Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:33]=[C:34](\[C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([F:50])[CH:39]=2)/[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1>C(Cl)Cl>[CH:28]1(/[CH:33]=[C:34](\[C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([F:50])[CH:39]=2)/[C:35]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1F
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 19.6 %

Procedure:
A solution of triphenylphosphine (262 mg, 1 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (178 mg, 1 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with (E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid (158 mg, 0.5 mmol). The reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (150 mg, 1.5 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (20 mL) and a 1N aqueous hydrochloric acid solution (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×15 mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded (E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-acrylamide (39 mg, 20%) as a white solid: mp 158-162° C.; EI-HRMS m/e calcd for C19H19FN6OS (M+)) 398.1325, found 398.1323.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.Cl[C:24]1[NH:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1.Cl>C(O)CCC.CN(C=O)C.O1CCOCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:24]4[NH:28][C:27]5[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=5[N:25]=4)=[CH:20][CH:21]=3)[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc(N)cc1
Reactant: Clc1nc2ccccc2[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCCCO
Solvent: C1COCCO1
Product: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc(Nc2nc3ccccc3[nH]2)cc1
Yield: 20.2 %

Procedure:
A solution of ethyl 4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (50.0 mg, 0.17 mmol) and 2-chlorobenzimidazole (30.2 mg, 0.17 mmol) in n-butanol (5 mL) and DMF (1 mL) were heated (90° C.) overnight in the presence of a trace amount of 4 M hydrogen chloride in dioxane. After cooling, the solution was concentrated under reduced pressure and the residue was purified by HPLC to afford the desired product (14.2 mg, 19%). 1H-NMR (300 MHz, DMSO-d6) 8.09 (s, 1H), 8.05 (br s, 1H), 7.89 (s, 1H), 7.79-7.85 (m, 2H), 7.24-7.34 (m, 4H), 6.89-6.99 (m, 2H), 5.14 (br, s, 1H), 4.06 (q, J=7.1 Hz, 2H), 1.09 (t, J=7.1 Hz, 3H); ES-MS m/z 414.3 (MH)+; HPLC RT (Method A) 2.57 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]([C:11]#[N:12])=[C:6](SC)[S:7][CH3:8])[CH3:2].FC(F)(F)C(O)=O.[CH:21]1([NH:24][C:25](=[O:35])[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([NH:33][NH2:34])[CH:27]=2)[CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]([S:7][CH3:8])=[N:34][N:33]([C:28]2[CH:27]=[C:26]([C:25](=[O:35])[NH:24][CH:21]3[CH2:23][CH2:22]3)[CH:31]=[CH:30][C:29]=2[CH3:32])[C:11]=1[NH2:12])=[O:13])[CH3:2]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NN
Reactant: CCOC(=O)C(C#N)=C(SC)SC
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(SC)nn(-c2cc(C(=O)NC3CC3)ccc2C)c1N
Temperature: 65 °C
Yield: 68.3 %

