Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)=[C:6]([O:30][CH3:31])[CH:5]=1)=[S:3].Cl[CH:33]([C:38](C)=O)[C:34]([O:36][CH3:37])=[O:35]>CCO>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C@H:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]3[CH:28]=[CH:29][C:4]([C:2]4[S:3][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][N:1]=4)=[CH:5][C:6]=3[O:30][CH3:31])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)[CH3:27]
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C(N)=S)cc3OC)ccc21
Solvent: CCO
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4ncc(C(=O)OC)s4)cc3OC)ccc21
Temperature: 70 °C
Yield: 49.5 %

Procedure:
Ethyl ((1S)-5-{3-[4-(aminocarbonothioyl)-2-methoxyphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (90 mg, 0.2 mmol) (Example 146) and methyl 2-chloroacetoacetate (37 mg, 0.24 mmol) were dissolved in EtOH (8 mL), and the mixture was heated at 70° C. for 6 h. The reaction was cooled to rt, and then concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc:hexane (v/v)=1:2) provided 52 mg (48%) of the title compound as a clear oil. LC-MS: RT=4.18 min, (M+H)+ 540.1.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH2:22][CH2:21][CH2:20][N:12]3[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]3[CH2:22][CH2:21][CH2:20][N:12]3[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:7][CH:8]=1)=[O:31]
Reactant: CSc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5.0 g (16.3 mmoles) of (4-methylthiophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole of Example 3 dissolved in 75 ml of chloroform, chilled in an ice bath, was added dropwise a solution of 3.30 g (16.3 mmoles) of 85% 3-chloroperbenzoic acid in chloroform. After stirring at 25° C. overnight, the reaction mixture was washed with 5% sodium carbonate, dried over anhydrous potassium carbonate, and stripped in vacuo. The residue was flash chromatographed on silica eluting with 5 to 10% methanol in methylene chloride: 2-propanol (9:1). The solvent was removed in vacuo and the residue recrystallized from ethyl acetate to give the desired titled compound, mp 163.5°-165.5° C. 1H NMR (360 MHz, CDCl3) δ 8.62 (2H,d), 7.68 (2H,d), 7.57 (2H,d), 7.25 (2H,d), 4.05 (2H,t), 3.02 (2H,t), 2.72 (s) superimposed upon 2.69 (m) (5H total). Mass Spec. ##STR25## (M+H) 324 (MW=323).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:17][S:18]([C:21]2[CH:22]=[C:23]([CH:27]=[CH:28][C:29](Cl)=[O:30])[CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=1>O1CCCC1>[OH:3][NH:2][C:29](=[O:30])[CH:28]=[CH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([S:18](=[O:20])(=[O:19])[NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH3:9])[CH:12]=2)[CH:22]=1
Reactant: NO
Reactant: COc1cccc(NS(=O)(=O)c2cccc(C=CC(=O)Cl)c2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(NS(=O)(=O)c2cccc(C=CC(=O)NO)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.39 g, 5.7 mmol) in tetrahydrofuran (6 ml) a saturated NaHCO3 solution (4.5 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-[3-(3-methoxy-phenylsulfamoyl)-phenyl]-acryloyl chloride (6i) (0.40 g) in tetrahydrofuran (4 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was crystallised from ethyl acetate-acetonitrile affording the title compound (0.15 g, 39%) as a lightly pink crystals. M.p. 137° C. 1H NMR (DMSO-d6, HMDSO) δ: 3.65 (3H, s); 6.38–6.78 (4H, m); 6.98–7.27 (1H, m); 7.34–8.03 (5H, m); 9.14 (1H, br s); 10.30 (1H, s); 10.83 (1H, br s). HPLC analysis on Symmetry C8 column: impurities 5% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 40:60; sample concentration 0.5 mg/ml; flow rate 1.2 ml/min; detector UV 254 nm). Anal. Calcd for C16H16N2O5S containing 1% of inorganic impurities, %: C, 54.67; H, 4.50; N, 8.09. Found, %: C, 54.61; H, 4.58; N, 7.96.