Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:21][NH:22][C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1.[Cl:41][C:42]1[C:47]([S:48](Cl)(=[O:50])=[O:49])=[CH:46][CH:45]=[CH:44][N:43]=1>O1CCCC1.O>[Cl:41][C:42]1[C:47]([S:48]([N:22]2[C:23]([C:24]3[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=3)=[C:19]([F:18])[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[CH:21]2)(=[O:50])=[O:49])=[CH:46][CH:45]=[CH:44][N:43]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2cccnc2Cl)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a suspension of sodium hydride (60% in oil, 39 mg) in tetrahydrofuran (6 mL) were added dropwise 15-crown-5 (0.19 mL), a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (243 mg) in tetrahydrofuran (1 mL) and 2-chloropyridine-3-sulfonyl chloride (239 mg) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→3:7) to give the title compound as a pale-yellow oil (yield 340 mg, 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(#N)C>[C:2]1([NH:1][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1ccccc1
Reaction time: 3 h
Yield: 87 %

Procedure:
According to Kotake et al. (Chem. Pharm. Bull. 1995, 43, 829-841), a stirred solution of aniline (15.3 g, 0.16 mol) and DIEA (56 ml, 0.33 mol) in acetonitrile (120 ml) is heated to 60° C. and ethyl bromoacetate (18.2 ml, 0.16 mmol) is added dropwise within 2 h. The reaction mixture is kept stirring at this temperature for another 3 h and is then evaporated to dryness. Water is added to the residue, the solid is filtered and thoroughly rinsed with H2O. Crystallization from toluene provided pure subtitle compound as beige crystals (25.5 g) in 87% yield. tR (LC-3) 2.33 min; ESI-MS (positive ion): m/z 180.27 [M+H]+ (calcd 179.22 for C10H13NO2). 1H-NMR (CDCl3): 1.29 (t, J=7.0 Hz, 3H); 3.90 (s, 2H); 4.25 (m, 3H); 6.61 (d, J=8.2 Hz, 2H); 6.75 (t, J=7.1 Hz, 1H); 7.21 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[O-]S(C(F)(F)[F:18])(=O)=O.ClC1C=[N+](F)C=C(Cl)C=1>ClCCl>[C:1]([C:3]1[S:4][C:5]2[C:11]([F:18])=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: N#Cc1nc2ccc(O)cc2s1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[n+]1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Product: N#Cc1nc2ccc(O)c(F)c2s1
Reaction time: 22 h

Procedure:
To a suspension of 2-cyano-6-hydroxybenzothiazole (2.0 g, 11.4 mmol) in dichloromethane (50 ml) in a 250-ml round-bottomed flask was added 3,5-dichloro-1-fluoropyridinium triflate (6.1 g, 19.3 mmol). The reaction flask was fitted with a reflux condenser and the mixture was brought to reflux under argon atmosphere for 53 hr. Additional 3,5-dichloro-1-fluoropydidinium toiflate was added (1.0 g, 3.2 mmol) and reaction continued for another 22 hr. Additional 3,5-dichloro-1-fluoropylidinium triflate was added (1.0 g, 3.2 mmol)and reaction continued for another 27 hr. Additional 3,5-dichloro-1-fluoropyridinium triflate was again added (1.0 g, 3.2 mmol) and reaction continued for another 72 hr. The reaction mixture was concentrated by rotoevaporation to give a brown residue that was purified by flash chromatography with 100 g of silica gel and methylene chloride as eluting solvent. The title compound was obtained as a white solid. Yield: 0.97 g (44%).
Reaction SMILES: C([O-])(O)=O.[Na+].Cl.[OH:7][CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[NH2:10].[CH2:19]([O:26][CH2:27][C:28](Cl)=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][CH2:27][C:28]([NH:10][C@H:9]1[C@@H:11]([OH:12])[C@H:13]([OH:14])[C@@H:15]([CH2:17][OH:18])[O:16][CH:8]1[OH:7])=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: O=C(Cl)COCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(COCc1ccccc1)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reaction time: 4 h
Yield: 68 %

