Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH2:8]([NH2:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[C:5]([NH:16][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])[CH3:6]
Reactant: NCCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)NCCc1ccccc1

Procedure:
350 ml. (3.14 mol) Acetic anhydride are added dropwise within the course of 50 minutes to a solution of 376 ml. (3.0 mol) phenethylamine in 1.5 liters toluene, the temperature thereby increasing to 68° C. The reaction mixture is heated under reflux for 1 hour, the toluene is evaporated off in a high vacuum and the residue is distilled at 1.5 mm.Hg. Yield 475 g. (97% of theory); b.p. 162°-166° C./1.5 mm.Hg; m.p. 50°-52° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]4)[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.ClC1C=C2C(C3N=C(N[C@H]4CCCNC4)C(F)=CN=3)=CNC2=NC=1.[CH2:49]([N:52]=[C:53]=[O:54])[CH2:50][CH3:51]>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][N:20]([C:53]([NH:52][CH2:49][CH2:50][CH3:51])=[O:54])[CH2:19]4)[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCCN=C=O
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1NC1CCCNC1
Agent: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1N[C@H]1CCCNC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCNC(=O)N1CCCC(Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-amine, 5b, (0.020 g, 0.058 mmol) in 1:1 mixture of CH2Cl2/pyridine (2 mL) was added propylisocyanate (0.005 mL, 0.058 mmol). The reaction mixture was stirred at room temperature for 12 hours. The resulting residue was purified by preparatory HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product, 196.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:26][C:27]1([C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:30][CH2:29][CH2:28]1)[C:9]1[N:14]=[N:13][C:12]([CH:15]2[N:19]=[C:18]([OH:20])[CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[S:16]2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:38]I.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:26][C:27]1([C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:30][CH2:29][CH2:28]1)[C:9]1[N:14]=[N:13][C:12]([CH:15]2[N:19]=[C:18]([O:20][CH3:38])[CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[S:16]2)=[CH:11][CH:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C1SC(c2ccc(N(CC3(c4ncccc4F)CCC3)C(=O)OC(C)(C)C)nn2)N=C1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1SC(c2ccc(N(CC3(c4ncccc4F)CCC3)C(=O)OC(C)(C)C)nn2)N=C1OC
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 53.7 %