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1.[C:55]([O:58][BH-](OC(=O)C)OC(=O)C)(=[O:57])C.[Na+].O>C(Cl)Cl>[CH:55]([OH:58])=[O:57].[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:49]3[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]3)=[CH:12][CH:11]=2)[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C1CCNCC1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C=O)cc4)c4ccccc43)cn12
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(CN5CCCCC5)cc4)c4ccccc43)cn12
Product: O=CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Intermediate 176b (0.188 mmol) and piperidine (37.2 μL, 0.38 mmol) in DCM (3 mL), sodium triacetoxyborohydride (59.8 mg, 0.28 mmol) was added. The mixture was stirred at RT for 1 h. Water was added and the mixture extracted with DCM. The combined organics were passed through a phase separator and concentrated to dryness. The resulting residue was purified by RP-HPLC (C18, 18 mL/min, 20-85% MeCN in H2O+0.1% HCO2H) and the relevant fractions combined and concentrated to dryness. The title product was isolated as an off white solid (14 mg). LCMS (Method 5): Rt 3.71 min, m/z 716.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.4 Hz), 1.27 (9H, s), 1.36 (2H, m), 1.47 (6H, m), 1.67 (2H, m), 1.76-1.96 (4H, m), 1.98-2.16 (2H, m), 2.33 (4H, m), 2.90 (1H, m), 3.15 (1H, m, obscured by solvent), 3.46 (2H, s, obscured by solvent), 4.81 (1H, m), 5.51 (1H, t, J=4.1 Hz), 6.33 (1H, s), 7.09 (1H, d, J=8.6 Hz), 7.19 (1H, dd, J=10.0, 2.2 Hz), 7.24-7.46 (8H, m), 7.64 (1H, d, J=10.0 Hz), 7.69 (1H, d, J=1.5 Hz), 8.09 (1H, s), 8.17 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:19][C:18]3[CH:17]=[N:16][N:15]([CH3:20])[C:14]=3[NH:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([OH:29])=[O:28].[CH2:30]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46]O)[CH2:42][CH2:41]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH2:30]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46][O:28][C:27](=[O:29])[CH2:26][CH2:25][C:3]2[CH:4]=[CH:5][C:6]([C:8]([N:10]3[CH2:19][C:18]4[CH:17]=[N:16][N:15]([CH3:20])[C:14]=4[NH:13][C:12]4[CH:21]=[CH:22][CH:23]=[CH:24][C:11]3=4)=[O:9])=[CH:7][C:2]=2[CH3:1])[CH2:42][CH2:41]1)=[O:39])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)O
Reactant: O=C(OCc1ccccc1)N1CCC(CO)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)OCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
WSCD (107 mg, 0.54 mmol) and DMAP (33 mg, 0.27 mmol) were added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid from Example E45 (106 mg, 0.27 mmol) and 4-hydroxymethyl-piperidine-1-carboxylic acid benzyl ester (81 mg, 0.32 mmol) in di-chloromethane (5 ml) and DIEA (0.095 ml, 0.54 mmol). The mixture was stirred for 3 h at room temperature, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; EtOAc) to yield the title compound (44 mg, 26%).
Reaction SMILES: O1[C:5]2([CH2:9][CH2:8][N:7]([CH2:10][C:11]3[NH:12][C:13](=[O:26])[C:14]4[S:19][C:18]([C:20]5[CH:21]=[N:22][NH:23][C:24]=5[CH3:25])=[CH:17][C:15]=4[N:16]=3)[CH2:6]2)[O:4]CC1.Cl.C(=O)([O-])O.[Na+]>CC(O)C>[CH3:25][C:24]1[NH:23][N:22]=[CH:21][C:20]=1[C:18]1[S:19][C:14]2[C:13](=[O:26])[NH:12][C:11]([CH2:10][N:7]3[CH2:8][CH2:9][C:5](=[O:4])[CH2:6]3)=[N:16][C:15]=2[CH:17]=1
Reactant: Cc1[nH]ncc1-c1cc2nc(CN3CCC4(C3)OCCO4)[nH]c(=O)c2s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1[nH]ncc1-c1cc2nc(CN3CCC(=O)C3)[nH]c(=O)c2s1
Temperature: 90 °C
Yield: 86.9 %