Procedure:
To a round-bottom flask containing sat. NaHCO3 (9 mL) was added mannosamine hydrochloride (500 mg, 2.30 mmol). The solution was stirred for 1 h under N2, at which point benzyloxyacetyl chloride (0.44 mL, 2.8 mmol) was added dropwise via syringe. The biphasic mixture was stirred vigorously for 4 h resulting in a clear light yellow solution. The solution was concentrated and the residue was purified by silica gel chromatography eluting with a gradient of 20:1 to 10:1 CHCl3/MeOH to afford 512 mg (68%) of a viscous oil. IR (thin film): 3331, 2918, 2356, 1652, 1524 cm−1. 1H NMR (400 MHz, D2O): δ 3.26 (s, 1H), 3.33 (app d, 1H, J=6.7), 3.45 (app t, 1H, J=9.7), 3.54-3.66 (m, 1H), 3.69 (app d, 1H, J=4.8), 3.72 (d, 1H, J=2.0), 3.74-3.86 (m, 2H), 3.98 (dd, 1H, J=4.5, 9.8), 4.06 (s, 2H), 4.10 (s, 1H), 4.24-4.27 (m, 1H), 4.38-4.40 (m, 1H), 4.55 (s, 2H), 4.57 (d, 1H, J=4.3), 4.97 (s, 1H), 4.99 (s, 1H), 7.32-7.36 (m, 10H), 7.49 (d, 1H, J=10.7), 7.58 (d, 1H, J=9.6). 13C NMR (100 MHz, D2O): δ 52.9, 60.4, 66.8, 68.5, 68.7, 72.0, 73.5, 76.5, 89.3, 92.8, 128.5, 128.6, 128.7, 128.8. HRMS (FAB) m/z 328.1396 (MH+C15H22NO7 requires 328.1396).
Reaction SMILES: [O:1]=[C:2]([C@H:16]([CH3:32])[C@@H:17]([O:23][C:24]([O:26][CH2:27][C:28]([Cl:31])([Cl:30])[Cl:29])=[O:25])[C@@H:18]([CH3:22])[CH2:19][CH:20]=[CH2:21])[C:3]([CH3:15])([CH3:14])[C@@H:4]([OH:13])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].N1C=CN=C1.[CH2:38]([Si:40](Cl)([CH2:43][CH3:44])[CH2:41][CH3:42])[CH3:39].O>CN(C)C=O>[O:1]=[C:2]([C@H:16]([CH3:32])[C@@H:17]([O:23][C:24]([O:26][CH2:27][C:28]([Cl:29])([Cl:30])[Cl:31])=[O:25])[C@@H:18]([CH3:22])[CH2:19][CH:20]=[CH2:21])[C:3]([CH3:14])([CH3:15])[C@@H:4]([O:13][Si:40]([CH2:43][CH3:44])([CH2:41][CH3:42])[CH2:38][CH3:39])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@H](CC(=O)OC(C)(C)C)O[Si](CC)(CC)CC

Procedure:
A solution of tert-butyl (3S,6R,7S,8S)-5-oxo-3-hydroxy-4,4,6,8-tetramethyl-7-(2,2,2-trichloroethoxycarbonyloxy)-10-undecenoate (1.8 g), imidazole (0.48 g), and triethylsilyl chloride (0.68 g) in 5 mL of dimethylformamide is stirred for 2 hours at ambient temperature, then poured into water and extracted with ether. The extract is washed with sat. aq. NaCl, dried over MgSO4, filtered, and evaporated. The product is purified by chromatography on SiO2 (20:1 toluene/ethyl acetate).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[CH2:24]([NH2:27])[CH2:25][CH3:26]>C(O)C>[CH2:24]([NH:27][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1)[CH2:25][CH3:26]
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Reactant: CCCN
Solvent: CCO
Product: CCCNc1ncc2c(=O)[nH]c(-c3ccccc3OCCC)nc2n1

