Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:12][C:13]([C:15]1[N:16]=[C:17]([N:20]2[CH2:23][CH:22](OS(C)(=O)=O)[CH2:21]2)[S:18][CH:19]=1)=[O:14])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:29]([O-:32])(=[S:31])[CH3:30].[K+]>CN(C)C=O>[C:29]([S:31][CH:22]1[CH2:21][N:20]([C:17]2[S:18][CH:19]=[C:15]([C:13](=[O:14])[NH:12][C@@H:10]([CH3:11])[CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3])[N:16]=2)[CH2:23]1)(=[O:32])[CH3:30]
Reactant: CC([O-])=S
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N[C@@H](C)CO[Si](C)(C)C(C)(C)C)cs2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of 1-{4-[(1S)-2-(t-butyldimethylsilyloxy)-1-methylethylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (1.16 g, 2.50 mmol) (obtained as described in Reference Example 35(5)) in dimethylformamide (60 ml) was added potassium thioacetate (1.71 mg, 15.0 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (4:1→2:1) as the eluant to afford 3-acetylthio-1-{4-[(1S)-2-(t-butyldimethylsilyloxy)-1-methylethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (709 mg, yield 60%) as a pale brown oil.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH:11]=[C:12]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:45])[CH2:27][C:28]2[CH:44]=[CH:43][C:31]3[N:32]=[C:33]([NH:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[CH3:42])[O:34][C:30]=3[CH:29]=2)=[CH:21][CH:20]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][CH2:9][CH2:10][CH2:11][CH:12]([C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:45])[CH2:27][C:28]2[CH:44]=[CH:43][C:31]3[N:32]=[C:33]([NH:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[CH3:42])[O:34][C:30]=3[CH:29]=2)=[CH:23][CH:24]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: [H][H]
Reactant: CCOC(=O)CC(=CCCOCc1ccccc1)c1ccc(NC(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(CCCO)c1ccc(NC(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)cc1
Yield: 84.2 %

Procedure:
A mixture of ethyl 6-benzyloxy-3-{4-[2-(2-o-tolylamino-benzoxazol-6-yl)-acetylamino]-phenyl}-3-hexenoate (640 mg, Reference Example 22(a)) and 10% palladium on charcoal (250 mg) in ethanol (50 mL) was hydrogenated at room temperature and pressure. After 24 hours further catalyst (200 mg) was added and the mixture again subjected to a hydrogen atmosphere for a further 24 hours. The mixture was filtered through filter-aid and the filtrate evaporated to dryness to give the title compound (460 mg) as a colourless oil.
Reaction SMILES: [C:1]1([C:7]2[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:12][C:11]=3[C:10]([C:20]#[N:21])=[C:9]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1C[O:32]CC1>>[O:32]=[C:12]1[C:11]2[C:10]([C:20]#[N:21])=[C:9]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: C1CCOC1
Reactant: N#Cc1c(N2CCCC2)cc(-c2ccccc2)c2c1Cc1ccccc1-2
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCC2)cc(-c2ccccc2)c2c1C(=O)c1ccccc1-2
Temperature: 2.5 °C

Procedure:
A solution of 4-phenyl-2-(pyrrolidin-1-yl)-9H-fluorene-1-carbonitrile (336 mg) in THF was added sodium hydride (25 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Light red solid; mp 166-168° C.; ESIMS 351 (M++1); IR (KBr) 2215 (CN), 1717 cm−1 (CO); 1H NMR (300 Hz, CDCl3) δ 1.97-2.10 (m, 4H, CH2), 3.67-3.73 (m, 4H, 2CH2), 6.43-6.48 (m, 1H, ArH), 6.59 (s, 1H, ArH), 7.04-7.12 (m, 2H, ArH), 7.40-7.47 (m, 2H, ArH), 7.48-7.54 (m, 3H, ArH), 7.55-7.59 (m, 1H, ArH); 13C NMR (75.53 MHz, CDCl3): δ 24.50, 49.37, 88.60, 115.58, 11927, 120.14, 123.11, 126.0, 127.12, 127.33, 127.49, 129.34, 132.13, 133.40, 136.26, 137.69, 141.23, 142.34, 149.32, 189.94.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]2=[N:14][C:15]3[C:20]([C:21](=[O:22])[N:12]2[CH:11]=[CH:10][CH:9]=1)=[CH:19][C:18](I)=[CH:17][CH:16]=3)=[O:7].[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O>[CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]2=[N:14][C:15]3[C:20]([C:21](=[O:22])[N:12]2[CH:11]=[CH:10][CH:9]=1)=[CH:19][C:18]([C:27]1[CH:26]=[N:25][C:34]2[C:29]([CH:28]=1)=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:17][CH:16]=3)=[O:7]
Reactant: CN(C)CCNC(=O)c1cccn2c(=O)c3cc(I)ccc3nc12
Reactant: OB(O)c1cnc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)CCNC(=O)c1cccn2c(=O)c3cc(-c4cnc5ccccc5c4)ccc3nc12
Temperature: 120 °C
Yield: 66.6 %

