Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([O:14][CH2:15][CH:16]2[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]2)[C:10]([CH3:24])=[CH:9][N:8]=1)(=O)=O.[SH:25][C:26]1[NH:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.C(N(CC)CC)C>O1CCCC1>[CH3:23][C:19]1([CH3:22])[O:18][CH2:17][CH:16]([CH2:15][O:14][C:11]2[C:10]([CH3:24])=[CH:9][N:8]=[C:7]([CH2:6][S:25][C:26]3[NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[N:27]=3)[C:12]=2[CH3:13])[CH2:21][O:20]1
Reactant: Cc1cnc(COS(C)(=O)=O)c(C)c1OCC1COC(C)(C)OC1
Reactant: Sc1nc2ccccc2[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cnc(CSc2nc3ccccc3[nH]2)c(C)c1OCC1COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 95.5 %

Procedure:
To a mixture of (4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methyl methanesulfonate (500 mg, 1.39 mmol), 2-mercaptobenzimidazole (209 mg, 1.39 mmol) and tetrahydrofuran (5 ml), triethylamine (0.387 ml, 2.78 mmol) was added and the mixture was stirred at room temperature for 14 hours and 25 minutes. The reaction mixture was concentrated under reduced pressure, and toluene and a 0.1N aqueous sodium hydroxide solution were added to the residue and insoluble substance was removed by filtration. The organic layer was taken out and the aqueous layer was extracted again with toluene. The organic layers were combined, washed with a saturated saline solution, dried over sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure. The residue was dissolved in n-heptane/ethyl acetate (1/1) and subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=1/1→0/1) to obtain the title compound (549 mg, 95.5%) as a colorless viscous oil.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40](O)=[O:41].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:21][CH2:22][N:23]([C:40]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=3)=[O:41])[CH2:24][CH2:25]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccn1
Reactant: O=C(C1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(c1ccccn1)N1CCC(C(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.2 %

Procedure:
To the solution of the compound obtained in Example 66 (391 mg, 0.80 mmol), picolinic acid (108 mg, 88 mmol) and 1-hydroxybenzotriazole (119 mg, 0.88 mmol) in DMF (8 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (307 mg, 1.60 mmol), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and to the concentrate were added a saturated aqueous solution of sodium hydrogen carbonate (15 mL) and water (5 mL). The mixture was extracted with ethyl acetate (15 mL×5). The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (5 mL×3), saturated sodium chloride solution (5 mL), successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1), and the desired fraction was concentrated under reduced pressure to give the titled compound (433 mg, 0.73 mmol, Yield 91%).
Reaction SMILES: [O:1]1[CH2:21][CH:2]1[CH2:3][N:4]1[C:8](=[O:9])[C:7]2([CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH3:17])[C:11]([CH3:19])([CH3:18])[CH2:10]2)[NH:6][C:5]1=[O:20].[CH2:22]([C:35]([OH:37])=[O:36])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33]>C(OCC)(=O)C>[OH:1][CH:2]([CH2:3][N:4]1[C:8](=[O:9])[C:7]2([CH2:14][C:13]([CH3:15])([CH3:16])[N:12]([CH3:17])[C:11]([CH3:19])([CH3:18])[CH2:10]2)[NH:6][C:5]1=[O:20])[CH2:21][O:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:35]([O:37][CH2:21][CH:2]([OH:1])[CH2:3][N:4]1[C:8](=[O:9])[C:7]2([CH2:10][C:11]([CH3:18])([CH3:19])[N:12]([CH3:17])[C:13]([CH3:16])([CH3:15])[CH2:14]2)[NH:6][C:5]1=[O:20])=[O:36])=[O:34]
Reactant: CN1C(C)(C)CC2(CC1(C)C)NC(=O)N(CC1CO1)C2=O
Reactant: O=C(O)CCCCCCCCCCC(=O)O
Solvent: CCOC(C)=O
Product: CN1C(C)(C)CC2(CC1(C)C)NC(=O)N(CC(O)COC(=O)CCCCCCCCCCC(=O)OCC(O)CN1C(=O)NC3(CC(C)(C)N(C)C(C)(C)C3)C1=O)C2=O
Temperature: 180 °C

