Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Sn:5]([CH2:14][CH2:15][CH2:16][CH3:17])([O:10]C(=O)C)[O:6][C:7](=[O:9])[CH3:8])[CH2:2][CH2:3][CH3:4].[CH2:18]([Sn:22](CCCC)([CH2:27][CH2:28][CH2:29][CH3:30])[O:23][C:24](=[O:26])[CH3:25])[CH2:19][CH2:20][CH3:21]>>[CH2:14]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([O:6][C:7](=[O:9])[CH3:8])[O:10][Sn:22]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:27][CH2:28][CH2:29][CH3:30])[O:23][C:24](=[O:26])[CH3:25])[CH2:15][CH2:16][CH3:17]
Reactant: CCCC[Sn](CCCC)(OC(C)=O)OC(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)OC(C)=O
Product: CCCC[Sn](CCCC)(OC(C)=O)O[Sn](CCCC)(CCCC)OC(C)=O

Procedure:
199.3 g of a mixture containing di-n-butyl diacetoxy tin, tri-n-butyl acetoxy tin and 1,1,3,3-tetra-n-butyl-1,3-diacetoxy distannoxane was obtained by carrying out the same method as step (2-2) of Example 2 with the exception of using 200.1 g of the mixture obtained in step (5-1) instead of the mixture obtained in step (2-1). The content of di-n-butyl diacetoxy tin in this mixture was 63.7 wt %, the content of tri-n-butyl acetoxy tin was about 1 wt %, and the content of 1,1,3,3-tetra-n-butyl-1,3-diacetoxy distannoxane was 32.3 wt %.
Reaction SMILES: C([N:8]1[CH2:14][CH:13]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][CH:13]1[CH2:14][NH:8][CH2:9][CH2:10][NH:11][CH2:12]1
Reactant: c1ccc(CN2CCN(Cc3ccccc3)CC(OC3CCCCO3)C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C1CCC(OC2CNCCNC2)OC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3.06 g of 1,4-dibenzyl-6-(tetrahydro-2H-pyran-2-yloxy)-1,4-diazepane was dissolved in 50 ml of methanol and 1 g of a 20% palladium hydroxide on carbon catalyst was added thereto. The resulting mixture was stirred under a hydrogen atmosphere at ordinary pressure and room temperature for 5 hours. The reaction solution was filtered and the solvent was concentrated to give the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[N:19][C:4]=2[CH:3]=1.[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[O:35][CH3:36])[CH3:24].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CCOC(C)=O>[CH:20]1([N:17]2[C:5]3[C:6]([O:8][C@@H:9]([C@H:11]4[CH2:15][NH:14][C:13](=[O:16])[CH2:12]4)[CH3:10])=[N:7][C:2]([C:29]4[CH:30]=[CH:31][C:26]([O:25][CH2:23][CH3:24])=[C:27]([O:35][CH3:36])[CH:28]=4)=[CH:3][C:4]=3[N:19]=[CH:18]2)[CH2:22][CH2:21]1
Reactant: C[C@@H](Oc1nc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CCOc1ccc(B(O)O)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2cc3ncn(C4CC4)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Temperature: 105 °C

Procedure:
To a 25 ml 3-neck flask with condenser and magnetic stir bar was added (R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-on (100 mg, 0.27 mmol), (4-ethoxy-3-methoxyphenyl)boronic acid (64 mg, 0.33 mmol) and Pd(PPh3)4 (32 mg, 0.027 mmol) then evacuated and filled with N2 3×. Added 2 mL DME and 2N SODIUM CARBONATE (0.41 ml, 0.82 mmol) via syringe and heated in a 105° C. oil bath for 2 hrs at which time LC-MS indicated a complete reaction. Let cool, added EtOAc and water, separated, washed with brine, dried over Na2SO4, filtered and concentrated. Purified by chromatography: ISCO 50 g C18 reverse phase 0-30% water/acetonitrile/0.1% TFA. Partially concentrated under reduced pressure added EtOAc and sat.aq.bicarb, separated, washed with brine, dried over Na2SO4, filtered and concentrated to give a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)[Cl:23].Cl>C(O)C>[ClH:23].[CH3:1][C:2]1[CH:9]=[CH:8][C:5]2[C:6]([NH2:7])=[N:17][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:4]=2[CH:3]=1
Reactant: Cl[Sn]Cl
Reactant: Cc1ccc(C#N)c(Nc2ccccc2[N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)Nc1ccccc1N=C2N
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
Combine 4-methyl-2-(2-nitro-phenylamino)-benzonitrile (2.46 g, 9.71 mmol), tin(II) chloride dihydrate (6.57 g, 29.71 mmol), 5N. HCl (40 ml), and ethanol (40.0 ml). Stir the mixture at reflux for 8 hours then cool it to ambient temperature. Allow the mixture to stand at ambient temperature overnight then chill it for 3 hours in the refrigerator. Remove the resulting precipitate by vacuum filtration and dry it under vacuum to give 1.24 g (49%) of the desired compound as a yellow solid: mass spectrum (ion spray): m/z=224.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[C:19]=3[O:21][CH3:22])[C:14]([OH:27])=[C:13]([C:28]([O:30][CH2:31]C)=[O:29])[C:12]=2[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C[O-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[C:19]=3[O:21][CH3:22])[C:14]([OH:27])=[C:13]([C:28]([O:30][CH3:31])=[O:29])[C:12]=2[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1c(C(=O)OCC)c(-c2ccc(OC)c(OC)c2)c2c(OC)c(OC)c(OC)cc2c1O
Agent: C[O-]
Agent: [Na+]
Product: CCOC(=O)c1c(C(=O)OC)c(O)c2cc(OC)c(OC)c(OC)c2c1-c1ccc(OC)c(OC)c1

