150 ml of TFA was added to 87.7 g of Boc-Ser(Bzl)-His(Tos)-Lys(Z)-OBzl dissolved in 130 ml of methylene chloride under cooling with ice, and the mixture was stirred at the same temperature for an hour and then at room temperature for an hour. Thereafter, procedures similar to those in (iv) in Example 1 were conducted to obtain 75.5 g of Compound 1.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].[H-].[Na+].Br[CH2:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:22]=1[C:23]([O:25][CH3:26])=[O:24].O>CN1C(=O)N(C)CCC1.C1COCC1>[CH3:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][O:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1c(C)cccc1CBr
Reactant: OCCCCNc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)c1c(C)cccc1COCCCCNc1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4-(Quinolin-2-ylamino)-butan-1-ol (432 mg, 2.0 mmol, EXAMPLE 42a) is dissolved in 20% DMPU in THF (5 mL) and cooled to 0° C. Sodium hydride (60%, 88 mg, 2.2 mmol) is added portionwise, and the contents are stirred for 10 min. Methyl 2-bromomethyl-6-methyl-benzoate (77%, 631 mg, 2.0 mmol, EXAMPLE 2a) is added and the contents are allowed to warm to r.t. and continue to stir overnight. The reaction contents are poured into water (100 mL) and extracted with ethyl acetate (3×75 mL). Sodium chloride is added to the aqueous layer on the second and third extractions. The organic fractions are pooled, washed with brine (2×150 mL), dried over MgSO4, filtered and reduced under vacuum to an oil. The crude material is purified by flash chromatography (silica, 3% methanol in dichloromethane) to give the title compound. MS (ESI) 379 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20]C(=O)C)[CH:15]=1)[CH3:2].[OH-].[Na+].O.C(OCC)(=O)C>CO>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=1)[CH3:2]
Reactant: CCOc1cc2[nH]ccc2cc1Oc1ccnc(NC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOc1cc2[nH]ccc2cc1Oc1ccnc(N)c1
Temperature: 75 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
N-(4-((6-ethoxy-1H-indol-5-yl)oxy)pyridin-2-yl)acetamide described in Production Example 15-5 (7.16 g, 23.0 mmol) was dissolved in methanol (50 mL), a 2 M sodium hydroxide solution (50 mL) was added under nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 75° C. for 2.5 hours. The reaction mixture was cooled to room temperature and then water and ethyl acetate were added for partition. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, then the resultant was filtered and concentrated under vacuum. A liquid mixture of diethyl ether and ethyl acetate was added to the residue, and the mixture was collected by filteration and washed to obtain the title compound (5.35 g, 86%).
Reaction SMILES: Cl.[N:2]1([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[N:3]1.[Cl:14][C:15]1[N:16]=[C:17]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:18]2[S:23][C:22]([CH:24]=O)=[CH:21][C:19]=2[N:20]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl.C(N(CC)CC)C>[Cl:14][C:15]1[N:16]=[C:17]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[C:18]2[S:23][C:22]([CH2:24][N:11]3[CH2:10][CH2:9][CH:8]([CH2:7][N:2]4[CH:6]=[CH:5][CH:4]=[N:3]4)[CH2:13][CH2:12]3)=[CH:21][C:19]=2[N:20]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: c1cnn(CC2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClCCl
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(Cn4cccn4)CC3)cc2n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-Pyrazol-1-ylmethyl-piperidine hydrochloride salt in 1,2-dichloroethane (5 ml) was added 2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (230 mg) and glacial acetic acid (50 μL). The reaction mixture was stirred at room temperature for 6 hours. Sodium triacetoxyborohydride (224 mg) and triethylamine (113 μL) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with a 50/50 mixture of saturated sodium bicarbonate solution and brine, dried (MgSO4) and the solvents removed in vacuo to give a crude product. This was purified by flash chromatography to yield 2-Chloro-4-morpholin-4-yl-6-(4-pyrazol-1-ylmethyl-piperidin-1-ylmethyl)-thieno[3,2-d]pyrimidine (154 mg).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[CH2:28]([O:14][C:11]1[CH:10]=[CH:9][C:8]([C@H:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][C@@H:2]2[OH:1])=[CH:13][CH:12]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(O)cc2)[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCc3ccccc3)cc2)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.1 %