Procedure:
To a solution of 2-cyano-3,3-bis-methylsulfanyl-acrylic acid ethyl ester 15 (78.0 mg, 0.359 mmol) in ethanol (3 ml) was added N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt (0.100 g, 0.313 mmol) and diisopropylethylamine (0.0626 ml, 0.359 mmol). The mixture was heated to 65° C. for 2 h. The mixture was cooled to room temperature. Solvents were removed in vacuo. EtOAc and ether was added to the residue and a solid precipitated. The solid was collected on a flitted funnel and was washed with EtOAc and ether to give the desired 5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid ethyl ester 16 as a white solid (80 mg, 59%). HPLC (4 minute 10-90 gradient) tR 2.18 min; MS m/z 375.1 [M+H]+; 1H NMR (DMSO-d6, 300 MHz) δ 8.47 (d, J=3.7, 1H), 7.90 (d, J=7.9, 1H), 7.78 (s, 1H), 7.49 (d, J=8.0, 1H), 6.81 (bs, 2H), 6.30 (s, 2H), 2.86 (m, 1H), 2.45 (s, 3H), 2.11 (s, 3H), 0.68 (m, 2H), 0.57 (m, 2H) ppm.HPLC (4 minute 10-90 gradient) tR1.66 min; MS m/z 378.1 [M+H]+; 1H NMR (DMSO-d6, 300 MHz) δ 8.50 (d, J=2.6, 1H), 7.92 (d, J=7.9, 1H), 7.81 (s, 1H), 7.51 (d, J=7.9, 1H), 6.24 (bs, 2H), 4.22 (q, J=6.6, 2H), 2.88 (m, 1H), 2.35 (s, 3H), 2.14 (s, 3H), 1.29 (t, J=6.7, 3H), 0.72 (m, 2H), 0.58 (m, 2H) ppm; 13C NMR (DMSO-d6, 125 MHz) δ 166.0, 163.1, 151.8, 148.5, 139.4, 135.8, 132.9, 131.1, 128.2, 126.7, 91.3, 58.9, 23.0, 17.2, 14.4, 12.3, 5.6 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][C:22]3[CH:35]=[CH:34][C:25]([CH:26]=[C:27]4[S:31][C:30](=[O:32])[NH:29][C:28]4=[O:33])=[CH:24][CH:23]=3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(OCC)(=O)C>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][O:21][C:22]3[CH:35]=[CH:34][C:25]([CH2:26][CH:27]4[S:31][C:30](=[O:32])[NH:29][C:28]4=[O:33])=[CH:24][CH:23]=3)=[CH:17][CH:18]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Oc2ccc(CCOc3ccc(C=C4SC(=O)NC4=O)cc3)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)Oc2ccc(CCOc3ccc(CC4SC(=O)NC4=O)cc3)cc2)cc1
Reaction time: 4 h
Yield: 41.4 %

Procedure:
1.2 g (2.35 mmole) 5-(4-[2-(4-(4-methoxyphenylsulfonyloxy)phenyl)ethoxy]benzylidene)thiazolidine-2,4-dione was mixed with 200 ml warm ethyl acetate, 2 ml acetic acid and 1.2 g Pd/C (5%, 50% water) and hydrogenated for 4 hours at room temperature. 1.2 g more of the catalyst was added after 2 hours. The catalyst was filtered off and the solvent was evaporated in vacuo. The crude product was purified by chromatography on silica gel using dichloromethane/diisopropyl ether (gradient) as eluent to give 0.5 g of the desired product.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[Br:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22](B(O)O)=[C:21]([CH3:29])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[Br:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([Pb+3:17])=[C:21]([CH3:29])[CH:20]=1
Reactant: [Pb+4]
Reactant: Cc1cc(Br)cc(C)c1B(O)O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(Br)cc(C)c1[Pb+3]
Temperature: 40 °C
Yield: 25.1 %

Procedure:
To a mixture of lead tetraacetate (112.16 g, 0.25 mol) and mercuric diacetate (4.8 g, 0.015 mol), thoroughly flushed with nitrogen, is added anhydrous chloroform (480 ml). This mixture is warmed to 40° C. and 4-bromo-2,6-dimethylphenylboronic acid (48 g, 0.21 mol) is added in one portion and the mixture is stirred and heated at this temperature for 4 hours. After cooling in an ice bath, powdered anhydrous potassium carbonate (350 g) is added rapidly followed by rapid stirring for 5 minutes. The solids are removed by filtration and the filtrate is concentrated to approximately a quarter of its volume. Hexane is added to induce crystallization and the solvents evaporated under reduced pressure. Trituration with hexane gives 4-bromo-2,6-dimethylphenyl lead triacetate (30 g).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH3:10])[CH:5]1[OH:11].[CH2:12]([O:19][C:20]1[C:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:23]([C:33](=[O:37])[N:34]([CH3:36])[CH3:35])[N:22]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:21]=1[C:46](OCC)=[O:47])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH2:12]([O:19][C:20]1[C:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:23]([C:33](=[O:37])[N:34]([CH3:35])[CH3:36])[N:22]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:21]=1[C:46]([O:11][CH:5]1[CH:6]([CH3:10])[CH2:7][CH2:8][CH2:9][CH:4]1[CH3:3])=[O:47])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Reactant: CC1CCCC(C)C1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2c(C(=O)OC3C(C)CCCC3C)c(OCc3ccccc3)c(OCc3ccccc3)c2C(=O)N(C)C)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 30.6 %

