Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH:11]O>C(O)(=O)C>[CH3:1][S:2]([C:3]1[NH:4][CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])=[O:11]
Reactant: CSc1[nH]ccc1[N+](=O)[O-]
Reactant: OO
Solvent: CC(=O)O
Product: CS(=O)c1[nH]ccc1[N+](=O)[O-]

Procedure:
A solution of 2-methylthio-3-nitropyrrole (2.5 g, 0.016 mol) in glacial acetic acid (70 ml) and hydrogen peroxide (2 ml, 0.017 mol, 100 vol) was heated at 60° for 41/2 hours. The solvent was removed in vacuo (after first checking that no peroxide remained), and the residue was recrystallised from propan-2-ol to give 2-methylsulphinyl-3-nitropyrrole (2.3 g, 85% m.p. 162°-164°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C([Li])CCC.[C:18](=[O:20])=[O:19].Cl>O1CCCC1.O.CCCCCC>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([C:9]([F:12])([F:10])[F:11])[C:3]=1[C:18]([OH:20])=[O:19]
Reactant: O=C=O
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c(C(F)(F)F)ccc(Cl)c1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
83.4 g of 3,4-dichlorobenzotrifluoride was dissolved in 800 ml of dried tetrahydrofuran, and 250 ml of hexane solution of n-butyl lithium(1.6 mol/1) was added to the solution dropwise over 15 minutes at -78° C. under nitrogen atmosphere. Following to stirring the solution for 2 hours at -78° C., 50 g of dry ice was then gradually added to the solution at the same temperature. After elevating the temperature of the solution up to room temperature, 250 ml of cold water was added to the solution to separate the resulting solution, and the aqueous layer obtained was adjusted to an acidic condition of a pH value of 1 with concentrated hydrochloric acid while cooling. Then, the aqueous layer was extracted with ether, and the extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure, and the oily residue obtained was crystalized with n-hexane, washed, filtered, and dried to obtain 89 g of the title compound(mp. 88-89° C.).
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH:18]([C:21]3[N:26]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:25](=[O:34])[C:24]4=[CH:35][CH:36]=[C:37]([Cl:38])[N:23]4[N:22]=3)[CH2:19][CH3:20])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C.CCOC(C)=O>[NH2:17][CH:18]([C:21]1[N:26]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25](=[O:34])[C:24]2=[CH:35][CH:36]=[C:37]([Cl:38])[N:23]2[N:22]=1)[CH2:19][CH3:20]
Reactant: CCC(NC(=O)OCC1c2ccccc2-c2ccccc21)c1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(N)c1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
A solution of (±)-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-propyl]-carbamic acid 9H-fluoren-9-ylmethyl ester (0.92 g, 1.7 mmol) and piperidine (0.5 mL) in DMF (10 mL) was allowed to stand at rt for 30 min. The reaction mixture was diluted with EtOAc to 100 mL, washed with 10% LiCl solution (2×50 mL) and dried over MgSO4. Concentration and purification of the crude product by flash column chromatography (SiO2, EtOAc/hexane 1:1) gave the title compound as colorless oil (0.462 g, 85.5%): 1H NMR (CDCl3) δ 7.26 (m, 2H), 7.20 (m, 1H), 7.10 (d, 2H, J=7.15 Hz), 7.00 (d, 1H, J=4.4 Hz), 6.42 (d, 1H, J=4.4 Hz), 5.43 (d, 1H, J=16.5 Hz), 5.23 (d, 1H, J=16.5 Hz), 3.67 (t, 1H, J=6.62 Hz), 1.83 (m, 1H), 1.57 (m, 1H), 0.83 (t, 3H, J=7.15 Hz); 13C NMR (CDCl3) δ 154.6, 136.3, 129.0, 127.8, 126.3, 117.7, 117.2, 110.0, 108.4, 53.6, 44.4, 29.7, 10.5; MS (ESI+), 316.99, 319.31 (M++H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][C:4]([C:13]([O:15]CC)=[O:14])=[N:3]1.[OH-].[Na+].Cl>C(O)C>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][C:4]([C:13]([OH:15])=[O:14])=[N:3]1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(C(=O)O)cc1-c1ccccc1
Yield: 103.5 %

Procedure:
