Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[C:19]#[N:20])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(OCC)(=O)C>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6]([C:7]1[N:8]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[C:9]2[C:10]([C:19]=1[NH2:20])=[CH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)=[O:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNc1ccc(C(F)(F)F)cc1C#N
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(N)c2cc(C(F)(F)F)ccc2n1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 35.1 %

Procedure:
To a solution of (2-cyano-4-trifluoromethylphenylamino)acetic acid tert-butyl ester 5B (11.7 g, 39.0 mmol) in anhydrous THF (60 mL) and anhydrous DMF (60 mL) at 0° C. was added potassium tert-butoxide (8.74 g, 78.0 mmol). The reaction mixture was stirred at 0° C. for 5 minutes and benzyl chloroformate 5C (10 g, 58.7 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. Ethyl acetate (500 mL) was added and the organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to provide 3-amino-1-benzyloxycarbonyl-5-trifluoromethylindole-2-carboxylic acid tert-butyl ester 5D (5.96 g, 13.7 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]#[C:25][CH2:26][CH3:27])[CH2:6][O:7][N:8]1C(=O)C2C(=CC=CC=2)C1=O.O.NN.Cl.O>CO.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]#[C:25][CH2:26][CH3:27])[CH2:6][O:7][NH2:8]
Reactant: CCC#CCOc1ccc(CON2C(=O)c3ccccc3C2=O)cc1OC
Agent: Cl
Agent: NN
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CCC#CCOc1ccc(CON)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(3-Methoxy-4-pent-2-ynyloxy-benzyloxy)-isoindole-1,3-dione (27 g, 74 mmol) is suspended in a mixture of 500 ml of methanol and 50 ml of N,N-dimethylformamide. After heating this mixture to +60° C., hydrazine hydrate (8.5 g, 0.17 mol) is added. The reaction is stirred for 3 hours at +60° C. and subsequently cooled down to room temperature. A mixture of 28 ml of concentrated hydrochloric acid and 80 ml of water is added to acidify the resulting suspension. Then it is filtered to remove a precipitation and the solid is washed with water/methanol. The filtrate is concentrated in vacuo to one third of its original volume. Sodium hydroxide (18 g, mol in 90 ml water) is added to the remainder and this mixture is extracted with diethyl ether. The combined organic layer is washed with water and brine, dried over magnesium sulfate and evaporated to give O-(3-methoxy-4-pent-2-ynyloxy-benzyl)-hydroxylamine as yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([N+:20]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl>CO>[NH2:20][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:17]([O:18][CH3:19])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)c(N)cc1OCc1ccccc1

Procedure:
A solution of 4-benzyloxy-5-methoxy 2-nitrobenzoic acid (18.18 g, 60 mmol)(D. E. Thurston et al., Synthesis (1990), 81) and SnCl2.2H2O (137 g, 0.6 mol) (Showa Chemical Company, Japan) in MeOH (800 mL) was stirred at 70° C. for 5 h. The mixture was concentrated under vacuum to a thick syrup. Ethyl acetate (300 mL) was then added. The organic phase was washed with water until it turned to a clear solution, then washed with brine, and dried over MgSO4. After removal of solvent, the crude was recrystallized from ethyl acetate to obtain the title compound in the form of a yellow solid with a yield of 15.1 g (92%).
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:19][CH2:20][CH3:21])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)[C:6]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[C:7]1[CH2:19][CH2:20][CH3:21]
Reactant: CCCc1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C
Reactant: Clc1ccccc1CBr
Product: CCCc1c(C(=O)C(C)C)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl

Procedure:
Methyl 1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole-6-carboxylate (533 mg) was prepared from methyl 3-isobutyryl-2-propylindole-6-carboxylate (440 mg, and 2-chlorobenzyl bromide (346 mg) in a similar manner to that of Example 1.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][C@@H:17]([O:41][C:42]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[CH2:56][CH2:55][C:54]4[CH:57]=[CH:58][CH:59]=[CH:60][C:53]=4[NH:52][C:51]3=[O:61])[CH2:46][CH2:45]2)=[O:43])[C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][C:36](=[O:40])[N:37]([CH3:39])[CH3:38])=[O:33])[CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[CH:11][C:10]=1[CH3:62])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[OH:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][C@@H:17]([O:41][C:42]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[CH2:56][CH2:55][C:54]4[CH:57]=[CH:58][CH:59]=[CH:60][C:53]=4[NH:52][C:51]3=[O:61])[CH2:46][CH2:45]2)=[O:43])[C:18]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][C:36](=[O:40])[N:37]([CH3:39])[CH3:38])=[O:33])[CH2:28][CH2:27]3)[CH2:24][CH2:25]2)=[O:19])=[CH:11][C:10]=1[CH3:62]
Reactant: [H][H]
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC(C(=O)OCC(=O)N(C)C)CC3)CC2)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC(C(=O)OCC(=O)N(C)C)CC3)CC2)cc(C)c1O