Procedure:
To a stirring solution of ethyl 2-(6-(t-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-hydroxy-2,5-dihydrothiazole-5-carboxylate (350 mg, 0.7 mmol) in DMF (4 mL) was added methyl iodide (200 μL, 3.3 mmol) and sodium hydride (60% dispersion in mineral oil, 40 mg, 1 mmol). The reaction was stirred at rt for 1 h and at 40° C. for 45 min. The reaction was then concentrated and quenched with water (5 mL), poured into ethyl acetate (150 mL), and washed with 0.1M HCl (50 mL, aq) and brine (50 mL). The organic layer was separated, dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (EtOAC/hexanes) to afford 205 mg of ethyl 2-(6-(tert-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-methoxy-2,5-dihydrothiazole-5-carboxylate. This compound was dissolved in methanol (4 mL) and 1M KOH (aq, 2 mL). The reaction mixture was heated to 75° C. and stirred for 45 min. The reaction was cooled and the pH was adjusted to 4 using 1M HCl. The reaction was then poured into ethyl acetate (50 mL), washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated to give 175 mg of 2-(6-(t-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-methoxy-2,5-dihydrothiazole-5-carboxylic acid as a white foam.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[N:10][C:5]2=[N:4][CH:3]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>ClCCl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH2:11][O:12][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: OCc1ccn2c(Br)cnc2n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccn2c(Br)cnc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
3-Bromoimidazo[1,2-α]pyrimidin-7-ylmethanol (912 mg, 4.00 mmol) was dissolved in dichloromethane (10 ml) and treated with imidazole (0.70 g, 10.3 mmol) and tert-butyldimethylsilyl chloride (0.77 g, 5.1 mmol) and the mixture left to stir at ambient temperature for 1 h. The reaction was diluted with dichloromethane (75 ml) and washed with 0.01N hydrochloric acid (2×50 ml). The organic phase was washed with saturated sodium hydrogencarbonate solution (50 ml), water (50 ml) and brine (50 ml), dried over anhydrous magnesium sulfate, filtered and evaporated to give crude 3-bromo-7-(tert-butyldimethylsilanyloxymethyl)imidazo[1,2-α]pyrimidine (1.37 g, 100%) as a yellow solid.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].CC(O)(C)C.[CH:13]1[C:26]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][C:14]=1[C:27]1[N:31]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[N:30]=[C:29]([C:39]([F:42])([F:41])[F:40])[CH:28]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:13]1[C:26]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][C:14]=1[C:27]1[N:31]([C:32]2[CH:33]=[CH:34][C:35]([NH:38][S:2]([NH2:5])(=[O:4])=[O:3])=[CH:36][CH:37]=2)[N:30]=[C:29]([C:39]([F:42])([F:40])[F:41])[CH:28]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc3c(ccc4ccccc43)c2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: NS(=O)(=O)Nc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc3c(ccc4ccccc43)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Chlorosulfonyl isocyanate (1 mmol) was added dropwise to an ice-cold solution of t-BuOH (1 mmol) in CH2Cl2, which was then added to a mixture of 4-(5-phenanthren-2-yl-3-trifluoromethyl-pyrazol-1-yl)-phenylamine (1 mmol), generated from step d, and triethylamine (1.5 mmol) in CH2Cl2. The reaction mixture was stirred at 25° C. for 1 h, and concentrated. The residue was treated with 20% trifluoroacetic acid in CH2Cl2 for 3 h, washed with 10% NaHCO3, dried, and concentrated. The residue was purified by flash column chromatograph to give 36 as off-white solid in 78% yield. 1H NMR (DMSO-d6) δ 7.35-7.15 (m, 7H), 7.46 (dd, J=1.8, 8.7 Hz, 1H), 7.73-7.65 (m, 2H), 7.88 (dd, J=9, 33.6 Hz, 2H), 8.00-8.05 (m, 1H), 8.09 (d, J=1.8 Hz, 2H), 8.82 (m 2H), 9.89 (br s, 1H). HRMS exact mass of C24H17F3N4O2S, (M+Na)+. 505.0922 amu; found: 505.0902 amu. Anal. calcd C 59.75, H 3.55, N 11.61; found C 59,98, H 3.71, N 11.51.
Reaction SMILES: C1O[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:7][CH2:6]2)[O:4]C1C.Cl>C(O)(=O)C.O>[F:22][C:19]([F:20])([F:21])[CH2:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]1
Reactant: CC1COC2(CCN(c3ccccc3OCC(F)(F)F)CC2)O1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCN(c2ccccc2OCC(F)(F)F)CC1

Procedure:
A solution of 51 (410 mg, 1.23 mmol) in acetic acid (20 mL), water (20 ml), and concetrated HCl (5 mL) was heated in an oil bath (60° C.) overnight. The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 4 mm, 10% EtOH-90% CHCl3) afforded the title compound (52)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:24][CH2:25][CH2:26][CH2:27][OH:28].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])=[O:21])=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: NCCCO
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCCO)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.4 %

Procedure:
To a solution of 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.6 mmol) and 3-amino-1-propanol (0.65 mmol) in THF (6 mL) at 0° C. were added 1-hydroxybenzotriazole hydrate (100.8 mg, 0.65 mmol), N-ethyldiisopropylamine (281.7 μl, 1.613 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidazole hydrochloride (126.2 mg, 0.65 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=3:1 to 1:4) afforded the title compound (73 mg, 70%) which was obtained as a white solid. MS: m/e=374.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16](OCC)=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][OH:17])=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[N:6]=1
Reactant: CCOC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Temperature: -78 °C
Yield: 89.8 %

