Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1.[Si:19]([O:26][CH2:27][CH2:28][C@H:29]1[CH2:40][CH2:39][C:38]2[S:37][C:36]3[N:35]=[CH:34][N:33]=[C:32](Cl)[C:31]=3[C:30]1=2)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C1COCC1>[Si:19]([O:26][CH2:27][CH2:28][C@H:29]1[CH2:40][CH2:39][C:38]2[S:37][C:36]3[N:35]=[CH:34][N:33]=[C:32]([O:3][CH:4]4[CH2:9][CH2:8][CH:7]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[CH2:6][CH2:5]4)[C:31]=3[C:30]1=2)([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H]1CCc2sc3ncnc(Cl)c3c21
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO[Si](C)(C)C(C)(C)C)CC4)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.9 g, 22.5 mmol, 4.60 equiv) was treated with tert-butyl N-(4-hydroxycyclohexyl)-N-methylcarbamate (1.8 g, 7.85 mmol, 1.6 equiv) in distilled THF (50 mL) at 0° C. for 1 h under nitrogen. Then a solution of 25.1 (1.8 g, 4.88 mmol, 1.00 equiv) in 15 mL of THF was added to the reaction mixture and the latter was stirred for 2 h at 60° C. The reaction was then quenched by the addition of 20 mL of water at 0° C. and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1:5) and purified to afford tert-butyl N-(4-[[(3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (34.1, 1.6 g, 58%) as a yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][CH3:22])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:19]([O:18][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:9]=1[OH:8])[NH:15][CH:14]=[CH:13]2)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCOc1cc2cc[nH]c2cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCOc1cc2cc[nH]c2cc1O
Yield: 90.2 %

Procedure:
6-Benzyloxy 5-butoxy indole (4 g, 0.0135 mole) is hydrogenated under 50 atmospheres of hydrogen in a reactor with 40 ml of ethanol and 0.6 g 10% palladium on carbon for 3 hours. After filtration and evaporation of the solvent, the residue is recrystallized in a mixture of benzene-hexane to produce 5-butoxy 6-hydroxy indole (2.5 g, yield 90%).
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[NH:48]1[CH2:53][CH2:52][S:51](=[O:55])(=[O:54])[CH2:50][CH2:49]1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([N:48]4[CH2:53][CH2:52][S:51](=[O:55])(=[O:54])[CH2:50][CH2:49]4)=[O:43])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=S1(=O)CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCS(=O)(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with thiomorpholine 1,1-dioxide (Syntech Development) to give the title compound. HR-MS (ES, m/z) calculated for C39H49Cl2N6O5S [(M+H)+] 783.2857, observed 783.2856.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[I:13]N1C(=O)CCC1=O.O>C(O)(=O)C>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([I:13])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(=O)c1cc(Cl)c(C)cc1O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c(C)c(I)c1O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96.6 %

Procedure:
To a stirred solution of 1-(5-chloro-2-hydroxy-4-methylphenyl)ethanone (from Oakwood, 50.0 g, 271 mmol) in acetic acid (300 mL) was added N-iodosuccinimide (73.1 g, 325 mmol) and the resulting mixture was stirred on a heating mantle between 60˜80° C. over 3.5 hours then cooled to room temperature and stirred overnight. Water (500 mL) was added to the mixture in portions, which caused a dark solid to form. After stirring for 10 minutes, the solids were filtered, washing with additional water. The light to dark brown solids were dried under vacuum for 4 hours then air dried over the weekend to give 81.3 g (97%) of the desired product. LCMS calculated for C9H9ClI2 (M+H)+: m/z=310.9; Found: 311.0. 1H NMR (300 MHz, CDCl3): δ 13.21 (s, 1H), 7.71 (s, 1H), 2.65 (s, 3H), 2.63 (s, 3H) ppm.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[Li]CCCC.[F:21]/[C:22](=[C:28](/[C:30]1[C:39]([O:40][CH2:41][CH2:42][CH3:43])=[CH:38][C:37]2[C:36]([CH3:45])([CH3:44])[CH2:35][CH2:34][C:33]([CH3:47])([CH3:46])[C:32]=2[CH:31]=1)\[CH3:29])/[CH:23]=[CH:24]/[C:25](=O)[CH3:26]>C1COCC1>[CH2:2]([O:3][C:4](=[O:5])/[C:6](/[F:7])=[C:25](\[CH3:26])/[CH:24]=[CH:23]/[C:22](/[F:21])=[C:28](\[C:30]1[C:39]([O:40][CH2:41][CH2:42][CH3:43])=[CH:38][C:37]2[C:36]([CH3:45])([CH3:44])[CH2:35][CH2:34][C:33]([CH3:47])([CH3:46])[C:32]=2[CH:31]=1)/[CH3:29])[CH3:1]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=O)C(C)(C)CCC2(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C(/F)C(=O)OCC)C(C)(C)CCC2(C)C