Procedure:
A mixture of (3R,4R)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (620 mg, 2.1 mmol, E-2 from step E), potassium carbonate (584 mg, 4.2 mmol), and benzyl bromide (0.25 mL, 2.1 mmol) in DMF (5 mL) was stirred at rt for 16 h. The solvent was removed by evaporation and the residue was treated with 50 mL of water. The aqueous mixture was then extracted 4 times with 50 mL of chloroform. The combined organic phases were dried over anhydous Na2SO4, filtered, and evaporated to yield 750 mg of (3R,4R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate which was used without further purification. LCMS (method F) RT 2.28 min, m/z=310 (M+H+−t-butyl −water), 328 (M+H+−t-butyl).
Reaction SMILES: [NH2:1][CH:2]=[C:3]([C:8](=[O:18])[C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[Cl:17])[C:4]([O:6][CH3:7])=[O:5].[F:19][C:20]1[CH:26]=[CH:25][C:23](N)=[CH:22][CH:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Cl:17][C:10]1[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=1[C:8]([C:3](=[CH:2][NH:1][C:23]1[CH:25]=[CH:26][C:20]([F:19])=[CH:21][CH:22]=1)[C:4]([O:6][CH3:7])=[O:5])=[O:18]
Reactant: COC(=O)C(=CN)C(=O)c1cc(F)c(F)cc1Cl
Reactant: Nc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)C(=CNc1ccc(F)cc1)C(=O)c1cc(F)c(F)cc1Cl

Procedure:
The preparation was carried out analogously to Example 10 with 1.0 g of the product from Example 5, 1.01 g of p-fluoroaniline and 0.69 g of p-toluenesulphonic acid.H2O.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]=1)=[O:13])[CH2:5]2.CS(O[CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][O:28]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:26][C@@H:27]3[CH2:31][CH2:30][CH2:29][O:28]3)=[CH:16][N:15]=1)=[O:13])[CH2:5]2
Reactant: CS(=O)(=O)OC[C@@H]1CCCO1
Reactant: O=C(N[C@@H]1Cc2ccc(Br)cc2C1)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N[C@@H]1Cc2ccc(Br)cc2C1)c1ccc(OC[C@@H]2CCCO2)cn1
Temperature: 60 °C

Procedure:
A mixture of N-((R)-5-bromoindan-2-yl)-5-hydroxypyridine-2-carboxamide (1.50 g), (S)-1-(tetrahydrofuran-2-yl)methyl methanesulfonate (0.81 g), cesium carbonate (1.46 g) and DMF (20 ml) was heated to 60° C. for 4 hours. The cooled reaction mixture was admixed with water and extracted with ethyl acetate. The organic phase was washed three times with water, dried over magnesium sulfate and concentrated. This afforded the product with the molecular weight of 417.31 (C20H21BrN2O3); MS (ESI): 417 (M+H+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([C:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:11]=1[CH2:22][C:23]([OH:25])=O)([CH3:9])[CH3:8].[S:26](=[O:44])(=[O:43])([O:28][C:29]1[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][C:32]([C:38]#[N:39])=[CH:31][C:30]=1[CH:40]([CH3:42])[CH3:41])[NH2:27].C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C=O>[C:38]([C:32]1[CH:31]=[C:30]([CH:40]([CH3:42])[CH3:41])[C:29]([O:28][S:26](=[O:43])(=[O:44])[NH:27][C:23](=[O:25])[CH2:22][C:11]2[C:10]([CH:7]([CH3:8])[CH3:9])=[CH:15][C:14]([CH:16]([CH3:17])[CH3:18])=[CH:13][C:12]=2[CH:19]([CH3:21])[CH3:20])=[C:34]([CH:35]([CH3:37])[CH3:36])[CH:33]=1)#[N:39]
Reactant: CC(C)c1cc(C#N)cc(C(C)C)c1OS(N)(=O)=O
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)O)c(C(C)C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(C#N)cc2C(C)C)c(C(C)C)c1
Reaction time: 8 h
Yield: 45.8 %

Procedure:
Oxalyl chloride (0.48 mL, 5.5 mmol) was added dropwise to a solution of 2,4,6-triisopropylphenyl acetic acid (1.21 g, 4.6 mmol) in 100 mL toluene with 4 drops of N,N-dimethylformamide as a catalyst. The resulting solution was stirred overnight and then concentrated in vacuo. The residue was re-dissolved in 150 mL dichloromethane. 2,6-Bis(l-methylethyl)-4-cyanophenyl sulfamate (1.30 g, 4.6 mmol) and triethylamine (1.6 mL) were added, and the resulting mixture was stirred for 6 hours. Washed with 1 M HCl, dried the organic layer over magnesium sulfate, filtered, and concentrated to give an oily solid. Chromatography on silica gel (20% ethyl acetate/hexanes) gave 1.11 g of the title compound as a white solid; mp 79-84° C.
Reaction SMILES: Cl.Cl.ClC1C=CC(C2C3C4CCNCCC4NC=3C=CC=2)=CC=1.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[C:32]1[C:33]2[C:34]3[CH2:54][CH2:53][NH:52][CH2:51][CH2:50][C:35]=3[N:36]([CH2:41][CH2:42][O:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:37]=2[CH:38]=[CH:39][CH:40]=1>>[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[C:32]1[C:33]2[C@@H:34]3[CH2:54][CH2:53][NH:52][CH2:51][CH2:50][C@@H:35]3[N:36]([CH2:41][CH2:42][O:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:37]=2[CH:38]=[CH:39][CH:40]=1
Reactant: Clc1ccc(-c2cccc3c2c2c(n3CCOc3ccccc3)CCNCC2)c(Cl)c1
Agent: Cl
Agent: Clc1ccc(-c2cccc3c2C2CCNCCC2N3)cc1
Product: Clc1ccc(-c2cccc3c2[C@@H]2CCNCC[C@@H]2N3CCOc2ccccc2)c(Cl)c1