Procedure:
1-(3,4-dimethoxyphenyl)-2,3-bis(ethoxycarbonyl)-4-hydroxy-6,7,8-trimethoxynaphthalene obtained in Example 10 is treated with a sodium methoxide solution in the same manner as described in Example 28, whereby 1-(3,4-dimethoxyphenyl)-2-ethoxycarbonyl-3-methoxycarbonyl-4-hydroxy-6,7,8-trimethoxynaphthalene is obtained as colorless prisms.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][C:3]=1[C:18]([OH:20])=[O:19].O1CCCC1.CCCCCC.C([Li])CCC>[Cl-].[Na+].O.O>[CH2:13]([O:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[C:3]([C:18]([OH:20])=[O:19])[CH:4]=1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCOc1cc(C(=O)O)c(Br)c2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCCCCOc1cc(C(=O)O)cc2ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
1-Bromo-4-pentyloxynaphthalene-2-carboxylic acid (400 mg, 1.19 mmol) and tetrahydrofuran (THF, 3 ml) were mixed in a reaction vessel replaced with argon, and this solution was cooled to -78° C. A hexane solution (1.6M, 1.63 ml) of n-butyllithium (2.61 mmol) was added, and the mixture was stirred for 1 hour. Water (0.5 ml) and saturated brine (2 ml) were added, and the aqueous layer was extracted 4 times with ethyl acetate (5 ml). The organic layers were combined and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=3/1-1/2) to give 4-pentyloxynaphthalene-2-carboxylic acid (149.6 mg, 49%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6]1)=[O:4].[Cl:20][S:21](O)(=[O:23])=[O:22]>ClCCl>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][C:14]([S:21]([Cl:20])(=[O:23])=[O:22])=[CH:15][C:10]=1[CH:7]1[CH2:8][CH2:9][N:5]([C:3](=[O:4])[C:2]([F:1])([F:18])[F:19])[CH2:6]1
Reactant: COc1ccccc1C1CCN(C(=O)C(F)(F)F)C1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Cl)cc1C1CCN(C(=O)C(F)(F)F)C1
Temperature: -5 °C
Reaction time: 18 h
Yield: 90.8 %

Procedure:
1.7 g of 2,2,2-trifluoro-1-(3-(2-methoxyphenyl)pyrrolidin-1-yl)ethanone (6.22 mmol) were dissolved in 5 mL of dichloromethane and the solution was cooled to −5° C. At this temperature, 14.5 g of chlorosulfonic acid (124 mmol) were slowly added dropwise. Stirring was continued for 1 h at −5° C. and 18 h at room temperature. The reaction was then cooled to 0° C. and slowly added into 30 g of a water/ice mixture. The suspension was extracted 5 times with 100 mL of dichloromethane and the combined organic phases were washed twice with 5% aqueous sodium hydrogencarbonate solution. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated to yield 2.1 g of the title compound as a yellowish solid (storage in the refrigerator under argon atmosphere).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(O)=O.BrC1[S:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][CH:15]=1.BrC1C=NC=CC=1>>[C:4]1([C:1]2[S:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][CH:15]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: O=C(O)c1ccc(Br)s1
Solvent: Brc1cccnc1
Product: O=C(O)c1ccc(-c2ccccc2)s1

