Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].Cl.[CH2:18]([O:25][C:26](=[O:31])[C@@H:27]([OH:30])[CH2:28][NH2:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH2:18]([O:25][C:26](=[O:31])[C@@H:27]([OH:30])[CH2:28][NH:29][C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Reactant: NC[C@H](O)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(=O)SCC(Cc1ccccc1)C(=O)NC[C@H](O)C(=O)OCc1ccccc1
Reaction time: 20 h

Procedure:
Add 2(R,S)-acetylthiomethyl-3-phenylpropionic acid (0.59 g) to (S)-isoserine benzyl ester, hydrochloride (0.578 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (0.53 g), 1-hydroxybenzotriazole (HOBT) (0.37 g) and N-methylmorpholine (0.80 ml) in dimethylformamide (DMF) (10 ml), and stir the resulting mixture for 20 hours. Concentrate the reaction mixture in vacuo and partition the residue between dichloromethane/water. Concentrate the dried (MgSO4) dichloromethane solution in vacuo. Chromatograph the resulting residue on a column of silica gel (1 L) using chloroform:methanol 19.5:1 as eluant to give the title compound, a colorless oil, [α]D26 =+12.3° (MeOH).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.COC1C=C(OC)C=CC=1C[N:21]1[CH2:27][CH2:26][C:25]([F:29])([F:28])[CH2:24][C@@H:23]([N:30]([CH2:40][C:41]2[CH:42]=[N:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)[S:31]([C:34]2[S:35][C:36]([Cl:39])=[CH:37][CH:38]=2)(=[O:33])=[O:32])[C:22]1=[O:49]>ClCCl>[F:29][C:25]1([F:28])[CH2:26][CH2:27][NH:21][C:22](=[O:49])[C@H:23]([N:30]([CH2:40][C:41]2[CH:42]=[N:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)[S:31]([C:34]2[S:35][C:36]([Cl:39])=[CH:37][CH:38]=2)(=[O:33])=[O:32])[CH2:24]1
Reactant: COc1ccc(CN2CCC(F)(F)C[C@@H](N(Cc3ccc(OC)nc3)S(=O)(=O)c3ccc(Cl)s3)C2=O)c(OC)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)s2)cn1

Procedure:
A mixture containing trifluoroacetic acid/trifluoromethanesulfonic acid (5:2 v/v, 0.62 ml) was added to 5-chloro-thiophene-2-sulfonic acid [(R)-1-(2,4-dimethoxy-benzyl)-5,5-difluoro-2-oxo-azepan-3-yl]-(6-methoxy-pyridin-3-ylmethyl)-amide (0.17 g, 0.19 mmol) in dichloromethane (10 ml). After 2 h the reaction mixture was concentrated under reduced pressure and the residue taken up in ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and brine, dried (Na2SO4), filtered, concentrated under reduced pressure and purified over silica gel (heptane-ethylacetate, 9:1-0:1): white solid 69 mg (77%);
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH:25][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNc1nccc(-n2cnc3ccccc32)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 2-methoxybenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 332.1 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.63 (s, 1H); 8.41 (br s, 1H); 8.12 (br s, 1H); 7.86 (m, 1H); 6.94 (m, 2H); 6.79 (d, J=5.2 Hz, 1H); 5.95 (br s, 1H); 4.74 (d, J=5.9 Hz, 2H); 3.92 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].I[CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:10]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH3:11]
Reactant: Oc1ccccc1F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccccc1F
Reaction time: 24 h
Yield: 92 %