Procedure:
Following the procedure for the preparation of 10-(4-chlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole dihydrochloride, making non-critical variations, starting from 10-(2,4-dichlorophenyl)-6-(2-phenoxyethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole the title compound was prepared: 1H NMR (CD3OD) δ 1.47, 1.55, 2.20, 2.66, 2.90, 3.19, 3.52-3.63, 4.13-4.21, 6.44, 6.50, 6.93, 7.15, 7.25-7.42, 7.57. HRMS (FAB) calcd for C26H26Cl2N2O2 (MH+) 453.1500, found 453.1520.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[Br:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br>>[Br:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][N:9]1[C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:11]=2[C:12](=[O:13])[N:7]([OH:6])[C:8]1=[O:21]
Reactant: COc1ccc(COn2c(=O)[nH]c3c(oc4ccccc43)c2=O)c(OC)c1
Reactant: BrCc1cccc(Br)c1
Product: O=c1c2oc3ccccc3c2n(Cc2cccc(Br)c2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-dimethoxy-benzyloxy)-1H-benzo[4,5]furo[3,2-d]pyrimidine-2,4-dione was alkylated with 3-bromobenzyl bromide and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 5.55 (s, 2H); 7.25-7.40 (m, 3H); 7.42-7.52 (m, 1H); 7.57-7.63 (m, 2H); 7.76-7.85 (m, 2H); Ret. time=2.64 min., m/z=386.0.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH:10](C=O)[CH2:9]2)[CH:5]=[CH:4][N:3]=[CH:2]1>O1CCOCC1.Cl>[N:1]1([CH2:6][CH2:7][CH:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=CC1CC(CCn2ccnc2)CCCN1
Agent: Cl
Solvent: C1COCCO1
Product: c1cn(CCC2CCCNCC2)cn1
Yield: 62.4 %

Procedure:
A mixture of hexahydro-4-[2-(1H-imidazol-1-yl)ethyl]-1H-azepine-carboxaldehyde (11 g, 0.05M) in dioxane (1.65 ml) and 2N HCl (82 ml) was heated and refluxed for 15 hrs. The solvent was removed, water (100 ml) was added and the resulting mixture was washed with methylene chloride (3×20 ml). After washing, the aqueous solution was basified with 4N NaOH to pH 12 and extracted with methylene chloride (4×75 ml). The combined extracts, dried over sodium sulfate, were stripped to yield hexahydro-4-[2-(1H-imidazol-1-yl)ethyl]-1H-azepine as an oil (6 g, 62% yield). This compound was characterized as dihydrochloride salt m.p. 176°-177° C.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]([CH3:18])=[C:16]([NH2:19])[S:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:20][C@@H:21]1[CH2:23][C@H:22]1[C:24](OCC1C=CC=CC=1)=[O:25]>ClCCl>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:17]([CH3:18])=[C:16]([NH:19][C:24]([C@@H:22]3[CH2:23][C@H:21]3[CH3:20])=[O:25])[S:15][N:14]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(-c2nsc(N)c2C)cc1
Reactant: C[C@@H]1C[C@H]1C(=O)OCc1ccccc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: COc1ccc(-c2nsc(NC(=O)[C@@H]3C[C@H]3C)c2C)cc1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 80.4 %

Procedure:
Add trimethylaluminum (2 M in toluene, 3.59 g, 45.5 mmol) to a 0° C. solution of 3-(4-methoxyphenyl)-4-methylisothiazol-5-ylamine (10.0 g, 45.5 mmol) in dichloromethane (455 mL). Stir 5 min and add benzyl (R,R)-2-methylcyclopropane-carboxylate (8.64 g, 45.5 mmol). Heat to 50° C. with nitrogen flow to remove solvent. The resulting oil is heated at 50° C. for 3 h. Quench with water and dilute with EtOAc (300 mL). Wash with 0.1 N HCl, dry (K2CO3), evaporate, and crystallize from hexane/EtOAc to afford (R,R)—N-[3-(4-methoxyphenyl)-4-methylisothiazol-5-yl]-2-methylcyclopropanecarboxamide. Yield: 80.4%. ES-MS: m/e 303.0 (m+1). (The mother liquor may be used for further recrystallizations.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)[NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C:20]2[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NCCc2cccc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(NCCc2cccc(F)c2)c2cccc(N)c2)cc1
Yield: 83.9 %