Procedure:
In a similar manner to Example 9 reaction of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.60 g) and n-propylamine (1.44 g) in ethanol (20 ml) yielded the title compound, 0.46 g, m.p. 185°-7° C. (recrystallised from ethanol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH:24]([CH3:26])[CH3:25])=[C:17]([NH:27][CH:28]3[CH2:33][CH2:32][N:31](CC4C=CC=CC=4)[CH2:30][CH2:29]3)[N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CO.C([O-])=O.[NH4+]>[Pd].O>[C:1]([O:5][C:6](=[O:41])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH:24]([CH3:26])[CH3:25])=[C:17]([NH:27][CH:28]3[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]3)[N:16]=2)[CH2:10][CH2:9]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)n1cnc2c(NC3CCN(Cc4ccccc4)CC3)nc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)n1cnc2c(NC3CCNCC3)nc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nc21

Procedure:
Add to a solution of trans-{4-[6-(1-benzyl-piperidin-4-ylamino)-9-isopropyl-9H-purin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (8b, 1 g, 1 mmol) and methanol (40 ml), a suspension of palladium black (0.25 g) in a little water. Then add a solution of ammonium formate (0.4 mg, 6.4 mmol) and 10 ml of water, and reflux overnight. Filter the reaction through Celite® and concentrate the filtrate to dryness. Dissolve the residue in methylene chloride (50 ml), extracted with water, and filter through Celite® to remove a milky white precipitate. Separate the organic layer, wash with brine, dry over sodium sulfate, filter and concentrate the filtrate to dryness. Purify the residue on a 40 gram silica gel column (Biotage) using DCM/methanol (4:1) to give 0.8 grams of trans-{4-[9-isopropyl-6-(piperidin-4-ylamino)-9H-purin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (9b).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[S:30](=O)(=[O:33])([OH:32])[OH:31]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Reactant: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CS(=O)(=O)c1ccc(-c2cc(S(=O)(=O)O)sc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (5 g), acetic anhydride (4.3 ml) and sulfuric acid (0.97 ml) in dichloromethane (47 ml) was stirred at ambient temperature overnight. The mixture was concentrated to give a crude blue oil of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-sulfonic acid (10.5 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]=O)=[C:9]([O:16][CH3:17])[CH:8]=2)[C:4]([CH3:18])=[N:3]1.CS(C1[N:24]=[CH:25][C:26]2[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=2[N:28]=1)(=O)=O>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:24]=[CH:25][C:26]4[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=4[N:28]=3)=[C:9]([O:16][CH3:17])[CH:8]=2)[C:4]([CH3:18])=[N:3]1
Reactant: CC(C)(C)CNc1nccc2cnc(S(C)(=O)=O)nc12
Reactant: COc1cc(-c2cn(C)nc2C)ccc1NC=O
Product: COc1cc(-c2cn(C)nc2C)ccc1Nc1ncc2ccnc(NCC(C)(C)C)c2n1
Yield: 21 %

Procedure:
The title compound was prepared according to Example 40 using N-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)formamide (Preparation 76) and 2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation 47). The residue was purified by silica gel column chromatography eluting with 50-100% EtOAc in cyclohexane to give the title compound (4 mg, 21%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:32][C:33]1[S:34][CH:35]=[N:36][N:37]=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:16]([NH:32][C:33]1[S:34][CH:35]=[N:36][N:37]=1)=[O:18])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nncs1
Reactant: CC(C)C(NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)C(NC(=O)OCc1ccccc1)C(=O)Nc1nncs1
Yield: 78.9 %