Procedure:
Sodium hydride (60 wt % in oil) (78 mg, 1.95 mmol) was added to a stirred solution of 2,6-dimethylcyclohexanol (250 mg, 1.95 mmol) in DMF (1.95 mL). The mixture was heated at 60° C. for 10 min and then ethyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (6) (206 mg, 0.39 mmol) was added in one portion. The reaction was allowed to stir at 70° C. for 16 h. The cooled reaction mixture was filtered through Celite, and the filtrate diluted with EtOAc (20 mL) and washed with water (3×10 mL), the organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (12 g, 0.5% MeOH (1% NH3) in DCM) to afford 2,6-dimethylcyclohexyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (45) (73 mg, 20%) as a brown oil. m/z 611 (M+H)+ (ES+)
Reaction SMILES: [C:1]1(/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][CH:2]=1.[CH3:21][O:22][C@H:23]1[O:28][C@H:27]([CH2:29][O:30][S:31]([O-:34])(=[O:33])=[O:32])[C@@H:26]([O:35][C@@H:36]2[O:41][C@@H:40]([C:42]([OH:44])=[O:43])[C@@H:39]([O:45][C@H:46]3[O:51][C@H:50]([CH2:52][O:53][S:54]([O-:57])(=[O:56])=[O:55])[C@@H:49]([O:58][C@@H:59]4[O:64][C@H:63]([C:65]([OH:67])=[O:66])[C@@H:62]([O:68][C@H:69]5[O:74][C@H:73]([CH2:75][O:76][S:77]([O-:80])(=[O:79])=[O:78])[C@@H:72]([OH:81])[C@H:71]([OH:82])[C@H:70]5[NH:83][S:84]([O-:87])(=[O:86])=[O:85])[C@H:61]([OH:88])[C@H:60]4[OH:89])[C@H:48]([O:90][S:91]([O-:94])(=[O:93])=[O:92])[C@H:47]3[NH:95][S:96]([O-:99])(=[O:98])=[O:97])[C@H:38]([OH:100])[C@H:37]2[O:101][S:102]([O-:105])(=[O:104])=[O:103])[C@H:25]([OH:106])[C@H:24]1[NH:107][S:108]([O-:111])(=[O:110])=[O:109].[Na+:112].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+]>O.[Pd]>[CH2:11]([C:12]1[CH:13]=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[CH:16][CH:17]=1)[CH2:10][C:1]1[CH:2]=[CH:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][CH:6]=1.[CH3:21][O:22][C@H:23]1[O:28][C@H:27]([CH2:29][O:30][S:31]([O-:34])(=[O:32])=[O:33])[C@@H:26]([O:35][C@@H:36]2[O:41][C@@H:40]([C:42]([OH:44])=[O:43])[C@@H:39]([O:45][C@H:46]3[O:51][C@H:50]([CH2:52][O:53][S:54]([O-:57])(=[O:56])=[O:55])[C@@H:49]([O:58][C@@H:59]4[O:64][C@H:63]([C:65]([OH:67])=[O:66])[C@@H:62]([O:68][C@H:69]5[O:74][C@H:73]([CH2:75][O:76][S:77]([O-:80])(=[O:78])=[O:79])[C@@H:72]([OH:81])[C@H:71]([OH:82])[C@H:70]5[NH:83][S:84]([O-:87])(=[O:85])=[O:86])[C@H:61]([OH:88])[C@H:60]4[OH:89])[C@H:48]([O:90][S:91]([O-:94])(=[O:93])=[O:92])[C@H:47]3[NH:95][S:96]([O-:99])(=[O:98])=[O:97])[C@H:38]([OH:100])[C@H:37]2[O:101][S:102]([O-:105])(=[O:104])=[O:103])[C@H:25]([OH:106])[C@H:24]1[NH:107][S:108]([O-:111])(=[O:110])=[O:109].[Na+:112].[Na+:112].[Na+:112].[Na+:112].[Na+:112].[Na+:112].[Na+:112].[Na+:112].[Na+:112].[Na+:112]
Reactant: O=C(O)c1ccc(/C=C/c2ccc(C(=O)O)cc2)cc1
Agent: [Pd]
Agent: CO[C@H]1O[C@H](COS(=O)(=O)[O-])[C@@H](O[C@@H]2O[C@@H](C(=O)O)[C@@H](O[C@H]3O[C@H](COS(=O)(=O)[O-])[C@@H](O[C@@H]4O[C@H](C(=O)O)[C@@H](O[C@H]5O[C@H](COS(=O)(=O)[O-])[C@@H](O)[C@H](O)[C@H]5NS(=O)(=O)[O-])[C@H](O)[C@H]4O)[C@H](OS(=O)(=O)[O-])[C@H]3NS(=O)(=O)[O-])[C@H](O)[C@H]2OS(=O)(=O)[O-])[C@H](O)[C@H]1NS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(CCc2ccc(C(=O)O)cc2)cc1