Procedure:
A mixture of 4.4 g of 3-(2,3-epoxypropyl)-7,7,8,9,9-pentamethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione and 1.6 g of 1,10-decanedicarboxylic acid was heated at 180° C. for 3 hours. After completion of the reaction, the reaction mixture was dissolved in ethyl acetate, treated with an aqueous alkaline solution and purified by column chromatography through silica gel eluted first with ethyl acetate, then with a 2:1 by volume mixture of ethyl acetate and methanol. The desired compound was obtained in the form of a white powder, melting point 53°-57° C.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[Br:15]Br>C(O)(=O)C>[Br:15][CH:8]([C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=1)[CH2:9][C:10]([OH:12])=[O:11]
Reactant: BrBr
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Solvent: CC(=O)O
Product: O=C(O)CC(Br)C(=O)c1ccc(F)cc1
Reaction time: 18 h

Procedure:
To a solution of 19.62 g. of 3-(p-fluorobenzoyl)propionic acid in 100 ml. of acetic acid, is added 16 g. of bromine. The mixture is stirred for 18 hours and then the solvent is removed. Ice and water are added to the residue and the mixture is filtered. The solid is washed with water and then dissolved in 80 ml. of acetone. The solution is diluted with 400 ml. of hexane and allowed to evaporate, at room temperature, to a volume of 125 ml. A 100 ml. portion of hexane is added and the mixture is filtered, giving 24.6 g. of the desired product as tan crystals, m.p. 131°-135° C.
Reaction SMILES: C(Cl)CCl.[O:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)=[CH:14][C:6]1=2.[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH2:30][NH:31][CH3:32].C1C=CC2N(O)N=NC=2C=1.O.CCN(CC)CC>CN(C=O)C>[O:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](/[CH:15]=[CH:16]/[C:17]([N:31]([CH3:32])[CH2:30][C:22]3[N:21]([CH3:20])[C:29]4[C:24]([CH:23]=3)=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:19])=[CH:14][C:6]1=2
Reactant: CNCc1cc2ccccc2n1C
Reactant: O=C(O)/C=C/c1cnc2c(c1)OCCN2
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)OCCN2
Yield: 65.7 %

Procedure:
EDC (230 mg, 1.2 mmole) was added to a solution (E)-3-(3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-7-yl)acrylic acid (206 mg, 1.0 mmole), 1-methyl-2-(methylaminomethyl)-1H-indole (209 mg, 1.2 mmole), HOBt.H2O (162 mg, 1.2 mmole), and Et3N (0.21 mL, 1.5 mmole) in dry DMF (5 mL) at RT. After 18 hr the mixture was concentrated. Flash chromatography on silica gel (5% EtOH/EtOAc) gave the title compound (238 mg, 66%) as a yellow solid: 1H NMR (400 MHz, d6-DMSO) δ 7.99-6.95 (m, 8H), 6.40 (s, 1H), 4.82 (s, 2H), 4.11 (bs, 2H), 3.72 (bs, 3H), 3.67 (bs, 2H), 3.08 (s, 3H); for minor rotomer δ 6.15 (s, 1H), 5.02 (s, 2H), 2.96 (s, 3H); MS (ES) m/e 363 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([Cl:11])=[CH:6][C:5]=1[N:12]([C:13]([O:15][CH:16]([CH3:17])[CH3:18])=[O:14])[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)c1cc(Br)c(Cl)cc1NC(=O)OC(C)C
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCCN(C(=O)OC(C)C)c1cc(Cl)c(Br)cc1C(=O)OC
Temperature: 60 °C
Yield: 85.8 %

Procedure:
To a mixture of 5-Bromo-4-chloro-2-isopropoxycarbonylamino-benzoic acid methyl ester (2.52 g, 7.19 mmol) and cesium carbonate (4.68 g, 14.4 mmol) in DMF (35 ml) under nitrogen was added methyl 4-bromobutyrate (2.60 g, 14.4 mmol) dropwise. The reaction mixture was heated to 60° C. for 4 hours and then cooled to room temperature. The mixture was diluted with ethyl acetate (100 ml), and then washed with 0.1N HCl(aq) (100 ml) and brine (3×100 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel chromatography (gradient eluent, 0-20% ethyl acetate in hexane) provided 5-Bromo-4-chloro-2-[isopropoxycarbonyl-(3-methoxycarbonyl-propyl)-amino]-benzoic acid methyl ester (2.78 g, 86%) as oil. MS (ES+): 450, 452 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([O:17][CH3:18])[CH:9]=1.Cl.[CH2:20]([NH:27][C@H:28]1[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]1[F:34])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(N(C)C)=O>[CH2:20]([NH:27][C@H:28]1[CH2:33][CH2:32][N:31]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([O:17][CH3:18])[CH:9]=2)[CH2:30][C@H:29]1[F:34])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: F[C@@H]1CNCC[C@@H]1NCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC[C@H](NCc3ccccc3)[C@H](F)C2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 59.9 %

