Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:20](CC)CC)C.ClC(OCC)=O>C(Cl)Cl>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([NH2:20])=[O:17])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)C1CCC(OCc2ccccc2)CC1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: NC(=O)C1CCC(OCc2ccccc2)CC1
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 96.9 %

Procedure:
To a solution of 4-(benzyloxy)cyclohexanecarboxylic acid (5.4 g, 23 mmol, 1.0 equiv) and triethylamine (4.82 mL, 34.57 mmol, 1.5 equiv) in DCM (dry, 40 mL) was added ethyl chloroformate (3.0 mL, 31.1 mmol, 1.35 equiv) dropwise between −20 and −10° C. under N2. The white precipitate appeared. The mixture was stirred at about −15° C. for 10 min, dried NH3 was bubbled rapidly into the liquid for 20 min. The mixture was stirred at −15° C. for 30 min, then put into the fridge (−20° C.) overnight. The flask was released the pressure and warm to room temperature. H2O (100 mL) was added. The layer was separated and the aqueous phase was extracted with DCM (3×100 mL). The combined organic solution was washed with brine (50 mL), dried over anhydrous Na2SO4, concentrated to give 5.2 g (96.7%) of 4-(benzyloxy)cyclohexanecarboxamide as a off-white solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:43])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:42])[CH2:21][CH2:22][NH:23][C:24]([C:26]3[C:27]([C:38]([F:41])([F:40])[F:39])=[N:28][N:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH3:37])[CH:30]=3)=O)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>C1COCC1.CO.O>[C:32]1([CH3:37])[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[N:29]1[CH:30]=[C:26]([CH2:24][NH:23][CH2:22][CH2:21][C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([C@H:10]3[CH2:9][CH2:8][C@H:7]([CH2:6][C:5]([OH:43])=[O:4])[CH2:12][CH2:11]3)=[CH:14][CH:15]=2)=[O:42])[C:27]([C:38]([F:41])([F:39])[F:40])=[N:28]1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3cn(-c4ccccc4C)nc3C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1-n1cc(CNCCC(=O)Nc2ccc([C@H]3CC[C@H](CC(=O)O)CC3)cc2)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
NaOH (52.6 mg, 1.3 mmol) was added to trans-[4-(4-{3-[(1-o-tolyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino]propionylamino}phenyl)cyclohexyl]acetic acid methyl ester (75 mg, 0.13 mmol) dissolved in THF/MeOH/water (20 mL, 3:2:1). The reaction mixture was stirred at 25° C. for 5 hours and concentrated under vacuum. The residue was acidified with 1M HCl up to pH of 2 and extracted with ethyl acetate. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was stirred with acetonitrile and filtered. The filtrate was eluted with a gradient of methanol/DCM (5-10%) on a silica gel by column chromatography and purified. Accordingly, the desired compound (70 mg, 96%) was obtained as a white solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](O)=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[N:21]2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C.ClCCl>[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([Cl:3])=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[N:21]2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 94.2 %

Procedure:
DMF (100 mL) was cooled to 0° C., and phosphorous oxychloride (27.5 mL, 0.295 mol) was added dropwise. The resulting solution was stirred for 25 minutes and then added dropwise to a mixture of 7-benzyloxy-3-nitroquinolin-4-ol (72.87 g, 0.2459 mol) in DMF (400 mL). Following the addition, the reaction was heated at 100° C. for 5 minutes, cooled to ambient temperature, and poured into ice water with stirring. A tan precipitate formed, which was isolated by filtration and dissolved in dichloromethane. The resulting solution was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 72.9 g of 7-benzyloxy-4-chloro-3-nitroquinoline as a light brown solid.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[CH:25]=[CH2:26].Cl>C(#N)C>[CH2:26]([N:15]1[CH2:16][CH2:17][CH:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])[C:2]=2[F:1])[CH2:13][CH2:14]1)[CH:25]=[CH2:24]
Reactant: C=CCBr
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CCC(c2cccc(S(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(methylsulfonyl)phenyl]piperidine (0.34 g, 1.32 mmol), acetonitrile (4 ml), potassium carbonate (0.34 g, 2.6 mmol) and allyl bromide (0.12 ml, 1.38 mmol). Yield: 0.2 g (51%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 259-261° C. MS m/z (relative intensity, 70 eV) 297 (M+, 87), 296 (82), 270 (bp, 268 (41), 133 (57).
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[C:27](=[O:28])[N:5]2[C:6]([C:24]([O-:26])=[O:25])=[C:7]([CH2:10][N+:11]3[N:12]([CH2:19][CH2:20][O:21]C=O)[C:13]([NH:16]C=O)=[CH:14][CH:15]=3)[CH2:8][S:9][C@H:4]12.C(OCC)(=O)C>CO>[ClH:1].[ClH:1].[ClH:1].[NH2:2][C@@H:3]1[C:27](=[O:28])[N:5]2[C:6]([C:24]([O-:26])=[O:25])=[C:7]([CH2:10][N+:11]3[N:12]([CH2:19][CH2:20][OH:21])[C:13]([NH2:16])=[CH:14][CH:15]=3)[CH2:8][S:9][C@H:4]12
Reactant: N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(NC=O)n3CCOC=O)CS[C@H]12
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cc[n+](CC2=C(C(=O)[O-])N3C(=O)[C@@H](N)[C@H]3SC2)n1CCO
Reaction time: 3 h

Procedure:
Concentrated hydrochloric acid (5.67 ml) was added to a mixture of di(trifluoroacetic acid) salt of 7β-amino-3-[3-formamido-2-(2-formyloxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (10 g) in methanol (50 ml) at ambient temperature. After being stirred at the same temperature for 3 hours, the mixture was added dropwise to ethyl acetate (500 ml). The resultant precipitate was collected by filtration to give 7β-amino-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate trihydrochloride (6.1 g).
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[C:19](F)(F)S(OC)(=O)=O>ClCCl>[CH3:19][N:4]1[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2](=[O:1])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)c1c[nH]n(-c2ccccc2)c1=O
Solvent: ClCCl
Product: CCOC(=O)c1cn(C)n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 21.1 %

Procedure:
To a solution of ethyl 3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate (1000 mg, 5.0 mmol) in dichloromethane (10 mL) was added methyl trifluoromethanesulfonate (1200 mg, 7.3 mmol). The red solution was stirred at room temperature. After 14 h, the mixture was partitioned between dichloromethane and NaHCO3 (sat). The aqueous was extracted with dichloromethane (2×). The combined organic was dried over Na2SO4, concentrated and purified on silica. The product was triturated with EtOAc-hexane-CHCl3 to give the pure product as crystals (260 mg, 21%). Calc'd for C12H12N2O3, 232.08; MS (ESI pos. ion) m/z: 233 (MH+). 1H NMR (400 MHz, CHLOROFORM-d): 1.36 (t, J=7.04 Hz, 3H), 3.39 (s, 3H), 4.32 (q, J=7.17 Hz, 2H), 7.32 (d, J=7.43 Hz, 2H), 7.42 (t, J=7.34 Hz, 1H), 7.50 (t, J=7.73 Hz, 2H), 7.99 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:44]=[CH:43][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][CH:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34](=[O:41])[N:35]6[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]6)[C:20]5=[N:19][C:18]=4[CH3:42])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:45]1(=[O:51])[O:50][C:48](=[O:49])[CH2:47][CH2:46]1.C(N(C(C)C)CC)(C)C.O>ClCCl>[F:1][C:2]1[CH:44]=[CH:43][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][CH:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([N:35]6[CH2:40][CH2:39][N:38]([C:45](=[O:51])[CH2:46][CH2:47][C:48]([OH:50])=[O:49])[CH2:37][CH2:36]6)=[O:41])[C:20]5=[N:19][C:18]=4[CH3:42])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2OCCCCCC(=O)N1CCNCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2OCCCCCC(=O)N1CCN(C(=O)CCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-(2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-9-((6-oxo-6-(piperazin-1-yl)hexyl)oxy)-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, prepared as described in Step B, (239 mg, 0.39 mmol) in dichloromethane (5 mL), under argon, was treated with succinic anhydride (43.15 mg, 0.43 mmol) and diisopropylethylamine (68.35 μL, 0.39 mmol). After stirring for 2 h at room temperature, the reaction mixture was poured into water (5 mL), and the aqueous layer was extracted with dichloromethane/methanol (95/5, three times 5 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC and triturated with diisopropylether, to give the title compound. (ESI-MS (M+1) 709); 1H NMR: (CDCl3, 360 MHz): δ ppm 1.10-2.80 (m, 31H), δ 3.20-4.00 (m, 13H), δ 4.24-4.30 (m, 1H), δ 7.07 (td, J=8.97, 1.83 Hz, 1H), δ 7.24 (d, J=1.83 Hz, 1H), δ 7.76 (dd, J=8.60, 4.94 Hz, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:15]1([NH2:18])[CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([NH:18][CH:15]1[CH2:17][CH2:16]1)=[O:5]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: NC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2 g (9.11 mmol) of 2-chloro-4-fluoro-5-nitrobenzoic acid were dissolved in 91 g of dichloroethane, 22.66 g of thionyl chloride were added and the mixture was boiled until the evolution of gas had ended. The volatile constituents were distilled off and the acid chloride thus obtained was used directly in the next step. 2.166 g (9.1 mmol) of 2-chloro-4-fluoro-5-nitrobenzoyl chloride were dissolved in 100 ml of dichloromethane, this solution was cooled to 0° C., and 0.52 g (9.1 mmol) of cyclopropylamine and 1.38 g (13.65 mmol) of triethylamine were added together, predissolved in 5 ml of dichloromethane. After stirring at room temperature for two hours, the volatile constituents were distilled off, the resulting residue was slurried with a little diethyl ether, the diethyl ether phase was decanted off and the residue was stirred with water.
Reaction SMILES: [CH:1]1([C:5]2[C:6](=[O:21])[NH:7][C:8]3[N:9]([N:11]=[N:12][C:13]=3[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH:10]=2)[CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:41][N:42]1[CH:46]=[N:45][C:44]([CH2:47]O)=[N:43]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:1]1([C:5]2[C:6]([O:21][CH2:47][C:44]3[N:45]=[CH:46][N:42]([CH3:41])[N:43]=3)=[N:7][C:8]3[N:9]([N:11]=[N:12][C:13]=3[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH:10]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cn1cnc(CO)n1
Reactant: O=c1[nH]c2c(-c3ccccc3F)nnn2cc1C1CCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1cnc(COc2nc3c(-c4ccccc4F)nnn3cc2C2CCC2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.6 %

Procedure:
6-Cyclobutyl-3-(2-fluorophenyl)-4H-1,2,3-triazolo[1,5-α]pyrimidin-5-one (50 g, 0.18 mmol), triphenylphosphine (120 mg, 0.44 mmol) and (1-methyl-1H-1,2,4-triazol-3-yl)methanol (50 g, 0.44 mmol) were suspended in dry tetrahydrofuran (1.5 ml). Diethyl azodicarboxylate (70 μl, 0.44 mmol) was added and a solution resulted immediately. The reaction was stirred at room temperature for 48 hours during which time a precipitate formed in the reaction mixture. The crude reaction mixture was evaporated and recrystallised from EtOAc. The pale pink crystalline solid thus produced was collected by filtration and washed with diethyl ether to afford 6-cyclobutyl-3-(2-fluorophenyl)-5-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[1,5-α]pyrimidine (40 mg, 60%) as pale needles, m.p. 202-205° C.; δH (400 MHz, CDCl3) 1.84-1.92 (1H, m, CH(CH2)3), 2.06-2.16 (3H, m, CH(CH2)3), 3.67 (1H, quintet, J=9 Hz, CH(CH2)3), 3.94 (3H, s, NCH3), 7.19-7.29 (2H, m, ArH), 7.32-7.36 (1H, m, ArH), 8.04 (1H, s, triazole CH), 8.12 (1H, td, J=7.5 and 1.8 Hz, ArH), 8.55 (1H, d, J=1.5 Hz, pyrimidine CH); m/z (ES+) 380 (M+H+).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]([NH:15][OH:16])=[NH:14])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([Cl:26])=O)=[CH:22][CH:21]=1>>[ClH:26].[CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]2[N:14]=[C:24]([C:23]3[CH:27]=[CH:28][C:20]([O:19][C:18]([F:17])([F:29])[F:30])=[CH:21][CH:22]=3)[O:16][N:15]=2)[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCC(CC(=N)NO)CC1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Product: CCC(CC)N1CCC(Cc2noc(-c3ccc(OC(F)(F)F)cc3)n2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 12, starting from 2-((1-ethylpropyl)piperidin-4-yl)-N-hydroxyacetamidine and 4-trifluoromethoxybenzoyl chloride.
Reaction SMILES: [CH:1]1([O:6][CH2:7][CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>ClCCl>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:9][CH2:8][CH2:7][O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: OCCOC1CCCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=S(=O)(OCCOC1CCCC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 572.7 %