Procedure:
A solution of 0.2 g of (E)-stilbene-4,4'-dicarboxylic acid bis-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylamide) decasodium salt (see Example 2) in 15 ml of water was hydrogenated at room temperature for 3 hours in the presence of 10% palladium on charcoal. The catalyst was filtered off and the filtrate was concentrated. The residue was purified over an ion exchange column and gave 4,4'-ethylene-dibenzoic acid bis-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylamide) decasodium salt, [α]D20 -4.8° (c 0.4; water), MS: m/z 1616.5 (reconstructed M).
Reaction SMILES: [C:1]([CH:4]1[CH2:13][CH2:12][C:11]2[NH:10][C:9](=[O:14])[N:8]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[N:17]=[C:7]3[C:6]=2[CH2:5]1)([OH:3])=O.[CH3:25][NH:26][CH3:27].O>CN(C=O)C>[CH3:25][N:26]([CH3:27])[C:1]([CH:4]1[CH2:13][CH2:12][C:11]2[NH:10][C:9](=[O:14])[N:8]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[N:17]=[C:7]3[C:6]=2[CH2:5]1)=[O:3]
Reactant: CNC
Reactant: O=C(O)C1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture containing 9-Carboxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (150 mg) and 1,1-carbonyldiimadazole (120 mg) in DMF (5 mL) was heated to 60° C. for 15 min after which time the reaction was cooled and 2 mL of dimethylamine added. The reaction was allowed to stand at room temperature for 1 hour. To the mixture was then added 10 mL of H2O and the resultant product was collected and dried to yield 9-(N,N-Dimethylcarbamyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (Compound 18), m.p.>325° C.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]3[CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22][C:17]=3[NH:16][N:15]=2)=[CH:10][CH:9]=1.Br[CH2:27][CH2:28][CH2:29][Cl:30].O>CN(C=O)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:18]3[CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22][C:17]=3[N:16]([CH2:27][CH2:28][CH2:29][Cl:30])[N:15]=2)=[CH:12][CH:13]=1
Reactant: ClCCCBr
Reactant: CC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)cc3)nn2CCCCl)C1
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
Cs2CO3 (2.66 g, 8.2 mmol) was added to a solution of 1-[3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (1.0 g, 5.4 mmol) in DMF (10 mL) and stirred for 15 min. 1-Bromo-3-chloropropane (1.28 g, 8.2 mmol) was added and stirred under N2 at room temperature for 36 h. Water (50 mL) was added to the reaction and stirred for 5 min. The product precipitated out. The aqueous portion was decanted and water was added to the residue and decanted again. The semisolid was taken up in CH2Cl2 and passed through a short plug of SiO2 (5% MeOH/EtOAc) to obtain 1.06 g (83%) of a pale yellow semisolid. MS (electrospray): exact mass calculated for C17H19Cl2N3O, 351.09; m/z found, 352.0 [M+H]+. 1H NMR (500 MHz, CDCl3, a mixture of 1:1 rotamers): 7.60 (d, J=8.3 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.36 (d, J=8.3 Hz, 1H), 4.77 (s, 1H), 4.61 (s, 1H), 4.20 (t, J=6.2 Hz, 2H), 3.94 (t, J=5.8 Hz, 1H), 3.76 (t, J=5.8 Hz, 1H), 3.52 (q, J=6.1 Hz, 2H), 2.84 (t, J=5.5 Hz, 1H), 2.77 (t, J=5.6 Hz, 1H), 2.37 (sextet, J=6.1 Hz, 2 H), 2.21 (s, 1.5 H), 2.16 (s, 1.5 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:16]=[C:15]([C:17]([OH:19])=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[N:3][CH:2]=1.Cl.[OH:21][C:22]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:16]=[C:15]([C:17]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:22]=4[OH:21])[CH2:27]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[N:3][CH:2]=1
Reactant: O=C(O)c1nc(-c2ccncn2)nc2ccccc12
Reactant: COc1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccncn3)nc3ccccc13)C2
Yield: 13 %