Procedure:
Following General Procedure B and using triethyl 2-fluoro-2-phosphonoacetate (0.3 mL, 1.44 mmol), THF (4 mL), n-BuLi (0.9 mL, 1.6 M in hexane, 1.44 mmol), (3E,5E)-5-fluoro-6-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-hepta-3,5-dien-2-one (Intermediate 9, 177 mg, 0.48 mmol) in THF (2 mL) at −78° C. for overnight, the title compound and its 2-E isomer were obtained by flash column chromatography on silica gel (3% EtOAc-hexane) as a ˜1.4:1 mixture (222 mg). Further purification by HPLC (2.5% EtOAc-hexane) afforded the title compound as a clear oil (102 mg, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]([CH3:11])([CH3:10])[C:8]#[N:9])=[CH:4][CH:3]=1.N[C:15]([CH3:19])([CH3:18])[CH2:16][OH:17].N>[Zn].C([O-])(=O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]([C:8]2[O:17][CH2:16][C:15]([CH3:19])([CH3:18])[N:9]=2)([CH3:10])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(N)CO
Reactant: CC(C)(C#N)Oc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: N
Agent: [Zn]
Solvent: ClC(Cl)Cl
Product: CC1(C)COC(C(C)(C)Oc2ccc(Cl)cc2)=N1
Reaction time: 48 h
Yield: 88 %

Procedure:
19.57 g (0.1 moles) of 2-(p-chlorophenoxy)-2-methyl-propionitrile are reacted under stirring for 34 hours with 17.83 g (0.2 moles) of 2-amino-2-methyl-1-propanol in the presence of 0.66 g (0.003 moles) of zinc-acetate catalyst at a temperature of 140°-150° C. The reaction takes place under an intensive development of ammonia gas. When the gas development is finished, the mixture is cooled, dissolved in 300 ml of chloroform and the solution washed with water to neutral reaction. After drying the solution over anhydrous magnesium sulphate, it is evaporated to dryness. The green-yellow colored oil (26.5 g) is subjected to fractional distillation in vacuo. The main fraction is a product 2-[(p-chlorophenoxy)-isopropyl]-4,4-dimethyl-2-oxazoline of 23.6 g (yield 88%), m.p.: 98°-100° C./0.02 mmHg. The distilled product crystallizes after standing for 48 hours, m.p.: 59°-61° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([OH:7])=[C:5]([C:8]([O:10][CH2:11][CH2:12][CH3:13])=[O:9])[S:4][C:3]=1[C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15].O1CCOCC1.C(=O)([O-])[O-].[K+].[K+].[Br:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>CC(C)=O>[CH3:1][C:2]1[C:6]([O:7][S:39]([C:36]2[CH:37]=[CH:38][C:33]([Br:32])=[CH:34][CH:35]=2)(=[O:41])=[O:40])=[C:5]([C:8]([O:10][CH2:11][CH2:12][CH3:13])=[O:9])[S:4][C:3]=1[C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCCOC(=O)c1sc(C(=O)OCCC)c(O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CCCOC(=O)c1sc(C(=O)OCCC)c(OS(=O)(=O)c2ccc(Br)cc2)c1C

Procedure:
A mixture of 2.3 g (8 mmol) of dipropyl 3-methyl-4-hydroxy-2,5-thiophene-dicarboxylate, 20 ml of dioxane, 40 ml of acetone, 1.6 g (12 mmol) of anhydrous potassium carbonate and 2.3 g (10 mmol) of 4-bromobenzene-sulfonyl chloride was refluxed for about 10 hours, removed of dioxane and acetone by distillation, added with ethyl ether, washed with water, and dried with anhydrous magnessium sulfate. The solvent was removed by distillation, and recrystallization was effected with use of methanol to give 3.8 g (94%) of the desired white crystalline compound, m.p. 73°-74° C.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([CH3:20])[CH3:19].[H-].[Na+].ClC(Cl)(Cl)[C:25]([N:27]=C=O)=[O:26]>CN(C=O)C.C(Cl)Cl>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:25]([NH2:27])=[O:26])[C:13](=[O:18])[C:12]2([CH3:19])[CH3:20]
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.3 %

