Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]2[N:3]=1.[C:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[CH:9]1([NH:8][C:6]2[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]3[N:3]=[C:2]([N:27]3[CH2:26][CH2:25][N:24]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:29][CH2:28]3)[CH:7]=2)[CH2:11][CH2:10]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(NC3CC3)n3ncc(C=O)c3n2)CC1
Temperature: 80 °C
Yield: 80.3 %

Procedure:
To 5-chloro-7-(cyclopropylamino) pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (500 mg, 2.11 mmol) in dimethylformamide was added 1-Boc-piperazine (1.17 g, 6.33 mmol), potassium carbonate (583 mg, 4.21 mmol) and diisopropyl ethylamine (0.41 mL, 2.5 mmol). The mixture was heated to 80° C. for overnight. Cooled the reaction mixture, added water and filtered the white precipitate to yield tert-butyl 4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate (655 mg, 80% yield). LCMS (M+1=387)
Reaction SMILES: [CH2:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH:6]=[CH:7][CH2:8]2)[CH2:3][NH:2]1.[CH:10]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)=[CH2:11].C(O)(=O)C>CO>[N:15]1[CH:16]=[CH:17][C:12]([CH2:10][CH2:11][N:2]2[CH2:3][C@H:4]3[C@H:9]([CH2:8][CH:7]=[CH:6][CH2:5]3)[CH2:1]2)=[CH:13][CH:14]=1
Reactant: C=Cc1ccncc1
Reactant: C1=CC[C@H]2CNC[C@H]2C1
Solvent: CC(=O)O
Solvent: CO
Product: C1=CC[C@H]2CN(CCc3ccncc3)C[C@H]2C1

Procedure:
A mixture of 0.64 g of cis-3a,4,7,7a-tetrahydroisoindoline, 0.6 mL of 4-vinylpyridine, 0.4 mL of acetic acid and 10 mL of methanol was heated under reflux for 16 hours. Removal of the solvent and short-path distillation of the residue (160° bath temperature, 0.002 mm) gave 0.74 g. of cis-2-(4-pyridylethyl)-3a,4,7,7a-tetrahydropyridine. 1H NMR (in CDCl3) δ8.5 (d, 2H); 7.1 (d, 2H); 5.8 (m, 2H); 3.0 (m, 2H); 2.7-2.8 (m, 4H); 2.4 (m, 2H); 2.2-2.3 (m, 4H) and 1.9 (d, 2H). The dihydrochloride hemi-hydrate had an indefinite melting point after crystallization from 2-propanol. Anal. Calcd. for C15H22Cl2N2.1/2H2O: C, 58.07; H, 7.47; N, 9.03. Found: C, 58.27; H, 7.47; N, 9.15.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:21])[CH2:19][CH3:20])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].[N:22]1([C:26]([C:28]2[CH:29]=[C:30]([Cl:35])[C:31](Cl)=[N:32][CH:33]=2)=[O:27])[CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:22]1([C:26]([C:28]2[CH:29]=[C:30]([Cl:35])[C:31]([O:1][C:2]3[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:21])[CH2:19][CH3:20])[CH:16]=3)[C:5]([NH:7][C:8]3[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=3)=[O:6])=[N:32][CH:33]=2)=[O:27])[CH2:25][CH2:24][CH2:23]1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Reactant: CC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Reaction time: 6 h
Yield: 91.4 %

Procedure:
A solution of 3-hydroxy-5-{[(1S)-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (116 mg, 0.4 mmol) and the 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (111 mg, 0.48 mmol) in acetonitrile (2 mL) containing potassium carbonate (111 mg, 0.8 mmol) was heated with stirring in the microwave reactor for 6 hours at 160° C. The reaction mixture was filtered and the filtrate evaporated to dryness under reduced pressure and purified by chromatography on silica, eluting with 50-100% ethyl acetate in hexane, to give the required product (177 mg).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:16])[NH:4][N:5]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=CC=CC=2)[CH:7]=1.C(OC1N=NC(C=C2CC2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1>CO>[CH:9]1([CH2:8][C:6]2[CH:7]=[C:2]([OH:1])[C:3](=[O:16])[NH:4][N:5]=2)[CH2:10][CH2:15]1
Reactant: O=c1[nH]nc(CCc2ccccc2)cc1O
Agent: C(=C1CC1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Solvent: CO
Product: O=c1[nH]nc(CC2CC2)cc1O
Yield: 46 %