Procedure:
A mixture of 2-(1,4-dioxa-7-azaspiro[4.4]non-7-ylmethyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one (150 mg) produced in Example 39, step D, 6M hydrochloric acid (3 mL) and propan-2-ol (3 mL) was stirred with heating at 90° C. for 5 hr. Saturated aqueous sodium hydrogen carbonate (20 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration, and washed successively with ethyl acetate (3 mL) and water (3 mL). The obtained pale-brown solid was crystallized from methanol/propan-2-ol/hexane to give the title compound (115 mg) as a pale-brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C[O:26]CC(Cl)=O.C(N(CC)CC)C>O1CCCC1>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:18])=[O:26])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCC(=O)Cl
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(N)c3)c2c1

Procedure:
The title compound was prepared using 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.150 g, 0.47 mmol) in tetrahydrofuran (5 mL), 2-methoxy acetyl chloride (0.086 mL, 0.94 mmol) and triethyl amine (0.327 mL, 2.35 mmol). The crude product was isolated after partition of the reaction mixture between ethyl acetate and water. The yield was not calculated: ES-MS (m/z) 391 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[C:16]3[C:11](=[C:12]([O:19][CH3:20])[C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](Cl)=[O:31])[CH:25]=[CH:26][C:27]=1[Cl:28]>C(Cl)(Cl)Cl>[ClH:21].[N:1]1([CH2:6][C:7]2([C:30](=[O:31])[CH2:29][C:24]3[CH:25]=[CH:26][C:27]([Cl:28])=[C:22]([Cl:21])[CH:23]=3)[C:16]3[C:11](=[C:12]([O:19][CH3:20])[C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Reactant: COc1ccc2c(c1OC)CCNC2CN1CCCC1
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1OC)CCNC2(CN1CCCC1)C(=O)Cc1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 105.7 %

Procedure:
Prepared as Ex. No. 33, from 1.3 g (4.71 mmoles) of 1-(pyrrolidin-1-yl)methyl-5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 1.1 g (4.92 mmoles) of 3,4-dichlorophenyl acetyl chloride in 40 ml of dry chloroform. The crude product was crystallized from 40 ml of ethyl acetate, to yield 1.3 g of the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:8][C:9](=[O:11])[O-:10])[CH2:3][N+:4]([CH3:7])([CH3:6])[CH3:5].[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14].CC(C)=O>FC(F)(F)C(O)=O>[C:12]([C:2]([CH2:8][C:9](=[O:10])[O-:11])([CH2:3][N+:4]([CH3:7])([CH3:5])[CH3:6])[OH:1])(=[O:16])[CH:13]([CH3:15])[CH3:14]
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Reactant: CC(C)C(=O)Cl
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)C(O)(CC(=O)[O-])C[N+](C)(C)C
Reaction time: 4 h
Yield: 57.6 %

Procedure:
To a solution of carnitine (3 grams; 0.015 mole) in trifluoroacetic acid (5 cc), isobutyryl chloride (10 cc; 0.096 moles) was added dropwise. The resulting mixture was kept at 45° C. for 4 hours, acetone was added thereto and the residual carnitine was filtered off. Anhydrous ethyl ether was added to the solution and the desired product (2 grams; yield 66%) was obtained by precipitation.
Reaction SMILES: [CH2:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH2:4][NH:3][CH2:2]1.Cl.Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)=O>[N+:18]([C:17]1[C:12]([N:3]2[CH2:2][CH:1]=[C:6]([C:7]([OH:9])=[O:8])[CH2:5][CH2:4]2)=[N:13][CH:14]=[CH:15][CH:16]=1)([O-:20])=[O:19]
Reactant: O=C(O)C1=CCNCC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=CO
Product: O=C(O)C1=CCN(c2ncccc2[N+](=O)[O-])CC1
Yield: 43.8 %

Procedure:
A well homogenised mixture of isoguvacine hydrochloride (497 mg, 3.04 mmol), 2-chloro-3-nitro-pyridine (482 mg, 3.04 mmol) and potassium carbonate (882 mg, 6.38 mmol), was stirred at 60° C. for 1.5 h. The reaction mixture was cooled, poured into a solution of water and formic acid (pH=3) and extracted with dichloromethane. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc—Petroleum Ether-Acetic Acid 20:80:0.05) affording the title product (332 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH2:4][CH2:3]1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:19]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH2:4][CH2:3]1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCc2cc(N3CCC(O)CC3)ccc2N1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC1CCN(c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 40 h
Yield: 96.5 %

