Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.C1(S)C=CC=CC=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:27][C:22]([S:21][C:18]1[S:17][C:16]([NH:15][C:14]([N:13]([C@H:29]2[CH2:30][CH2:31][C@H:32]([CH3:35])[CH2:33][CH2:34]2)[CH2:12][CH2:11][CH2:10][S:9][C:4]2[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:28])=[N:20][CH:19]=1)([CH3:26])[C:23]([OH:25])=[O:24]
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Agent: Sc1ccccc1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCSc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using thiophenol and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]([CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:20](=[O:29])[C@H:19]([NH:30]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1>ClCCl>[NH2:30][C@@H:19]1[CH2:18][CH2:17][C@@H:16]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=2[F:8])[CH2:22][N:21]([CH2:23][CH2:24][S:25]([CH3:28])(=[O:26])=[O:27])[C:20]1=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CCS(C)(=O)=O)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](N)C1=O
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-1-[2-(methylsulfonyl)ethyl]-2-oxoazepan-3-ylcarbamate (23.7 mg, 0.053 mmol) in dichloromethane (2 mL). After 4 h, the solution was concentrated. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 347 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([C:18]2[CH:26]=[CH:25][C:21]3OCO[C:20]=3[CH:19]=2)[CH:5]=1.COC(=O)C1C=C(OS(C(F)(F)[F:42])(=O)=O)C=C(OCC2C=CC=CC=2)C=1.FC1C=C(B(O)O)C=CC=1>>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:18]2[CH:26]=[CH:25][CH:21]=[C:20]([F:42])[CH:19]=2)[CH:7]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1)=[O:27]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(-c2ccc3c(c2)OCO3)c1
Agent: OB(O)c1cccc(F)c1
Product: COC(=O)c1cc(OCc2ccccc2)cc(-c2cccc(F)c2)c1

Procedure:
The title compound was prepared in the same way as 3-benzo[1,3]dioxol-5-yl-5-benzyloxy-benzoic acid methyl ester (described in Method B, step 3) from 3-benzyloxy-5-trifluoromethanesulfonyloxy-benzoic acid methyl ester and 3-fluorophenylboronic acid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[Cl:23][C:18]1[CH:17]=[C:16]([CH:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][CH:6]([CH2:4][OH:3])[CH2:15]2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: CCOC(=O)C1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
A solution of 10 (2.55 g, 7.3 mmol) in THF (40 ml) was added dropwise to a stirring mixture of LiAlH4 (0.304 g, 8.0 mmol) in THF (20 ml) at 0° C. The resulting suspension was stirred at room temperature for 3 hours, then, the mixture was cooled to 0° C., and water (0.15 ml) was added dropwise to destroy the excess hydride. The mixture was filtered, and the solvent was evaporated in vacuo to give colorless oil. The residue was purified by chromatography, CombiFlash silica gel column, MeOH/CH2Cl2, MeOH from 0% to 3%, to give 11 as a clear oil (mixture of cis and trans diastereomers, 1.80 g, 80%). 1H NMR (CDCl3) δ 1.31-1.54 (m, 1H), 1.92-1.98 (m, 2H), 2.10-2.26 (m, 1H), 2.54-2.71 (m, 1H), 2.92-3.03 (m, 1H), 3.53-3.75 (m, 2H), 4.07 (dd, J=12 Hz, 5.2 Hz) and 4.25 (t, J=3.6 Hz, total 1 H), 6.72-7.38 (m, 7H). 13C NMR (CDCl3) δ 32.0, 32.5, 33.4, 34.6, 37.5, 37.6, 43.3, 46.3, 67.5, 67.9, 126.3, 126.4, 126.6, 127.0, 128.4, 128.5, 129.5, 129.7, 130.2, 130.5, 130.7, 130.9, 132.4, 132.7, 136.7, 136.9, 138.8, 147.5, 147.9.