Procedure:
95 mg (0.11 mmol) dimethylcarbamoylmethyl 1′-{(R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-4-carboxylate in 10 mL THF were combined with 50 mg 10% Pd/C and hydrogenated at 50° C. and 50 psi hydrogen for 6 h. The catalyst was removed by suction filtering and the solvent was concentrated by evaporation i.vac. The residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: C[CH:2](Cl)[C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])=[O:4].[CH3:22][CH:23]([NH2:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O1CCOC[CH2:33]1>C(OCC)C>[ClH:20].[C:25]1([CH2:24][CH:23]([CH3:22])[NH:31][CH2:2][C:3]([N:5]([C:6]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=2[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH3:33])=[O:4])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(Cl)C(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CC(N)Cc1ccccc1
Reactant: C1COCCO1
Solvent: CCOCC
Product: CC(Cc1ccccc1)NCC(=O)N(C)c1ccc(Cl)cc1C(=O)c1ccccc1
Product: Cl
Yield: 58 %

Procedure:
8 g of 2-(methyl-chloroacetamido)-5-chlorobenzophenone and 6.8 g of DL-amphetamine (= DL 1-phenyl-2-aminopropane) in 150 ml of anhydrous dioxan are heated to reflux for 4 hours whilst stirring. The turbid solution is filtered after cooling and evaporated in vacuo and the oily residue is triturated with three times 100 ml of water and dried in vacuo. The oily crude base (8.3 g) thus obtained is dissolved in 400 ml of anhydrous diethyl ether and filtered. 6.5 g of DL-2-(5-phenyl-N-methyl-4-methyl-3-aza-pentanamido)-5-chlorobenzophenone hydrochloride (58% of theory), with a melting point of 132°-135°, are obtained by passing in dry hydrogen chloride gas.
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH:13]1([C:16](Cl)=O)[CH2:15][CH2:14]1.C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.O>[CH:13]1([C:16]2[O:12][C:11]3[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=3)[N:2]=2)[CH2:15][CH2:14]1
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: O=C(Cl)C1CC1
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)c1cccc2oc(C3CC3)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.4 %

Procedure:
To a mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (0.25 g, 1.07 mmol) and cyclopropanecarbonyl chloride (0.10 mL, 1.07 mmol) in dichloromethane (8 mL) was added triethylamine (0.60 mL, 4.28 mmol) dropwise, then the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with dichloromethane, and then washed with 2 N HCl. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in toluene (8 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (204 mg, 1.07 mmol). The reaction mixture was then heated to reflux for 5 h. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was separated then washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel, 9:1 to 3:1 ethyl acetate/methanol) to afford 2-cyclopropylbenzoxazole-4-carboxylic acid (0.14 g, 65%) as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 12.92 (br s, 1H), 7.85 (dd, J=8.0, 0.6 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 2.37-2.31 (m, 1H), 1.26-1.16 (m, 4H); MS (ESI+) m/z 204 (M+H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[CH:8]1([CH2:12][N:13]([CH2:26][CH3:27])[C:14]2[C:23]([CH:24]=O)=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:11][CH2:10][CH2:9]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH:8]1([CH2:12][N:13]([CH2:26][CH3:27])[C:14]2[C:23]([CH2:24][NH:7][C:4]3[CH:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: CCN(CC1CCC1)c1nc2ccccc2cc1C=O
Reactant: Cc1cc(N)no1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCN(CC1CCC1)c1nc2ccccc2cc1CNc1cc(C)on1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.8 %