0.55 g of ethyl 1-methyl-5-phenyl-1H-3-pyrazolecarboxylate was dissolved in 10 ml ethanol. 2 ml of 5N aqueous sodium hydroxide solution was added thereto, followed by heating under reflux for 1 hour. The reaction mixture was ice-cooled, neutralized with 2N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated, to give 0.5 g of 1-methyl-5-phenyl-1H-3-pyrazolecarboxylic acid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.C(N(C(C)C)CC)(C)C.[CH:29]([C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([C:42]([F:45])([F:44])[F:43])[C:39]=1[O:40][CH3:41])[C:34](Cl)=[O:35])=[O:30]>ClCCl>[CH:29]([C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([C:42]([F:43])([F:45])[F:44])[C:39]=1[O:40][CH3:41])[C:34]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:35])=[O:30]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(C=O)cc(C(=O)Cl)cc1C(F)(F)F
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1c(C=O)cc(C(=O)N2CSc3ccccc32)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (1.55 g) and 37% formalin (1.0 mL) in the same manner as in Example 1 was dissolved in dichloromethane (15 mL), and diisopropylethylamine (2.7 mL) and 3-formyl-4-methoxy-5-trifluoromethylbenzoyl chloride (2.42 g) were added to the solution, and then the mixture was stirred at room temperature for 14 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the title compound (1.44 g) as a yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][CH:5]=1.C[O:13][C:14]([C:16]1[CH:26]=[C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:19]2[CH2:20][C:21]([CH3:24])([CH3:23])[O:22][C:18]=2[CH:17]=1)=O>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:14]([C:16]2[CH:26]=[C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:19]3[CH2:20][C:21]([CH3:24])([CH3:23])[O:22][C:18]=3[CH:17]=2)=[O:13])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: COC(=O)c1cc(OCC(C)C)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1ccc(NC(=O)c2cc(OCC(C)C)c3c(c2)OC(C)(C)C3)nc1

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from 6-aminonicotinic acid methyl ester (1.0 g, 6.57 mmol) and 4-isobutoxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (14a) (185 mg, 0.66 mmol). Purification by column chromatography eluting with 15-25% EtOAc in hexane gave a pale yellow solid (127 mg, 48% yield). 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J=1.52 Hz, 1 H) 8.69 (s, 1 H) 8.42-8.48 (m, 1 H) 8.35 (dd, J=8.72, 2.15 Hz, 1 H) 6.96 (s, 1 H) 6.87 (s, 1H) 3.95 (s, 3 H) 3.82 (d, J=6.32 Hz, 2 H) 3.01 (s, 2 H) 2.06-2.14 (m, J=13.33, 6.60, 6.60 Hz, 1 H) 1.51 (s, 6 H) 1.04 (d, J=6.82 Hz, 6 H); LCMS for C22H26N2O5 m/z 399.10 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[C@H:8]([C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[N:7]2[C:25](=[O:37])[C@@H:26]([NH:27][C:28](=[O:36])[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:6]2[S:5][CH:4]=1)=[O:2].O.C(OCC)(=O)C.O1C[CH2:48][CH2:47][CH2:46]1>>[OH:2][CH:1]([C:3]1[C@H:8]([C:9]([O:11][CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:10])[N:7]2[C:25](=[O:37])[C@@H:26]([NH:27][C:28](=[O:36])[CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C@H:6]2[S:5][CH:4]=1)[CH2:48][CH:47]=[CH2:46]
Reactant: C1CCOC1
Reactant: O=CC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCC(O)C1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
A mixture of dimethyl (R,R)-2-allyl-1,3,2-dixoaborolane-4,5-dicarboxylate (0.67M in toluene, 1.8 ml, 1.2 mmol) and 0.4 nm molecular sieves (50 mg) was stirred at 20° C. for 10 minutes and then cooled to −70° C., and then a solution of diphenylmethyl (4R, 6R, 7R)-3-formyl-7-phenylacetamidoceph-2-em-4-carboxylate (100 mg, 0.2 mmol) in tetrahydrofuran (0.5 ml) was added dropwise. After 2 h at −70° C. the mixture was warmed to 20° C. and water and ethyl acetate were added. The organic layer was dried (MgSO4) and evaporated and the residue purified by chromatography as in part a to give the title compound S-diastereomer, 45 mg (43%), and the R-diastereomer 8 mg (8%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH2:16][N:15]([C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:31])[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:4][N:3]=1>N1CCOCC1>[N:32]1([C:30]([N:15]2[CH2:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[CH2:18][CH:13]([C:11]3[O:10][N:9]=[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:7]=4)[N:12]=3)[CH2:14]2)=[O:31])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccnc(Cl)c3)no2)C1