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH2:17])=[CH:13][N:12]([CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[C:11]1=[O:27])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:42][CH2:43][CH2:44][CH2:45][C:46](Cl)=[O:47]>ClCCl>[C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH:17][C:46](=[O:47])[CH2:45][CH2:44][CH2:43][Cl:42])=[CH:13][N:12]([CH2:18][C:19]2[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=2[F:25])[C:11]1=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(N)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(NC(=O)CCCCl)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a solution of {(R)-2-[5-amino-3-(2,6-difluoro-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (42 mg, 0.089 mmol) in dichloromethane (2 mL) were added triethylamine (25 μl, 0.178 mmol) and 4-chloro-butyryl chloride (11 μl, 0.097 mmol) in the order. The solution was stirred at room temperature for 2 hrs and concentrated. The residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate/dichloromethane, 2/1/1) and dried in a vacuum to afford 40 mg of the compound as a colorless oil (yield 78%). 1H NMR (300 MHz, CDCl3) δ 1.33 (9H, s), 2.17 (2H, p), 2.57 (2H, t), 3.63 (2H, t), 4.10 (1H, m), 4.34 (1H, t), 4.99-5.14 (3H, m), 5.47 (1H, d), 6.96 (2H, m), 7.24-7.39 (6H, m), 7.72 (1H, s), 8.65 (1H, s)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[C:43](Br)[CH:42]=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.[CH3:52][CH2:53]O.CC1(C)C(C)(C)OB(C=C)O1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[C:43]([CH:52]=[CH2:53])[CH:42]=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: CCO
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4cc(Br)ccc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C=CB1OC(C)(C)C(C)(C)O1
Solvent: O
Product: C=Cc1ccc(-n2ccc(C)n2)c([C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCC)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)c1
Temperature: 80 °C

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(5-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (500 mg, 0.65 mmol) in 4:1 EtOH:H2O (25 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (150 mg, 0.971 mmol), KHCO3 (648 mg, 6.47 mmol), and PdCl2(PPh3)2 (68 mg, 0.097 mmol). The reaction mixture was heated to 80° C. for 1.75 h, then cooled to RT, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification via a 40 g Isco RediSep silica cartridge eluting (EtOAc/hepate) provides (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:8]([O:12][C:13]([NH:15][C:16](=[N:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])SC)=[O:14])([CH3:11])([CH3:10])[CH3:9]>O1CCCC1.O>[C:23]([O:22][C:20]([N:19]=[C:16]([NH:15][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: NCCCC(=O)O
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NCCCC(=O)O)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
4-Aminobutyric acid (100 mg, 0.97 mmol) was dissolved in tetrahydrofuran (0.3 mL) and water (0.03 mL), combined with 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (340 mg, 1.2 mmol) and stirred at 60° C. overnight. The reaction solution was concentrated under reduced pressure, and the residue was subjected to a column chromatography to obtain 4-(2,3-di-tert-butoxycarbonylguanidino)butyric acid (compound 8; yield: 181 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:2]1.C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>ClCCl>[CH3:21][S:18]([O:10][CH2:9][CH2:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC1CCCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCC1CCCOC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(tetrahydro-2H-pyran-3-yl)-1-propanol (2.64 g) in dry dichloromethane (78 ml) at 0° C. was added triethylamine (6.21 ml) followed by mesyl chloride (1.85 ml). The reaction mixture was allowed to warm to room temperature as the ice melted and allowed to stir for three hours. The reaction mixture was washed with sodium hydrogen carbonate. The organic layer was separated, dried by passing through a hydrophobic frit and concentrated in vacuo. to give a yellow oil (4.42 g). The product was purified by silica chromatography (80 g) (ISCO) using a gradient elution of 0-50% cyclohexane:ethyl acetate to afford the title compound as a clear oil (3.79 g).