Procedure:
DMA (60 ml) and potassium carbonate (5.65 g, 40.86 mmol) were added to the flask containing 4-fluoro-2-methoxy-1-nitrobenzene (1.748 g, 10.22 mmol) and (3R,4S)—N-benzyl-3-fluoropiperidin-4-amine HCl salt (INTERMEDIATE 46, 2.5 g, 10.22 mmol). The reaction was heated to 120° C. for 5 h. The reaction mixture was cooled to rt, and filtered. The filtrate was diluted with EtOAc (50 ml) and the solution was washed with brine (2×100 ml). The organic layer was dried over Na2SO4, filtered, and concentrated to give a crude yellow liquid. It was purified using silica gel chromatography (80-100% EtOAc/hexane) to give the title product (2.200 g, 59.9%). m/z 361.
Reaction SMILES: O[Li].O.C[O:5][C:6]([C:8]1([C:12]2[CH:49]=[CH:48][CH:47]=[CH:46][C:13]=2[CH2:14][CH2:15][C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH:33]4[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]4)=[CH:29][CH:28]=3)[N:17]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7].O.C(Cl)Cl>C1COCC1>[C:42]([O:41][C:39]([N:36]1[CH2:35][CH2:34][CH:33]([C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:18]3[N:17]=[C:16]([CH2:15][CH2:14][C:13]4[CH:46]=[CH:47][CH:48]=[CH:49][C:12]=4[C:8]4([C:6]([OH:7])=[O:5])[CH2:11][CH2:10][CH2:9]4)[C:21]([C:22]([F:24])([F:23])[F:25])=[CH:20][N:19]=3)=[CH:32][CH:31]=2)[CH2:38][CH2:37]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: COC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)CCC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(=O)O)CCC4)n3)cc2)CC1

Procedure:
LiOH.H2O (41 mg, 0.97 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(1-(methoxycarbonyl)cyclobutyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate A55 (31 mg, 0.049 mmol) in THF (5 mL) and H2O (0.5 mL) and the mixture was stirred at 40° C. overnight. Additional LiOH.H2O (400 mg, 9.53 mmol) was added and the mixture was heated at reflux for 12 days. Upon cooling DCM (50 mL) and water (50 mL) were added and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organics were dried (Na2SO4) and the volatiles were removed in vacuo to give the title compound A56 as a yellow oil (30 mg, 98%). LCMS-A: rt 7.586 min, m/z 625 [M+H]+.
Reaction SMILES: C([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]1[C:12]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])([CH3:16])[O:13][CH2:14][CH2:15][C:8]2=1)C.COC1C=C2C(C3CCOC(CNC(=O)C)(C)C=3N2)=CC=1.C1(COC2C=C3C(=CC=2)NC2C(CNC(=O)C)(C)OCCC3=2)C=CC=CC=1>>[CH3:16][C:12]1([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[C:9]2[NH:10][C:11]3[C:7]([C:8]=2[CH2:15][CH2:14][O:13]1)=[CH:6][CH:5]=[CH:4][CH:3]=3
Reactant: CCc1cccc2c3c([nH]c12)C(C)(CNC(C)=O)OCC3
Agent: CC(=O)NCC1(C)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Agent: COc1ccc2c3c([nH]c2c1)C(C)(CNC(C)=O)OCC3
Product: CC(=O)NCC1(C)OCCc2c1[nH]c1ccccc21