Solvent: C1COCCN1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccnc(N4CCOCC4)c3)no2)C1

Procedure:
69 mg (0.13 mmol) of 4-({3-[3-(2-chloropyridin-4-yl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)phenyl]piperidin-1-yl}carbonyl)morpholine (Example 88) were reacted in 0.6 ml of morpholine according to the General Method 3. Yield: 38 mg (50% of theory)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([NH2:23])=[N:9]2)=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([NH:23][C:24](=[O:26])[CH3:25])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(N)nn2-c2ccc(F)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazol-3-amine (0.7 g) and acetic anhydride (0.22 ml) in dichloromethane (15 ml) was stirred at ambient temperature for 3 hours, and concentrated. The residue was purified by column chromatography on silica gel (15 g) eluting with a mixture of toluene and ethyl acetate (2:1). The desired product (0.63 g) was recrystallized from ethanol to give pale brown crystals of N-{1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-pyrazolyl}acetamide (0.52 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([O:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:20]([O:22]C)=[O:21].CO.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([O:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:20]([OH:22])=[O:21]
Reactant: COC(=O)c1cc2c(OCCCO)cccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c(OCCCO)cccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 16 h

Procedure:
Methyl N-(3,4-Dichlorobenzyl)-4-(3-hydroxypropyloxy)indole-2-carboxylate (6.9 g) was dissolved in THF (140 ml) and methanol (140 ml) and sodium hydroxide (3M, 110 ml) was added and the reaction stirred for 16 hours. The reaction was then concentrated in vacuo and the residue dissolved in water. The solution was acidified by dropwise addition of acetic acid, resulting in the precipitation of a white solid which was filtered, washed with water and dried in vacuo to give the desired end product (5.58 g. 84%); NMR d (CD3SOCD3) 1.92 (m, 2H), 3.60 (dd, 2H), 4.13 (dd, 2H), 5.89 (s, 2H), 6.52 (s, 1H), 6.94-7.11 (m, 4H), 7.32 (d, 1H), 7.47 (d, 1H); M/z (−) 392 (M−H+).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4](C)[N:3]=1.C[C:11](C)([O-:13])C.[K+].Br[CH2:17][CH:18]1[O:22][CH2:21][CH2:20][O:19]1>CN(C)C=O>[O:19]1[CH2:20][CH2:21][O:22][CH:18]1[CH2:17][O:8][C:6]1[CH:5]=[C:4]([O:13][CH3:11])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Cc1cc(=O)[nH]c(N)n1
Reactant: BrCC1OCCO1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OCC2OCCO2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.9 %

Procedure:
A solution of 8.5 g (0.060 mol) 2-amino-6-methyl-4-pyrimidinone in 45 mL anhydrous dimethylformamide (DMF) was treated with 6.7 g (0.060 mol) potassium t-butoxide then stirred for 10 minutes at ambient temperature. Subsequently, 7.6 mL (0.073 mol) of 2-bromomethyl-1,3-dioxolane was added and the mixture heated to 120° for 3 hours. The DMF was then evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The aqueous phase was extracted with two additional portions of ethyl acetate then the combined organic phase was washed with water, brine, then dried (MgSO4) and evaporated to an oil. Chromatography on silica gel with 10% ethyl acetate/CH2Cl2 as the eluant afforded 2.3 g of the title compound as a viscous oil. NMR (CDCl3): δ 3.9 (s, 3H), 4.0 (m, 4H), 4.3 (d, J=4 Hz, 2H), 5.15 (NH, br), 5.27 (t, J=4 Hz, 1H), 5.55 (s, 1H) ppm.