Procedure:
A mixture of 2-fluorophenol (8.6 g, 77 mmol), iodoethane (9.2 mL, 120 mmol) and potassium carbonate (21 g, 150 mmol) (finely powdered) was stirred in acetone (100 mL) at 50° C. overnight, then at room temperature for 24 h. The mixture was filtered over a pad of silica gel, and was rinsing with ether. The solution was carefully concentrated (due to volatility of product), then microfiltered to give 1-ethoxy-2-fluoro-benzene (92%) as a yellow oil. 1H NMR (CDCl3, 500 MHz), δ 7.12-6.94 (m, 2H), 6.91-6.86 (m, 1H), 6.83-6.77 (m, 1H), 4.01 (q, J=7.0 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(C(C)C)CC)(C)C.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37]>C(Cl)Cl>[CH2:14]([N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:35](=[O:38])[CH:36]=[CH2:37])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: C=CC(=O)Cl
Reactant: CCCCCCCCCCCCNCCCCCCCCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N(CCCCCCCCCCCC)CCCCCCCCCCCC
Temperature: 0 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
To a solution of didodecylamine 66 (25 g, 70.7 mmol) and diisopropylethylamine (18 g, 141 mmol) in anhydrous CH2Cl2 (700 mL) at −10° C., a solution of acryloyl chloride (7.68 g, 85 mmol) in CH2Cl2 (100 mL) was added dropwise over a period of 20 min. After the completion of the addition the reaction mixture was stirred for 4 h at 0° C. after which the TLC of the reaction mixture showed the completion of the reaction. The reaction mixture was washed with satd. NaHCO3 solution (200 mL), water (200 mL), brine (100 mL) and dried over NaSO4. Concentration of the organic layer provided the product 71 (28.4 g, 100%) which was used as such in the next step. 1H NMR CDCl3 δ 0.94 (t, J=6.5 Hz, 6H), 1.05-1.69 (m, 40H), 3.15-3.60 (dt, 4H), 5.64 (d, 1H), 6.36 (d, 1H), 6.63 (m, 1H).
Reaction SMILES: O[C@H:2]([CH3:15])[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[NH2:47][C:48]([CH3:52])([CH3:51])[CH2:49][OH:50]>CC#N>[C:5]1([C@:3]2([OH:4])[O:50][CH2:49][C:48]([CH3:52])([CH3:51])[NH:47][C@H:2]2[CH3:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: C[C@@H](O)C(=O)c1cccc2ccccc12
Reactant: CC(C)(N)CO
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: C[C@@H]1NC(C)(C)CO[C@@]1(O)c1cccc2ccccc12
Yield: 41.5 %

Procedure:
Compound 4q was synthesized by a procedure similar to that described for (2S,3S)-4a employing (R)-2-hydroxy-1-(naphthalen-1-yl)propan-1-one (10h, 1.15 g, 0.058 mol), Proton sponge (1.5 g, 0.070 mol), triflic anhydride (1.1 mL, 64 mmol), and 2-amino-2-methyl-1-propanol (1.1 g, 0.012 mol) in CH3CN (45 mL). After purification, 1.35 g (86%) of the free base 4q was isolated and converted to the D-tartrate salt, which was recrystallized from H2O-MeOH-Et2O solvent system: mp 115-116+C.; [α]20D −9.5° (c 0.74, CH3OH); 1H NMR (methanol-d4) δ 8.89 (d, 1H, J=8.4 Hz), 7.97-7.89 (m, 3H), 7.54-7.50 (m, 3H), 4.33 (s, 1H), 3.70 (d, 1H, J=12.2 Hz), 3.48 (q, 1H, J=7.0 Hx), 1.77 (s, 3H), 1.41 (s, 3H), 0.96 (d, 3H, J=6.6 Hz); 13C NMR (methanol-d4) δ 136.5, 132.3, 131.9, 130.5, 130.2, 128.1, 127.4, 127.0, 126.1, 99.0, 75.1, 68.1, 67.3, 53.9, 24.8, 22.9, 15.8, 15.2; LCMS (ESI) m/z 272.3 [(M-tartrate)+, M=C19H24NO5]; Anal. (C19H24NO5.0.75H2O) calcd: C, 63.41; H, 7.14; N, 3.89. found: C, 63.63; H, 7.44; N, 3.70.
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:4]([Cl:21])=[CH:5][C:6]([Cl:20])=[C:7]([C:9]2[C:13]([Cl:14])=[C:12]([O:15][CH:16]([F:18])[F:17])[N:11]([CH3:19])[N:10]=2)[CH:8]=1.S(=O)(=O)(O)[OH:24]>>[Cl:14][C:13]1[C:9]([C:7]2[CH:8]=[C:3]([CH:2]=[O:24])[C:4]([Cl:21])=[CH:5][C:6]=2[Cl:20])=[N:10][N:11]([CH3:19])[C:12]=1[O:15][CH:16]([F:18])[F:17]
Reactant: Cn1nc(-c2cc(C(Br)Br)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Reactant: O=S(=O)(O)O
Product: Cn1nc(-c2cc(C=O)c(Cl)cc2Cl)c(Cl)c1OC(F)F

Procedure:
Analogously to Example 12, 45.5 g (91 mmol) of 3-(5-dibromomethyl-2,4-dichlorophenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole were introduced into 65 ml of concentrated sulfuric acid. After working up, 20 g of the product were obtained. 1H-NMR (270 MHz, in CDCl3): δ [ppm]=10.41 (s,1H), 8.02 (s,1H), 7.65 (s,1H),6.77 (t,1H), 3.87 (s,3H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH:28]1([C:32](O)=[O:33])[CH2:31][CH2:30][CH2:29]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32]([CH:28]5[CH2:31][CH2:30][CH2:29]5)=[O:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C1CCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C1CCC1