Procedure:
Prepared in the same manner as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-(cyclopropylidenemethyl)pyridazine (Intermediate 65) except that methanol was used as the reaction solvent. The crude compound was purified by preparative HPLC to yield 6-(cyclopropylmethyl)-4-hydroxypyridazin-3(2H)-one (46% yield)
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.CC(C)C([O:15][C@@H:16]1[C@@H:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](=[O:32])[O:22][CH2:21][C@H:20]([NH:33][C:34]([C:36]2[C:41]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[C:40]([O:50][CH3:51])[CH:39]=[CH:38][N:37]=2)=[O:35])[C:19](=[O:52])[O:18][C@H:17]1[CH3:53])=O>C(Cl)Cl>[CH2:25]([C@@H:24]1[C@@H:16]([OH:15])[C@H:17]([CH3:53])[O:18][C:19](=[O:52])[C@@H:20]([NH:33][C:34]([C:36]2[C:41]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[C:40]([O:50][CH3:51])[CH:39]=[CH:38][N:37]=2)=[O:35])[CH2:21][O:22][C:23]1=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](Cc3ccccc3)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](Cc3ccccc3)[C@@H](O)[C@H](C)OC2=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.8 %

Procedure:
Diisobutylaluminum hydride (1.0 M in CH2Cl2, 24.8 mmol) was added dropwise to a −78° C. solution of (2) (8.27 mmol, 5.0 g) in CH2Cl2 (40 mL). The mixture was stirred an additional 15 min, quenched with EtOAc (200 mL) and warmed to ambient temperature. Hydrochloric acid (2N, 100 mL) was added slowly and stirred vigorously for 15 min. The layers were separated and the organic layer dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (1% acetic acid/acetone) to give 1.54 g (35%) of 4 as a glassy, white solid, m.p. 110-114° C. 1H-NMR and MS (M+1 535) were consistent with the desired product.
Reaction SMILES: [O:1]=[C:2]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21](=[O:27])[NH:22][CH:23]2[CH2:26][CH2:25][CH2:24]2)=[O:15])[N:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]=1)=[O:6].N1C=CC=CC=1.[C:46](Cl)(=[O:51])[CH2:47][CH2:48][CH2:49][CH3:50]>ClCCl.CN(C1C=CN=CC=1)C>[O:1]=[C:2]([N:34]1[CH2:39][CH2:38][N:37]([C:46](=[O:51])[CH2:47][CH2:48][CH2:49][CH3:50])[CH2:36][CH2:35]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21](=[O:27])[NH:22][CH:23]2[CH2:24][CH2:25][CH2:26]2)=[O:15])[N:9]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:8]=1)=[O:6]
Reactant: CCCCC(=O)Cl
Reactant: O=C(NCC(=O)N1CCNCC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 50 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide in 4 ml dichloromethane were added at 0° C. 15 l pyridine, 13 l valeryl chloride and a catalytic amount of DMAP. After stirring for 12 h it was concentrated and the residue obtained was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=O)[NH:13][CH:12]=[N:11][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:14]1[C:15]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][S:9][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=c1[nH]cnc2scc(-c3ccccc3)c12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2scc(-c3ccccc3)c12
Temperature: 0 °C
Reaction time: 18 h