Procedure:
Ethyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate (9.00 g) was dissolved in tetrahydrofuran (100 ml), the solution was cooled to −78° C., and a 1 N solution of diisobutylaluminum hydride in toluene (65 ml) was added dropwise with stirring. After completion of the dropping, the cooling bath was removed to raise the inner temperature to −20° C. Sodium sulfate decahydrate (10.0 g) was added to the reaction mixture, and the temperature was raised to room temperature. The reaction mixture was filtered, and the residue on the filter paper was washed with ethyl acetate. The filtrate was concentrated to give crystals of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropanol (7.00 g, 86%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2.[C:32]1(=[O:38])[O:37][C:35](=[O:36])[CH2:34][CH2:33]1>N1C=CC=CC=1>[C:32]([O:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2)(=[O:38])[CH2:33][CH2:34][C:35]([OH:37])=[O:36]
Reactant: O=C1CCC(=O)O1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Solvent: c1ccncc1
Product: Cc1c(C)c2c(c(C)c1OC(=O)CCC(=O)O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reaction time: 8 h

Procedure:
A mixture of 1.0 g of 5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine -2,4-dione (prepared as described in Example 28), 0.31 g of succinic anhydride and 1 ml of pyridine was allowed to stand overnight at room temperature. The reaction mixture was then washed 3 times, each time with 10 ml of cyclohexane, and the insoluble residue obtained was purified by silica gel column chromatography (eluted by mixtures of benzene and ethyl acetate ranging from 5:1 to 1:1) to give the title compound melting at 197°-202° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][CH2:17]3)=[CH:12][N:11]=2)=[CH:5][C:4]([C:26]2[CH:27]=[N:28][CH:29]=[C:30]([N:34]3[C:46](=[O:47])[C:45]4[S:44][C:43]5[CH2:42][CH2:41][CH2:40][CH2:39][C:38]=5[C:37]=4[CH2:36][CH2:35]3)[C:31]=2[CH:32]=[O:33])=[CH:3]1.[BH4-].[Na+]>CO>[OH:33][CH2:32][C:31]1[C:30]([N:34]2[C:46](=[O:47])[C:45]3[S:44][C:43]4[CH2:42][CH2:41][CH2:40][CH2:39][C:38]=4[C:37]=3[CH2:36][CH2:35]2)=[CH:29][N:28]=[CH:27][C:26]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:20][CH2:21]3)=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1cc(-c2cncc(N3CCc4c(sc5c4CCCC5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2cncc(N3CCc4c(sc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a solution of 3-[1-methyl-5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridine-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]-5-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-5-yl}pyridine-4-carbaldehyde 105g (130 mg, 0.20 mmol) in methanol (5 mL) at 0° C. was added sodium borohydride (22 mg, 0.6 mmol) and stirred for 30 minutes. Then the reaction mixture was quenched with water (1.0 mL) and concentrated. The residue was purified by reverse-phase prep-HPLC to afford 105 (90 mg, 65%). LCMS: [M+H]:654. 1H NMR (500 MHz, DMSO) δ 8.58 (d, J=2.0, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 8.41 (s, 1H), 7.86 (s, 1H), 7.36 (m, 2H), 7.24-7.22 (m, 1H), 5.14 (t, J=3.0, 1H), 4.56-4.42 (m, 6H), 4.08-3.90 (m, 2H), 3.60 (s, 3H), 3.43 (d, J=3.5, 1H), 3.07 (s, 4H), 2.89-2.79 (m, 4H), 2.55-2.53 (m, 2H), 2.39-2.37 (m, 4H), 1.80-1.81 (m, 4H)
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19].S(=O)(=O)(O)O>O>[O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(O)C(=O)O
Reactant: Oc1ccc(COc2ccccc2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(Oc1ccc(COc2ccccc2)cc1)C(=O)O

