Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([NH:13]S(C(C)(C)C)=O)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO.C(=O)([O-])[O-].[K+].[K+]>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([NH2:13])[C:9]([F:10])([F:11])[F:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(=O)NC(c1ccc(Br)nc1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: NC(c1ccc(Br)nc1)C(F)(F)F

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid [1-(6-bromo-pyridin-3-yl)-2,2,2-trifluoro-ethyl]amide (1.17 g, 3.26 mmol) in methanol (15 mL) was added a 4 N solution of HCl in dioxane (2 mL, 8.0 mmol). The reaction was monitored by TLC (ethyl acetate-hexanes 3:7). The mixture was diluted with saturated aqueous potassium carbonate and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (3×15 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography eluting with ethyl acetate-hexanes (1:9, then 2:8) to afford the title compound as a clear oil.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:11](OCCN1CCNCC1)C#C>>[CH3:11][O:10][CH2:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C#CCOCCN1CCNCC1
Reactant: OCCCN1CCNCC1
Product: COCCCN1CCNCC1

Procedure:
The title compound was prepared from 1-piperazinepropanol in the same manner as in Preparation Example 9(1) to (4).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8][OH:9].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8][O:9][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1
Reactant: Cc1cccc(CCO)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(CCOc2ccc([N+](=O)[O-])cn2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of 4.8 g of sodium hydride (50% oily suspension) in 130 ml of dimethylformamide, was added dropwise 13.6 g of 3-methylphenethyl alcohol in 20 minutes, and the resultant mixture was heated at 60° C. for 2 hours. After cooling, a solution of 15.9 g of 2-chloro-5-nitropyridine in 80 ml of dimethylformamide was added dropwise thereto at a temperature below 20° C. under ice-cooling. After standing at room temperature overnight, the reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The extracts were washed with water and dried over magnesium sulfate. The oily products were purified by column chromatography on silica gel using benzene as an eluent to give 20.4 g of 2-(3-methylphenethyloxy)-5-nitropyridine as white crystals. M.P., 73.5°-74.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[CH:9][C:10](=O)[C:3]=12.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl>C(O)C>[ClH:24].[NH:22]([N:23]=[C:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:9]1)[C:19]([NH2:21])=[NH:20]
Reactant: Cc1ccccc1C1=CC(=O)c2c(C)ccnc21
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1C1=CC(=NNC(=N)N)c2c(C)ccnc21
Yield: 71.8 %

Procedure:
A mixture of 4-methyl-7-(2-methylphenyl)-5-oxo-cyclopenta[2,1-b]pyridine (48 mg), aminoguanidine hydrochloride (25 mg) and concentrated hydrochloric acid (40 mg) in ethanol (1 ml) was refluxed for 2 hours. The reaction solution was cooled, and precipitated crystals were filtered, washed with ethanol and dried to give 5-guanidinoimino-4-methyl-7-(2-methylphenyl)cyclopenta[2,1-b]pyridine hydrochloride (Compound 91) (48 mg) as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=2F)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][CH3:32])(=[O:30])[CH2:28][SH:29].C1COCC1.[H-].[Na+]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([OH:26])[CH:28]([C:27]([O:31][CH3:32])=[O:30])[S:29][C:16]3[C:17]([C:21]([F:22])([F:24])[F:23])=[CH:18][CH:19]=[CH:20][C:15]2=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CS
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cccc(C(F)(F)F)c2F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1Sc2c(C(F)(F)F)cccc2C1(O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 55 °C
Reaction time: 1.67 h
Yield: 56 %

Procedure:
To a room temperature solution of 4-(2-fluoro-3-trifluromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (9.00 g, 24.0 mmol), methyl thioglycolate (2.40 mL, 26.8 mmol), and anhydrous THF (200 mL) under nitrogen was added NaH (1.15 g of a 60% oil dispersion, 28.7 mmol) in one portion. After the gas evolution ceased, the reaction was stirred at 55° C. After 100 min, the reaction was cooled to room temperature and diluted with ethyl acetate (500 mL). The mixture was washed with water (300 mL) and brine (300 mL) successively, dried over magnesium sulfate, filtered, and the solvent removed to afford a sticky white solid. Trituration with 20% ethyl acetatetheptane afforded 6.20 g (56%) of the desired product as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19](O)[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:25][C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>>[O:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[S:25][CH:19]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:13][CH:14]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: Sc1nc2ccccc2o1
Reactant: COC(=O)C(O)Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Product: COC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)Sc1nc2ccccc2o1
Yield: 115.1 %