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:12][C:13]([CH3:29])([C:26](=[O:28])[CH3:27])[CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O.O>CO>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([CH3:29])([CH3:14])[C:26](=[O:28])[CH3:27])=[CH:7][CH:6]=1
Reactant: CC(=O)C(C)(C)COS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)C(C)(C)COc1ccc(Cl)cc1
Yield: 55.5 %

Procedure:
29.7 g (0.55 mole) of sodium methylate were dissolved in 500 ml of methanol, and 70.4 g (0.55 mol) of 4-chlorophenol were added, while stirring. After stirring the mixture for 10 minutes, the solvent was distilled off under reduced pressure and the residue was taken up in 100 ml of glycol. This solution was added to a solution of 135 g (0.5 mole) of 2,2-dimethyl-1-tosyloxy-butan-3-one in 200 ml of glycol. The reaction mixture was stirred at 100° to 120° C. for 48 hours, cooled and stirred into 2,000 ml of water. The mixture was extracted twice with 250 ml of diethyl ether each time and the combined organic phases were washed three times with 100 ml of water each time, once with 100 ml of 10% strength sodium hydroxide solution and once more with 100 ml of water, dried over sodium sulphate and distilled. 62.9 g (55.7% of theory) of 1-(4-chlorophenoxy)-2,2-dimethyl-butan-3-one of boiling point 135°-140° C./0.4 mm Hg were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18](Br)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2].[C:23]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18]([C:34]3[CH:33]=[C:32]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:37]=[CH:36][CH:35]=3)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3cccc(-c4ccccc4)c3)o2)c1
Temperature: 100 °C

Procedure:
Bromo-derivative (99) (70 mg, 0.19 mmol) was coupled to biphenyl-3-boronic acid (42 mg, 0.21 mmol) acid using Method E, except that the reaction was heated at 100° C. The crude product was purified by column chromatography eluting with a stepped gradient of 0-10% EtOAc in heptane to give the title compound.
Reaction SMILES: NC1C=CC(OCC2C=CC(Cl)=CC=2)=CN=1.Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1.[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][OH:33])=[CH:30][CH:29]=1>>[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][O:33][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=2)=[CH:30][CH:29]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: OCc1ccc(Br)cc1
Agent: Nc1ccc(OCc2ccc(Cl)cc2)cn1
Product: O=[N+]([O-])c1ccc(OCc2ccc(Br)cc2)nc1

Procedure:
The substituted amino-pyridine compounds of formula (I) wherein W is oxygen can be prepared by the reaction of a hydroxy-nitropyridine with a substituted phenalkyl halide to obtain the corresponding substituted nitro-pyridine which is reduced to the desired substituted amino-pyridine of formula (I). For example, the reaction of 5-hydroxy-2-nitropyridine and 4-chlorobenzyl bromide gives 5-(4-chlorobenzyloxy)-2-nitropyridine which is then reduced to 2-amino-5-(4-chlorobenzyloxy)-pyridine of formula I. Alternatively, the compounds of formula I can be prepared by the reaction of a halo-nitropyridine with a substituted phenalkyl alcohol or substituted phenalkyl thiol followed by reduction of the nitro group. For example, the reaction of 2-chloro-5-nitropyridine and 4-bromobenzyl alcohol gives 2-(4-bromobenzyloxy)-5-nitropyridine which is then reduced using, for example, iron powder to give 5-amino-2-(4-bromobenzyloxy)pyridine of formula (I).