Procedure:
Reaction of 2-(4-pyrimidinyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 70 (13% yield) as a light brown solid. 1H NMR (300 MHz, DMSO-d6) δ 2.61 and 2.90 (2t, 2H), 3.49 and 4.04 (2t, 2H), 3.73 and 3.80 (2s, 3H), 4.38 and 4.92 (2s, 2H), 6.30 and 6.77 (2d, 1H), 6.70 and 6.91 (2d, 1H), 7.90-8.31 (m, 4H), 8.48-8.54 (m, 1H), 8.68-8.74 (2s, 1H), 9.06-9.43 (m, 1H), 9.44 (s, 1H); MS (ESI) m/z 414 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl[C:28]([O:30]C)=[O:29].[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36]>C(Cl)Cl.C(O)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36].[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:28](=[O:29])[OH:30])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: COC(=O)Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)NCCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 1 h

Procedure:
A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.0 gm, 7.6 mmol) and triethylamine (1.0 gm, 10 mmol) in DCM (50 ml) was treated with methyl chloroformate (860 mg, 9.12 mmol) dropwise at room temperature. The mixture was stirred for 1 hr. The reaction mixture was diluted with DCM and washed with brine. The organic solution was dried over MgSO4 and concentrated to a crude oil. The purification was done by flash chromatography over a silica gel column (28 gm of Sorbsil C-30, eluted with DCM and MeOH/DCM). The pure oil thus obtained weighed 2.34 gm. It was converted to a fumarate salt by treatment with fumaric acid (840 mg, 1.0 eq) in ethanol. Crystallization was induced by adding drops of isopropyl ether, yield: 2.31 gm, m.p.=163°-165° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH:12]([OH:24])[C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH2:11][CH2:10][CH2:9]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH:8]1([C:12]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][CH:23]=2)=[O:24])[CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)c1ccc(C(O)C2CCC2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(C(=O)C2CCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
Trifluoroacetic acid (613 mg, 5.38 mmol) was added dropwise to a 0° C. solution of ethyl 4-(cyclobutyl(hydroxy)methyl)benzoate (700 mg, 3 mmol) in dichloromethane (10 mL). Then Dess-Martin periodinane (2.03 g, 4.78 mmol) was added and the reaction was warmed to room temperature and stirred for 2 hours. The reaction was quenched with 1 N aqueous sodium hydrosulfite (10 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave ethyl 4-(cyclobutanecarbonyl)benzoate (540 mg, 78%) as an oil. 1H NMR (400 MHz, CDCl3, δ): 8.04 (d, J=8.4 Hz, 2H), 7.86 (d, J=8.4 Hz, 2H), 4.33 (q, J=7.2 Hz, 2H), 3.90-3.99 (m, 1H), 2.20-2.40 (m, 4H), 2.00-2.09 (m, 1H), 1.81-1.90 (m, 1H), 1.34 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1O[CH:7]=[CH:6][C:4](=[O:5])[C:3]=1[OH:9].[NH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>O>[N:11]1([N:10]2[CH:7]=[CH:6][C:4](=[O:5])[C:3]([OH:9])=[C:2]2[CH3:1])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NN1CCCCC1
