Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:10][OH:11]>CO.O>[CH:1](=[N:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: ON=Cc1ccccc1
Yield: 86.2 %

Procedure:
10.0 mmol of benzaldehyde was dissolved in 30 mL of 30% CH3OH solution in H2O and then added into a conical flask equipped with magnetic stirrer. 10.0 mmol of hydroxylamine hydrochloride was added under stirring. After hydroxylamine hydrochloride was dissolved, 5.0 mmol of dry and porphyrized sodium carbonate was slowly added. The reaction was carried out at room temperature. After the completion of the reaction monitored by TLC, the system was evaporated to remove methanol under reduced pressure. The mixture was extracted by the addition of 30 mL H2O, and then dichloromethane (3×30 mL). The organic layers were combined, and then dried over anhydrous sodium sulfate. The solvent was removed to afford a crude product of benzaldehyde oxime in 86.2% yield. The crude material was directly used in the next reaction without separation and purification.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[N:31]=[C:30](S(C)(=O)=O)[N:29]=1>O1CCCC1>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([C:30]1[N:31]=[C:32]([O:34][CH3:35])[CH:33]=[C:28]([O:27][CH3:26])[N:29]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)Cc1ccccc1C
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(c1nc(OC)cc(OC)n1)c1ccccc1C
Temperature: -75 °C
Reaction time: 0.25 h
Yield: 60.1 %

Procedure:
n-Butyllithium (10 ml of 2N solution in pentane) was added dropwise to a stirred solution of di-isopropylamine (2.0 g) in dry tetrahydrofuran (40 ml) under nitrogen at -10° C. After stirring at this temperature for 15 minutes, the solution was cooled to -75° C., and a solution of ethyl (2-methylphenyl)acetate (3.56 g) in tetrahydrofuran (20 ml) was added dropwise. After stirring at -75° C. for one hour, 4,6-dimethoxy-2-(methylsulphonyl)pyrimidine (4.36 g) was added in one portion, and the resulting suspension was allowed to warm slowly to room temperature before stirring overnight. The reaction mixture was then poured onto water (400 ml) and the resulting oil was extracted into ether (2×150 ml). The combined extracts were washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated to give a yellow oil which was purified by chromatography to give 3.8 g of the desired product as a colourless oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][NH:13][C:12](=S)[C@@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1.[NH2:24][CH2:25][CH:26]([OH:32])[CH2:27][C:28]([F:31])([F:30])[F:29].C(N(CC)CC)C>C(O)C.[Hg](Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][NH:13][C:12](=[N:24][CH2:25][CH:26]([OH:32])[CH2:27][C:28]([F:31])([F:30])[F:29])[C@@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=S
Reactant: NCC(O)CC(F)(F)F
Agent: Cl[Hg]Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=NCC(O)CC(F)(F)F
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl [(3S,5S)-5-(2,3-difluorophenyl)-2-thioxopiperidin-3-yl]carbamate (75.0 mg, 0.219 mmol) in ethanol (2.19 mL) was added the hydrochloride salt of 1-amino-4,4,4-trifluorobutan-2-ol (98.0 mg, 0.548 mmol), mercury(II) chloride (77.0 mg, 0.285 mmol), and triethylamine (73.3 μL, 0.526 mmol). The mixture was stirred 10 min, filtered, and concentrated giving the crude title compound. MS 452.17 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].OC1OC[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)[C:9]1=O>C(Cl)Cl.CN(C=O)C>[Cl:4][CH:2]1[O:3][CH2:9][N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:22])[F:23])[CH:14]=2)[C:1]1=[O:5]
Reactant: O=C1C(O)OCN1c1cccc(OC(F)(F)F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1C(Cl)OCN1c1cccc(OC(F)(F)F)c1
Temperature: 25 °C

Procedure:
Oxalyl chloride (2.7 ml) was added dropwise over 1 min to a stirred solution of 5-hydroxy-3-(3-trifluoromethoxyphenyl)oxazolidin-4-one (8.17 g) in DCM (60 ml) containing DMF (1 drop) at 0° C. The mixture was allowed to warm to room temperature and once gas evolution had stopped the solvent was removed in vacuo to give the sub-title compound (8.5 g) which was used directly in the next step.
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.C(O)(=[O:18])C1C=CC=NC=1.[Na].C(O)(=O)C1C=CC=NC=1>>[OH:18][C:4]1[N:3]=[CH:2][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: O=C(O)c1cccnc1
Agent: [Na]
Product: O=C(O)c1cccnc1O
Reaction time: 120 h
Yield: 72.5 %