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using methyl 3-[4-(2-t-butoxycarbonylaminoethoxy)phenyl]-2-hydroxypropionate (415 mg), which is obtained in a similar manner to that described in Reference example 39(a), 2-mercaptobenzoxazole (277 mg), tributylphosphine (0.46 ml) instead of triphenylphosphine and 1,1′-(azodicarbonyl)dipiperidine (460 mg) instead of diethylazodicarboxylate and the reaction mixture was treated to afford the desired compound (665 mg) as a colorless oil which contained some impurities.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([N:8]([CH:9]2[CH2:10][CH2:11]2)[S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1NC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(c2ccc(Cl)cc2[N+](=O)[O-])C2CC2)cc1
Temperature: 25 °C
Yield: 60.9 %

Procedure:
To a suspension of sodium hydride (60%, 0.10 g (2.50 mmol)) in DMF (3.0 ml), 4-chloro-N-cyclopropyl-2-nitroaniline (0.40 g (1.88 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, p-toluenesulfonyl chloride (0.38 g (1.99 mmol)) was added. After one hour's stirring at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography with ethyl acetate-hexane (1:3) as eluent, to give 0.42 g (61%) of the title compound as yellow crystals
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]([N:16]([CH3:18])[CH3:17])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:19][C:20]([F:36])([F:35])[C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29]([OH:31])=[O:30])[N:22]=1.[ClH:37]>O1CCOCC1>[CH3:17][N:16]([CH3:18])[CH:13]([C:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:9][CH:10]=1)[CH2:14][NH:15][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([C:23]2[N:22]=[C:21]([C:20]([F:36])([F:35])[F:19])[O:25][N:24]=2)[CH:27]=1.[ClH:37].[CH3:17][N:16]([CH3:18])[CH:13]([C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:9][CH:10]=1)[CH2:14][NH:15][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([C:23]2[N:22]=[C:21]([C:20]([F:19])([F:36])[F:35])[O:25][N:24]=2)[CH:27]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CN(C)C(CN)c1coc(-c2ccc(F)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccc(F)cc2)n1

Procedure:
N-(2-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide was synthesized from 1-(2-(4-fluorophenyl)oxazol-4-yl)-N1,N1-dimethylethane-1,2-diamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6. The free base was then stirred with HCl in dioxane solution (4 mL) for 0.5 h at 0° C. to room temperature. The reaction mixture was concentrated and triturated with diethyl ether to afford N-(2-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide hydrochloride (130 mg, yield 16%) as light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (br s, 1H), 9.18-9.15 (t, J=5.6 Hz, 1H), 8.55-8.54 (m, 2H), 8.27-8.25 (m, 1H), 8.21-8.19 (m, 1H), 8.11-8.07 (m, 2H), 7.79-7.75 (t, J=7.8 Hz, 1H), 7.45-7.41 (t, J=8.9 Hz, 2H), 4.84-4.81 (t, J=6.1 Hz, 1H), 4.20-4.13 (m, 1H), 3.87-3.82 (m, 1H), 2.87-2.84 (dd, J=6.9 Hz, 5.0 Hz, 6H). MS (ESI) m/z: Calculated for C23H19F4N5O3: 489.14. found: 490.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1([CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)[C:9](O)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:25][C:26]([O:29][C:30]([NH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:31])([CH3:28])[CH3:27]>>[OH:1][C:2]1([CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:13]=2)[C:9]([N:36]2[CH2:35][CH2:34][CH:33]([NH:32][C:30](=[O:31])[O:29][C:26]([CH3:25])([CH3:27])[CH3:28])[CH2:38][CH2:37]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)C(c1cccc(Oc2ccccc2)c1)C1(O)CCCCC1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)C(c2cccc(Oc3ccccc3)c2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 1′ step 1, tert-butyl (1-{(1-hydroxycyclohexyl)[3-(phenoxy)phenyl]acetyl}piperidin-4-yl)carbamate was prepared from (1-hydroxycyclohexyl)[3-phenoxyphenyl]acetic acid (Reference Example 1-ccc) and 4-N-BOC-aminopiperidine. MS (ESI) m/z 509 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[C:3]=1[C:17]#[N:18].C(O[CH:22](OCC)[N:23]([CH3:25])[CH3:24])C>C1(C)C=CC=CC=1>[C:17]([C:3]1[C:4]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH3:16])=[CH:12][CH:13]=2)=[N:5][NH:6][C:2]=1[N:1]=[CH:22][N:23]([CH3:25])[CH3:24])#[N:18]
Reactant: CCOc1ccc(Nc2n[nH]c(N)c2C#N)cc1
Reactant: CCOC(OCC)N(C)C
Solvent: Cc1ccccc1
Product: CCOc1ccc(Nc2n[nH]c(N=CN(C)C)c2C#N)cc1
Temperature: 20 °C