Procedure:
In the same manner but replacing indole-3-ethanol with an equivalent amount of 7-ethylindole-3-ethanol, 6-methoxyindole-3-ethanol or 5-phenylmethoxy-indole-3-ethanol, the following compounds of formula 11a are obtained, respectively: N-[(8-ethyl-1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)methyl]-acetamide, N-[(7-methoxy-1,3,4,9-tetrahydro-1methylpyrano-[3,4-b]indol-1-yl)methyl]-acetamide and N-[(6-phenylmethoxy-1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)methyl]-acetamide.
Reaction SMILES: C[O:2][C:3](=[O:13])[CH:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].C(OCC)(=O)C.[OH-].[Na+]>O>[NH2:5][C@H:4]([C:3]([OH:13])=[O:2])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C(N)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
A mixture of 1.15 grams of D,L-phenylalanine methyl ester in 2.5 milliliters of water was added to 5.0 milliliters of ethyl acetate. The pH was adjusted to 6.5 with 2.5 milliliters of sodium hydroxide. Two milligrams of chymotrypsin was added and the reaction was stirred gently at room temperature. A white precipitate appeared after 1.5 hours. The precipitate was isolated after 2 hours yielding 0.22 grams with an optical rotation equivalent to 98% pure L-phenylalanine.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:40])([F:39])[CH:26]([F:38])[O:27][C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])[CH:6]=1)(=O)[CH3:2].[H-].[Na+].Br[CH2:44]C#C.O>CN(C)C=O.C(OCC)(=O)C>[F:23][C:11]1[CH:12]=[C:13]([CH3:22])[C:14]([S:16][CH2:17][C:18]([F:19])([F:20])[F:21])=[CH:15][C:10]=1[N:9]1[C:5]([NH:4][CH2:1][C:2]#[CH:44])=[CH:6][C:7]([O:24][C:25]([F:39])([F:40])[CH:26]([F:38])[O:27][C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30]([F:31])([F:32])[F:33])=[N:8]1
Reactant: CC(=O)Nc1cc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCNc1cc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
0.7 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(heptafluoropropoxy)ethoxy}pyrazole was dissolved in 5 mL of dimethylformamide, and under cooling with ice, the solution was dropwise added to a suspension having 50 mg of sodium hydride suspended in 10 mL of dimethylformamide, and after completion of the dropwise addition, stirring was carried out at room temperature for 30 minutes. The reaction solution was cooled with ice again, and 0.15 g of 1-bromo-2-propyne was added, followed by stirring at room temperature for 1 hour. Then, the reaction mixture was poured into water, extraction with ethyl acetate was carried out, and after washing with water, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was dissolved in 20 mL of ethanol, and 20 mL of a 35mass % hydrochloric acid aqueous solution was added, followed by stirring under reflux with heating for 2 hours. The reaction mixture was poured into water, extraction with ethyl acetate was carried out, and after washing with water, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 0.3 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-(2-propynylamino)-3-{1,1,2-trifluoro-2-(heptafluoropropoxy)ethoxy}pyrazole.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:31][CH:30]=1)[C:9](=[O:28])[NH:10][C@H:11]([C:17](=[O:27])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=1[F:26])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])(C)(C)C.Cl.O1CCOCC1>C(#N)C>[F:26][C:20]1[CH:21]=[C:22]([I:25])[CH:23]=[CH:24][C:19]=1[NH:18][C:17](=[O:27])[C@@H:11]([NH:10][C:9](=[O:28])[C@H:8]([NH2:7])[C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:33][CH:34]=1)[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C[C@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(OCCOC(C)(C)C)cc1)C(=O)Nc1ccc(I)cc1F
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: CC(C)(C)C[C@H](NC(=O)[C@H](N)c1ccc(OCCOC(C)(C)C)cc1)C(=O)Nc1ccc(I)cc1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a solution of {(R)-[4-(2-tert-butoxy-ethoxy)-phenyl]-[(S)-1-(2-fluoro-4-iodo-phenylcarbamoyl)-3,3-dimethyl-butylcarbamoyl]-methyl}-carbamic acid tert-butyl ester (652 mg, 0.91 mmol) in acetonitrile (6 mL) was added 4 N hydrogen chloride in dioxane (1 mL, 4 mmol) and the mixture stirred at 40° C. for 30 minutes. The reaction mixture was concentrated in vacuo and the residue suspended in ice cold water. The aqueous suspension was neutralized to basic pH with saturated aqueous sodium carbonate solution then extracted with dichloromethane (three times). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo and the residue purified by chromatography over silica gel gradient eluted from 100% dichloromethane up to 10% methanol/90% dichloromethane in 30 minutes. Concentration of the product containing fractions gave (S)-2-{(R)-2-amino-2-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetylamino}-4,4-dimethyl-pentanoic acid (2-fluoro-4-iodo-phenyl)-amide (490 mg, 87%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][NH:4][S:3]1(=[O:8])=[O:7].[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.O>CN(C)C=O>[O:7]=[S:3]1(=[O:8])[N:2]([CH3:1])[CH2:6][CH2:5][N:4]1[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CN1CCNS1(=O)=O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68.5 %