Procedure:
10 g of N-benzyloxycarbonyl-DL-valine, 4.1 g of triethylamine, 150 ml of chloroform, 4.4 g of ethyl chlorocarbonate and 4.1 g of 2-amino-1,3,4-thiadiazole were reacted in the same manner as in Example 1(i) to obtain 10.5 g (yield: 79%) of 2-(N-benzyloxycarbonyl-DL-valylamino)-1,3,4-thiadiazole as white crystals having a melting point of 162°-164° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20]([C:22]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[C:25]([CH:35]=O)[NH:24][CH:23]=1)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[C:25]([CH:35]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])[NH:24][CH:23]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1c[nH]c(C=O)c1-c1ccc(OC)cc1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: CCOC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)c1-c1ccc(OC)cc1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 5-formyl-4-(4-methoxyphenyl)-1H-pyrrole-3-carboxylic acid ethyl ester to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([O:9][CH2:10][C@@H:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])=[N:4][O:5][C:6]=1[CH:7]=[O:8].P([O-])(O)(O)=[O:22].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>O.CC(O)(C)C>[C:16]([O:15][C:14]([NH:13][C@@H:11]([CH3:12])[CH2:10][O:9][C:3]1[C:2]([F:1])=[C:6]([C:7]([OH:22])=[O:8])[O:5][N:4]=1)=[O:20])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=P([O-])(O)O
Reactant: C[C@@H](COc1noc(C=O)c1F)NC(=O)OC(C)(C)C
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@@H](COc1noc(C(=O)O)c1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a mixture of tert-butyl {(1S)-2-[(4-fluoro-5-formylisoxazol-3-yl)oxy]-1-methylethyl}carbamate (244 mg), sodium dihydrogen phosphate (305 mg), 2-methylbut-2-ene (449 mL), 2-methylpropan-2-ol (5 mL) and water (1 mL) was added sodium chlorite (115 mg) at room temperature, and the obtained mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate/2-propanol (volume ratio 3/1). The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a white powder (256 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[C:44]([CH3:50])=[N:45][N:46]([CH3:49])[C:47]=2[CH3:48])=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:51])=[CH:38][C:39]([C:43]6[C:44]([CH3:50])=[N:45][N:46]([CH3:49])[C:47]=6[CH3:48])=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2c(C)nn(C)c2C)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6c(C)nn(C)c6C)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-(4-bromo-3,5-dimethyl-phenyl)-1,3,5-trimethyl-pyrazole following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 9): tR=1.24 min; Mass spectrum (ESI+): m/z=555 [M+H]+.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[F:26][C:27]([F:34])([F:33])[CH2:28][CH2:29][C:30](O)=[O:31]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:30](=[O:31])[CH2:29][CH2:28][C:27]([F:34])([F:33])[F:26])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)CCC(F)(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(CCC(F)(F)F)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (12.8 mg, 35.2%), MS (ISP) m/z=455.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (29.4 mg, 0.080 mmol) and 4,4,4-trifluorobutanoic acid
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=2)=[N:5][N:4]2[CH2:14][CH2:15][CH2:16][C:3]=12.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.C([Li])CCC>O1CCCC1>[CH3:13][C:9]1[N:8]=[C:7]([C:6]2[C:2]([B:17]([OH:22])[OH:18])=[C:3]3[CH2:16][CH2:15][CH2:14][N:4]3[N:5]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cccc(-c2nn3c(c2Br)CCC3)n1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(-c2nn3c(c2B(O)O)CCC3)n1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 72.3 %