Procedure:
A mixture of N-[2-(dimethylamino)ethyl]-2-iodo-11-oxo-11H-pyrido[2,1-b]quinazoline-6-carboxamide (750 mg), 3-quinolinylboronic acid (743.47 mg), tetrakis-(triphenylphosphine)palladium(0) (198.67 mg) and sodium carbonate (4.3 ml of 2 M (8.6 mmol))and 33 ml of toluene was heated at 120° C. for 7 hours and cooled to room temperature. The reaction mixture was diluted with 70 ml of water and extracted with 3×70 ml CHCl3. The organic layer was dried over Na2SO4 and evaporated in vacuo to a residue. The residue was purified by column chroma-tography on silica gel by elution with 5-10% MeOH/CHCl3 to give 501 mg of a yellow solid.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[C@@H:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C@@H:25]([CH2:28][CH3:29])[CH2:26]O)[C:5]1=[O:30])[CH:2]=[CH2:3].[CH2:32]([S:34]([NH2:37])(=[O:36])=[O:35])[CH3:33]>>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[C@@H:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C@@H:25]([CH2:28][CH3:29])[CH2:26][NH:37][S:34]([CH2:32][CH3:33])(=[O:36])=[O:35])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: CCS(N)(=O)=O
Reactant: C=CC[C@@]1(C)C[C@H](c2cc(F)cc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Product: C=CC[C@@]1(C)C[C@H](c2cc(F)cc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)CC)C1=O

Procedure:
(3S,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (100 mg, 0.215 mmol; Example 393, Step B) and ethanesulfonamide (70.5 mg, 0.646 mmol) were coupled by the procedure as described in Example 202, Step C to form the title compound, isolated after silica gel chromatography (4 g column; eluent 0 to 50% EtOAC/hexanes) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5](S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1.C(OCC)(=O)C>C(#N)C>[CH3:1][O:2][C:3](=[O:37])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=2)[CH:8]=1
Reactant: COC(=O)CN(Cc1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CNCc1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1

Procedure:
N-(2-Nitrobenzenesulfonyl)-N-[[2-(3,4,5-trimethoxy-phenyl)pyridin-4-yl]methyl]glycine methyl ester (11.35 g) was dissolved in acetonitrile (30 mL), and to the solution potassium carbonate (3.39 g) was added. Thiophenol (2.37 g) was then added to the mixture, and the resultant mixture was stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, and the resultant mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then purified by column chromatography on silica gel (chloroform:methanol=20:1) to obtain the title compound.
Reaction SMILES: Cl.[O:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[S:17][C:16]([NH:18][C:19](=[O:21])[CH3:20])=[N:15][CH:14]=3)=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:23]1[C:28]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[C:27]([CH3:37])[N:26]=[CH:25][N:24]=1.C(N(C(C)C)CC)(C)C>CN1CCCC1>[F:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][C:28]2[C:23]([N:5]3[CH2:6][C:7]4[CH:12]=[C:11]([C:13]5[S:17][C:16]([NH:18][C:19](=[O:21])[CH3:20])=[N:15][CH:14]=5)[CH:10]=[CH:9][C:8]=4[O:2][CH2:3][CH2:4]3)=[N:24][CH:25]=[N:26][C:27]=2[CH3:37])=[CH:35][CH:34]=1
Reactant: CC(=O)Nc1ncc(-c2ccc3c(c2)CNCCO3)s1
Reactant: Cc1ncnc(Cl)c1Cc1ccc(F)cc1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ncc(-c2ccc3c(c2)CN(c2ncnc(C)c2Cc2ccc(F)cc2)CCO3)s1
Temperature: 120 °C
Yield: 46.9 %