Procedure:
A mixture of 20 g. of 4-phenoxymethylphenol and 13.2 g. of the ethyl ester of 2-hydroxyisobutyric acid is combined with 15 g. of sulfuric acid, and the reaction mixture is agitated for 2 hours at 50°-60°. After cooling, the mixture is combined with water and worked up as usual, obtaining the ethyl ester of 2-(4-phenoxymethylphenoxy)-2methyl-propionic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21](=[O:30])[C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=1>>[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)/[C:22](=[C:23](\[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([F:9])[CH:4]=3)/[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)/[C:21]2=[O:30])[CH:14]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Reactant: Fc1ccc(I)cc1F
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(F)c(F)c3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1,2-difluoro-4-iodo-benzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.90 (s, 3H), 4.96 (s, 2H), 6.58 (d, 1H), 6.70 (m, 2H), 7.07-7.32 (m, 4H), 7.34-7.43 (m, 6H), 7.50 (d, 1H), 7.94 (d, 1H), 8.02 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[C:4](=[N:6][OH:7])Cl.[CH2:13]([O:15][C:16](=[O:20])[C:17]#[C:18][CH3:19])[CH3:14].CCN(CC)CC>CCOCC>[CH2:13]([O:15][C:16]([C:17]1[C:4]([C:3]2[C:8]([F:12])=[CH:9][CH:10]=[CH:11][C:2]=2[I:1])=[N:6][O:7][C:18]=1[CH3:19])=[O:20])[CH3:14]
Reactant: ON=C(Cl)c1c(F)cccc1I
Reactant: CC#CC(=O)OCC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(-c2c(F)cccc2I)noc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of 2-iodo-6-fluorobenzoyl chloride oxime (26.6 mmol) and ethyl-2-butynoate (3.72 ml, 31.92 ml, 1.2 eq.) in Et2O (106 ml) under N2, stirring at 0-5° C. added dropwise a solution of Et3N (4.81 ml, 34.6 mmol, 1.3 eq) in Et2O (13 ml) over 1 h. The reaction was allowed to warm to room temperature and stirred overnight. Et2O was added and then washed with H2O, brine, dried (MgSO4), filtered, and concentrated. The crude residue was chromatographed on silica gel using ethyl acetate in hexanes (1-20%) to give the title compound (8.21 g, 82%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:12]=1Br)=[O:10].C(=O)([O-])[O-].[K+].[K+].O.C(OCC)(=O)C>CS(C)=O>[CH3:17][C:14]1[S:13][C:12]2[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[NH:8][C:9](=[O:10])[C:11]=2[C:15]=1[CH3:16]
Reactant: Cc1sc(Br)c(C(=O)Nc2ccccc2O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1sc2c(c1C)C(=O)Nc1ccccc1O2
Temperature: 165 °C
Reaction time: 0.33 h
Yield: 56.4 %

Procedure:
To a solution of N-(2-hydroxyphenyl)-2-bromo-4,5-dimethyl-3-thiophenecarboxamide (3.3 g) in dimethyl sulfoxide (50 ml) was added potassium carbonate (2.8 g) and the mixture was stirred at 160-170° C. for 20 minutes. The reaction system was cooled to room temperature and the reaction mixture was poured into water-ethyl acetate. The insoluble matter was filtrated and the filtrate was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 2,3-dimethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.4 g).
Reaction SMILES: [Si:1]([C:8]#[C:9][C:10]1[S:14][C:13]([N+:15]([O-])=O)=[C:12]([C:18]([NH2:20])=[O:19])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pt]>[NH2:15][C:13]1[S:14][C:10]([C:9]#[C:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:11][C:12]=1[C:18]([NH2:20])=[O:19]
Reactant: CC(C)(C)[Si](C)(C)C#Cc1cc(C(N)=O)c([N+](=O)[O-])s1
Agent: [Pt]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)C#Cc1cc(C(N)=O)c(N)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 5-{[tert-butyl(dimethyl)silyl]ethynyl}-2-nitrothiophene-3-carboxamide (100 mg, 0.32 mmol) in MeOH (8.0 mL) was added 3% Pt/C doped with 0.6% V (21 mg, 3.2 μmol). The reaction was stirred under an H2 balloon at room temperature for 2 h. The solution was diluted with MeOH, filtered through Celite, combined with silica gel, and evaporated. Flash chromatography (dry load, 25-100% EtOAc/hexanes) afforded the title compound as a tan solid.
Reaction SMILES: [NH:1]([C:3](=[O:25])[C:4]([NH:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1)=[O:5])[NH2:2].[F:26][CH:27]([F:38])[O:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=S)=[CH:31][CH:30]=1.CCN=C=NCCCN(C)C.[OH-].[Na+].Cl>CN(C=O)C.CO.C1COCC1.O>[F:26][CH:27]([F:38])[O:28][C:29]1[CH:30]=[CH:31][C:32]([NH:35][C:36]2[O:25][C:3]([C:4]([NH:6][C:7]3[CH:8]=[CH:9][C:10]([O:11][C@H:12]4[CH2:13][CH2:14][C@H:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17]4)=[CH:23][CH:24]=3)=[O:5])=[N:1][N:2]=2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](Oc2ccc(NC(=O)C(=O)NN)cc2)CC1
Reactant: FC(F)Oc1ccc(N=C=S)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(O[C@H]2CC[C@H](C(=O)O)CC2)cc1)c1nnc(Nc2ccc(OC(F)F)cc2)o1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
Ethyl trans-4-(4-{[hydrazino(oxo)acetyl]amino}phenoxy)cyclohexanecarboxylate (Intermediate 3, 698 mg, 2.00 mmol) was added in one portion to a stirred solution of 4-(difluoromethoxy)phenyl isothiocyanate (483 mg, 2.40 mmol) in DMF (10 mL) and the reaction mixture was stirred at 65° C. for 30 mins. EDCI (461 mg, 2.40 mmol) was added in one portion and the reaction mixture was heated to 85° C. for 3 h. The mixture was cooled to ambient temperature and water (15 mL) was added and the resulting suspension was filtered to provide a cream solid. The solid was taken up in a mixture of MeOH (8 mL) and THF (4 mL) and a 2N aqueous solution of NaOH (4 mL) was added in one portion and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was acidified by the addition of a 2M aqueous solution of HCl and the resulting precipitate was filtered, washed with water (10 mL) and dried under high vacuum to leave a solid. The solid was recrystallised from refluxing glacial acetic acid to give the title compound as a white solid (392 mg, 40%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:35])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-])=O)[CH:27]=3)=[CH:4][C:3]=2[O:2]1.Cl[Sn]Cl.O>CCO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:35])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[CH:27]=3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C(/C=C/c1cccc([N+](=O)[O-])c1)N1CCc2c([nH]c3ccccc23)C1c1ccc2c(c1)OCO2
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)c1
Yield: 21.3 %