Procedure:
Place tetrahydrofuran (28.0 mL) in a 100 mL round-bottom flask equipped with a temperature probe, a magnetic stirrer, and a septum and put under a nitrogen atmosphere. Add 3-bromo-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (Preparation 1, 1.44 g, 5.18 mmol) and triisopropyl borate (3.10 mL, 13.5 mmol). Cool the mixture to −78° C. using a dry ice/acetone bath. Add 1.4M n-butyllithium in hexanes (8.80 mL, 12.4 mmol) dropwise via a syringe pump over 10 min keeping the temperature below −40° C. Remove the dry ice/acetone bath and allow the reaction mixture to warm to room temperature. Add saturated aqueous ammonium chloride (10 mL) and extract with chloroform (2×1 00 mL). Combine the organic layers, dry over solid sodium chloride, and remove the solvent under reduced pressure to afford an oil. Purify the oil by normal phase flash chromatography (120 g Biotage KP-Sil 40 L: 100% ethyl acetate in hexanes for 25 min, 0-10% methanol in ethyl acetate in ramp over 15 min, then 10% methanol in ethyl acetate) to yield the title compound (910 mg, 73%). MS ES+ m/e 244 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].FC(F)(F)S(O[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.O>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C=O)cc2)CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
To 400 mg (2.67 mmol) of 4-formyl-phenylboronic acid diluted in a dimethoxyethane/water mixture (40 ml/4 ml) are respectively added 1.33 g (5.78 mmol) of tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate, 154 mg (0.133 mmol) of palladium tetrakistriphenylphosphine and 1.74 g (5.34 mmol) of cesium carbonate. The solution is purged under argon then stirred at 80° C. for 18 h and filtered on Celite with ethyl acetate. The filtrate is washed with water, then with sodium chloride saturated solution, dried over magnesium sulfate, and concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 85:15 to 70:30) to yield 677 mg of tert-butyl 4-(4-formylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate in the form of a yellow oil.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH3:28][O:29][C:30]([C@H:32]1[CH2:37][CH2:36][C@H:35]([C@H:38]2[CH2:43][CH2:42][C@H:41]([C@H:44]3[CH2:49][CH2:48][C@H:47]([CH2:50][CH2:51][CH:52]=O)[CH2:46][CH2:45]3)[CH2:40][CH2:39]2)[CH2:34][CH2:33]1)=[O:31].O>C1COCC1>[CH3:28][O:29][C:30]([C@H:32]1[CH2:37][CH2:36][C@H:35]([C@H:38]2[CH2:39][CH2:40][C@H:41]([C@H:44]3[CH2:45][CH2:46][C@H:47]([CH2:50][CH2:51][CH:52]=[CH2:2])[CH2:48][CH2:49]3)[CH2:42][CH2:43]2)[CH2:34][CH2:33]1)=[O:31]
Reactant: COC(=O)[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H]3CC[C@H](CCC=O)CC3)CC2)CC1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H]3CC[C@H](C(=O)OC)CC3)CC2)CC1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
A mixture of 130 g (322 mmol) of methyltriphenylphosphonium iodide and 1.3 liters of THF was cooled to -50° C. To this mixture was added 33.4 g (110 mmol) of t-BuOK and the resulting mixture was stirred for one hour. To this mixture was added dropwise, while maintaining a temperature at below -50° C., a solution of 90.0 g (248 mmol) of crude trans-4-(trans-4-(trans-4-(2-formylethyl)-cyclohexyl)cyclohexyl)cyclohexane carboxylic acid methyl ester in 900 ml of THF. After the dropwise addition, the temperature of the reaction solution was gradually allowed to rise up to room temperature and the mixture was stirred for further 5 hours. After the reaction was completed by adding 500 ml of water, the reaction mixture was filtered through Celite, the solvent was distilled off under reduced pressure and the filtrate was extracted with 1.0 liter of toluene. The organic layer was washed three times with 500 ml of water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to a silica gel column chromatography (a developing solvent: toluene) to give 40.0 g of crude trans-4-(trans-4-(trans-4-(3-butenyl)cyclohexyl)cyclohexyl)-cyclohexane carboxylic acid methyl ester.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]2[N:10]=[CH:11][N:12]=[CH:13][C:8]=2[C:7](=[O:14])[NH:6][CH:5]=1.CI.[CH3:17]C(=O)OCC>CN(C=O)C>[Br:3][C:4]1[C:9]2[N:10]=[CH:11][N:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:17])[CH:5]=1
Reactant: O=c1[nH]cc(Br)c2ncncc12
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(Br)c2ncncc2c1=O
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
Sodium hydride (21 mg, 0.53 mmol, 60% in mineral oil) was added to the title compound of step 2 (100 mg, 0.44 mmol) in DMF (10 mL) at 0° C. After stirring 0.5 h, MeI (126 mg, 0.88 mmol) was added and stirring continued at 0° C. for 2 h. Following extractive work up with EA, the title compound (80 mg, yield: 75.3%) was obtained as a yellow solid. 1H NMR: (DMSO-d6, 400 MHz) δ: 9.47 (s, 1H), 9.46 (s, 1H), 8.53 (s, 1H), 3.54 (s, 3H). LCMS: 240.0, 242.0 (M+H)+.