Reaction SMILES: Cl.Cl.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[O:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]3)=[CH:18][NH:19]2)=[CH:15][CH:14]=1.CCN(CC)CC.[C:37](OC(=O)C)(=[O:39])[CH3:38]>C(Cl)Cl>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[O:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([NH:29][C:37](=[O:39])[CH3:38])[CH2:25][CH2:24]3)=[CH:18][NH:19]2)=[CH:15][CH:14]=1
Reactant: NC1CCN(Cc2c[nH]c3cc(Oc4nc5ccccc5s4)ccc23)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(Cc2c[nH]c3cc(Oc4nc5ccccc5s4)ccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
To a suspension of 1-[6-(benzothiazol-2-yloxy)-1H-indol-3-ylmethyl]-piperidin-4-ylamine 2HCl (200 mg, 0.44 mmol) in DCM (4 mL) was added Et3N (0.37 mL, 270 mg, 2.7 mmol) and acetic anhydride (0.067 mL, 68 mg, 0.66 mmol) and the resulting reaction mixture was stirred (rt, 24 h). The reaction mixture was partitioned with EtOAc (50 mL) and brine (50 mL) and the organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified silica gel flash column chromatography using MeOH (0.2 M NH3):DCM (0-15%) to provide the title compound as a white solid (111 mg, 60%). MS (ESI): mass calcd. for C23H24N4O2S, 420.5; m/z found, 421.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.00 (s, 1H), 7.73 (d, J=6.0, 1H), 7.71 (d, J=5.2, 1H), 7.63 (d, J=7.5, 1H), 7.39-7.36 (m, 1H), 7.31 (br s, 1H), 7.26-7.24 (m, 1H), 7.10 (br s, 1H), 7.07 (dd, J=8.6, 2.1, 1H), 5.55 (br d, 1H), 3.80-3.70 (m, 1H), 3.68 (s, 2H), 2.89 (d, J=11.7, 2H), 2.17-2.13 (m, 2H), 1.96 (s, 3H), 1.89 (d, J=11.0, 2H), 1.48-1.40 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[NH2:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH2:24][CH3:25])=[N:15][N:16]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>CO.CC(=O)OCC>[CH:19]1([N:16]2[C:17]3[C:13](=[CH:12][CH:11]=[C:10]([NH:9][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:18]=3)[C:14]([CH2:24][CH3:25])=[N:15]2)[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CCc1nn(C2CCCC2)c2cc(N)ccc12
Reactant: O=Cc1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1nn(C2CCCC2)c2cc(NCc3cccnc3)ccc12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a mixture of 3-pyridinecarboxaldehyde (106 mg, 1.0 mol) in methanol (5.0 mL) was added 6-amino-1-cyclopentyl-3-ethyl-1H-indazole (240 mg, 1.05 mmol) and p-toluenesulfonic acid monohydrate (2.0 mg). The reaction mixture was stirred for 4 h. The flask was then cooled to 0° C. and sodium borohydride (0.09 g, 2.3 mmol) was added portion-wise over 4 h. The reaction fixture was allowed to warm to room temperature over 16 h with stirring. TLC indicated the reaction was complete (1:3 hex:EA). The solvent was evaporated and diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, and concentrated to yield the desired product. 1H NMR (300 MHz) δ 8.64 (s, 1H), 8.51 (m,1H), 7.70 (m, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.25 (m, 1H), 6.50 (m,1H), 6.33 (s,1H), 4.68 (p,J=7.8 Hz, 1H), 4.55 (br,1H), 4.40 (s,1H), 2.90 (q,J=7.7 Hz, 2H), 2.1-1.8 (m,6H), 1.8-1.6 (m,2H), 1.34 (t,J=7.7 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH2:19]([N:26]1[CH2:31][CH2:30][CH:29]([N:32](CC)[C:33]2[C:38](NCC)=CC=CN=2)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:19]([N:26]1[CH2:31][CH2:30][CH:29]([N:32]([CH2:33][CH3:38])[C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=2)[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCNc1cccnc1N(CC)C1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(c1ncnc(Cl)c1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
4,6-Dichloro-5-nitropyrimidine (8.88 g) is dissolved in 400 ml of methylene chloride and cooled to -78°. Then triethylamine (6.7 ml) and 1-benzyl-4-N-ethylaminopiperidine (EXAMPLE 205, 10.00 g) is added and the reaction is stirred 1 hr at -78° and slowly warmed to 20°-25°. The reaction is poured into saturated aqueous sodium bicarbonate, extracted with methylene chloride, washed with saline, dried and concentrated under reduced pressure. Purification by flash column chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) gives the title compound.