Procedure:
Following the procedure of Preparation 1(a), except substituting phenylboronic acid for 4-carboxybenzeneboronic acid and 5-bromo-2-thiophenecarboxylic acid for 3-bromopyridine, afforded the title compound.
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.[N:38]1([C:42](=O)[CH2:43]Cl)[CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:42][CH2:43][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[C@@H:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: O=C(CCl)N1CCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CCC3)cc2)c1
Yield: 59.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 1-azetidin-1-yl-2-chloroethanone (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.8 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6]O.[Br:11]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][Br:11]
Reactant: OCCc1cccc(Cl)c1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: Clc1cccc(CCBr)c1
Yield: 92.5 %

Procedure:
According to Scheme 11, a solution of 3-chlorophenethyl alcohol (5 g, 32 mmol) in 50 mL of dry MeCN was treated with dibromotriphenylphosphorane (13.54 g, 32 mmol) for 24 h. The reaction mixture was filtered and the solvent was removed in vacuo. The residue was triturated with hexane and filtered. Evaporation of the solvent provided 6.5 g of 3-chlorophenethyl bromide. A solution of the bromide (6.5 g, 29.6 mmol) in 50 mL of dry DMSO containing NaCN (2.17 g, 44 mmol) was heated to 100° C. overnight. The reaction mixture was diluted with water and extracted with ether. The ether layer was washed with water, dried and the solvent was removed in vacuo. Chromatography (silica gel, hexane:ethyl acetate, 4:1) provided 3.7 g of nitrile 89.
Reaction SMILES: [CH2:1]([O:3][CH:4]([N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:9]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[N:8]=[CH:7]1)[CH3:5])[CH3:2].CN(CCN(C)C)C.C([Li])CCC.CON(C)[C:42](=[O:47])[C:43]([F:46])([F:45])[F:44]>C1COCC1.C(OCC)C>[CH2:1]([O:3][CH:4]([N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:9]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[N:8]=[C:7]1[C:42](=[O:47])[C:43]([F:46])([F:45])[F:44])[CH3:5])[CH3:2]
Reactant: CON(C)C(=O)C(F)(F)F
Reactant: CCOC(C)n1cnc(-c2ccc(F)cc2)c1-c1ccc(SC)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(C)n1c(C(=O)C(F)(F)F)nc(-c2ccc(F)cc2)c1-c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-(1-Ethoxyethyl)-4-(4-fluorophenyl)-5-[4-(methyl-thio)phenyl]-1H-imidazole (Example 83 Step 1) (403.8 mg; 1.04 mmol) and TMEDA (582.7 mg; 5.01 mmol) in 6 ml of THF at −78° C. was added 1.23 ml of 2.5 M n-butyllithium in hexanes. After stirring for 15 minutes, a solution of N-methoxy-N-methyltrifluoracetamide, (167 mg; 1.41 mmol) in 1 ml of THF was added. The solution was warmed to 25° C. over one hour. The reaction was diluted with diethyl ether and washed with a saturated, aqueous, solution of sodium bicarbonate. The organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure to give the crude product, which was purified by flash chromatography (SiO2; 25% ethyl acetate/hexane) to give 81 mg of 1-[1-(1-ethoxyethyl)-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-1H-imidazol-2-yl]-2,2,2-trifluoroethanone which was used directly in the next step.
Reaction SMILES: Cl[C:2](=[O:8])[CH2:3][O:4]C(=O)C.[O:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[C:18]1[C:19]([NH2:38])=[N:20][CH:21]=[C:22]([C:24]2[C:25]([CH2:35][O:36][CH3:37])=[N:26][N:27]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:28]=2)[CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[NH2:38][C:19]1[N:20]=[CH:21][C:22]([C:24]2[C:25]([CH2:35][O:36][CH3:37])=[N:26][N:27]([CH:29]3[CH2:34][CH2:33][N:32]([C:3](=[O:4])[CH2:2][OH:8])[CH2:31][CH2:30]3)[CH:28]=2)=[CH:23][C:18]=1[C:10]1[O:9][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COCc1nn(C2CCNCC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCc1nn(C2CCN(C(=O)CO)CC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
(2-chloro-2-oxo-ethyl)acetate (0.029 ml) was added in one portion to a stirred mixture of 3-(1,3-benzoxazol-2-yl)-5-[3-(methoxymethyl)-1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (90 mg) and triethylamine (0.062 ml) in CH2Cl2 (5 ml) at 23° C. The resulting mixture was stirred at 23° C. for 2 hours and concentrated to dryness. Methanol (20 ml) and water (1 ml) were added to the residue followed by lithium hydroxide hydrateaqueous solution (0.334 g, 2M). The resulting solution was stirred at 23° C. After 4 hours the reaction mixture was concentrated and the crude product was purified by flash chromatography on silica gel eluting with 0 to 5% methanolic ammonia (7 N) in dichloromethane. The fractions were evaporated to dryness to afford 1-[4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-(methoxymethyl)pyrazol-1-yl]-1-piperidyl]-2-hydroxy-ethanone (42.0 mg) as a solid. NMR Spectrum: (DMSOd6): 1.77-1.87 (m, 1H), 1.88-2.00 (m, 1H), 2.05-2.14 (m, 2H), 2.79-2.89 (m, 1H), 3.11-3.21 (m, 1H), 3.41 (s, 3H), 3.78-3.88 (m, 1H), 4.08-4.21 (m, 2H), 4.40 (s, 2H), 4.41-4.51 (m, 2H), 4.58 (t, 1H), 7.40-7.48 (m, 2H), 7.66 (bs, 2H), 7.78 (dd, 1H), 7.84 (dd, 1H), 8.23 (s, 1H), 8.42 (d, 1H), 8.50 (d, 1H); Mass spectrum: M+H+ 463.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)=[CH2:2].[CH2:13]([SH:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].N(C(C)(C)C#N)=NC(C)(C)C#N>>[C:3]1([CH2:1][CH2:2][S:21][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1cccc2ccccc12
Reactant: CCCCCCCCS
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCCCCCSCCc1cccc2ccccc12
Temperature: 110 °C
Reaction time: 68 h