Reactant: Cc1occc(=O)c1O
Solvent: O
Product: Cc1c(O)c(=O)ccn1N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Maltol (3.6 g, 30 mmol) and 1-aminopiperidine (4.5 g, 45 mmol) were suspended in 100 mL of water. The mixture was heated to reflux for 2 days. The mixture was cooled to room temperature, and the solvent was removed under vacuum to give a dark brown liquid. The residue was allowed to stand overnight, a solid was formed. The solid was collected by filtration and was then recrystallized in water to give brownish microcrystals. The product was collected by filtration, washed with water, and dried under vacuum overnight. The yield was 0.64 g (˜10.2%). LC-MS: M/z=209.3 for [C11H16N2O2]+. 1H NMR (600 MHz, in CD3OD, chemical shift in ppm relative to TMS): 1.34 (m, 1H, CH2); 1.81 (m, 5H, CH2); 2.40 (s, 3H, CH3); 3.00 (m, 4H, CH2); 6.43 (d, 1H, JHH=7.5 mHz, CH2/pyridinone); and 7.99 (d, 1H, JHH=7.5 mHz, CH/pyridinone).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([O:21][CH3:22])[C:8]([Cl:23])=[C:7]([CH3:24])[C:6]=1[C:25](=[O:27])[CH3:26].Cl.[F:29][C:30]1([F:34])[CH2:33][NH:32][CH2:31]1>>[Cl:23][C:8]1[C:7]([CH3:24])=[C:6]([C:25](=[O:27])[CH3:26])[C:5]([O:4][CH2:3][CH2:2][N:32]2[CH2:33][C:30]([F:34])([F:29])[CH2:31]2)=[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]=1[O:21][CH3:22]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCCc1ccccc1
Reactant: FC1(F)CNC1
Agent: Cl
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CC(F)(F)C2)c1OCCCc1ccccc1
Yield: 20 %

Procedure:
Example 34b (105 mg, 0.23 mmol) was reacted with 3,3-difluoroazetidine hydrochloride (2.0 eq.) as described under General Procedure J and the crude mixture was purified by flash chromatography (silica gel, hexane/Et2O 70:30) to afford the title compound (21 mg, 20%) as a light orange oil. 1H NMR (300 MHz, CDCl3) δ 7.33-7.20 (m, 5H), 4.07 (t, J=6.5 Hz, 2H), 4.01 (t, J=5.6 Hz, 2H), 3.88 (s, 3H), 3.63 (t, J=12.0 Hz, 4H), 2.85-2.80 (m, 4H), 2.51 (s, 3H), 2.20 (s, 3H), 2.12-2.06 (m, 2H). MS (ES+) m/z 468.2 (M+H+).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:17][CH:18]=1)=[O:13])[CH3:10].C1(C)C=CC=CC=1>C(O)(=O)C>[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:17][C:18]=1[Br:1])=[O:13])[CH3:10]
Reactant: CCOC(=O)c1csc(-c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(-c2ccccc2)sc1Br
Reaction time: 8 h
Yield: 56.5 %

Procedure:
N-Bromosuccinimide (1.22 g, 6.83 mmol) was added to a solution of ethyl-2-phenylthiophen-4-carboxylate (6.83 mmol) in acetic acid (10 mL) and stirred overnight. Toluene was added and the solvent was removed under vacuum. The product was purified by flash chromatography on silica, eluting with 0%-10% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (1.2 g). LCMS m/z 312.52 [M+H]+ R.T.=4.55 mins (Analytical Method 5).