Procedure:
A suspension of 4.86 g (19.98 mmol) of 5-amino-4-cyano-3-(4-ethoxy-phenylamino)-pyrazole in 3.94 ml (23 mmol) of N,N-dimethylformamide diethyl acetal and 60 ml of toluene is heated under reflux for 2 hours. The reaction mixture is then cooled to 20° C. and filtered and the filter residue is washed with toluene, yielding the title compound; m.p. 246-247° C. (decomp.).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:28]2[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=2)([OH:27])[CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:37].[Na+]>CO.O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:28]2[CH:29]=[CH:30][C:31]([S:34]([CH3:35])=[O:37])=[CH:32][CH:33]=2)([OH:27])[CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSc1ccc(C(O)(CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)c1ccc(C(O)(CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.8 %

Procedure:
To a stirred solution of 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-1-(4-methylsulfanyl-phenyl)-ethanol (5 g, 10 mmol) in methanol (100 mL) and water (30 mL) was added sodium metaperiodate (4.3 g, 20 mmol) at room temperature. The resulting mixture was stirred at room temperature for 18 h, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-1-(4-methaneylsulfinyl-phenyl)-ethanol (5.1 g, quant.) as a light yellow solid: LC/MS m/e calcd for C27H27FN2O4S2 [M+H]+ 527.65, observed 527.0.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.[F:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[C:31]([CH2:34]Cl)=[N:32][N:33]=[C:29]3[CH2:28][N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:25]=2[CH:42]=1>CC(N(C)C)=O>[F:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[C:31]([CH2:34][O:1][N:2]4[C:3](=[O:12])[C:4]5=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]5[C:6]4=[O:7])=[N:32][N:33]=[C:29]3[CH2:28][N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:25]=2[CH:42]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Fc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 1, N-hydroxyphthalimide and triethylamine in dimethylacetamide is treated with 8-fluoro-6-phenyl-1-(Chloromethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 8-fluoro-6-phenyl-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]([Sn:9](=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:19]([CH:21]([CH2:24][CH3:25])[CH2:22][OH:23])[CH3:20]>>[CH2:1]([Sn:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([O:23][CH2:22][CH:21]([CH2:24][CH3:25])[CH2:19][CH3:20])[O:18][Sn:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:23][CH2:22][CH:21]([CH2:24][CH3:25])[CH2:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[Sn](=O)CCCCCCCC
Reactant: CCC(CC)CO
Product: CCCCCCCC[Sn](CCCCCCCC)(OCC(CC)CC)O[Sn](CCCCCCCC)(CCCCCCCC)OCC(CC)CC
Temperature: 25 °C
Yield: 99 %

Procedure:
893 g (2.48 mol) of di-n-octyl tin oxide (Sankyo Organic Chemicals Co., Ltd., Japan) and 2403 g (23.6 mol) of 2-ethyl-1-butanol were placed in a 5000 mL volumetric pear-shaped flask. The flask was connected to an evaporator to which was connected an oil bath equipped with a temperature controller, a vacuum pump and a vacuum controller. The purge valve outlet of this evaporator was connected to a line containing nitrogen gas flowing at normal pressure. After closing the purge valve of the evaporator to reduce pressure inside the system, the purge valve was opened gradually to allow nitrogen to flow into the system and return to normal pressure. The oil bath temperature was set to about 165° C., the flask was immersed in the oil bath and rotation of the evaporator was started. After heating for about 40 minutes in the presence of atmospheric pressure nitrogen with the purge valve of the evaporator left open, distillation of 2-ethyl-1-butanol containing water began. After maintaining in this state for 7 hours, the purge valve was closed, pressure inside the system was gradually reduced, and excess 2-ethyl-1-butanol was distilled with the pressure inside the system at from 74 to 25 kPa. After the fraction no longer appeared, the flask was taken out of the oil bath. After allowing the flask to cool to the vicinity of room temperature (25° C.), the purge valve was opened gradually and the pressure inside the system was returned to atmospheric pressure. 1114 g of reaction liquid were obtained in the flask. Based on the results of 119Sn-, 1H- and 13C-NMR analyses, 1,1,3,3-tetra-n-octyl-1,3-bis(2-ethylbutyloxy) distannoxane was confirmed to have been obtained at a yield of 99% based on di-n-octyl tin oxide. The same procedure was then repeated 12 times to obtain a total of 13380 g of 1,1,3,3-tetra-n-octyl-1,3-bis(2-ethylbutyloxy) distannoxane.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11](CC)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Cl:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50](Cl)(=[O:52])=[O:51]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([S:50]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[Cl:43])(=[O:52])=[O:51])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(S(=O)(=O)c3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-chlorobenzene-1-sulfonyl chloride and isolated as brown solid. MS (m/e): 457.3 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[CH3:15][O-:16].[Na+]>CO>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:16][CH3:15])=[CH:3][C:4]=1[O:11][CH:12]([CH3:14])[CH3:13])([O-:10])=[O:9]
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(OC(C)C)c1
Temperature: 65 °C
Yield: 94.3 %