Procedure:
5.0 grams (32.4 mmol, MW: 154.21) 1-vinylnaphthalene, 7.1 grams (48.6 mmol, MW: 146.29) octanethiol and 0.266 grams (1.62 mmol, MW: 164.21) 2,2′-azobis(2-methylpropionitrile) (AIBN) were charged in a 25 milliliter thick sealed glass reactor. After addition, the reaction mixture was stirred for 68 hours at 110° C. The reaction was then stopped and cooled down to room temperature. The excess of unreacted octanethiol was removed by air bath oven at 200° C. under vacuum for 1 hour. The final product was determined by IR, 1HNMR. Yield: 8.8 grams (90%). IR: (cm−1) 30045, 2924, 2853, 1596, 1510, 1459, 1394, 1377, 1261, 1219, 1165, 1016, 779, 730. 1H NMR (CDCl3): 8.03-7.33 (7H, m), 3.32 (2H, t), 2.91 (2H, t), 2.55 (2H, t), 1.57 (2H, m) 1.46-1.27 (10H, m), 0.87 (3H, t).
Reaction SMILES: [C:1]([C:3]1([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)#N.C[Mg+].[Br-].C1(C)C=CC=CC=1.C1COCC1>C1COCC1>[OH:20][CH:17]1[CH2:18][CH2:19][N:14]([C:3]2([CH3:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:15][CH2:16]1
Reactant: CCOC(=O)N1CCC(C#N)(N2CCC(O)CC2)CC1
Agent: C[Mg+]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(C)(N2CCC(O)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.5 %

Procedure:
To a stirred solution of ethyl 4-cyano-4-(4-hydroxy-1-piperidyl)piperidine-1-carboxylate (2.45 g, 8.69 mmol) in THF (20 mL) was added a 1.4 M solution of MeMgBr in toluene/THF (18.6 mL, 26.1 mmol) at 0° C., and the mixture was stirred at room temperature for 12 h. The reaction was then quenched with saturated aqueous ammonium chloride, and the mixture was extracted with dichloromethane (2×25 mL). The combined extracts were concentrated in vacuo to afford the title compound (1.54 g, 65%), which was used in the next step without further purification. MS (M+1): 271.26.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH3:15][O:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>CN(C=O)C>[CH3:15][O:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Reactant: COc1ccccc1N
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Nc2ccccc2OC)[nH]c1=O
Reaction time: 8 h
Yield: 74.1 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (5 g) and 2-methoxyaniline (3.4 g) are added to DMF (20 ml), and the mixture is refluxed with stirring for 8 hours. After cooling, the precipitate is collected by filtration and recrystallized from DMF to give ethyl 1,6-dihydro-2-(2-methoxyanilino)-6-oxo-5-pyrimidinecarboxylate (5 g). M.p. 217°-219° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH:33]1([CH2:36]O)[CH2:35][CH2:34]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH:33]1([CH2:36][O:32][C:29]2[CH:28]=[CH:27][C:26]([C:24]3[NH:25][C:21]([CH:13]([C:10]4[CH:11]=[CH:12][C:7]([S:4]([CH:1]5[CH2:3][CH2:2]5)(=[O:6])=[O:5])=[CH:8][CH:9]=4)[CH2:14][CH:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:22][CH:23]=3)=[N:31][CH:30]=2)[CH2:35][CH2:34]1
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(O)cn3)[nH]2)cc1)C1CC1
Reactant: OCC1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(OCC4CC4)cn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.5 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-ol (0.260 g) in tetrahydrofuran (10 mL) were added cyclopropylmethanol (83 mg), tributylphosphine (0.29 mL) and 1,1′-(azodicarbonyl)dipiperidine (290 mg), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in toluene (10 mL), and hexane (10 mL) was added. The obtained suspension was filtered to remove the precipitate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-70:30, volume ratio) to give the title compound (0.240 g, yield 83%) as a colorless amorphous solid. MS: 507 (MH+).
Reaction SMILES: CC1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH3:15])[N:9]=2)C(C)=CC=1.Cl.NO.[OH-].[Na+].C(Cl)Cl>CCO.O>[CH2:14]([C:10]1[N:9]=[C:8]([NH2:3])[CH:13]=[CH:12][CH:11]=1)[CH3:15]
Reactant: CCc1cccc(-n2c(C)ccc2C)n1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CCc1cccc(N)n1
Temperature: 100 °C