Procedure:
5-Phenyl-3H-thieno[2,3-d]pyrimidin-4-one (294.6 g, 1.29 mol) was added in portions to stirred phosphoryl chloride (1000 ml), then the stirred suspension was warmed gently to reflux temperature, heated under reflux for 4 hours, and allowed to stand at ambient temperature for 18 hours. The resulting dark solution was removed by decantation from a solid residue and concentrated in vacuo to give a gummy solid. The two solids were combined and added to crushed ice (1000 ml). The product was extracted into dichloromethane (3×500 ml), then the combined extracts were washed with water (2×300 ml) and saturated aqueous sodium hydrogen carbonate solution (500 ml) and dried and decolourised (MgSO4+charcoal). The solvent was removed in vacuo to give 4-Chloro-5-phenyl-thieno[2,3-d]pyrimidine as a yellow/orange solid which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:52]=[CH:51][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][C:28](=[O:35])[N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:25][C:19]=3[N:18]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]([N:45]4[CH2:49][CH:48]=[CH:47][CH2:46]4)=[O:44])=[CH:39][CH:38]=3)[C:17](=[O:50])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.C=O.[C:55](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][C:28]([N:29]4[CH2:34][CH2:33][N:32]([CH3:55])[CH2:31][CH2:30]4)=[O:35])=[CH:25][C:19]=3[N:18]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]([N:45]4[CH2:46][CH:47]=[CH:48][CH2:49]4)=[O:44])=[CH:39][CH:38]=3)[C:17](=[O:50])[CH2:16]2)=[O:14])=[CH:51][CH:52]=1
Reactant: O=C(CCc1ccc2c(c1)N(Cc1ccc(C(=O)N3CC=CC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2)N1CCNCC1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(C(=O)CCc2ccc3c(c2)N(Cc2ccc(C(=O)N4CC=CC4)cc2)C(=O)CN(C(=O)c2ccc(Cl)cc2)C3)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 mg (0.014 mmol) of 4-(4-chlorobenzoyl)-1-[4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzyl]-8-[3-oxo-3-(1-piperazinyl)propyl]-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on trifluoroacetate was dissolved in 2 ml of dichloromethane. 5 mg of paraformaldehyde and 0.005 ml (0.09 mmol) of acetic acid were added to the obtained solution and they were stirred at room temperature for 30 minutes. 24 mg (0.12 mmol) of sodium triacetoxyborohydride was added to the obtained mixture and they were stirred at room temperature overnight. The solvent was evaporated and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].Cl[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][CH3:21]>C(Cl)(Cl)Cl>[CH2:10]([O:9][C:7](=[O:8])[C:6]([C:18]1[CH:17]=[CH:16][C:15]([S:20][CH3:21])=[C:14]([Cl:13])[CH:19]=1)=[O:12])[CH3:11]
Reactant: CSc1ccccc1Cl
Reactant: CCOC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=O)c1ccc(SC)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
A solution of aluminum trichloride (34.8 g, 261.4 mmol) in chloroform (120 mL) cooled to 0° C. was treated with a solution of ethyl chlorooxoacetate (18.7 mL, 167.5 mmol) in chloroform (120 mL). The mixture was stirred at 0° C. for 30 min. At this time, a solution of 2-chlorothioanisole (25.0 g, 156.5 mmol) in chloroform (120 mL) was added dropwise to the reaction mixture. It was then allowed to warm to 25° C. and stirred for an additional 3.5 h at 25° C. At this time, the reaction was quenched by the slow addition of water (500 mL) and extracted with chloroform (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded (3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (31.37 g, 77%) as a yellow oil: EI-HRMS m/e calcd for C18H24Cl2N2O3 (M+) 386.1164, found 386.1154.
Reaction SMILES: [CH:1]1([C@@H:4]([NH:9][C:10]2[C:22]3[C:21]4[CH:20]=[CH:19][C:18]([C:23]#[CH:24])=[CH:17][C:16]=4[NH:15][C:14]=3[C:13]([C:25]([NH2:27])=[O:26])=[CH:12][N:11]=2)[C:5]([F:8])([F:7])[F:6])[CH2:3][CH2:2]1.[Si]([N:32]=[N+:33]=[N-:34])(C)(C)C>>[CH:1]1([C@@H:4]([NH:9][C:10]2[C:22]3[C:21]4[CH:20]=[CH:19][C:18]([C:23]5[N:32]=[N:33][NH:34][CH:24]=5)=[CH:17][C:16]=4[NH:15][C:14]=3[C:13]([C:25]([NH2:27])=[O:26])=[CH:12][N:11]=2)[C:5]([F:8])([F:6])[F:7])[CH2:3][CH2:2]1
Reactant: C#Cc1ccc2c(c1)[nH]c1c(C(N)=O)cnc(N[C@H](C3CC3)C(F)(F)F)c12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Product: NC(=O)c1cnc(N[C@H](C2CC2)C(F)(F)F)c2c1[nH]c1cc(-c3c[nH]nn3)ccc12
Temperature: 25 °C

Procedure:
1-{[(1R)-1-Cyclopropyl-2,2,2-trifluoroethyl]amino}-7-ethynyl-5H-pyrido[4,3-b]indole-4-carboxamide (0.13 g, 0.36 mmol) in TMS-azide (4 mL, 30 mmol) was heated to 150° C. for 18 h, cooled to room temperature, concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CD3SOCD3) δ 11.73 (s, 1H); 8.50 (d, 1H); 8.48 (s, 1H); 8.30 (br s, 1H); 8.22 (s, 1H); 7.93 (br s, 1H); 7.72 (d, 1H); 7.26 (br s, 1H); 6.98 (d, 1H); 4.85 (m, 1H); 1.58 (m, 1H); 0.72 (m, 1H); 0.62 (m, 1H); 0.51 (m, 1H); 0.31 (m, 1H). LRMS (APCI) calc'd for (C19H16F3N7O) [M+H]+, 416.1. found 416.1.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:17](=[O:24])[C:18]3[C:23]([C:15]=2[C:14]2[C:9](=[CH:10][C:11]([O:25]C)=[CH:12][CH:13]=2)[N:8]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:3].Br>C(O)(=O)C>[CH3:3][N:2]([CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:17](=[O:24])[C:18]3[C:23]([C:15]=2[C:14]2[C:9](=[CH:10][C:11]([OH:25])=[CH:12][CH:13]=2)[N:8]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:1]
Reactant: COc1ccc2c3c(c(NCCN(C)C)nc2c1)C(=O)c1ccccc1-3
Agent: Br
Solvent: CC(=O)O
Product: CN(C)CCNc1nc2cc(O)ccc2c2c1C(=O)c1ccccc1-2
Yield: 73.2 %

Procedure:
To a solution of 6-(((dimethylamino)ethyl)amino)-3-methoxy-7H-indeno[2,1-c]quinoline-7-on obtained in example 1 (3 g, 8.6 mmol) in acetic acid (40 ml) was added 47% aqueous hydrobromic acid (40 ml), and the mixture was-refluxed with heat for 60 hours. The reaction mixture was distilled to dryness. To the residue was added water and the solution was adjusted to a pH of about 8 with aqueous ammonia, and subsequently extracted with chloroform. The chloroform layer was dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol:water 8:3:1(v/v/v)) and crystallized from cyclohexane to give 2.1 g (yield: 73.0%) of title compound. The physicochemical properties thereof are shown in table 1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[O:17][CH3:18])\[CH3:7])[CH3:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[O:17][CH3:18])\[CH2:7][Br:20])[CH3:2]
Reactant: CCOC(=O)/C=C(\C)Oc1cccc(OC)c1OC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1cccc(OC)c1OC
Yield: 56.1 %

Procedure:
To a stirred mixture of (E)-3-(2,3-dimethoxy-phenoxy)-but-2-enoic acid ethyl ester (4.20 g, 0.016 mol) in carbon tetrachloride (25 mL) under a nitrogen atmosphere was added N-bromosuccinimide (4.22 g, 0.024 mol) and benzoyl peroxide (380 mg, 0.002 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(2,3-dimethoxy-phenoxy)-but-2-enoic acid ethyl ester (3.10 g, 57%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21](O)=[O:22])[C:16]=1[CH3:24].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.[CH3:55][O:56][C:57](=[O:60])[CH2:58][NH2:59]>[Cl-].[Na+].O.CN(C=O)C>[CH3:55][O:56][C:57](=[O:60])[CH2:58][NH:59][C:21]([C:17]1[C:16]([CH3:24])=[C:15]([CH:14]=[N:13][N:12]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:19][C:18]=1[CH3:20])=[O:22]
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CNC(=O)c1c(C)[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.1 %

Procedure:
5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (328 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzo-triazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and glycine methyl ester hydrochloride (151.8 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (244 mg, 61% yield) as a red solid. LC-MS (m/z) 400 (M+1).
Reaction SMILES: [Cl-].[C:2]([IH+:6]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:5])([CH3:4])[CH3:3].C([O-])([O-])(OCC)C.[F:24][C:25]1[C:30]([S:31]([OH:34])(=[O:33])=[O:32])=[C:29]([F:35])[C:28]([F:36])=[C:27]([F:37])[C:26]=1[F:38]>C(Cl)(Cl)Cl>[F:24][C:25]1[C:30]([S:31]([O-:34])(=[O:33])=[O:32])=[C:29]([F:35])[C:28]([F:36])=[C:27]([F:37])[C:26]=1[F:38].[C:13]([IH+:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: O=S(=O)(O)c1c(F)c(F)c(F)c(F)c1F
Agent: CC(C)(C)[IH+](c1ccccc1)C(C)(C)C
Agent: CCOC(C)([O-])[O-]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: O=S(=O)([O-])c1c(F)c(F)c(F)c(F)c1F
Yield: 77 %