Procedure:
The title compound, white solid (22.1 mg, 65.5%), MS (ISP) m/z=414.2 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and cyclobutanecarboxylic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2].[CH3:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:20]([CH3:19])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2]
Reactant: CCCCCCCCNC
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Product: CCCCCCCCN(C)c1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A mixture of 9.23 g. of 3-nitro-4-chloro-benzophenone, 10 ml. of ethanol and 10.3 g. of N-methyl-N-octylamine is stirred at 80° to 85° C. for 30 minutes, and then the mixture is poured onto 100 ml. of ice water. The aqueous phase is extracted with 2×75 ml. of benzene. The benzene phases are combined, washed with distilled water until chloride-free, dried over anhydrous magnesium sulphate, filtered, and evaporated in vacuo. 11.57 g. of 3-nitro-4-(N-methyl-N-octylamino)-benzophenone are obtained in the form of an oily residue. On the basis of thin layer chromatographical examination, a pure, uniform product is obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][NH:29][CH2:28][CH2:27][NH:26]2)[CH:20]=1.N1C=CC=CC=1>CCOCC>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:29]3[CH2:28][CH2:27][NH:26][CH:25]([C:21]4[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=4)[CH2:30]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: c1cncc(C2CNCCN2)c1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cccnc4)C3)cc21
Temperature: 25 °C
Yield: 39.7 %

Procedure:
A mixture of 177 mg of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 342 mg of 2-(3-pyridinyl)piperazine and 5 ml of pyridine was heated at 90°-95° C. in a pressure bottle for 5 hours, then cooled at room temperature, then at 0° C. Ether was added to triturate the mixture, then the solid was collected and washed with methanol and ether. This solid was redissolved in a hot mixture of chloroform and methanol, filtered and triturated with ether. The precipitate was collected and dried in vacuo, giving 110 mg of the desired product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O>>[Cl:17][C:14]1[CH:13]=[C:12]2[C:11](=[CH:16][CH:15]=1)[NH:10][C:7](=[O:9])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[C:18]2[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)Cc1cccs1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)c1-c1cccs1
Yield: 55 %

Procedure:
from thiophen-2-yl acetic acid and (2-amino-5-chloro-phenyl)-phenyl-methanone according to general procedure 2. Yield 55%.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[CH:17]([NH:19][C:20]1[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH2:30])[CH:26]=3)[N:21]=1)[CH2:16][CH2:15]2>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[CH:17]([NH:19][C:20]1[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:30][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[CH:26]=3)[N:21]=1)[CH2:16][CH2:15]2
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Product: COc1cccc2c1C(Nc1ccc3cc(NS(=O)(=O)N(C)C)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method described in example 66 from dimethylsulfamoyl chloride and rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example 172); MS: m/e=412.6 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[H-].[Li+].[CH3:21][Si:22]([CH3:46])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH:23]1[CH2:28][CH:27]2[C:25]([CH2:29][OH:30])([O:26]2)[CH:24]1[CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:27]2[C:25]([OH:26])([CH2:29][OH:30])[CH:24]([CH2:31][O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:23]([Si:22]([CH3:46])([CH3:21])[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:28]2)=[C:4]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: C[Si](C)(c1ccccc1)C1CC2OC2(CO)C1COCc1ccccc1
Reactant: Nc1nc(OCc2ccccc2)c2[nH]cnc2n1
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(c1ccccc1)C1CC(n2cnc3c(OCc4ccccc4)nc(N)nc32)C(O)(CO)C1COCc1ccccc1
Temperature: 60 °C
Yield: 37.7 %

Procedure:
To a 1-L 3-necked round bottomed flask equipped with a mechanical stirrer and a thermometer, was charged 2-amino-6-benzyloxypurine (24 g, 0.1 moles), lithium hydride (0.48 g, 0.06 moles) and DMF (40 mL). The mixture was heated at 60° C. for about 1 hour under an atmosphere of argon. 77 (60 g, 0.1 moles) in 20 mL DMF was added. The reaction temperature was heated at 105° C. for 5 hours, cooled to room temperature and diluted with EtOAc (600 mL). The organic layer was washed with brine (300 mL), 1 M citric acid (150 mL), and NaHCO3 solution (100 mL). The organic layer was concentrated in vacuo to furnish crude title product (60 g) as an oil. It was crystallized from EtOAc and hexane to give 23 g of the title compound as a crystalline solid.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]3)[C:9]2=[O:28])C=CC=CC=1.[H][H]>CCOC(C)=O.C(O)(=O)C.[Pd]>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]2)[C:9]1=[O:28]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Yield: 65.8 %