Procedure:
5-Methyl-isoxazol-3-ylamine (0.098 g, 1 mmol) was added to a solution of 2-(cyclobutylmethyl-ethyl-amino)-quinoline-3-carbaldehyde (0.268 g, 1 mmol) in anhydrous methanol (5 mL) and acetic acid (0.15 mL) under nitrogen. After being stirred for 15 minutes at ambient temperature, sodium cyanoborohydride (0.19 g, 3 mmol) was added slowly, and the reaction mixture was stirred overnight. Afterwards, the solvent was evaporated in vacuo, and water (30 mL) and ethyl acetate (30 mL) were added to the residue. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with 1-5% methanol in dichloromethane, to afford the title compound (0.150 g, yield: 43%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](OCCN)=[CH:33][C:32]=2[CH3:41])=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=O)C.[CH3:45][S:46]([NH:49][CH:50](OC1C=CC=CC=1)OC1C=CC=CC=1)(=[O:48])=[O:47].[NH2:65][CH2:66][CH2:67][OH:68]>O1CCCC1>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:68][CH2:67][CH2:66][NH:65][C:50]([NH:65][CH2:66][CH2:67][OH:68])=[N:49][S:46]([CH3:45])(=[O:47])=[O:48])=[CH:33][C:32]=3[CH3:41])=[C:28]([CH:42]([CH3:43])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CS(=O)(=O)NC(Oc1ccccc1)Oc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCN)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCCO
Solvent: C1CCOC1
Product: Cc1cc(OCCNC(=NS(C)(=O)=O)NCCO)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of dichlorophenoxymethane (1 g) in acetonitrile (10 mL) was added methanesulfonamide (0.39 g) under ice-cooling, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 1-(N-methanesulfonylamino)-1,1-diphenoxymethane (0.95 g). To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole (50 mg) in tetrahydrofuran (1 mL) was added 1-(N-methanesulfonylamino)-1,1-diphenoxymethane (26 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 2-aminoethanol (49 mg), and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (2 mL). To the solution was added sodium methoxide (28% methanol solution, 0.008 mL), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added acetic acid (0.01 mL). The resulting mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (38 mg).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H](C#N)[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-:22].[K+].[CH2:24]([OH:26])[CH3:25]>O>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:25]([C:24]([OH:22])=[O:26])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(CC[C@H]2CC[C@H](C#N)CC2)cc1
Reactant: CCO
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: CCCCCc1ccc(CC[C@H]2CC[C@H](C(=O)O)CC2)cc1