Procedure:
To a solution of 200 mg of 6-(4-hydroxypiperidino)-3,4-dihydrocarbostyril in 2 ml of pyridine were added 92 mg of acetic anhydride and 10 mg of 4-dimethylaminopyridine. After stirring at room temperature for 40 hr, the reaction mixture was concentrated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography to give 226 mg of 6-(4-acetoxypiperidino)-3,4-dihydrocarbostyril.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:6]=[CH:5][C:4]=1[C:15]([O:17]CC)=[O:16])#[N:2].C([OH:22])C.[OH-].[K+]>O>[C:15]([C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[C:3]=1[C:1]([NH2:2])=[O:22])([OH:17])=[O:16]
Reactant: CCOC(=O)c1cnn(-c2cccc(C)c2)c1C#N
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(-n2ncc(C(=O)O)c2C(N)=O)c1

Procedure:
A 9 g. portion of ethyl 5-cyano-1-(3-methylphenyl)-4-pyrazolecarboxylate was dissolved in 200 ml. of ethanol, and 5.8 g. of potassium hydroxide wasadded. The mixture was stirred under reflux for 4 hours, and then was cooled, diluted with water and made acid. The mixture was filtered, and the solids were washed with ethyl acetate as shown above in Example 8 to obtain 3.8 g. of the desired product, m.p. 209°-211° dec. Itwas identified by elemental analysis.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][CH2:12][C:13](=O)[N:14]([CH3:16])[CH3:15])=[CH:9][NH:8][C:7]=1[CH3:18])=[O:5])[CH3:2].B.O1CCCC1.CO>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[CH:9][NH:8][C:7]=1[CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CCC(=O)N(C)C)c[nH]c1C
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1c(CCCN(C)C)c[nH]c1C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To a heterogeneous mixture of 4-(2-dimethylcarbamoyl-ethyl)-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (1.01 g, 4 mmol) in tetrahydrofuran (9 mL) was added dropwise 8 mL of borane-tetrahydrofuran complex (1M solution in tetrahydrofuran). The mixture was heated to reflux overnight. Nine mL of methanol was added slowly to the reaction and the heating was continued for another 2 hours. The cooled reaction was quenched with 1 N hydrochloric acid and extracted with ethyl acetate. The aqueous layer was basified with aqueous potassium hydroxide, extracted with ethyl acetate, and the organic layer washed with brine, dried and concentrated to give 616 mg (65% yield) of 4-(3-dimethylamino-propyl)-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester as a faint orange oil. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 10.84 (br s, 1H, NH), 6.36 (d, 1H), 4.12 (q, 2H, OCH2), 2.52 (m, 2H, CH2), 2.34 (s, 3H, CH3), 2.17 (m, 2H, CH2), 2.08 (s, 6H, N(CH3)2), 1.57 (m, 2H, CH2), 1.23 (t, 3H, CH3).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][N:10]2[C:19]3[C:14](=[C:15]([CH:20]4[O:24][CH2:23][CH2:22][O:21]4)[CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][C:11]2=[O:25])[CH:6]=[CH:5][CH:4]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.O.C(O)(=O)C>C(OCC)(=O)C>[O:21]1[CH2:22][CH2:23][O:24][CH:20]1[C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[CH2:13][CH2:12][C:11](=[O:25])[N:10]2[CH2:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[N:8]=1
Reactant: O=C1CCc2c(C3OCCO3)cccc2N1Cc1cccc(CCl)n1
Reactant: C1CCNCC1
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCc2c(C3OCCO3)cccc2N1Cc1cccc(CN2CCCCC2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
1-(6-Chloromethylpyridin-2-ylmethyl)-5-(1,3-dioxolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (1.0 g, 2.8 mmol) was added to piperidine (2 ml), followed by stirring in an argon atmosphere at 100° C. for 2 hours. After cooling to room temperature, water and a small quantity of acetic acid were added to the reaction mixture, and extraction with ethyl acetate was performed twice. The organic layers were combined, washed twice with water and once with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The dry product was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 0.73 g (yield: 64%) of 5-(1,3-dioxolan-2-yl)-1-(6-piperidinomethylpyridin-2-ylmethyl)-3,4-dihydro-1H-quinolin-2-one as a light yellow amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19])[CH3:2].[H][H]>C1COCC1.[Pd]>[NH2:10][C:8]1[CH:7]=[CH:6][C:5]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:19])=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=1
Reactant: [H][H]
Reactant: CCOc1cc([N+](=O)[O-])ccc1N1CCCCC1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOc1cc(N)ccc1N1CCCCC1=O