Procedure:
The microorganisms with the designation Ki101 (DSM 6920) were incubated in 800 ml of mineral salt medium (Table 1 below) with addition of 8 mmol of 6-methylnicotinic acid in a 1 l Fernbach flask at 30° C. on a shaker at 100 rpm. The inoculum was 5 percent (v/v). After 5 days, the OD650 was about 0.5. Then the cells were harvested and washed once with 50 m molar phosphate buffer, pH 7.0. Then the cells were resuspended in 20 ml of 50 mM of phosphate buffer, pH 7.0 containing 200 mg (1.38 mmol) of nicotinic acid-sodium salt. The OD650 was 20. After 6 hours incubation on a shaker at 30° C., no more nicotinic acid could be detected by thin-layer chromatography. Then the biomass was centrifuged off and the supernatant acidified to pH 2.5 to precipitate the 2-hydroxynicotinic acid. No contamination in the isolated product could be detected by 1H-NMR (DMSO) analysis. Altogether 140 mg (1 mmol) of 2-hydroxynicotinic acid corresponding to a yield of 72 percent relative to nicotinic acid could be isolated.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[CH3:17][C:18]1([CH3:49])[CH:27]=[C:26](OS(C(F)(F)F)(=O)=O)[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:36]#[C:37][C:38]3[CH:48]=[CH:47][C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:40][CH:39]=3)[CH:24]=2)[O:19]1>C1COCC1.CCCCC.[Cl-].[Cl-].[Zn+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:2][C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:36]#[C:37][C:38]4[CH:48]=[CH:47][C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:40][CH:39]=4)[CH:24]=3)[O:19][C:18]([CH3:17])([CH3:49])[CH:27]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CC(C)(C)O3)cc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(C)(C)C)cc2)=CC(C)(C)O3)cc1
Temperature: 25 °C

Procedure:
A solution of 4-tert-butylbromobenzene (280.0 mg, 1.61 mmol) in 3.0 mL of THF was cooled to -78° C. and tert-butyllithium (206.3 mg, 3.22 mmol, 1.7 ml of a 1.7M solution in pentane) was added to give a yellow solution. After 30 minutes a solution of ZnCl2 (380.0 mg, 3.22 mmol) in 5.0 mL THF was slowly added via cannula. The resulting solution was warmed to room temperature and transferred via cannula to a solution of ethyl 4-((2,2-dimethyl-4-trifluoromethanesulfonyloxy-(2H)-chromen-6-yl)ethynyl)-benzoate (Compound 264, 150.0 mg, 0.31 mmol) and tetrakis(triphenylphosphine) palladium(0) (24.0 mg, 0.02 mmol) in 2.0 mL THF. This solution was heated to 50° C. for 2 hours, cooled to room temperature, and the reaction quenched by the addition of saturated aqueous NH4Cl. This solution was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 85.0 mg (59%), was isolated by column chromatography (2.5% EtOAc/hexanes) as a colorless solid. 1H NMR (300 MHz, CDCl3) δ: 7.99 (2H, d, J=8.3 Hz), 7.53 (2H, d, J=8.3 Hz), 7.45 (1H, d, J=8.4 Hz), 7.37 (1H, dd, J=2.0, 8.3 Hz), 7.32-7.28 (3H, m), 6.89 (1H, d, J=8.3 Hz), 5.66 (1H, s), 4.39 (2H, q, J=7.1 Hz), 1.52 (6H, s), 1.40 (3H, t, J=7.1 Hz), 1.39 (9H, s).
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.C([N-]C(C)C)(C)C.[Li+].[O:28]1CC[CH2:30][CH2:29]1.CCCCCCC.C(C1C=CC=CC=1)C.C(=O)C>C1COCC1>[CH3:1][N:2]1[C:10]([CH:29]([OH:28])[CH3:30])=[C:9]2[C:4]([C:5]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:6][CH:7]=[CH:8]2)=[N:3]1
Reactant: Cc1cc(C)c(-c2cccc3cn(C)nc23)c(C)c1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: CC=O
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: Cc1cc(C)c(-c2cccc3c(C(C)O)n(C)nc23)c(C)c1
Temperature: 2.5 °C