Procedure:
To a solution of 1′-(diphenylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (2.10 g, 4.70 mmol) in EtOAc (100 mL) and acetic acid (0.10 mL) was added palladium on carbon (1.00 g). The reaction mixture was hydrogenated under 60 psi of hydrogen at ambient temperature for 5 days and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography to yield the title compound (0.87 g, 66%) as a white powder: mp 252° C. (dec.); 1H NMR (300 MHz, CDCl3) δ 10.55 (s, 1H), 7.25-6.84 (m, 4H), 6.64 (s, 1H), 6.22 (s, 1H), 5.88 (s, 2H), 4.76-4.57 (dd, 2H); MS (ES+) m/z 282.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:60]1[S:61][CH:62]=[C:63]([C:65]#[N:66])[N:64]=1>C(O)(C)(C)C>[C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:60]2[S:61][CH:62]=[C:63]([C:65]#[N:66])[N:64]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1csc(Br)n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2nc(C#N)cs2)C1
Temperature: 25 °C

Procedure:
To a 500 mL round bottom flask were added (R)-piperidin-3-yl-carbamic acid tert-butyl ester (10.3 g, 51.6 mmol), cesium carbonate (33.6 g, 103 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (BrettPhos, CAS number 1070663-78-3) (369 mg, 688 μmol) and 2-bromothiazole-4-carbonitrile (6.5 g, 34.4 mmol) followed by tert-butanol (225 mL). The mixture was degassed under vacuum (˜50 mmHg) while sonicating and the flask then charged with argon. Degassing repeated twice. Tris-(dibenzylideneacetone)dipalladium(0) (CAS number 51364-51-3) (315 mg, 344 μmol) was added and the flask evacuated and recharged with argon. Repeated twice. The reaction flask was transferred to an aluminum block heating mantle and heated to reflux under argon for 5 hours. The reaction mixture was cooled to ambient temperature and poured into water (1 L), extracted with ethyl acetate (3×200 mL), the combined organic extracts washed with brine (2×200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography using a 330 g silica column gradient eluted from 10% up to 40% ethyl acetate in hexanes at a flow rate of 100 mL/min Product containing fractions were combined and concentrated in vacuo to give of [(R)-1-(4-cyano-thiazol-2-yl)-piperidin-3-yl]-carbamic acid tert-butyl ester as an off white solid (8.75 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[CH3:27][S:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([S:28][CH3:27])=[CH:30][CH:31]=3)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Reactant: CSc1ccc(N)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1ccc(SC)cc1
Yield: 42 %

Procedure:
The title compound was prepared according to the procedure as described for step-6 of Intermediate-26 by using methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.150 g, 0.380 mmol), 4-(methylthio)aniline (0.079 g, 0.570 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) and dry toluene (5.0 mL) to afford 0.080 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.46 (s, 3H), 3.94 (s, 3H), 7.26 (d, J=8.4 Hz, 2H), 7.69-7.72 (m, 6H), 7.78 (d, J=6.9 Hz, 1H), 7.82 (s, 1H), 10.06 (s, 1H), 12.76 (br s, 1H); MS (m/z): 501.0 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:32])[CH3:31])[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24](C)=[C:23](F)[CH:22]=3)[C:19]=2[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C(=O)C(C[O:46][S:47]([CH3:50])(=O)=[O:48])=CC(C2C=CC(S(C)(=O)=O)=CC=2)=N1)C(C)C.N1(C(OC(C)(C)C)=O)CCNCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:32])[CH3:31])[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([S:47]([CH3:50])(=[O:48])=[O:46])=[CH:23][CH:22]=3)[C:19]=2[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1nc(-c2ccc(S(C)(=O)=O)cc2)cc(COS(C)(=O)=O)c1=O
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: Cc1c(-c2ccc(S(C)(=O)=O)cc2)nn(CC(C)C)c(=O)c1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 75.9 %

Procedure:
Following the procedure of Example 1 (10), 2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 75.9%).
Reaction SMILES: [OH:1][CH:2]([C:29]([F:32])([F:31])[F:30])[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:14][N:13]=2)=[CH:8][CH:7]=1.[C:33](Cl)(=[O:42])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:33]([O:1][CH:2]([C:29]([F:31])([F:32])[F:30])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:14][N:13]=2)=[CH:10][CH:11]=1)(=[O:42])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(CCCC(O)C(F)(F)F)cc2)nc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCOc1cnc(-c2ccc(CCCC(OC(=O)CCCCCCCC)C(F)(F)F)cc2)nc1

Procedure:
1.1 g (2.5 mmol) of (-)-2-(4-(4-hydroxy-5,5,5-trifluoro-1-pentyl)phenyl)-5-decyloxypyrimidine was dissolved in 10 ml of pyridine, followed by addition of 0.53 g (3 mmol) of nonanoyl chloride and 2-hour reaction at 20°-30° C. The reaction mixture was diluted with 100 ml of toluene, and the toluene layer was washed with 4N hydrochloric acid, water, a 5% sodium bicarbonate solution and water successively in that order and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using toluene/ethyl acetate as eluent to obtain 1.25 g of (+)-2-(4-(4-nonanoyloxy-5,5,5-trifluoro-1-pentyl) phenyl-5-decyloxypyrimidine.