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-[2-(3-fluorophenyl)ethyl]amine (2.51 g) [prepared as described in step (a) above] in methanol (50 ml), nickel chloride hexahydrate (3.14 g) and sodium borohydride (1.0 g) were reacted, to afford the title compound (1.94 g) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:16]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.[BH4-].[Na+].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH:16]1([NH:1][C:2]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCCC1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1NC1CCCC1
Temperature: 0 °C
Reaction time: 9 h
Yield: 89.7 %

Procedure:
To a solution of ethyl 2-amino-5-nitrobenzoate (5.00 g), cyclopentanone (9.00 g) and sodium borohydride (4.05 g) in anhydrous tetrahydrofuran (100 mL) was added sulfuric acid (6 mL) under ice-water cooling. The mixture was stirred for 9 hours at 0° C. and then for 15 hours at ambient temperature. The mixture was neutralized with an aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (5:1). The obtained product was triturated with hexane to give ethyl 2-cyclopentylamino-5-nitrobenzoate as yellow powders (5.94 g).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][CH2:44][F:45]>C(#N)C>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:28][CH2:27][CH2:26][N:25]([CH2:43][CH2:44][F:45])[CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: O=C1N=C(N2CCCNCC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1N=C(N2CCCN(CCF)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
A solution 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one (0.016 g, 0.03 mmol) in acetonitrile (1.5 mL) was treated with potassium carbonate (0.022 g, 0.15 mmol) and 1-bromo-2-fluoro-ethane (0.04 g, 0.3 mmol). Reaction mixture was stirred at 70° C. for 18 hours and the solvent evaporated in vacuo. The residue was partitioned between dichloromethane and water. The dichloromethane layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (5% methanol in dichloromethane) to yield the title compound (17 mg, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19]([CH2:21][CH3:22])[C:18]([O:23][CH2:24][CH:25]=[CH2:26])=[C:17](Br)[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[Na+].[Na+].C(O[Na])=O.[NH4+].[Cl-]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(N(C)C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19]([CH2:21][CH3:22])[C:18]3[O:23][CH:24]=[C:25]([CH3:26])[C:17]=3[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: C=CCOc1c(Br)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)cc1CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: CCc1cc(C(Nc2ccc(C#N)cc2)C(=O)OC)cc2c(C)coc12
Temperature: 80 °C
Yield: 27.2 %

Procedure:
Following the general procedure of Larock et al (Tetrahedron Lett, 1988, 29:4687), a mixture of methyl 2-(4-cyanophenylamino)-2-(4-(allyloxy)-3-bromo-5-ethylphenyl)acetate 4 (5.00 g, 11.7 mmol), Na2CO3 (3.09 g, 29.1 mmol), HCO2Na (800 mg, 11.7 mmol), Bu4N+C− (3.56 g, 12.8 mmol) and DMA was degassed by bubbling N2 for 1 h. Palladium(II) acetate (130 mg, 0.58 mmol) was added, the flask was sealed with a glass stopper and heated at 80° C. for 19 h. The mixture was poured into ½-saturated NH4Cl (500 mL) and extracted with diethylether (Et2O, 4×125 mL). The combined organic layers were washed with saturated NH4Cl (1×125 mL), water (1×125 mL), brine (1×125 mL), dried over magnesium sulfate (MgSO4), filtered, and concentrated. The residue was adsorbed onto Celite®, then purified by silica gel chromatography (SiO2, gradient elution 10–15–20% ethyl acetate/hexanes) to yield 1.11 g (27%) of methyl 2-(4-cyanophenylamino)-2-(7-ethyl-3-methylbenzofuran-5-yl)acetate 5 as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][C:10]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)(O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:25].S(Cl)(Cl)=O.N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH:9]=[C:10]([C:16]2[CH:17]=[C:18]([Cl:23])[CH:19]=[C:20]([Cl:22])[CH:21]=2)[C:11]([F:13])([F:14])[F:12])=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a solution of 0.3 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-3-hydroxy-4,4,4-trifluorobutane-1-one synthesized under Synthetic Example 1 in 3 g toluene, 0.391 g of thionyl chloride and 0.104 g of pyridine were added at room temperature and the mixture was stirred for 1 hour at 80° C. After the end of reaction, the reaction solution was cooled to room temperature, added with toluene and 2N hydrochloric acid and separated, and then an organic layer was washed with water and dried with anhydrous magnesium sulfate to distill off the solvent under reduced pressure. The resulting residue, which although contains mixed geometrical isomers, was purified using silica gel column chromatography that was eluted with ethyl acetate-hexane (1:10), and 0.244 g of aimed product was obtained as yellow solid.