Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:20][C:19]([C:21]5([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23][CH2:22]5)=[CH:18][C:17]=4[CH:37]=3)[N:9]=2)=[CH:4][C:3]=1[Cl:38].[S:39]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40]1.C([O-])(O)=O.[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:38][C:3]1[CH:4]=[C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:20][C:19]([C:21]5([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23][CH2:22]5)=[CH:18][C:17]=4[CH:37]=3)[N:9]=2)[CH:6]=[CH:7][C:2]=1[C:41]1[CH:42]=[CH:43][S:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)NC1(c2cc3cc(-c4noc(-c5ccc(Br)c(Cl)c5)n4)ccc3o2)COC(C)(C)OC1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2cc3cc(-c4noc(-c5ccc(-c6ccsc6)c(Cl)c5)n4)ccc3o2)COC(C)(C)OC1
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a stirred mixture of the product of Example 38, Step C (0.09 g, 0.15 mmol) and 3-thiophene-boronic acid (0.028 g, 0.22 mmol) in a mixture of dioxane and H2O (5 ml:1 ml), Pd(PPh3)4 (0.03 g) was added at 80° C., followed by the NaHCO3 solution (0.065 g in 1 ml H2O) and this was stirred for 2 h. The solvent was distilled off and the residue was diluted to 20 ml with EtOAc, washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated and the residue was purified by FCC (SiO2, hexane/EtOAc), to give the title compound (0.065 g, 71%), as pale paste. 1H-NMR (CDCl3) 8.45 (d, 1H, J=1.53 Hz); 8.25-8.22 (m, 2H); 7.94 (dd, 1H, J=8.7, 1.8 Hz); 7.55-7.42 (m, 3H); 7.38-7.37 (m, 2H); 6.78 (s, 1H); 5.43 (bs, 1H); 4.29-4.13 (m, 4H); 1.46 (s, 9H); 1.27 (b, 6H).
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:26])[CH3:25])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[OH:26][C:24]([CH:21]1[CH2:20][CH2:19][N:18]([C:16]([O:15][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:17])[CH2:23][CH2:22]1)([C:7]1[S:6][CH:10]=[CH:9][N:8]=1)[CH3:25]
Reactant: c1cscn1
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(C)(O)c2nccs2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
n-Butyl lithium (0.281 mL, 0.702 mmol) was added dropwise to a stirred, cooled (−78° C.) mixture of thiazole (0.050 mL, 0.702 mmol) in THF (2.55 mL) and the mixture was stirred at −78° C. for 30 min. A solution of 4-acetyl-piperidine-1-carboxylic acid tert-butyl ester in THF (0.638 mL) was then added dropwise. Temperature was maintained at −78° C. for 30 min and then allowed to reach room temperature. The reaction was quenched with saturated NH4Cl solution and extracted with EtOAc (×2). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography to give tert-butyl 4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]piperidine-1-carboxylate (180 mg, 0.576 mmol, 90%) as a colorless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([N:9]([C@@H:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]2[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH:27]([CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1)=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O.C(OCC)(=O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]([CH3:10])[C@@H:11]2[CH2:16][CH2:15][N:14]([CH2:27][CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])[CH2:31][CH2:30]3)[CH2:13][C@H:12]2[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(CC2CCN(C(=O)OC(C)(C)C)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 58.9 %

Procedure:
To a mixture of 4-chloro-N-[(3R,4R)-3-(3,4-dichlorophenyl)piperidin-4-yl]-N-methylbenzamide monohydrochloride (300 mg) obtained in Example 137a, tert-butyl 4-formylpiperidine-1-carboxylate (735 mg) and triethylamine (105 μL) in acetic acid (0.69 mL)-ethyl acetate (10 mL) was added sodium triacetoxyborohydride (731 mg), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 60→90% ethyl acetate/hexane, and then 0→30% methanol/ethyl acetate) to give the title compound (242 mg, 58%) as a white powder.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18]C)=[C:14](OC)[CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[F:22][C:23]1[CH:40]=[CH:39][C:26]2[S:27][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:29][C:25]=2[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:22][C:23]1[CH:40]=[CH:39][C:26]2[S:27][C:28]([C:2]3[N:6]4[N:7]=[C:8]([NH:11][C@H:12]5[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]5)[CH:9]=[CH:10][C:5]4=[N:4][CH:3]=3)=[CH:29][C:25]=2[CH:24]=1