Procedure:
A mixture of N-[5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1,3-thiazol-2-yl]acetamide hydrochloride (220 mg, 0.68 mmol), 4-chloro-5-[(4-fluorophenyl)methyl]-6-methylpyrimidine (reagent preparation 5) (152 mg, 0.64 mmol) and diisopropylethylamine (500 mg, 3.87 mmol) in N-methylpyrrolidine (4 mL) was heated in a microwave reactor at 120° C. for 3 h. The reaction mixture was concentrated, diluted with water (10 mL), the precipitate was filtered off, washed with water (2×5 mL) and methanol (5 mL), and dried to provide N-[5-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidine-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1,3-thiazol-2-yl]acetamide (147 mg, 47% yield) as a off-white solid. MS (EI) C26H24FN5O2S: 490 (MH+).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[CH:26]=[CH:25][C:11]([C:12]([CH3:24])=[CH:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[CH:10][CH:9]=1)=[O:7])C>O.C(O)C>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([CH3:24])=[CH:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[CH:25][CH:26]=1)([OH:7])=[O:5]
Reactant: CCOC(=O)c1ccc(C(C)=Cc2ccc3ccccc3c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=Cc1ccc2ccccc2c1)c1ccc(C(=O)O)cc1
Yield: 76.8 %

Procedure:
10 g of potassium hydroxide are dissolved in 50 cm3 of water and 200 cm3 of ethanol. 10 g of the compound prepared in Example 7 are added and the reaction mixture is heated under reflux for one hour, cooled and then acidified. The precipitate is filtered off and the insoluble matter is recrystallised from acetic acid. 7 g of the expected product are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C@@H:27]2[C@@H:32]3[CH2:33][C@@H:29]([CH:30]=[CH:31]3)[C@@H:28]2[C:34]([NH2:36])=[O:35])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:13][C:12]=3[O:24][CH3:25])[NH:8][C:5]2=[N:6][CH:7]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38].C(N(CC)CC)C>ClCCl>[C:37]([N:21]1[CH2:22][CH2:23][N:18]([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:9]3[NH:8][C:5]4=[N:6][CH:7]=[C:2]([Cl:1])[C:3]([NH:26][C@@H:27]5[C@H:32]6[CH2:33][C@@H:29]([CH:30]=[CH:31]6)[C@@H:28]5[C:34]([NH2:36])=[O:35])=[C:4]4[N:10]=3)=[C:12]([O:24][CH3:25])[CH:13]=2)[CH2:19][CH2:20]1)(=[O:39])[CH3:38]
Reactant: COc1cc(CN2CCNCC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CN2CCN(C(C)=O)CC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@@H]3C4)c(Cl)cnc2[nH]1
Yield: 33.1 %