Procedure:
To a solution of the above-prepared impure 2-methyl-7-(2,4,6-trimethyl-phenyl)-2H-indazole (0.500 g) in 10 mL of THF at −78° C. was added a 2.0 M solution of lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene (1.2 mL, 2.4 mmol). The yellow solution was stirred at 0-5° C. for 15 m, and the resulting purple solution rechilled to −78° C. for 15 m. Acetaldehyde (0.14 mL, 2.5 mmol) was added, and the resulting yellow solution was stirred for 90 m then quenched with silica gel and concentrated. Column chromatography (0→50% EtOAc/hexanes) afforded of 1-[2-methyl-7-(2,4,6-trimethyl-phenyl)-2H-indazol-3-yl]-ethanol (12a: R=Me, R′=2,4,6-trimethylphenyl, E=CH(OH)Me; 0.280 g; 48%; m.p. 246) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.[CH3:14][N:15]1[CH2:21][C:19](=[O:20])[NH:18][C:16]1=[O:17]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:21]2[N:15]([CH3:14])[C:16](=[O:17])[NH:18][C:19]2=[O:20])[CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11]
Reactant: CN1CC(=O)NC1=O
Reactant: COc1cc(C=O)cc(OC)c1O
Product: COc1cc(C=C2C(=O)NC(=O)N2C)cc(OC)c1O
Yield: 33.5 %

Procedure:
Prepared according to the procedure described in Example 99 using 3,5-dimethoxy-4-hydroxybenzaldehyde (5.8 g, 31 mmoles) and 1-methyl hydantoin (3.5 g, 30 mmoles). Recrystallization from ethanol gave the pure product (2.8 g),mp 194°-196° C.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)[S:15][C:8]=23)=[C:4]([F:27])[CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([N:39]=[C:40]=[S:41])=[O:38]>CCO.C1(C)C=CC=CC=1>[F:27][C:4]1[CH:3]=[C:2]([NH:1][C:40]([NH:39][C:37](=[O:38])[CH2:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[O:29][CH3:28])=[S:41])[CH:26]=[CH:25][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[S:15][C:8]=12
Reactant: COc1ccccc1CC(=O)N=C=S
Reactant: COc1cccc(Nc2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cccc(Nc2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5OC)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.5 %

Procedure:
A solution of 449 (40 mg, 0.10 mmol) in 1:1 mixture of EtOH/toluene (2 mL) was treated with 2-(2-methoxyphenyl)acetyl isothiocyanate (394 mg, 2.22 mmol) and stirred at room temperature for 2 hours. The reaction mixture was then concentrated and purified by flash chromatography using the gradient 75-100% EtOAc in hexanes as an eluent, yielding 447 (15 mg, 24% yield). CDCl3 12.39 (s, 1H), 9.47 (s, 1H), 8.34 (d, J=5.7 Hz, 1H), 7.92 (dd, J=2.0, 11.8 Hz, 1H), 7.36 (m, 2H), 7.22 (m, 2H), 7.01 (m, 3H), 6.80 (s, 2H), 6.59 (d, J=7.4 Hz, 2H), 6.39 (d, J=5.6 Hz, 1H), 4.00 (s, 3H), 3.80 (s, 3H), 3.72 (s, 2H) LCMS: (M+H) 589.0
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[C:13]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][C:16]2=[O:22])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.C1([O:31][C:32](=O)[NH:33][C:34]2[CH:39]=[C:38]([O:40][CH:41]([CH3:43])[CH3:42])[C:37]([C:44]#[N:45])=[CH:36][N:35]=2)C=CC=CC=1>CN(C1C=CN=CC=1)C.C(#N)C>[C:44]([C:37]1[C:38]([O:40][CH:41]([CH3:43])[CH3:42])=[CH:39][C:34]([NH:33][C:32]([N:7]2[C:6]3[C:11](=[CH:12][C:13]([CH2:14][N:15]4[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][C:16]4=[O:22])=[C:4]([CH:3]([O:23][CH3:24])[O:2][CH3:1])[N:5]=3)[CH2:10][CH2:9][CH2:8]2)=[O:31])=[N:35][CH:36]=1)#[N:45]
Reactant: CC(C)Oc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Reactant: COC(OC)c1nc2c(cc1CN1CCN(C)CC1=O)CCCN2
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: COC(OC)c1nc2c(cc1CN1CCN(C)CC1=O)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1

Procedure:
A mixture of 1-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-4-methylpiperazin-2-one (intermediate 81, 268 mg, 0.641 mmol), phenyl(5-cyano-4-isopropoxypyridin-2-yl)carbamate (intermediate 96, 834 mg, 1.122 mmol) and DMAP (7.83 mg, 0.064 mmol) in acetonitrile (2.6 ml) was heated at reflux for 3.5 h. The reaction mixture was evaporated and applied to a 24 g RediSep silica column as a DCM solution and purified by normal phase chromatography, eluting with a gradient from DCM to 10% MeOH in DCM. Product containing fractions were combined and evaporated to give the title compound as an off-white solid. (UPLC-MS 6) tR 0.92; ESI-MS 538.7 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:15][CH:14]=1)[C:5]2=O.O.[NH2:28][NH2:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)=[CH:7][NH:29][N:28]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: NN
Reactant: O=c1c(-c2ccc(-c3ccc(F)cc3)cc2)coc2cc(O)c(Cl)cc12
Solvent: O
Product: Oc1cc(O)c(-c2n[nH]cc2-c2ccc(-c3ccc(F)cc3)cc2)cc1Cl
Yield: 63.7 %