Reactant: CC1(C)OB(c2cc3cc(F)ccc3s2)OC1(C)C
Reactant: COc1ccc(Nc2ccc3ncc(Br)n3n2)cc1OC
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O[C@H]1CC[C@H](Nc2ccc3ncc(-c4cc5cc(F)ccc5s4)n3n2)CC1

Procedure:
To a solution of 3-bromo-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine (118 mg, 0.338 mmol, 1.0 equiv) in acetonitrile (3.79 mL) was added 2-(5-fluorobenzo[b]thiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (158 mg, 0.569 mmol, 1.5 equiv), bis(triphenylphosphine)palladium(II)dichloride (27 mg, 0.0379 mmol, 0.1 equiv), then sodium carbonate (3.79 mL, 1.0 M aqueous solution, 10 equiv). The reaction mixture was irradiated in the microwave at 150° C. for 10 min. Purification by column chromatography gave 90 mg of the yellow solid, 62%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[C:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([OH:31])=[O:30]>>[Cl:28][C:4]1[CH:3]=[C:2]([C:35]2[CH:36]=[CH:37][C:32]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:27])[C:9]([OH:14])([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=2[CH:26]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Product: CC(c1ccc(-c2ccc(C(=O)O)cc2)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with 4-carboxyphenylboronic acid to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=518.2 [M−H+].
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([OH:28])[CH:3]=1.[CH3:29][O:30][C:31](=[O:34])[CH2:32]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:29][O:30][C:31](=[O:34])[CH2:32][O:28][C:4]1[CH:3]=[C:2]([Cl:1])[CH:27]=[CH:26][C:5]=1[O:6][CH2:7][C:8]([N:10]1[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:12][C@H:11]1[CH3:25])=[O:9]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)COc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 169.8 %

Procedure:
To a solution of 2-(4-chloro-2-hydroxy-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.30 g, 0.75 mmol) and bromo-acetic acid methyl ester (0.14 mL, 1.5 mmol) in dioxane (3 mL) was added cesium carbonate (0.50 g, 1.5 mmol). The resulting mixture was stirred at ambient temperature overnight. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound (0.61 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)[C:3]=1[C:31]#[N:32].[NH2:33][NH2:34]>CC(O)C>[NH2:32][C:31]1[C:3]2[C:2](=[N:7][C:6]([C:8]3[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=3)=[CH:5][C:4]=2[C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][CH:23]=2)[NH:34][N:33]=1
Reactant: CC(=O)Nc1cccc(-c2cc(-c3ccc(Oc4ccccc4)cc3)c(C#N)c(Cl)n2)c1
Reactant: NN
Solvent: CC(C)O
Product: CC(=O)Nc1cccc(-c2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)n[nH]c3n2)c1
Temperature: 160 °C
Yield: 41 %

Procedure:
A mixture of N-(3-(6-chloro-5-cyano-4-(4-phenoxyphenyl)pyridin-2-yl)phenyl)acetamide (25 mg, 0.057 mmol) and 35% aqueous hydrazine (0.051 mL, 0.568 mmol) in 2-propanol (1.5 mL) was heated to 160° C. under microwave for 1 h then cooled to room temperature. Purification with reverse phase HPLC (Sunfire S10 30×250 mm column), eluting with 60-90% solvent B (10% methanol-90% water-0.1% TFA) in solvent A (90% methanol-10% water-0.1% TFA), gave Example 25 as the faster eluting peak (18 mg, 41% yield, yellow solid) and Example 24 as the slower eluting peak (3 mg, 8% yield, yellow solid).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([OH:14])[C:3]=1[C:15](=[O:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].[C:24](Cl)(=O)[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.O>CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]2[C:3]=1[C:15](=[O:17])[CH:16]=[C:24]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[O:14]2
Reactant: CC(=O)c1c(O)cc(N2CCOCC2)cc1O
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(-c2cc(=O)c3c(O)cc(N4CCOCC4)cc3o2)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 5.4 %

Procedure:
To a suspension of 1-(2,6-dihydroxy-4-morpholin-4-yl-phenyl)-ethanone (112 mg, 0.472 mmol) and K2CO3 (326 mg, 2.36 mmol) in acetone (3 mL) was added p-anisoyl chloride (0.066 mL, 0.472 mmol). The reaction vessel was sealed and heated to 80° C. for 4 days. After cooling to room temperature, water (about 2 mL) was added, and the mixture was allowed to stir for about 15 min. The contents were transferred to a separatory funnel containing water (5 mL) and extracted with EtOAc (3×15 mL). The organic layer was dried (MgSO4) and concentrated. The concentrate was purified via Biotage chromatography with gradient elution from 100% hexanes to 30% EtOAc/hexanes to yield 9 mg (5%) of 5-hydroxy-2-(4-methoxy-phenyl)-7-morpholin-4-yl-chromen-4-one. Me is CH3—.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.CON(C)[C:23]([C:25]1([C:28]([F:31])([F:30])[F:29])[CH2:27][CH2:26]1)=[O:24].[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:23]([C:25]2([C:28]([F:31])([F:30])[F:29])[CH2:27][CH2:26]2)=[O:24])=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: CON(C)C(=O)C1(C(F)(F)F)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1ccc(Br)cc1)C1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 4-bromoiodobenzene (2150 mg, 7.60 mmol) in tetrahydrofuran (20 mL) was added dropwise a solution of 1.67 mol/L n-butyllithium in hexane (4.50 mL, 7.52 mmol) at −78° C. under argon atmosphere. The mixture was stirred at the same temperature for 1 hour, and then thereto was added dropwise a solution of N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropanecarboxamide (synthesized by the method of Organic Process Research and Development 2009, 13, 576, 1000 mg, 5.07 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred at the same temperature for 1 hour. To the reaction solution was added saturated aqueous ammonium chloride solution at −78° C., and then the mixture was warmed to room temperature and extracted with ethyl acetate three times. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5) to give (4-bromophenyl)[1-(trifluoromethyl)cyclopropyl]methanone (783 mg, 76%) as a pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][CH:13]([CH3:28])[C:14]([CH2:16][N:17]3[C:21](=[O:22])[C:20]4=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]4[C:18]3=[O:27])=O)[CH2:9][N:8]=[C:7]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[C:6]=2[CH:36]=1>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:14]([CH2:16][N:17]4[C:21](=[O:22])[C:20]5=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]5[C:18]4=[O:27])=[C:13]([CH3:28])[N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[C:6]=2[CH:36]=1
Reactant: CC(NC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)CN1C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Product: Cc1nc2n(c1CN1C(=O)c3ccccc3C1=O)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In the manner given in example 20 a suspension of 7-chloro-5-(o-chlorophenyl)-2-[(3-phthalimido-1-methylacetonyl)amino]-3H-1,4-benzodiazepine, ethylene ketal in concentrated sulfuric acid is stirred at room temperature under nitrogen for 18 hours and the reaction mixture poured onto ice, treated with base and the product isolated to give 8-chloro-1-(phthalimidomethyl)-2-methyl-6-(o-chlorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([C:5]1[N:9]2[C:10]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:23](=[O:24])[CH2:22][S:21][C:20]3=[O:25])=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1)=[O:4].[CH:28](=O)[CH2:29][CH2:30][CH3:31].N1CCCCC1>C(O)C>[CH:28](=[C:22]1[S:21][C:20](=[O:25])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][S:14][C:10]2[N:9]3[C:5]([C:3](=[O:4])[C:2]([F:26])([F:1])[F:27])=[CH:6][N:7]=[C:8]3[CH:13]=[CH:12][CH:11]=2)[C:23]1=[O:24])[CH2:29][CH2:30][CH3:31]
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2ncc(C(=O)C(F)(F)F)n12
Reactant: CCCC=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCCCSc2cccc3ncc(C(=O)C(F)(F)F)n23)C1=O

Procedure:
To a solution of 250 mg (0.6 mmol) of 3-[4-(3-trifluoroacetylimidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 54 μl (0.6 mmol) of n-butyraldehyde in 5 ml of ethanol, 6 μl (0.06 mmol) of piperidine was added, followed by refluxing for 1 hour. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=2/1) to yield 200 mg (70.0%, light yellow oily substance) of the desired product.