Procedure:
To a solution of 2-methyl-1,2,5-thiadiazolidine-1,1-dioxide (2.02 g, 14.8 mmol) in anhydrous dimethylformamide (30 ml) was added sodium hydride (60% dispersion in oil; 0.59 g) and the mixture was stirred at room temperature under nitrogen for 40 minutes. A solution of 1-fluoro-4-nitrobenzene (2.09 g, 14.8 mmol) in anhydrous dimethylformamide (15 ml) was added to the above solution and the mixture was refluxed for 1 hour. Water (200 ml) was added and products were extracted with ethyl acetate (2×150 ml), dried (MgSO4) and concentrated to an orange solid. Crystallisation from ethyl acetate (150 ml) afforded 2.61 g (68.7%) of the title compound as a pale orange solid; mp 155°-163° C.; δH (250 MHz, DMSO-d6) 8.29 (2H, d, J=9.3 Hz, Ar--H), 7.34 (2H, d, J=9.3 Hz, Ar--H), 4.00 (2H, t, J=6.4 Hz, --CH2 --), 3.57 (2H, t, J=6.4 Hz, --CH2 --), 2.78 (3H, s, --CH3); m/z (EI) 257 (M+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7](F)[C:3]=1[C:4]([OH:6])=[O:5].Cl.CN.[CH2:16]([N:18](CC)CC)C>N1C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH:18][CH3:16])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(F)cc(F)cc1F
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: c1ccncc1
Product: CNc1cc(F)cc(F)c1C(=O)O
Temperature: 110 °C
Reaction time: 15 h
Yield: 91.4 %

Procedure:
To a solution of 2,4,6-trifluorobenzoic acid (6.0 g, 34.1 mmol) and methylamine hydrochloride (12.0 g, 170 mmol) in pyridine (24 mL), triethylamine (24 mL, 170 mmol) was added. The reaction was stirred at 110° C. for 15 h and then concentrated in vacuo. The residue was acidified with 1N HCl (100 mL). The precipitate was collected by filtration to give 5.83 g of clean desired product as an orange solid (91%). 1H NMR (400 MHz, DMS O-d6): δ 13.09 (s, 1H), 7.91 (s, 1H), 6.33 (s, 1H), 6.30 (s, 1H), 2.81 (s, 3H). MS (ES) [m+H] calc'd for C8H7F2NO2, 188; found 188.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:33])[N:4]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:24][CH:23]=2)=[O:21])[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3](=[O:33])[N:4]([CH2:19][CH:20]([C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:24][CH:23]=2)[OH:21])[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:16])[CH3:17])[C@H:10]1[CH3:18]
Reactant: CCN(CC)c1ccc(C(=O)Cn2ncc(N[C@@H]3C[C@@H]4C[C@H]([C@H]3C)C4(C)C)c(Cl)c2=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(C(O)Cn2ncc(N[C@@H]3C[C@@H]4C[C@H]([C@H]3C)C4(C)C)c(Cl)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.2 %

Procedure:
4-Chloro-2-{2-[4-(diethylamino)phenyl]-2-oxoethyl-}-5-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one (42 mg, 0.0891 mmol) in tetrahydrofuran (2 mL) was added dropwise to lithium aluminum hydride (11 mg, 0.315 mmol) in tetrahydrofuran (2 mL) at 0° C. and stirred at room temperature for 10 minutes. After completion of the reaction, the reaction solution was mixed with aqueous sodium hydroxide, anhydrous, sodium sulfate, then filtered and evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (hexane/ethyl acetate=1/1) to give the desired product (14 mg, 33% yield).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(Br)c2)[C@H](c2ccccc2)C1
Reactant: CN1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CCN(c2cccc([C@H]3CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)C[C@H]3c3ccccc3)c2)CC1
Yield: 37.9 %

Procedure:
To a solution of rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(3-bromo-phenyl)-3-phenyl-piperidin-1-yl]-methanone (500 mg, 0.899 mmol) in 5 mL dry toluene was added 1-methyl-piperazine (0.123 mL, 1.08 mmol), sodium tert.-butoxide (125 mg, 1.26 mmol), bis(dibenzylidenacetone)palladium (2.1 mg, 0.002 mmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.3 mg, 0.007 mmol) and than refluxed overnight. The reaction mixture was diluted with 10 mL water and extracted three times with 20 mL ethyl acetate. Organic phases were pooled, dried with magnesium sulfate and evaporated. Flash chromatography on silica gel with hexane/ethyl acetate/triethyl amine 10:10:1 gave the desired product (196 mg, 38%), MS: m/e=576.1 (M+H+).