Procedure:
1.45 g (5 mmol) 5-(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (Example 3) in 30 ml DMF were cooled to 0° C. 0.12 g (5 mmol) sodium hydride from a 55% dispension in mineral oil was added and the mixture was stirred for 0.5 hr at 0° C. then 0.5 hr at 20° C. After cooling to 0° C. a solution of 1 g trichloroacetyl isocyanate in 5 ml dry methylene chloride was added dropwise. The reactional mixture was stirred at room temperature overnight. The solvent was evaporated under vacuum, the residue taken up in 50 ml ethyl acetate and 40 g neutral aluminum oxide was added. The compound was then extracted from the aluminum oxide on a column with ethyl acetate. The solvent was evaporated and the residue was purified by chromatography on silica (eluent:methylene chloride/ethyl acetate: 2/1) to yield 0.37 g (22%) of the desired compound.
Reaction SMILES: [Ni:1].[C:2]1([CH3:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O-:12])(=[O:11])C>>[Ni:1].[CH2:2]([CH:7]([CH2:6][CH2:5][CH2:4][CH3:3])[C:9]([OH:12])=[O:11])[CH3:8]
Reactant: CC(=O)[O-]
Reactant: Cc1ccccc1
Agent: [Ni]
Product: CCCCC(CC)C(=O)O

Procedure:
The concentration of nickel in the acetate solution is practically 1 ppm or more, preferably, 10 ppm or higher. In case of using a nonpolar solvent such as toluene for obtaining a solution of 2-ethyl hexanoic acid nickel, the oxide 13 is unnecessary and the solution can be directly formed on the amorphous silicon film.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:35]2[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=2)[CH2:38]Cl)[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32]>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:38][C:37]2[CH:40]=[CH:41][CH:42]=[C:35]([C:27]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=3)[CH:36]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Reactant: COc1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Product: COc1ccccc1N(Cc1cccc(-c2cc(OC)c(OC)c(OC)c2)c1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
4-(o-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:9]1([CH3:14])[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:15][C:16]1[C:21]([C:22]#[N:23])=[CH:20][C:19]([F:24])=[C:18](Cl)[N:17]=1.C(N(CC)CC)C>C1COCC1>[Cl:15][C:16]1[N:17]=[C:18]([NH:1][C@@H:2]([C:9]2([CH3:14])[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:19]([F:24])=[CH:20][C:21]=1[C:22]#[N:23]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: CCOC(=O)CC(N)C1(C)CCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H](Nc1nc(Cl)c(C#N)cc1F)C1(C)CCCC1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a solution of racemic ethyl 3-amino-3-(1-methylcyclopentyl)propanoate, 33a, (0.40 g, 2.01 mmol) and 2,6-dichloro-5-fluoro-pyridine-3-carbonitrile (0.46 g, 2.41 mmol) in THF (20 mL) was added triethylamine (0.67 mL, 4.82 mmol). The reaction mixture was stirred at 90° C. in a pressure tube for 18 hours. The reaction mixture was filtered and the resulting filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (25% EtOAc/Hexanes) to afford 380 mg of the desired product as a racemic mixture: 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J=9.7 Hz, 1H), 5.56 (d, J=8.9 Hz, 1H), 4.68 (td, J=9.6, 3.6 Hz, 1H), 4.07 (q, J=7.1 Hz, 2H), 2.68 (dd, J=14.8, 3.7 Hz, 1H), 2.46 (dd, J=14.8, 9.3 Hz, 1H), 1.77-1.62 (m, 4H), 1.61-1.49 (m, 2H), 1.47-1.37 (m, 1H), 1.35-1.26 (m, 1H), 1.19 (t, J=7.1 Hz, 3H), 1.01 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.81 minutes (M+H) 354.98. The racemic mixture was submitted to SFC chiral separation to give the individual enantiomers, 143a and 143b. The (R)-enantiomer, 143a, was taken forward into the next synthetic step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:26])[C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)[CH:12]=[CH:13][CH:14]=2)[CH:5]=[C:4]([CH3:27])[N:3]=1.CCO.Cl>[Fe].O>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6]3[CH:5]=[C:4]([CH3:27])[N:3]=[C:2]([NH2:1])[N:7]=3)[CH:10]=2)=[O:26])=[CH:18][CH:19]=1
Reactant: Cc1cc(Nc2cccc(NC(=O)c3ccc([N+](=O)[O-])cc3)c2)nc(N)n1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(Nc2cccc(NC(=O)c3ccc(N)cc3)c2)nc(N)n1
Yield: 14.2 %