Procedure:
A solution of Example 60 (1.36 g, 2.9 mmol), SnCl2.H2O (2.8 g, 5 equiv.) in EtOH was refluxed overnight. After evaporation of the solvent, the residue was taken up in 50 mL of NaOH (1N). The aqueous phase was extracted with 2×100 mL of DCM and 2×50 mL of EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Flash chromatography (SiO2, DCM:MeOH (95:5) and recrystallization from EtOH:DCM gave the title compound (0.27 g, 21%) as a pale yellow powder.
Reaction SMILES: CN([CH:4]=[C:5]1[C:13](=O)[C:12]2[N:11]([CH2:15][CH2:16][OH:17])[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]=2[CH2:7][CH2:6]1)C.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[CH:32][C:33]([O:40][C:41]([F:44])([F:43])[F:42])=[C:34]([NH:36][C:37]([NH2:39])=[NH:38])[CH:35]=2)[CH2:26][CH2:25]1.O>CN(C=O)C>[OH:17][CH2:16][CH2:15][N:11]1[C:12]2[C:13]3[N:39]=[C:37]([NH:36][C:34]4[CH:35]=[C:30]([N:27]5[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]5)[CH:31]=[CH:32][C:33]=4[O:40][C:41]([F:44])([F:42])[F:43])[N:38]=[CH:4][C:5]=3[CH2:6][CH2:7][C:8]=2[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:10]1
Reactant: CCOC(=O)c1nn(CCO)c2c1CCC(=CN(C)C)C2=O
Reactant: CN1CCN(c2ccc(OC(F)(F)F)c(NC(=N)N)c2)CC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nn(CCO)c2c1CCc1cnc(Nc3cc(N4CCN(C)CC4)ccc3OC(F)(F)F)nc1-2
Temperature: 110 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
To a solution of 2.66 g (8.34 mmol) of ethyl 6-[(dimethylamino)methylene]-7-oxo-1-(2-hydroxy-ethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate in 15 mL of DMF, 2.64 g (8.34 mmol) of N-[5-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenyl]-guanidine was added. The mixture was stirred for 4 h at 110° C. After cooling the mixture was poured into water (100 mL) and stirred for 30 minutes. The precipitate was filtered, washed with water and dried to yield 2.86 g of title compound (61%).