Procedure:
A mixture of 5.0 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene, 4.07 g of sodium methoxide and 200 mg of 18C6 in 100 ml of methanol is heated at 65° C. for 2 h. The mixture is then concentrated and the residue is taken up with a mixture of water and ethyl acetate. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over anhydrous magnesium sulfate, filtered and then concentrated to dryness under reduced pressure, so as to obtain 5.0 g of 1-nitro-4-methoxy-2-(propan-2-yloxy)benzene.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.O1[C:16]2([CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[NH:30][C:31]3[C:32]4[C:39]([CH3:40])=[C:38]([C:41]([O:43][CH3:44])=[O:42])[S:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:18][CH2:17]2)[O:15]CC1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O>[F:29][C:27]1[CH:26]=[CH:25][C:24]([NH:30][C:31]2[C:32]3[C:39]([CH3:40])=[C:38]([C:41]([O:43][CH3:44])=[O:42])[S:37][C:33]=3[N:34]=[CH:35][N:36]=2)=[C:23]([O:22][CH:19]2[CH2:20][CH2:21][C:16](=[O:15])[CH2:17][CH2:18]2)[CH:28]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCC4(CC3)OCCO4)c2c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCC(=O)CC3)c2c1C

Procedure:
1.000 g p-toluenesulfonic acid was added to 0.500 g methyl 4-(2-(1,4-dioxaspiro[4.5]decan-8-yloxy)-4-fluorophenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (cpd.19.1) in 10 ml THF and 5 ml water. After refluxing overnight the reaction mixture was adjusted to pH 8 using aq. Na2CO3. The aq. layer was extracted with chloroform. The combined extracts were passed through a hydrophobic frit and concentrated to give the desired compound.
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:20][CH2:19][N:18](CC2C=CC=CC=2)[CH2:17][C@@H:16]1[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)C1C=CC=CC=1>ClC(Cl)C>[C:32]([C:31]1[CH:30]=[CH:29][C:28]([C@H:16]2[CH2:17][NH:18][CH2:19][CH2:20][NH:15]2)=[CH:35][CH:34]=1)#[N:33]
Reactant: N#Cc1ccc([C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: N#Cc1ccc([C@H]2CNCCN2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
1-Chloroethyl chloroformate (2.7 g, 18.9 mmol) was added to a solution of 4-((2S)-1,4-dibenzylpiperazin-2-yl)benzonitrile (1.4 g, 3.81 mmol) in dichloroethane (30 ml). The reaction mixture was vigorously stirred at room temperature for 10 hours. The solvent was evaporated under reduced pressure and methanol (40 ml) was added to the residue. The mixture was heated at 80° C. for one hour and the solvent was evaporated under reduced pressure to afford (2S)-2-(4-cyanophenyl)piperazine as white crystals. Di-tert-butyl di-carbonate (1.9 g, 8.71 mmol) was added to a solution of triethylamine (1.2 g, 11.9 mmol) and (2S)-2-(4-cyanophenyl)piperazine in tetrahydrofuran (50 ml) at room temperature and the mixture was stirred at 50° C. for one hour. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 10-20% ethyl acetate in hexane to furnish di-tert-butyl
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:14][CH:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:6]
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)NC(CO)Cc1ccccc1
Yield: 87 %

Procedure:
5 g (27.6 mmol) of 2-methyl-5-nitrobenzoic acid were reacted with (S)-2-amino-3-phenyl-1-propanol by the method of procedure 3c. 7.5 g (87%) of the product were obtained.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[N:22][CH:23]=2)[CH2:14][C@H:13]1[O:29][CH3:30])=O)C1C=CC=CC=1>[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[N:22][CH:23]=2)[CH2:14][C@H:13]1[O:29][CH3:30]
Reactant: CCOC(=O)c1cncc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)c1
Agent: [Pd]
Product: CCOC(=O)c1cncc(N2CC[C@H](N)[C@H](OC)C2)c1
Yield: 46.7 %

Procedure:
The same operation as in Example (160c) was performed using methyl cis(±)-4-(4-{[benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)pyridine-2-carboxylate obtained in Example (162a) (436 mg) and a 10% palladium-carbon catalyst (500 mg), to obtain 137.5 mg of the title compound as a colorless oily substance. The resulting compound was used for the next reaction without purification.