Procedure:
To a refluxing suspension of amide E3 (7.89 g, 20.00 mmol) in 2:1 EtOH:H2O (500 mL) were sequentially added Fe dust (4.40 g, 79 mmol) and c.HCl (2% v/v, 10 mL), and the resulting mixture refluxed for ˜14 h. After this time, the hot reaction mixture was filtered through a pad of Celite, and the solvent was removed under reduced pressure. The residue was re-dissolved in hot H2O, and the resulting suspension filtered through a pad of Celite. Solvent was removed under reduced pressure, and the residue dried via three MeOH azeotrope cycles. The resulting residue was reprecipitated from acidified MeOH:EtOAc to give amine E4 as an amorphous tan solid (0.95 g, 12%); 1H NMR (400 MHz, DMSO): δ 12.71 (br s, 1H, pyrimidinyl-N+—H), 10.55 (br s, 1H, ArC(O)NHAr), 9.95 (s, 1H, ArNHAr), 8.10-7.40 (m, 7H, ArH & ArNH2), 7.32 (m, 1H, ArH), 6.77 (d, J=8.30 Hz, 2H, ArH), 6.18 (s, 1H, ArH), 2.28 (s, 3H, ArCH3); LCMS (APCl+): 335 (100%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3=[N:19][CH:20]=[C:21]([NH2:24])[C:22]([CH3:23])=[C:17]3[N:16]=[C:15]2[CH2:25][CH3:26])=[CH:10][CH:9]=1)(=[O:4])[CH2:2][CH3:3].N1C=CC=CC=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[C:1]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3=[N:19][CH:20]=[C:21]([NH:24][S:34]([CH3:33])(=[O:36])=[O:35])[C:22]([CH3:23])=[C:17]3[N:16]=[C:15]2[CH2:25][CH3:26])=[CH:10][CH:9]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)OCCc1ccc(-n2c(CC)nc3c(C)c(N)cnc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)OCCc1ccc(-n2c(CC)nc3c(C)c(NS(C)(=O)=O)cnc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.9 %

Procedure:
To a stirred solution of 2-[4-(6-amino-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl propionate (step 4, 1.0 g, 3.0 mmol) and pyridine (280 mg, 3.5 mmol) in dichloromethane (18 mL) was added methanesulfonyl chloride (372 mg, 3.3 mmol) at 0° C., and the mixture was stirred at room temperature for 16 h. The reaction was quenched with water (10 mL), and the mixture was extracted with dichloromethane (50 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), and concentrated. Purification by flash column chromatography on silica gel eluting with ethyl acetate (gradient elution from 1:1 to 1:2) afforded 890 mg (70%) of the title compound as an amber oil: 1H-NMR (CDCl3) δ 8.26 (1H, s), 7.43 (2H, d, J=8.4 Hz), 7.32 (2H, d, J=8.2 Hz), 7.00 (1H, br.s), 4.35 (2H, t, J=7.0 Hz), 3.03–3.01 (5H, m), 2.85 (2H, q, J=7.5 Hz), 2.75 (3H, s), 2.35 (2H, q, J=7.5 Hz), 1.30 (3H, t, J=7.5 Hz), 1.14 (3H, t, J=7.5 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Ni].CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)S(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Product: CN(C)S(=O)(=O)Cc1cccc(N)c1
Reaction time: 4 h
Yield: 95.8 %