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.C(O[C:32]1(O[Si](C)(C)C)[CH2:34][CH2:33]1)C.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][N:10]=[C:11]([N:19]3[CH2:20][CH2:21][N:22]([CH:32]4[CH2:34][CH2:33]4)[CH2:23][CH2:24]3)[C:12]=2[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2n[nH]c(N3CCNCC3)c2-c2ccncc2)cc1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Clc1ccc(-c2[nH]nc(N3CCN(C4CC4)CC3)c2-c2ccncc2)cc1
Reaction time: 0.08 h
Yield: 63 %

Procedure:
To a solution of 3-(4-chlorophenyl)-4-(4-pyridyl)-5-(4-piperazinyl)pyrazole (1.95 g; 5.8 mmoles; prepared as set forth in Example A-169) and acetic acid (3.6 g, 60 mmol) containing 5A molecular sieves (6 g) was added [(1-ethoxycyclopropyl)oxy]trimethylsilane (6 g, 35 mmol). After stirring for 5 minutes, sodium cyanoborohydride (1.7 g, 26 mmol) was added and the mixture was refluxed under a nitrogen atmosphere for 6 hours. The reaction mixture was filtered hot and the filtrate concentrated in vacuo. Water (50 mL) was added and the solution made basic with 2N sodium hydroxide. The resultant gel was extracted with dichloroethane and the combined organic extracts dried (MgSO4). Evaporation again yielded a gel which was treated with hot methanol. Upon cooling, the product crystallized to give 1.4 g (63%) of 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl)-4-cyclopropylpiperazine, m.p. 264-265° C. Anal. Calc'd. for C21H22ClN5.1.5H2O: C, 61.99; H, 6.19; N, 17.21. Found: C, 62.05; H, 5.81; N, 16.81.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][S:14]([NH:17][C:18](=[O:21])[O:19][CH3:20])(=[O:16])=[O:15].[CH3:22][CH:23]([CH2:26]O)[CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[S:14](=[O:15])(=[O:16])[N:17]([C:18]([O:19][CH3:20])=[O:21])[CH2:24][CH:23]([CH3:26])[CH2:22]1
Reactant: COC(=O)NS(=O)(=O)Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CC(CO)CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)N1CC(C)CN(c2c(Cl)cc(C(F)(F)F)cc2Cl)S1(=O)=O
Temperature: -20 °C
Reaction time: 5 h
Yield: 56.7 %

Procedure:
Methyl N-(2,6-dichloro-4-(trifluoromethyl)phenyl)sulfamoylcarbamate (6.00 g, 16.34 mmol), 2-methylpropane-1,3-diol (2.21 g, 24.51 mmol) and triphenylphosphine (10.71 g, 40.85 mmol) were dissolved in anhydrous THF (100 mL) in a reactor, and then cooled down −20° C. after removal of air in the reactor by purging nitrogen gas. DIAD (8.2 g, 40.8 mmol) was dropwisely added to the reaction mixture and agitated for 5 hr at room temperature. The resultant was concentrated under reduced pressure and purified by column chromatography (dichloromethane:hexane:ethyl acetate=5:4:1), finally yielding the title compound (3.9 g, 70%, white solid). 1H NMR (300 MHz, CDCl3): δ 7.66 (s, 2H), 4.45-4.39 (m, 1H), 3.88 (s, 3H), 3.84-3.75 (m, 2H), 3.54-3.37 (m, 1H), 2.72-2.69 (m, 1H), 1.02 (d, 3H, J=6.7 Hz).