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-3-(4′-fluorobiphenyl-4-yl)-7-hydroxy-chromen-4-one (0.12 g, 0.33 mmol), Hydrazine hydrate (5 ml). The quenched reaction was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give 4-Chloro-6-[4-(4′-fluoro-biphenyl-4-yl)-1H-pyrazol-3-yl]-benzene-1,3-diol as a white solid (0.08 g, 63.7%).
Reaction SMILES: Cl[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[NH:28]1[C:32]([CH2:33][C:34]([OH:36])=[O:35])=[N:31][N:30]=[N:29]1>C1COCC1.CCOC(C)=O>[C:2]([N:28]1[C:32]([CH2:33][C:34]([OH:36])=[O:35])=[N:31][N:30]=[N:29]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)Cc1nnn[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.7 %

Procedure:
In an argon atmosphere, TrCl (936 mg, 3 mmol) and Et3N (556 μL, 3 mmol) were added to a solution of 1H-tetrazole-5-acetic acid (128 mg, 1 mmol) in THF (10 mL) and stirred for 3 hours at room temperature. The reaction mixture was diluted with EtOAc, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated at a reduced pressure. The resulting residue was purified by neutral flash silica gel column chromatography (1.5×6, MeOH in CH2Cl2 0-0.5%) to give 2-(1-trityl-1H-tetrazol-5-yl)acetic acid (62 mg, 18%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:24]3[CH2:29][CH2:28][C@H:27]([CH2:30]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:26][CH2:25]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:42][NH2:43]>CO>[CH3:42][NH:43][CH2:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[N:9]=2)[CH2:25][CH2:26]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](c3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)nccn43)CC2)cc1
Solvent: CO
Product: CNC[C@H]1CC[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)CC1

Procedure:
A solution of trans-toluene-4-sulfonic acid 4-[8-amino-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexylmethyl ester (15.0 mg, 0.0264 mmol), 2.0 M of methylamine in MeOH (0.5 mL) and MeOH (2 mL) was microwaved at 300 watt, 100° C. for 1 h. The material was concentrated and purified by a prep TLC plate, eluting with 8% (7N NH3 in MeOH) in DCM, to afford the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 1.10-1.22 (m, 2H), 1.60-1.69 (m, 1H), 1.81-1.95 (m, 2H), 1.97-2.03 (m, 2H), 2.10 (d, J=11.4 Hz, 2H), 2.46 (s, 3H), 2.51 (d, J=6.6 Hz, 2H), 2.87-2.97 (m, 1H), 5.09 (br. s., 2H), 7.04-7.18 (m, 6H), 7.23 (d, J=5.1 Hz, 1H), 7.34-7.41 (m, 2H), 7.59-7.66 (m, 2H). MS (ES+): m/z 427.89 (100) [MH+]. HPLC: tR=1.89 min (polar—5 min).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH2:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]#[CH:8]>ClCCl>[CH2:6]([O:9][C:10]1[CH:15]=[CH:14][C:13]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:12][CH:11]=1)[C:7]#[CH:8]
Reactant: O=S(=O)(O)Cl
Reactant: C#CCOc1ccccc1
Solvent: ClCCl
Product: C#CCOc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
Referring to FIG. 39, chlorosulfonic acid (19.9 mL, 0.299 mol) was added dropwise to (prop-2-yn-1-yloxy)benzene (17.2 g, 0.130 mol) in dichloromethane (100 mL) at 0° C. The reaction was stirred at 0° C. for 1 hour and then poured into ice-water and extracted with dichloromethane. The extract was washed with water, dried (MgSO4), and evaporated. The residue was purified by Biotage flash column chromatography (30% EtOAc/Hep) to give product as an oil (17.9 g, 60%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:8](=[N:15][OH:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:25](Cl)(=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[C:25]([O:16][N:15]=[C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:7]1[CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]([OH:20])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)(=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCC(=O)Cl
Reactant: CC(C)(C)c1cc(C(=NO)c2ccccc2)cc(C(C)(C)C)c1O
Product: CCCCCCCC(=O)ON=C(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
3,5-di-t-butyl-4-hydroxybenzophenone oxime and octanoyl chloride were treated in the same was as in Example 3 to give 3,5-di-t-butyl-4-hydroxybenzophenone O-octanoyloxime.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-])=O>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:4]=1[NH2:13]
Reactant: COc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(F)(F)F)cc1N