Reaction SMILES: [C:1]1([CH2:11][C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Na+].[Na+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl.C(OCC)(=O)C.CCCCCC>O1CCCC1>[OH:30][CH2:29][CH:28]1[CH2:26][C@@:11]1([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:12]#[N:13]
Reactant: ClCC1CO1
Reactant: N#CCc1cccc2ccccc12
Agent: C[Si](C)(C)[NH-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#C[C@]1(c2cccc3ccccc23)CC1CO
Temperature: -15 °C
Reaction time: 0.75 h
Yield: 69.7 %

Procedure:
1-Naphthylacetonitrile (30 g, 180 mmole) was dissolved in dry tetrahydrofuran (THF, 300 mL) under nitrogen atmosphere, cooled to −15° C. and sodium-bis (trimethylsilylamide) in 1M tetrahydrofuran (180 mL) was added drop wise at −15° C. The resulting brown mixture was stirred for 45 min at −10° C. to 0° C. Then cooled the reaction mass to −15° C. A solution of S-(+) epichlorohydrin (16.6 g, 180 mmol) in tetrahydrofuran (20 mL) was added drop wise at −15° C. and stirred for 30 minutes. Sodiumbis (trimethylsilylamide) in 1M THF (180 mL) is added drop wise at −15° C. and the mixture was stirred for 45 min. The temperature of the reaction mass was then gradually raised to room temperature and maintained at room temperature for 30 minutes. The reaction is monitored by TLC (ethyl acetate/hexane (1:1)). The reaction was quenched with water (80mL). The aqueous layer was extracted with ethyl acetate (2×75 mL).The combined organic layer was washed with brine solution (200 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 55 g of crude oil, which was purified by column chromatography (silica gel, ethyl acetate/hexane (10:90) to yield 28 g (69%) of product. The 1H NMR shows mixture of diasteromers (2:1 cis/trans). 1H NMR δ((300 MHz,CDCl3, partial assignment): 1.57-1.62 (2H,m), 1.92-2.03 (1H,m), 3.10-3.25 (1H,br,s), 3.91-3.97 (1H,m) 4.22-4.27 (1H,m), 7.37-7.69 (4H,m), 7.82-7.92 (2H,m), 8.36-8.49 (1H,m).