Reaction SMILES: [F:1][C:2]([F:28])([CH:13]1[CH2:18][CH2:17][CH:16]([CH:19]2[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)[O:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[C:6]([F:12])[CH:5]=1.[H-].[Na+].Cl/[CH:32]=[CH:33]/[C:34]([F:37])([F:36])[F:35].O>CN1C(=O)CCC1>[F:12][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([F:10])[C:7]=1[O:11]/[CH:32]=[CH:33]/[C:34]([F:37])([F:36])[F:35])[O:3][C:2]([F:1])([F:28])[CH:13]1[CH2:14][CH2:15][CH:16]([CH:19]2[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20]2)[CH2:17][CH2:18]1
Reactant: FC(F)(F)/C=C/Cl
Reactant: CCCC1CCC(C2CCC(C(F)(F)Oc3cc(F)c(O)c(F)c3)CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCC1CCC(C2CCC(C(F)(F)Oc3cc(F)c(O/C=C/C(F)(F)F)c(F)c3)CC2)CC1
Temperature: 130 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
4-(Difluoro(4′-propyl-[1,1′-bi(cyclohexane)]-4-yl)methoxy)-2,6-difluorophenol (3.0 g, 7.45 mmol) prepared by known methods and sodium hydride (55%) (0.325 g, 7.45 mmol) were stirred in NMP (N-methylpyroridone) at 60° C. for 30 minutes. (E)-1-Chloro-3,3,3-trifluoro-1-propene (2.43 g, 18.6 mmol) was then added to the reaction solution, and the mixture was stirred at 130° C. for 24 hours. The reaction solution was poured into water, which was extracted with toluene. The combined organic layers were washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off with an evaporator and the residue was purified by silica gel chromatography and then by recrystallization to give (E)-4-((3,5-difluoro-4-((3,3,3-trifluoro-1-propen-1-yl)oxy)phenoxy)difluoromethyl)-4′-propyl-1,1′-bi(cyclohexane) (56% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[C:19]([O:26][CH3:27])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[C:19]([O:26][CH3:27])=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC)c(OC)c(OC)c1NC(=O)c1ccc(Cl)cc1

Procedure:
A solution of 20.3 g of 4-chlorobenzoyl chloride in 60 ml of THF was added dropwise to the solution of 25.3 g of methyl 2-amino-3,4,5-trimethoxybenzoate and 16 ml of triethylamine in 100 ml of THF. The mixture was refluxed for 1 hour (h), cooled in an ice bath and filtered. After concentration, a colorless residue remained. Yield: 34.1 g. Melting point (m.p.): 116° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][C:47]2[CH:52]=[CH:51][C:50](/[CH:53]=[CH:54]/[CH2:55][C:56](O)=[O:57])=[CH:49][CH:48]=2)[C:43]([CH3:59])=[CH:42][C:41]=1[O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:68][C:69]([CH3:73])([CH3:72])[CH2:70][OH:71].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>O.C(Cl)(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][C:47]2[CH:48]=[CH:49][C:50](/[CH:53]=[CH:54]/[CH2:55][C:56]([NH:68][C:69]([CH3:73])([CH3:72])[CH2:70][OH:71])=[O:57])=[CH:51][CH:52]=2)[C:43]([CH3:59])=[CH:42][C:41]=1[O:60][CH2:61][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(N)CO
Reactant: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(/C=C/CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(/C=C/CC(=O)NC(C)(C)CO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To a chloroform solution (2.2 mL) of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[(1E)-3-carboxyprop-1-en-1-yl]benzyl]-4-methylphenyl]-D-glucitol (200 mg, 0.223 mmol) were added 2-amino-2-methyl-1-propanol (40 mg, 0.446 mmol), 1-hydroxy benzotriazole (33 mg, 0.245 mmol) and WSC (60 mg, 0.312 mmol), and the mixture was stirred overnight at room temperature. To the reaction solution was added water, and the resulting mixture was extracted with chloroform. The organic layer was washed with brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=5:1 to 1:2) to obtain the title compound (120 mg, 56%) as an orange-yellow oily compound.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH3:20][CH:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:25][CH2:24][CH2:23][CH2:22][CH:21]([CH3:26])[CH3:20])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Reactant: CC(C)CCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCCNCc1ccc(Oc2ccc(C(N)=O)nc2)c(F)c1
Reaction time: 8 h
Yield: 54.4 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.650 g, 2.50 mmol), 4-methylpentylamino (Example 433, Part A) (0.278 g, 2.75 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (12 mL), cap and stir overnight. Add NaBH4 (slight excess) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 10% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound (0.470 g, 55%): TOF MS ES+ 346.2 (M+H)+, HRMS calcd for C19H25N3O2F 346.1931 (M+H)+, found 346.1922, time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.6 min, 100% purity.