Procedure:
2-Methoxy-5-trifluoromethyl-nitrobenzene (283 mmol, 62,67 g) suspended in ethanol (500 ml) is hydrogenated over palladium on carbon 5% (1.7 g) and the reaction mixture is filtered through celite. The filtrate is concentrated in vacuo yielding the title compound as light grey crystals M.p. 61° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH2:10])=[O:9])[CH2:2]1.[CH3:15][N:16]=[C:17]=[O:18]>C1C=CC=CC=1>[CH3:15][NH:16][C:17]([N:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH2:10])=[O:9])[CH2:2]1)=[O:18]
Reactant: NC(=O)c1ccccc1OC1CNC1
Reactant: CN=C=O
Solvent: c1ccccc1
Product: CNC(=O)N1CC(Oc2ccccc2C(N)=O)C1
Reaction time: 24 h

Procedure:
To 8.0 g. (0.028 mole) of 2-(3-azetidinyloxy)benzamide stirring in 100 ml of dry benzene was added dropwise 1.6 g. (0.028 mole) of methylisocyanate with ice bath cooling. Stirring was continued at room temperature for 24 hours. The solid material was filtered and was recrystallized from 95% ethanol. The product (4.0 g., 57%) melted at 236°-240° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:7][CH2:6]1.[NH3:18].O>ClCCl>[CH:5]1([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:18])=[O:14])=[CH:11][CH:10]=2)[CH2:7][CH2:6]1
Reactant: O=C(O)c1ccc(SC2CC2)cc1
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1ccc(SC2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (340 μL, 4.7 mmol) is added to a solution of 4-cyclopropylsulfanyl-benzoic acid (prepared as described in WO07003960, 190 mg, 0.98 mmol) in dichloromethane (1.9 mL), and the mixture is heated at reflux for 30 min. All volatiles are removed under reduced pressure, and the residue is dissolved in chloroform (1.9 mL). Concentrated aqueous ammonia (28%, 770 μL, 9.8 mmol) is added and the mixture is stirred at room temperature for 1 h. Water is added and the phases are separated. The organic layer is concentrated under reduced pressure. Yield: 137 mg (72% of theory); ESI mass spectrum: [M+H]+=194; r.t. HPLC: 0.45 min (X011_S03).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[C:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:9][CH:10]=1)([CH3:3])[CH3:2].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:26]=1.C(N(CC)CC)C>CS(C)=O.O>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=2)[CH:18]=[C:19]2[CH2:20][CH2:21][N:22]([C:32]([NH:31][C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)=[O:33])[CH2:23][CH2:24]2)=[N:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: CC(C)Oc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnc4)CC3)c2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a solution of 5-isopropoxy-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine (0.18 g, 0.55 mmol) in DMSO (3 mL) was added phenyl pyridin-3-ylcarbamate (0.118 g, 0.55 mmol) followed by triethylamine (0.235 mL, 1.692 mmol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% acetone, 70% hexane) to give the title compound (0.22 g, 89.2%). 1H NMR (500 MHz, CDCl3): δ 8.46 (s, 1H), 8.25 (d, J=3.5 Hz, 1H), 8.02 (d, J=8 Hz, 1H), 7.86 (d, J=3 Hz, 1H), 7.27 (m, 2H), 7.23 (m, 1H), 6.98 (d, J=7.5 Hz, 1H), 6.93 (m, 2H), 6.85 (d, J=9 Hz, 1H), 6.68 (s, 1H), 6.39 (s, 1H), 4.45 (m, 1H), 3.60 (m, 2H), 3.50 (m, 2H), 2.58 (m, 2H), 2.44 (m, 2H), 1.33 (d, J=6 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ 157.34, 155.19, 154.58, 150.73, 143.84, 141.11, 138.80, 137.68, 136.27, 135.56, 129.41, 128.34, 127.50, 124.80, 124.61, 123.60, 120.61, 118.36, 112.49, 71.68, 45.69, 44.71, 35.73, 29.15, 21.96; m/z (445.2, M+ H+); HPLC: 96.0%.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH2:22][C:23](O)=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1)[CH3:27]>>[CH2:26]([N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1)[C:23](=[O:24])[CH2:22][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][N:8]=1)(=[O:11])=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH3:27]
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccc(C(C)C)cn1
Reactant: CCNCc1cccc(C)n1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-(2-methoxy-phenyl)-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine