Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[N:8]=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[C:19]([N:28]3[CH:32]=[N:31][N:30]=[N:29]3)[CH:18]=2)[S:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[OH2:33]>C(OCC)(=O)C>[OH:33][C:25]([CH3:27])([CH3:26])[CH2:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:9]2[S:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([CH3:6])[N:8]=2)=[CH:18][C:19]=1[N:28]1[CH:32]=[N:31][N:30]=[N:29]1
Reactant: CCOC(=O)c1sc(-c2ccc(OC=C(C)C)c(-n3cnnn3)c2)nc1C
Reactant: O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)(C)O)c(-n3cnnn3)c2)nc1C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A solution was prepared by dissolving 33.1 mg of ethyl 2-[4-hydroxy-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate in 1.0 mL of dimethylformamide. A reaction mixture solution prepared by adding 20.7 mg of potassium carbonate and 16.2 mg of 3-bromo-2-methylpropene to the solution was heated under stirring at 100° C. for 4 hours. The reaction mixture solution was cooled to room temperature and then 3 mL of water and 4 mL of ethyl acetate were added under stirring, followed by concentrating the organic phase to obtain 34.1 mg of ethyl 4-methyl-2-{4-[(2-methylpropen-1-yl)oxy]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylate. (2) A reaction mixture solution prepared by adding 1.0 mL of 35% sulfuric acid aqueous solution to 34.1 mg of ethyl 4-methyl-2-{4-[(2-methylpropen-1-yl)oxy]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylate was heated under stirring at 80° C. for 4 hours. The reaction mixture solution was cooled to room temperature and then 3 mL of water and 4 mL of ethyl acetate were added under stirring, and the organic phase was concentrated and purified using a conventional method to obtain 9.9 mg of ethyl 2-[4-(2-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:13])[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19]N(C=O)C.[H-].[Na+].CI>[Cl-].[Na+].O>[Br:1][C:2]1[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:13])[N:5]([CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1c(C)[nH]c(-c2ccccc2)c1Br
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCOC(=O)c1c(Br)c(-c2ccccc2)n(C)c1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 115 %

Procedure:
Ethyl 4-bromo-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (3.31 g, 11.4 mmol) was dissolved into anhydrous DMF (50 mL). After stirring at 0° C. for 15 min, to this solution was added NaH (60%, 0.55 g, 13.7 mmol). The mixture was held at 0° C. for 10 min and then MeI (2.13 mL, 34.2 mmol) was added to the mixture. The reaction mixture was gradually warmed to RT and stirred overnight. The mixture was poured into brine (100 mL) and extracted with ethyl acetate (200 mL). The organic phase was dried over MgSO4 and evaporated under vacuum. The residue was further purified by flash column chromatography to provide the crude intermediate ethyl 4-bromo-1,2-dimethyl-5-phenyl-1H-pyrrole-3-carboxylate (4.23 g, 13.1 mmol, 115%).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH:16]=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:30][C:26]1[CH:25]=[C:24]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH2:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCC=C(c2ccccc2)c2cccc(Cl)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOCC=C(c2ccccc2)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.5 %

Procedure:
(R)-N-(2-(3-(3-Chlorophenyl)-3-phenyl-2-propen-1-yloxy)-ethyl)-3-piperidinecarboxylic acid ethyl ester (3.0 g, 7.0 mmol) dissolved in 96% ethanol (10 ml) and a 12 N sodium hydroxide solution (1.75 ml) was added. The reaction mixture was stirred at room temperature for 5 h. The solvent was evaporated in vacuo and dichloromethane was added (100 ml). A concentrated hydrochloric acid solution (2.9 ml) was added with cooling on an ice-bath. The phases were separated, and from the organic phase the solvent was evaporated in vacuo. Water (100 ml) was added to the residue and the aqueous solution was washed with small portions of ethyl acetate. The aqueous phase was reduced in vacuo to approx. 50 ml and dichloromethane (250 ml) was added. A 4 N sodium hydroxide solution was added until the pH was measured as 8.3. The phases were separated and the organic phase was dried (Na2SO4). The solvent was evaporated in vacuo to give 2.7 g (96%) of the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16].Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[CH3:24][Si:23]([CH3:26])([CH3:25])[O:18][C:13]([O:19][CH2:20][CH3:21])=[CH:14][CH:15]([CH3:17])[CH3:16]
Reactant: CCOC(=O)CC(C)C
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=CC(C)C)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 197.3 %

Procedure:
A 2 liter flask was equipped with a mechanical stirrer, addition funnel, reflux condenser, nitrogen inlet and thermometer. The flask was dried with external heat and then charged with 563 milliliters of dry tetrahydrofuran, 75.9 grams (0.75 mol) of diisopropylamine and cooled to 0° C. Over a 30 minute period 523 milliliters of 1.6 M n-butyl lithium (0.94 mol) was added dropwise. The reaction mixture was stirred at 0° C. for 15 minutes, then cooled to -76° C. in a dry ice-acetone bath and 97.65 grams (0.75 mol) of ethyl isovalerate was added dropwise over about 30 minutes. When this addition was complete, the reaction mixture was stirred for 15 minutes at -76° C., then 205 milliliters (2.20 mol) of chlorotrimethylsilane was added dropwise. When this addition was complete, the dry ice-acetone bath was removed and the reaction mixture allowed to come to room temperature. The reaction mixture was then filtered and concentrated under reduced pressure to give a residue which was triturated with ether and filtered. The filtrate was concentrated under vacuum to give a residue and the residue was vacuum distilled through a vigreux column to give 136.44 grams (1.48 mol) of 1-trimethylsilyloxy-1-ethoxy-3-methylbutene having a boiling point of 78°-88° C. at 30 millimeters pressure.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH2:12][C:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=1)=O)C.C(OCC)(=O)C.O>C(OCC)C.O1CCCC1>[OH:9][CH2:10][CH2:12][C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]=1
Reactant: CCOC(=O)CC1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(CCO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.66 g (17.5 mM) of lithium aluminum hydride in 100 ml of diethyl ether was added a solution of 4.719 g (17.521 mM) of tert-butyl 4-(ethoxycarbonylmethyl)-3,6-dihydro-2H-pyridine-1-carboxylate in 50 ml of tetrahydrofuran dropwise under ice-cooling and the mixture was stirred at room temperature for 1 hour. To this reaction mixture was added ethyl acetate with ice-cooling to decompose the excess lithium aluminum hydride. Then, water was added until a white precipitate had formed. The precipitate was filtered off with the aid of celite and the celite was washed with ethyl acetate. The filtrate and washes were pooled and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to provide the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[NH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:21][CH2:20]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[F:17][C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([C:25]([OH:28])([CH3:26])[CH3:27])[CH2:21][CH2:20]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Fc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: CC(C)(O)[C@H]1CC[C@H](N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(O)[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(F)c4)n3n2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of give 6-chloro-3-(3-fluorophenyl)imidazo[1,2-b]pyridazine (100 mg, 0.404 mmol) in NMP (2 mL) was added 2-(trans-4-aminocyclohexyl)propan-2-ol (95 mg, 0.6 mmol) and NaHCO3 (101.8 mg, 1.21 mmol). The mixture was purged with nitrogen and kept at 180° C. for 30 min with M.W. reaction. LCMS showed the reaction was complete. The mixture was partitioned between water (100 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (50 mL*3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep. HPLC to give EX. 8-75 (10.6 mg, 7.2%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)=[C:6](O)[N:5]=[C:4]([S:19][CH3:20])[N:3]=1.C(OCC)C>P(Cl)(Cl)(Cl)=O>[CH3:20][S:19][C:4]1[N:3]=[C:2]([OH:1])[C:7]2[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=3)[O:17][C:6]=2[N:5]=1
Reactant: CSc1nc(O)c(NC(=O)c2cccc(C)c2)c(O)n1
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: CSc1nc(O)c2nc(-c3cccc(C)c3)oc2n1
Yield: 38.6 %

Procedure:
21 g of N-(4,6-dihydroxy-2-methylsulfanyl-pyrimidin-5-yl)-3-methyl-benzamide in 100 ml of phosphorus oxychloride were heated to 70° C. for 3 h. After cooling, the mixture was poured into 500 ml of diethyl ether. The precipitate was filtered off and washed with diethyl ether. 7.6 g of the title compound were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]1([CH2:27]O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:12]1=[O:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:26]=[C:12]1[C:11]2([CH2:27][O:1][C:2]3[CH:10]=[C:9]4[C:5](=[CH:4][C:3]2=3)[CH2:6][CH2:7][CH2:8]4)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)CCC3)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCC4)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.4 %

Procedure:
To a solution of ethyl [3-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate (4.20 mmol) in anhydrous THF (60.0 mL) was added triphenylphosphine (1.43 g, 5.46 mmol) and diethyl azodicarboxylate (0.95 g, 5.46 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h and quenched with saturated ammonium chloride (20.0 mL). The mixture was extracted with ethyl acetate (3×50.0 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/4) to give the title compound (0.25 g, 16% in three steps): 1H NMR (300 MHz, CDCl3) δ 7.29 (td, 1H), 7.22-7.17 (m, 1H), 7.07 (t, 1H), 6.81 (s, 1H), 6.78 (d, 1H), 6.65 (s, 1H), 4.95 (d, 1H), 4.71 (d, 1H), 4.64 (d, 1H), 4.42 (d, 1H), 4.24 (q, 2H), 2.84 (t, 2H), 2.73-2.65 (m, 2H), 2.10-1.95 (m, 2H), 1.29 (t, 3H); MS (ES+) m/z 364 (M+1).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C(Cl)Cl>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reaction time: 48 h
Yield: 77.6 %

Procedure:
To a mixture of 5.5 g of dry tert.-butanol and 7.08 g of dry pyridine is added a solution of 9.79 g of 4-bromobenzoyl chloride in 20 ml of anhydrous methylene chloride. The mixture is stirred under nitrogen for 2 days. The reaction mixture is then diluted with methylene chloride, and the organic solution extracted with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residual oil is distilled under reduced pressure to give 8.9 g (70%) of tert.-butyl 4-bromobenzoate as a colorless oil: b.p. 91°-92° C./1.2 mm; NMR (CDCl3, 80 MHz) delta 1.59 (s, 9H), 7.53 (d, 2H, J=8.7 Hz); IR (neat) 2970, 1710, 1585, 1475, 1390, 1290, 1160, 1110, 1070, 845 and 745 cm-1. Anal. Calcd. for C11H13BrO2 : C, 51.38; H, 5.09; Br, 31.08. Found: C, 51.41; H, 5.36; Br, 30.38.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl-].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][Zn+]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:34][C:33]5[CH:36]=[CH:37][CH:38]=[C:31]([O:30][CH3:29])[CH:32]=5)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COc1cccc(C[Zn+])c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Agent: [Cl-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3cccc(OC)c3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-methoxy-benzylzinc chloride following a procedure analogous to that described in Step 6 of Intermediate 1. LC (method 4): tR=1.22 min; Mass spectrum (ESI+): m/z=492 [M+Na]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: c1ccncc1
Product: O=C(Nc1ccc2oc3c(c2c1)CCCC3)c1ccccc1
Yield: 51.5 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol) and benzoyl chloride (0.64 mL, 5.5 mmol) in pyridine (10 mL) provided N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-benzamide (0.75 g). Mp 178-180° C.; Anal. Calcd. for C19H17NO2: C, 78.33; H, 5.88; N, 4.81; Found: C, 78.10; H, 5.86; N, 4.81.
Reaction SMILES: [CH:1]([CH:4]1[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH:7]([CH:16]([CH3:18])[CH3:17])[N:6]=[N:5]1)([CH3:3])[CH3:2].[H][H]>C(O)(C)(C)C.[Rh].[Al]>[NH2:5][CH:4]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]([NH2:6])[CH:16]([CH3:18])[CH3:17])[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)C1CC=CCCC=CCC(C(C)C)N=N1
Reactant: [H][H]
Agent: [Rh]
Agent: [Al]
Solvent: CC(C)(C)O
Product: CC(C)C(N)CCCCCCCCC(N)C(C)C
Yield: 92.8 %

Procedure:
250 g (1 mol) of 3,12-diisopropyl-1,2-diaza-1,5,9-cyclododecatriene (diastereoisomeric mixture) is dissolved in 1000 ml of t-butanol in an autoclave with stirrer. After the addition of 25 g of a rhodium/aluminium catalyst (5% by weight of rhodium), hydrogen is injected up to a pressure of 130-150 bars, and hydrogenation is then performed at 150°-180° C. until completion of hydrogen absorption. After cooling, the excess hydrogen is released, the suspension is drawn out by suction, and the catalyst is filtered off through a small amount of "Hyflo" (filtering agent). The filtrate is concentrated in a rotary evaporator, and the product is purified by distillation. There is obtained, as the main fraction, 238 g (94% of theory) of 3,12-diamino-2,13-dimethyltetradecane in the form of colourless oil [b.p. 106°-109° C./0.01 Torr; nD20 =1.4600; IR (liquid) inter alia bands at 3355, 3278 and 1613 cm-1 ].
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>N1C=CC=CC=1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[F:11])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(NNc1ccc(F)cc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
To a stirred mixture of 80.0 g of 4-fluorophenylhydrazine hydrochloride in 500 ml of dry pyridine, under nitrogen and cooled in an ice bath, was added, dropwise, 85.8 g of 2-fluorobenzoyl chloride. Upon completion of the addition, the ice bath was removed and the reaction mixture stirred at ambient temperature for 16 hours. The reaction mixture was poured into water and a precipitate formed. The precipitate was recrystallized from ethanol-water to give 97.1 g (80%) of 2-fluorobenzoic acid, 2-(4-fluorophenyl)hydrazide.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>>[CH3:14][C:5]1([CH3:15])[CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9]2[C:10]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:11][CH:2]=[CH:3][C:4]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Reactant: C#C[Si](C)(C)C
Product: CC1(C)CCC(C)(C)c2c(C#C[Si](C)(C)C)cccc21
Yield: 66.1 %

Procedure:
Following the basic procedure of Example 1(a), by reacting 26.7 g (0.1 mol) of 2-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene with 20 g (0.204 mol) of trimethylsilylacetylene, 18.8 g (66%) of the expected compound were obtained in the form of a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:37]1[CH:42]=[CH:41][C:40]([C:43](=[NH:45])[NH2:44])=[CH:39][C:38]=1[C:46](=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)(=O)=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([O:16][C:37]1[CH:42]=[CH:41][C:40]([C:43](=[NH:44])[NH2:45])=[CH:39][C:38]=1[C:46](=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Oc1ccc(C(=N)N)cc1C(=O)c1ccccc1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: N=C(N)c1ccc(OC(=O)CCNC(=O)OCc2ccccc2)c(C(=O)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
Into 50 ml of anhydrous pyridine, was dissolved 3.3 g of 3-benzyloxycarbonylaminopropionic acid. To the solution, while being cooled in ice, was added 3.7 g of DCC. The mixture was stirred for 30 minutes. After addition of 5.0 g of 4-amidino-2-benzoylphenol methanesulfonate, the mixture was further stirred overnight. The precipitate which was formed was separated by filtration and washed with pyridine. Ethyl ether was added to the filtrate to separate an oily substance which solidified upon stirring. The solidified substance was collected by filtration, washed with ethyl ether, and dissolved in DMF. The crystals precipitated out of the DMF solution by the addition of ethyl ether were recrystallized from ethanol to yield 3.9 g of colorless granular crystals of 4-amidino-2-benzoylphenyl 3-benzyloxycarbonylaminopropionate methanesulfonate.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[Cs+].[Cs+].CCCCCC>CN(C)C=O>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH3:16]
Reactant: c1ccc2c(c1)CNC2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)CN1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.1 %

Procedure:
Into a solution of isoindoline (1.788 g, 15 mmol) and ethyl bromoacetate (2.756 g, 16.5 mmol) in N,N-dimethylformamide (20 mL), was added Cs2CO3 (5.376 g, 16.5 mmol) under N2. The mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the resulting mixture was subjected to silica gel chromatography, eluting with 33:66 ethyl acetate:hexane to afford Intermediate 200(a) (1.14 g, 5.56 mmol) as a yellow oil in 37% yield.
Reaction SMILES: [C:1]1([CH:7](O)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.CS([Cl:24])(=O)=O>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:24][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.7 %

Procedure:
Under ice cooling, to a solution of 1-phenyl-1-propanol (1.0 g, 7.34 mmol) and N-ethyldiisopropylamine (1.42 g, 11.01 mmol) in dichloromethane (10 ml) was added methanesulfonyl chloride (690 μl, 8.81 mmol), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent:ethyl acetate/hexane:5/1) to give 1-chloro-1-phenylpropane (610 mg, 54%) as pale yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([OH:27])=O)=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[OH:35][C@@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([N:38]5[CH2:39][CH2:40][C@@H:36]([OH:35])[CH2:37]5)=[O:27])=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1
Reactant: CC1Cc2ccc(-c3ccc(C(=O)O)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: O[C@@H]1CCNC1
Product: CC1Cc2ccc(-c3ccc(C(=O)N4CC[C@@H](O)C4)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50B starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 50B, Step 1) and (R)-3-hydroxypyrrolidine (Aldrich, Cat. No. 382981). LCMS (M+H)+: m/z=529.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:22][C:23](=[O:25])[CH3:24])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[Cl:26]N1C(=O)CCC1=O.C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:22][C:23](=[O:25])[CH3:24])=[C:8]2[C:16]([Cl:26])=[CH:15][N:14]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2CCC(C)C)c1OC(C)=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2CCC(C)C)c1OC(C)=O
Yield: 55.8 %

Procedure:
A solution of 4-acetoxy-7-cyano-1-(3-methyl-butyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (0.44 g, 1.28 mmol) and N-chlorosuccinimide (0.188 g, 1.41 mmol) in 8 mL of N,N′-dimethylformamide was heated at 100° C. for 1 h. Ethyl acetate (100 mL) was added. The organic solution was washed with water, dried over anhydrous sodium sulfate, and concentrated. The crude produce was purified by flash chromatography from silica gel with a gradient of 0-40% ethyl acetate in hexanes to afford 0.27 g of the title compound as a white solid. MS: (+) m/z 378.3 (M+1).