Procedure:
235 mg (0.889 mmol) of the product from example 90A are dissolved in 40 ml of THF and admixed with 50 mg of 10% palladium on activated carbon. Hydrogenation is effected in a hydrogen atmosphere under standard pressure overnight, then the mixture is filtered with suction through kieselguhr, washed three times with THF and concentrated cautiously under reduced pressure. This affords 262 mg of crude product, which is converted further without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1.Cl.[OH:19][CH:20]1[CH2:23][NH:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:22]2[CH2:23][CH:20]([OH:19])[CH2:21]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: OC1CNC1
Reactant: Clc1cc(Cl)n2nc(-c3ccccc3)cc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: OC1CN(c2cc(Cl)nc3cc(-c4ccccc4)nn23)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
There was dissolved, in 1,4-dioxane (2 mL), 5,7-dichloro-2-phenyl-pyrazolo-[1,5-a]pyrimidine (64.5 mg, 0.244 mM), then 3-hydroxy-azetidine hydrochloride (29.4 mg, 0.268 mM) and potassium carbonate (74.2 mg, 0.537 mM) were added to the solution and the mixture was stirred at room temperature for 3 hours. The solvent was removed from this reaction mixture through distillation, the resulting residue was diluted with water and then extracted with methylene chloride. The resulting extracts were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with diethyl ether to thus give the title compound (42.4 mg, yield: 58%).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:23]1[CH:27]2[CH2:28][CH:29](Br)[CH:25]([CH2:26]2)[CH2:24]1>O>[CH:25]12[CH2:26][CH:27]([CH2:28][CH2:29]1)[CH2:23][CH:24]2[O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1]
Reactant: COc1ccc(C=O)cc1O
Reactant: BrC1CC2CCC1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OC1CC2CCC1C2
Temperature: 80 °C
Yield: 87.2 %

Procedure:
Isovanillin (50 g, 0.328 mol) is placed in a 1 liter round bottom flask which is equipped with a stir bar and reflux condenser and is charged with 500 ml of dimethylformamide, Potassium carbonate (45.3 , 0.328 mol) is added to the reaction mixture which is heated to 80° C. At this temperature exo-2-bromonorbornane (12.57 g, 0.072 mol, 0.219 equivalents) is added and the reaction mixture is heated to 120° C. for 48 hours. The reaction is then cooled to room temperature and poured into 300 ml of water. The aqueous layer is extracted with ethyl ether (3×100 ml). The ethereal layer is washed with 1N sodium hydroxide solution. (4×100 ml), water (3×100) ml) and saturated sodium chloride solution (3×100 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield 15.47 g of a green/brown oil. The crude product is purified with flash chromatography using a gradient eluent system of ethyl acetate/hexane [10% ethyl acetate/hexane →20% ethyl acetate/hexane] to yield 7.76 g (14.4%) of the aldehyde as a white solid. MP: 75.5° C.-79.5° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:6]=1[CH:7]=[O:8].[OH-:32].[Na+].[CH3:34]O>>[CH3:34][O:32][C:2]1[N:3]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:6]=1[CH:7]=[O:8]
Reactant: CO
Reactant: [OH-]
Reactant: NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(-c3ccccc3)nc(Cl)c2C=O)cc1
Agent: [Na+]
Product: COc1nc(-c2ccccc2)n(Cc2ccc(-c3ccccc3S(N)(=O)=O)cc2)c1C=O

Procedure:
700 mg of 4′-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonamide (Example 11 b) and 620 mg of NaOH were dissolved in 10 ml of methanol and heated under reflux for 1 hour. The solvent was removed in vacuo, the residue was taken up with 20 ml of water, the solution was adjusted to pH=7 using aqueous HCl solution and the precipitate was filtered off. It was dried in vacuo, and 650 mg of a colorless solid were obtained,