Reaction SMILES: [OH:1][C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=O.Cl.[NH2:25][OH:26].C([O-])(=O)C.[Na+].O>CO>[OH:1][C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3]/[C:4](/[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=[N:25]\[OH:26]
Reactant: NO
Reactant: O=C(CC(O)(c1ccccc1)c1ccccc1)c1ccncc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O/N=C(\CC(O)(c1ccccc1)c1ccccc1)c1ccncc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.7 %

Procedure:
To a solution of 3-hydroxy-3,3-diphenyl-1-pyridin-4-yl-propan-1-one (115 mg) in methanol (4 ml) were added hydroxylamine hydrochloride (63 mg) and sodium acetate (75 mg). The mixture was stirred at room temperature for 6 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried using MgSO4, filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 4:1 to 1:3) to give the title compound (60 mg) as a colorless solid, MS (ESI+): m/z=319.1 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([NH2:19])=[N:13][C:14]=2[C:15]([F:18])([F:17])[F:16])O1.B(O[O-])=[O:22].O.[Na+].CCOC(C)=O>C1COCC1.O>[NH2:19][C:12]1[N:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[C:9]([OH:22])=[CH:10][CH:11]=1
Reactant: CC1(C)OB(c2ccc(N)nc2C(F)(F)F)OC1(C)C
Reactant: O=BO[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(O)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
A solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridin-2-amine (0.598 g, 2.076 mmol) in THF (10 mL) and water (10 mL) was treated with sodium perborate monohydrate (0.332 g, 3.32 mmol) and stirred at RT overnight. The mixture was treated with EtOAc and the solids removed via filtration through diatomaceous earth. The filtrate was treated with brine, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 6-amino-2-(trifluoromethyl)pyridin-3-ol (92 mg, 25%). 1H NMR (400 MHz, DMSO-d6): δ 9.47 (s, 1H), 7.15 (d, J=8.9 Hz, 1H), 6.58 (d, J=8.9 Hz, 1H), 5.70 (s, 2H); MS (ESI) m/z: 179.1 (M+H+).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[NH:9][C:8]1=[O:18])(O)=[O:2].B>O1CCCC1>[OH:2][CH2:1][CH2:4][CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[NH:9][C:8]1=[O:18]
Reactant: O=C(O)CCCn1c(=O)[nH]c(=O)c2ccccc21
Agent: B
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)n(CCCCO)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a stirred suspension of 1-(3-carboxypropyl)-2,4(1H,3H)-quinazolinedione (2.00 g) in tetrahydrofuran (40 ml) was added 1M borane in tetrahydrofuran (24.2 ml) on an ice-bath, and the mixture was stirred for additional 2 hours at room temperature. The reaction mixture was quenched with 1N hydrochloric acid, and the organic solvent was evaporated. The residue was triturated with water, filtered and washed in turn with water and ethyl ether to give 1-(4-hydroxybutyl)-2,4(1H,3H)-quinazolinedione (1.74 g) as a crystal.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Li+].[OH-].Cl>O1CCOCC1>[N:1]1([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(Cn2cnc3ccccc32)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Cn2cnc3ccccc32)cc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A solution of methyl 4-((1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.25 mmol) in dioxane (1 mL) was treated with aqueous LiOH (1 M, 1.0 mL). After stirring at 23° C. for 2 h, the reaction was neutralized with aqueous HCl (1 M, 2.0 mL) and the resulting solid was isolated by filtration. The filter cake was rinsed with water and allowed to dry in vacuo to yield 4-((1H-benzo[d]imidazol-1-yl)methyl)benzoic acid.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH2:8]([CH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)[CH3:9].N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:16][CH:13]1[CH2:14][CH2:15][CH:10]([CH2:8][CH3:9])[CH2:11][CH2:12]1)[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCC1CCC(O)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1CCC(OC(=O)OC(C)Cl)CC1
Reaction time: 20 h

Procedure:
A solution of 1-chloroethyl chloroformate (5.46 g) in dry dichloromethane (20 ml) was added dropwise, under nitrogen at 0°, to a stirred solution of 4-ethylcyclohexanol (5 g) in dry dichloromethane (20 ml) in presence of 3A molecular sieves. A solution of pyridine (3 g) in dry dichloromethane (20 ml) was added dropwise to the reaction mixture during 20 min at 0° the mixture was then warmed to 20°, stirred for 20 hours, washed with brine (2×50 ml) and dried. The solvent was removed under vacuum and the residue was distilled to give the title compound as a colourless oil (7.9 g; b.p. 130°/5.2 mbar; t.l.c. cyclohexane/ethyl acetate 9/1 Rf=0.88; IR (CDCl3), Vmax (cm-1): 1757 (C=O); 1H-NMR (300 MHz, CDCl3): 6.43 (q), 6.42 (q), 4.93 (bs), 4.59 (tt), 2.14-2.01 (bs), 2.00-1.88 (bs), 1.88-1.78 (m), 1.83 (d), 1.82 (d), 1.60-1.50 (m), 1.50-1.32 (m), 1.30-1.15 (m), 1.28-1.18 (m) 1.05-0.95 (m), 0.95-0.85 (m).