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34]([NH:36][CH3:37])=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.[C:45](Cl)(=[O:47])[CH3:46].COC(O[Si](C)(C)C)=C(C)C>ClCCl>[C:45]([N:36]([CH3:37])[C:34]([C:24]1[C:23]2[CH:38]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]4[O:12][CH2:11][N:6]5[C:7]6[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=6[CH:4]=[C:5]5[C:14]=4[N:15]=3)[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]=2[O:26][C:25]=1[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)=[O:35])(=[O:47])[CH3:46]
Reactant: CC(=O)Cl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Agent: COC(O[Si](C)(C)C)=C(C)C
Solvent: ClCCl
Product: CC(=O)N(C)C(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (500 mg, 0.81 mmol) in dichloromethane (2 ml) was added acetyl chloride (174 μl, 2.44 mmol) and ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (495 μl, 2.44 mmol). The resulting mixture was stirred at room temperature overnight. Concentrated in vacuo and added Et3N (5 ml). Silica gel chromatography (eluted with 0-5% MeOH/dichloromethane) to provide N-acetyl-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (500 mg, yield: 94%) MS (M+H)+: 657.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:27]([CH:28]=1)[C:8]1[N:9]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[C:10](=[O:17])[C:11]3[C:16]([C:7]=1[N:6]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3.[C:29]([O:32][CH2:33][CH2:34]Br)(=[O:31])[CH3:30].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:9]2[C:8]3[N:27]4[CH:28]=[C:2]([O:1][CH2:34][CH2:33][O:32][C:29](=[O:31])[CH3:30])[CH:3]=[CH:4][C:5]4=[N:6][C:7]=3[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:17])=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: CC(=O)OCCBr
Reactant: O=c1c2ccccc2c2nc3ccc(O)cn3c2n1-c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1ccc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
A mixture of compound 10 (1.0 equiv., 0.806 mmol, 0.300 g), 2-bromoethyl acetate (2.0 equiv., 1.611 mmol, 0.269 g) and K2CO3 (3.0 equiv., 2.417 mmol, 0.334 g) in dry DMF (5 ml) was stirred at 60° C. for 4 h. Water was added to the reaction mixture and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried with MgSO4 and concentrated in vacuo. Purification by column chromatography (dichloromethane/methanol 97.2:2.5) afforded 6-(4-nitrophenyl)-9-[2-[(1-oxoethyl)oxy]-ethoxy]-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (73) (0.245 g, yield=66%, purity (LC)=97%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]2=1)([O-])=O.C(O)C>[C].[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]2=1
Reactant: O=C1CCCc2c1[nH]c1c([N+](=O)[O-])cccc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cccc2c3c([nH]c12)C(=O)CCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A mixture of 8-nitro-2,3,4,9-tetrahydro-1H-carbazol-1-one (1.50 g), 10% palladium-carbon (0.20 g), ethanol (5 mL) and tetrahydrofuran (10 mL) was stirred at room temperature overnight under a hydrogen atmosphere. Palladium-carbon was filtered off, and the filtrate was concentrated to give the title compound (1.20 g, yield 92%) as yellow crystals. melting point 233-234° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][N:18]=2)[CH2:10][C@H:9]1[C:25]([N:27]1[CH2:31][CH2:30][S:29][CH2:28]1)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.Cl.C(C1C=CC(NCCN[C@@H]2CN[C@H:49]([C:52](N3CCSC3)=[O:53])C2)=NC=1)#N.C(Cl)(=O)C.C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[C:52]([N:13]([C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:25]([N:27]2[CH2:31][CH2:30][S:29][CH2:28]2)=[O:26])[CH2:10]1)[CH2:14][CH2:15][NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][N:18]=1)(=[O:53])[CH3:49]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NCCNc2ccc(C#N)cn2)C[C@H]1C(=O)N1CCSC1
Reactant: N#Cc1ccc(NCCN[C@@H]2CN[C@H](C(=O)N3CCSC3)C2)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N(CCNc1ccc(C#N)cn1)[C@H]1C[C@@H](C(=O)N2CCSC2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-{(2S,4S)-1-tert-Butoxycarbonyl-4-{2-[(5-cyano-2-pyridyl)amino]ethyl}amino-2-pyrrolidinylcarbonyl}-1,3-thiazolidine [product of Example 319 (1), 800 mg] and triethylamine (0.42 mL) were dissolved in dichloromethane (20 mL), and acetyl chloride (0.18 mL) was added thereto under ice-cooling. The mixture was stirred at room temperature for 5 hr. The reaction mixture was added to saturated aqueous sodium hydrogencarbonate solution and the mixture was extracted with chloroform. The extract was washed with brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 3-[(2S,4S)-4-(N-acetyl-N-{2-[(5-cyano-2-pyridyl)amino]ethyl}amino)-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]-1,3-thiazolidine (786 mg) as a white solid.