Procedure:
The product from Example 8a (4.93 g, 0.025 mol) was dissolved in a mixture of EtOH (80 mL) and water (30 mL). To this was added hydroxylamine hydrochloride (8.6 g, 0.123 mol) and the resulting mixture heated to 100° C. for 8 h. The reaction mixture was poured into dilute sodium hydroxide solution and the crude product isolated by extraction with CH2Cl2 and dried over MgSO4 filtered and concentrated under vacuum giving the title compound. The material was used as isolated.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C([O-])([O-])=O.[K+].[K+].[C:18]([O:22][C:23]([N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].CCOC(C)=O>CC#N>[C:18]([O:22][C:23]([N:25]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:2][CH2:3][C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: O=C(CCCl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCN(CCC(=O)c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 17 h
Yield: 80 %

Procedure:
3-Chloropropiophenone (7.14 g, 24.4 mmol). K2CO3 (8.79 g, 1.50 equiv) and KI (1.41 mg, 0.2 equiv) were added to a solution of the purified 1-(tert-butyloxycarbonyl)homopiperazine (8.486 g, 42.4 mmol) in CH3CN (60 mL). The reaction mixture was stirred at 70° C. for 17 h and then AcOEt (200 mL) was added to the cooled mixture. The precipitated solid was removed by filtration and washed with AcOEt (50 mL). The combined filtrate was evaporated to afford an oil which was purified by column chromatography (SiO2, 0%-20% CH3CN/AcOEt) to give 1-(tert-Butyloxycarbonyl)-4-(3-phenyl-3-oxopropyl)homopiperazine: 11.27 g, 80% yield, pale yellow oil: 1H NMR (CDCl3, 300 MHz) δ 1.40-1.65 (m, 9H), 1.80-1.95 (m, 2H), 2.65-2.85 (m, 4H), 3.01 (t, 2H, J=6.9 Hz), 3.19 (t, 2H, J=6.9 Hz), 3.35-3.55 (m, 4H), 7.47 (t, 2H, J=7.7 Hz), 7.55-7.65 (m, 1H), 7.90-8.02 (m, 2H). The purity was determined by RPLC/MS (Method B). RPLC tR=5.53 min (95%), 220 nm; ESI/MS m/e 333.4 (M++H, C19H29N2O3).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O)([O-:3])=[O:2].[CH3:11][NH2:12]>>[CH3:11][NH:12][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][N+:1]([O-:3])=[O:2]
Reactant: COC(=O)CCC[N+](=O)[O-]
Reactant: CN
Product: CNC(=O)CCC[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.6 %

Procedure:
To a sealed reaction vessel was added methyl 4-nitrobutyrate (1.00 g, 6.80 mmol) and methylamine (2.0 M methylamine in MeOH, 50.0 mL, 100 mmol). The resulting yellow solution was stirred at room temperature for 20 h. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, load: CH2Cl2, elution with EtOAc:Hexanes, 1:1) to give the title product (0.97 g, 98%) as a white solid. 1H NMR (CDCl3): 5.84 (br s, NH, 1H), 4.54-4.48 (m, 2H), 2.82 (d, J=4.7 Hz, 3H), 2.36-2.32 (m, 4H).