Procedure:
A mixture of 567 mg of trans-4-[2-(p-pentylphenyl)ethyl]cyclohexanecarbonitrile and 20 ml of a 10:1 mixture of 2N potassium hydroxide and ethanol was heated to reflux for 2 hours while gassing with argon in a round flask fitted with a reflux condenser. The cooled mixture was diluted with 20 ml of water and extracted twice with 30 ml of diethyl ether each time. The separated aqueous phase was acidified with about 20 ml of 2N sulphuric acid and extracted three times with 50 ml of diethyl ether each time. The organic phases were washed twice with 50 ml of saturated sodium chloride solution each time, dried over magnesium sulphate and concentrated. There were obtained 490 mg (81%) of trans-4-[2-(p-pentylphenyl)ethyl]cyclohexanecarboxylic acid as colourless crystals which were purified further by recrystallization from hexane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[CH:43]=[CH2:44])=[O:36])([CH3:33])([CH3:32])[CH3:31].C(N(CC)CC)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1P(C(C)(C)C)C(C)(C)C)(C)(C)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1/[CH:43]=[CH:44]/[C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH2:17][C:18](=[O:29])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:20]2(=[O:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: C=CC1CCCCN1C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C)C(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCCC1/C=C/c1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (120 mg, 0.22 mmol) in MeCN (2 mL) is added 2-vinylpiperidine-1-carboxylic acid tert-butyl ester (51 mg, 0.242 mmol), triethylamine (33 mg, 0.33 mmol), 2,2′-bis(di-t-butylphosphino)biphenyl (2.6 mg) and Pd(OAc)2 (1.0 mg). The vessel is flushed with nitrogen and the mixture is stirred at 100° C. for 4 h. The mixture is partitioned between EtOAc/water and the organic phase is washed with water, brine and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using a gradient of EtOAc/hexane (5 to 25%) as eluent to give the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(O)(=O)C>[F:15][C:16]([F:25])([F:26])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl piperidin-4-ylcarbamate (0.15 g, 0.75 mmol) and 3-(trifluoromethyl)benzaldehyde (0.12 mL, 0.156 mmol) in dichloroethane (5 mL) was added sodium triacetoxyborohydride (0.24 g, 1.12 mmol) and a few drops of acetic acid, and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with dichloroethane and washed with saturated aqueous NaHCO3 solution. The organic layer was separated, dried over MgSO4, and chromatographed on silica gel, eluting with 30% ethyl acetate/hexane to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.58 (s, 1H), 7.45 (m, 3H), 4.41 (m, 1H), 3.50 (m, 2H), 3.50 (m, 1H), 2.77 (d, J=12.21 Hz, 2H), 2.11 (t, J=11.70 Hz, 2H), 1.91 (d, J=11.53 Hz, 2H), 1.41 (s, 9H), 1.34 (m, 2H); MS (DCI) m/z 359 (M+H)+.
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].[NH:6]([C:13]1[N:18]=[C:17]([C:19]2[N:23]([CH:24]3[CH2:27][CH2:26][CH2:25]3)[C:22]([CH3:28])=[N:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:29]1([CH2:32][NH2:33])[CH2:31][CH2:30]1.Cl>S(Cl)(Cl)=O.CO.CCOCC>[CH:24]1([N:23]2[C:19]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH:6][C:7]4[CH:8]=[CH:9][C:10]([S:2](=[O:5])(=[O:3])[NH:33][CH2:32][CH:29]5[CH2:31][CH2:30]5)=[CH:11][CH:12]=4)[N:18]=3)=[CH:20][N:21]=[C:22]2[CH3:28])[CH2:27][CH2:26][CH2:25]1
Reactant: Cc1ncc(-c2ccnc(Nc3ccccc3)n2)n1C1CCC1
Reactant: NCC1CC1
Reactant: O=S(=O)(O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: CO
Product: Cc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)NCC4CC4)cc3)n2)n1C1CCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
Chlorosulphonic acid (150 μl, 2.16 mmol) was added dropwise to solution of 2-anilino-4-(1-cyclobutyl-2-methylimidazol-5-yl)pyrimidine (Method 61; 165 mg, 0.54 mmol) in thionyl chloride (3 ml), cooled to 0° C. and the mixture stirred at 0° C. for 10 minutes then heated at 90° C. for 90 minutes. The volatiles were removed by evaporation and the residue was dried under high vacuum (<2 mmHg) for 1 hour. The resulting solid was placed under nitrogen and a solution of cyclopropylmethylamine (700 μl, 8.1 mmol) in MeOH (3 ml) added. The mixture was stirred for 30 minutes and the volatiles were evaporated in vacuo. Water (20 ml) was added and the precipitated solid was collected by filtration, washed with water (2×10 ml). The solid was dissolved in MeOH and poured onto an Isolute amine column and eluted first with MeOH (30 ml). The solvent was evaporated in vacuo and the resultant foam triturated with ether. The solid was collected by filtration and washed with ether (2×10 ml) and dried under vacuum at 60° C. to yield a beige solid. The solid was slurried in ether (6 ml), 1M HCl in ether (2 ml, 2 mmol) and the solvent evaporated in vacuo. The resultant solid was triturated with ether, collected by filtration and dried in vacuo to yield the title compound (174 mg, 63%) as a hygroscopic solid. NMR: 0.05 (m, 2H), 0.34 (m, 2H), 0.79 (m, 1H), 1.70 (m, 2H), 2.37 (m, 4H), 2.62 (m, 2H), 2.75 (s, 3H), 5.40 (m, 1H), 7.23 (d, 1H), 7.54 (brs, 1H), 7.76 (d, 2H), 7.91 (d, 2H), 8.14 (s, 1H), 8.68 (d, 1H), 10.26 (brs, 1H); m/z 429.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO.O1CCCC1>[Si:1]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([OH:27])[CH3:26])=[CH:21][CH:20]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(O)c1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
5 g of the 1-(4-{[t-butyl(diphenyl)silyl]oxy}phenyl)-1-ethanone [79-1] was dissolved in a mixture solvent of 50 mL of methanol and 30 mL of tetrahydrofuran, 606 mg of sodium borohydride was added thereto, and stirred at room temperature for 3 hours. The reaction mixture was added with 30 mL of water, and concentrated under reduced pressure. The residue was added with 150 mL of ethyl acetate, washed with water and saturated brine in the subsequent order, and the obtained organic layer was dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to obtain 5.02 g of 1-(4-{[t-butyl(diphenyl)silyl]oxy}phenyl)-1-ethanol [79-2] as a colorless oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)C(OO)=O.[CH2:12]([N:14]([CH2:33][CH3:34])[C:15]([N:17]1[CH:21]=[C:20]([CH:22]([F:24])[F:23])[C:19](SC2C=CC=C(Cl)C=2)=[N:18]1)=[O:16])[CH3:13].[S:35]([O-:38])([O-])=[O:36].[Na+].[Na+]>ClCCCl>[CH2:33]([N:14]([CH2:12][CH3:13])[C:15]([N:17]1[CH:21]=[C:20]([CH:22]([F:23])[F:24])[C:19]([S:35]([C:4]2[CH:9]=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)(=[O:38])=[O:36])=[N:18]1)=[O:16])[CH3:34]
Reactant: CCN(CC)C(=O)n1cc(C(F)F)c(Sc2cccc(Cl)c2)n1
Reactant: O=S([O-])[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCCl
Product: CCN(CC)C(=O)n1cc(C(F)F)c(S(=O)(=O)c2cccc(Cl)c2)n1
Temperature: 50 °C
Yield: 87 %

Procedure:
250 mg of 3-chloroperoxybenzoic acid were added to a solution of 179 mg of 1-(diethylcarbamoyl)-3-(3-chlorophenylthio)-4-difluoromethylpyrazole [prepared as described in step (4) above] in 4 ml of 1,2-dichloroethane, and the resulting mixture was heated at 50° C. for 1.5 hours. At the end of this time, the reaction mixture was poured into an aqueous solution of sodium sulfite and extracted with methylene chloride. The extract was washed with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, eluted with an 8:1 by volume mixture of hexane and ethyl acetate, to afford 170 mg (yield 87%) of the title compound as an oil.