Procedure:
(3-nitrophenyl)-N,N-dimethylmethanesulfonamide (2.32 g, 9.5 mmol) was hydrogenated over Raney nickel (0.5 g) in methanol at 50° C. and 70 psi for 4 h, then catalyst was filtered off, washed with warm methanol, combined filtrates were evaporated to give 1.95 g (96%) of (3-aminophenyl)-N,N-dimethylmethanesulfonamide.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH:32]1([NH2:35])[CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH:32]1([NH:35][CH2:27][C:23]2[CH:22]=[C:21]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:11][CH2:10]3)[CH:26]=[CH:25][CH:24]=2)[CH2:34][CH2:33]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNC5CC5)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.113 mmol) in DCM (2 mL) was added cyclopropanamine (19.3 mg, 0.339 mmol). The reaction solution was stirred at ambient temperature for 30 min prior to addition of HOAc (1 drop) and NaBH(OAc)3 (75 mg, 0.545 mmol). The resulting mixture was stirred overnight at ambient temperature after which time the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (18.2 mg, 34%).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([CH2:15][O:16]C(=O)C)[O:8][CH:7]=[CH:6]1)(=O)C.C[O-].[Na+].CCOC(C)=O>CO>[O:8]1[C@H:9]([CH2:15][OH:16])[C@@H:10]([OH:11])[C@H:5]([OH:4])[CH:6]=[CH:7]1
Reactant: CC(=O)OC[C@H]1OC=C[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: OC[C@H]1OC=C[C@@H](O)[C@@H]1O
Reaction time: 0.33 h

Procedure:
The Tri-O-Acetyl-D-Glucal [SM-A](100 g, 367 mmol) is dissolved in dry MeOH [1.5 L], and then NaOMe (110 mmol, 5.95 g) is added into reaction mixture. Within about 20 minutes, TLC (40% EtOAc/60% hexanes & 100% EtOAc) confirmed de-acetylated glucal. The reaction is quenched with 50WX4 cation exchange resin until pH is near 7.0 by pH strip paper. The mixture is filtered and evaporated to dryness under vacuum to yield syrupy glucal intermediate IntA1(59 g). Theoretical yield 100 g×(146/272) 53.7 g TLC IntA1Rf=0.1, SiO2, 100% Ethyl Acetate
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27]([SH:29])[CH3:28]>C(C(C)=O)C(C)C>[CH2:27]([S:29][C:7]1[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=[C:3]([C:2]([F:20])([F:19])[F:1])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:28]
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)c1c(SCC)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 69.7 %

Procedure:
A mixture of 3.0 g (0.009 mol) of product of Example 9, 1.55 g (0.011 mol) of K2CO3 and 3.5 ml (0.047 mol) of ethanethiol in 15 ml of methyl isobutyl ketone was stirred at reflux for 60 hours. The reaction mixture was concentrated. The residue was taken up in ether, washed with 10% NaOH and water, dried (MgSO4) and concentrated in vacuo to 2.98 g of dark oil which was purified by HPLC using 5% ethyl acetate/cyclohexane as eluting solvent affording 2.18 g (69.8%) of product as a tan solid; mp 36°-37.5° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.[CH3:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O.C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[NH:7][C:4]1[NH:3][C:2]([CH3:1])=[N:6][N:5]=1
Reactant: Cc1nnc(N)[nH]1
Reactant: COC1CCCCC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC1CCCCC1Nc1nnc(C)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.3 %

Procedure:
To a solution (50 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (2.5 g) and 2-methoxycyclohexanone (3.9 g) in acetic acid was added sodium cyanoborohydride (8.1 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (2.8 g, 51%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:16]=1>N1C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:17]([C:15]2[CH:16]=[C:11]([F:10])[CH:12]=[CH:13][C:14]=2[CH3:21])(=[O:18])=[O:19])[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1ccc(F)cc1S(=O)(=O)Nc1cc(Br)cnc1Cl
Temperature: 25 °C
Yield: 59.3 %

Procedure:
3-Amino-5-bromo-2-chloropyridine (797 mg) in dry pyridine (10 ml) was treated with 5-fluoro-2-methylbenzenesulfonyl chloride (962 mg) then stirred at RT over the weekend. The reaction was purified by prep-HPLC. Desired fractions were concentrated under reduced pressure, diluted with saturated sodium bicarbonate (aq) and brine and extracted into DCM. The solvent was dried over magnesium sulfate, filtered then evaporated to give title compound (865 mg).