Procedure:
To a solution of 2-(cyclopentyloxy)-1-ethanol (prepared as described in J. Org. Chem., 1968, 33, 2271-2284: 127 mg, 0.97 mmol) and triethylamine (101 mg, 0.1 mmol) in dichloromethane (3 mL) at 0° C. was added 4-bromobenzenesulfonyl chloride (255 mg, 0.1 mmol) in dichloromethane (2 mL) dropwise over 5 minutes. The reaction was then warmed to room temperature and stirred for 16 hours. The mixture was then poured into water (3 mL) and the two layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a crude residue. This was purified by column chromatography on silica gel (50 g), eluting with a gradient of dichloromethane:hexane (50:50 to 0:100), to give the title compound (200 mg, 59%) as a colourless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:22]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:22])=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc(SCc2ccccn2)cc1
Agent: Cl
Solvent: ClCCl
Product: O=S(Cc1ccccn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 37.8 %

Procedure:
A suspension of 2-(((4-chlorophenyl)thio methyl) pyridine, hydrochloride (2.0 g) in methylene chloride (50 ml) at 0° C. was treated with a solution of m-chloroperoxybenzoic acid (1.7 g) in CH2Cl2 (25 ml). The mixture was allowed to warm to ambient temperature and was stirred for 5 hours. The solution was washed with saturated sodium carbonate solution and water, then dried (MgSO4). The residue was dissolved in acetone and converted into the hydrochloride with ethereal HCl. N.m.r. showed approximately 20% of starting material remaining so the material was suspended in methylene chloride (50 ml) and treated with further m-chloroperoxybenzoic acid (2×500 g). The solution was washed with saturated sodium carbonate solution and water, dried (MgSO4) evaporated and the residue was dissolved in acetone and the hydrochloride precipitated with ethereal HCl solution. Recrystallisation from acetone-ether gave the title compound as the hydrochloride (0.7 g) mp 170° C. decomp. (Found: C,49.2; H,3.8; N,4.5 C12H10ClNOS.HCl.1/4 H2O requires C,49.2; H,4.0; N,4.8%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:9](Br)[N:8]([CH2:22][CH2:23][C@@H:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:25]=[CH2:26])[C:4]=2[N:5]=[CH:6][N:7]=1.NC1C2C(C3C=NC4C(C=3)=CC=CC=4)=C3N(C=2N=CN=1)C[C@@H](NC(=O)OC(C)(C)C)CC3>>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:9]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH2:22][N:8]3[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C=C[C@@H](CCn1c(Br)c(-c2cnc3ccccc3c2)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N[C@H]1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Product: CC(C)(C)OC(=O)N[C@H]1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2CC1
Yield: 52 %

Procedure:
In accordance with Example 10, except that the (R)-tert-butyl (5-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)penta-1-en-3-yl)carbamate (994 mg) obtained in Reference Example 10 was used in place of the (S)-tert-butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate obtained in Example 10, the title compound (439 mg) (yield: 52%) was obtained as a yellow solid.
Reaction SMILES: BrC1C=CC(S(O[CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)(=O)=O)=CC=1.[I-:25].[Na+]>CC(C)=O>[I:25][CH2:12][CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1
Reactant: O=S(=O)(OCCOc1ccc2ccccc2c1)c1ccc(Br)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCOc1ccc2ccccc2c1
Temperature: 35 °C
Yield: 72.1 %

Procedure:
To a solution of 2-(2-naphthyloxy)ethyl 4-bromobenzenesulfonate (Preparation 10, 380 mg, 0.93 mmol) in acetone (5 mL) at room temperature was added sodium iodide (1.0 g, 6.66 mmol). The mixture was heated at 35° C. for 16 hours and then cooled. The residual precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was partitioned between diethyl ether (20 mL) and water (20 mL). The two layers were separated and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (200 mg, 72%) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=O)[C:16]3[C:11](=[CH:12][C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=3)[O:10][CH:9]=2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:16]3[CH:15]=[C:14]([Cl:19])[C:13]([OH:20])=[CH:12][C:11]=3[OH:10])=[N:22][NH:23][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=c1c(-c2ccc(Br)cc2)coc2cc(O)c(Cl)cc12
Solvent: CCO
Solvent: O
Product: Oc1cc(O)c(-c2n[nH]cc2-c2ccc(Br)cc2)cc1Cl