Procedure:
Di-tert-butylphenyliodonium chloride (443 mg; 1 mmol), ethyl orthoacetate (342 mg; 2 mmol), and pentafluorobenzenesulfonic acid (298 mg; 1.2 mmol) were dissolved in chloroform (5 ml), and the resultant mixture was refluxed for 2 hours while being stirred. The solvent was removed through distillation, and the thus-obtained solid matter was washed with ether, to thereby yield 436 mg of the target compound as white crystals (yield: 68%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.[OH-].[K+].I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].ICCCCCCCCCC>C(#N)C>[CH2:26]([N:11]1[CH:10]=[CH:9][N:8]=[C:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: CCCCCCCCCCCCI
Reactant: c1ccc(-c2ncc[nH]2)nc1
Agent: CCCCCCCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCCCCCCCCn1ccnc1-c1ccccn1
Yield: 103.7 %

Procedure:
A mixture of 14.5 g (0.1 mole) 2-(2-pyridyl)imidazole, 6 g (0.11 mole) ground KOH, 30 g (0.1 mole) iodododecane in about 150 ml of acetonitrile was stirred and refluxed for about 2 hours. The iododecane gradually went into solution as the reaction proceeded. After the 2 hours the reaction mixture was cooled and filtered. The resulting residue was extracted with hexane to give 32.5 g of crude product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][C:35]1([CH3:45])[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][OH:44])[CH2:36]1.O1CCN(CCO)CC1>>[CH:30]1([C:26]2[N:25]=[C:24]([CH2:23][N:18]3[C:19]4[C:15](=[C:14]([NH:13][C:11]([C:8]5[N:5]6[CH:6]=[CH:7][C:2]([O:44][CH2:43][CH2:42][N:37]7[CH2:38][CH2:39][N:40]([CH3:41])[C:35]([CH3:45])([CH3:34])[CH2:36]7)=[CH:3][C:4]6=[N:10][CH:9]=5)=[O:12])[CH:22]=[CH:21][CH:20]=4)[C:16]([CH3:33])=[N:17]3)[CH:29]=[CH:28][CH:27]=2)[CH2:31][CH2:32]1
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Reactant: CN1CCN(CCO)CC1(C)C
Agent: OCCN1CCOCC1
Product: Cc1nn(Cc2cccc(C3CC3)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C)C(C)(C)C5)ccn34)c12
Yield: 19 %

Procedure:
Prepared according Example 1, Step B, substituting N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide (Example 16, Steps A-G) for 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and 2-(3,3,4-trimethylpiperazin-1-yl)ethanol for 2-morpholinoethanol to give the title compound (19%). MS (APCI), positive scan, m/z=593.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)C(OC)=O.[OH-].[Li+]>CO>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1
Reactant: COC(=O)C(c1ccc([N+](=O)[O-])cc1)c1cccn1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cn1cccc1Cc1ccc([N+](=O)[O-])cc1
Yield: 66.2 %

Procedure:
Methyl 2-(1-methylpyrrol-2-yl)-2-(4-nitrophenyl)acetate (9.2 g, 33.54 mmol) [prepared as in Example 21, Step (a)], was dissolved in methanol (100 ml) and an aqueous solution of lithium hydroxide (3.52 g in 50 ml of water) was added. After 1.5 h the reaction mixture was concentrated to dryness in vacuo and the resulting residue was dissolved in water (100 ml). The solution was acidified to pH 1 with 6 M HCl and then extracted with ethyl acetate. The organic extracts were washed with water, and brine, and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatography (hexane-ethyl acetate, 9:1) to give 4-(1-methylpyrrol-2-ylmethyl)nitrobenzene (4.8 g, 66%) as a yellow oil. ##STR63##
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:39])[N:18]([C@@H:28]3[CH2:31][C@H:30]([O:32][CH2:33]C(OCC)=O)[CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].C[Mg]Br.[Cl-].[NH4+]>O1CCCC1>[OH:32][C:30]([CH3:31])([CH3:29])[CH2:33][O:32][C@@H:30]1[CH2:31][C@H:28]([N:18]2[C:17](=[O:39])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)[CH2:29]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@@H](OCC(=O)OCC)C2)c2ncnn12
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@@H](OCC(C)(C)O)C2)c2ncnn12
Reaction time: 6 h
Yield: 154.1 %

Procedure:
Ethyl [(cis-3-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutyl)oxy]acetate (0.2 g) was dissolved in tetrahydrofuran (10 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 1.2 mL) was added at room temperature. The reaction mixture was stirred for 6 hr, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.15 g, 78%).