Procedure:
This compounds was synthesised in the same manner as described above. 3-(4-Bromo-phenyl)-6-chloro-7-hydroxy-chromen-4-one (0.1 g, 0.28 mmol), hydrazine hydrate (4 ml), ethanol (10 ml). 4-[4-(4-Bromo-phenyl)-1H-pyrazol-3-yl]-6-chloro-benzene-1,3-diol precipitated out on quenching as a white solid (0.073 g, 71.2%); Rf 0.34 Cf SM 0.55 ethyl acetate/hexane (75/25).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:11][C:12]([F:26])([F:25])[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[CH2:16]Br>CN(C)C=O>[C:1]([O:4][CH2:16][C:15]1[CH:18]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:20]=[C:13]([C:12]([F:11])([F:25])[F:26])[CH:14]=1)(=[S:3])[CH3:2]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC(O)=S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=S)OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
Thioacetic acid (5.13 ml) was added to a suspension of caesium carbonate (11.7 g) in dimethylformamide (120 ml) at room temperature. The solution was stirred for 10 min and a solution of 3,5-bis(trifluoromethyl)benzyl bromide (20 g) in dimethylformamide (10 ml) was added. The resulting solution was stirred for 16 h, in the dark. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water, dried (Na2SO4) and the solvent was removed leaving an orange oil. The off was chromatographed on silica gel in 5% ethyl acetate/petrol giving 3,5-bis(trifluoromethyl)benzyl thioacetate (14.8 g) as a yellow oil. 1H NMR (360 MHz, CDCl3) δ 2.39 (3H, s), 4.17 (2H, s), 7.75 (3H, s); m/z (CI+) 303 (M+ +1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12](CC#N)=[N:11][S:10][N:9]=1.[OH-:16].[Na+].Cl.[CH2:19]([OH:21])[CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([CH2:20][C:19]([OH:16])=[O:21])=[N:11][S:10][N:9]=1
Reactant: N#CCc1nsnc1-c1ccccc1Cl
Reactant: [OH-]
Reactant: CCO
Agent: Cl
Agent: [Na+]
Product: O=C(O)Cc1nsnc1-c1ccccc1Cl

Procedure:
In N,N-dimethylformamide, 290 mg of 3-bromomethyl-4-(2-chlorophenyl)-1,2,5-thiadiazole, and 49 mg of sodium cyanide were stirred at 90° C. for 3 hours. After spontaneous cooling, the reaction mixture was poured into water, and was extracted with diethyl ether. The diethyl ether layer was washed with dilute sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 150 mg of 3-(2-chlorophenyl)-4-cyanomethyl-1,2,5-thiadiazole. The obtained 150 mg of 3-(2-chlorophenyl)-4-cyanomethyl-1,2,5-thiadiazole, 6 mL of 5% sodium hydroxide solution, and 2 mL of ethanol were mixed and refluxed by heating for one hour. After spontaneous cooling, the reaction mixture was poured into dilute hydrochloric acid, and was extracted with diethyl ether. The diethyl ether layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 120 mg of [3-(2-chlorophenyl)-1,2,5-thiadiazole-4-yl]acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:14])([F:23])[F:24])[CH:17]=2)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1cccc(C(F)(F)F)c1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(F)c([N+](=O)[O-])c1

Procedure:
A mixture of the product from Example 86A was reacted with 3-Trifluoromethyl-phenylamine to produce 4-Fluoro-3-nitro-N-(3-trifluoromethyl-phenyl)-benzamide according to the procedure of Example 86B, which was treated sequentially using the procedures from Examples 86C and 86D to provide the title product.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:13]=1[C:14](Cl)=[O:15].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:5]1[S:9][C:8]([NH:10][C:14](=[O:15])[C:13]2[CH:17]=[C:18]([C:21]([F:22])([F:23])[F:24])[CH:19]=[CH:20][C:12]=2[F:11])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nnc(N)s1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nnc(NC(=O)c2cc(C(F)(F)F)ccc2F)s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.1 %

Procedure:
To a solution of 5-tert-butyl-1,3,4-thiadiazol-2-amine (1.57 g, 10 mmol) and 2-fluoro-5-(trifluoromethyl)benzoyl chloride (2.27 g, 10 mmol) in CH2Cl2 (45 mL) at 0° C. was added dropwise triethylamine (1.7 mL, 12 mmol) and the reaction was allowed to warm to ambient temperature and stirred for 12 hours. The mixture was then washed with water, brine, dried with MgSO4, filtered, and concentrated under reduced pressure to afford 3.2 g of the title compound. MS (DCI/NH3) m/z 348 (M+H)30.