Procedure:
(1S,2S,3R,4R)-3-[6-Chloro-2-(2-methoxy-4-piperazin-1-ylmethyl-phenyl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (Compound XLII) (254 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (10 mL) and treated with acetic anhydride (1 mL, 10.0 mmol) and triethylamine (1.0 mL, 7.2 mmol) for one hour at ambient temperature. The reaction was concentrated and the product was purified by reverse phase chromatography (Gilson) to afford following neutralization of desired fractions a pale yellow solid as the title compound (91 mg, 30%). Mp 109-113° C. 1H NMR (d-chloroform): 11.12 (br s, 1H), 8.34 (d, J=7 Hz, 1H), 7.99 (s, 1H), 7.11 (m, 2H), 6.37 (m, 3H), 5.72 (d, J=7 Hz, 1H), 5.36 (m, 1H), 5.22 (t, J=8 Hz, 1H), 4.10 (s, 3H), 3.66 (m, 2H), 3.59 (s, 2H), 3.50 (m, 2H), 3.17 (s 1H), 2.92 (s, 1H), 2.85 (d, J=7 Hz, 1H), 2.48 (m, 4H), 2.34 (d, J=8 Hz, 1H), 2.10 (s, 3H), 1.73 (d, J=7 Hz, 1H). MS: 550.2 (M+H). HPLC retention time: 1.70 minutes (G Method).
Reaction SMILES: C[O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([CH:23]3[CH2:25][CH2:24]3)[CH3:22])[CH:15]=2)=[CH:8][CH:7]=1.[OH-].[K+].Cl>CO.O1CCCC1>[CH:23]1([N:21]([CH2:20][C:16]2[CH:15]=[C:14]([C:13]#[C:12][C:9]3[CH:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[C:3]([OH:26])=[O:2])=[CH:7][CH:8]=3)[CH:19]=[CH:18][CH:17]=2)[CH3:22])[CH2:24][CH2:25]1
Reactant: COC(=O)/C=C/c1ccc(C#Cc2cccc(CN(C)C3CC3)c2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1cccc(C#Cc2ccc(/C=C/C(=O)O)cc2)c1)C1CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35.8 %

Procedure:
A solution of (E)-3-(4-{3-[(cyclopropyl-methyl-amino)-methyl]-phenylethynyl}-phenyl)-acrylic acid methyl ester (Intermediate 92, 0.11 g, 0.32 mmol) in methanol (3 mL) and tetrahydrofuran (2 mL) was treated with a 3M solution of potassium hydroxide (1 mL, 3 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 days. The reaction mixture was neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 10% methanol in ethyl acetate as the eluent to afford the title product as a yellow solid (0.038 g, 36%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][CH:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:19])[CH:14]=[CH:13][C:5]=1[CH:6]=[CH:7][C:8]([O:10]CC)=[O:9])[CH3:2].[OH-].[Na+].Cl>C(O)C.O>[CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][CH:21]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:19])[CH:14]=[CH:13][C:5]=1[CH:6]=[CH:7][C:8]([OH:10])=[O:9])[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1cc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)ccc1C=CC(=O)O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Ethyl 2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-cinnamate (330 mg, 0.62 mmol) is dissolved in ethanol (10 ml) and, after the addition of 4N sodium hydroxide solution (4 ml), stirred for 3 hours at 50° C. Then the mixture is neutralized with 4N hydrochloric acid (4 ml), diluted with water and filtered off from the precipitate. It is then recrystallized from aqueous ethanol.
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:33])[NH:15][C:16](=[O:32])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][CH2:28][CH2:29][CH2:30]O)[CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:54]>ClCCl>[Br:54][CH2:30][CH2:29][CH2:28][CH2:27][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([C:17]2[C:16](=[O:32])[NH:15][C:14](=[O:33])[C:13]=2[C:1]2[C:11]3=[C:12]4[C:7](=[CH:8][CH:9]=[CH:10]3)[CH2:6][CH2:5][CH2:4][N:3]4[CH:2]=2)=[CH:19]1
Reactant: BrC(Br)(Br)Br
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1cn(CCCCO)c2ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1cn(CCCCBr)c2ccccc12
Reaction time: 3 h
Yield: 80.4 %

Procedure:
A solution of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-[1-(4-hydroxybutyl)-1H-indol-3-yl]pyrrole-2,5-dione (0.11 g, 0.25 mmol) and triphenylphosphine (0.08 g, 0.31 mmol) in dichloromethane (3 mL) was treated with carbon tetrabromide (0.095 g, 0.286 mmol) and stirred for 3 hours. The reaction mixture was then concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with 2% methanol in dichloromethane. Fractions containing product were combined and concentrated under reduced pressure to provide 0.101 g (80%) of the title compound as a dark red foam.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([Br:16])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2].[CH:17]([C:19]1[N:20]=[C:21]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[S:22][CH:23]=1)=O.[OH-].[Na+].O>C1COCC1>[NH2:9][C:8]1[C:7]2[C:10]([Br:16])=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:6]=2[O:5][C:4]=1[C:1](=[O:3])[CH:2]=[CH:17][C:19]1[N:20]=[C:21]([NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[S:22][CH:23]=1
Reactant: COc1ccc2oc(C(C)=O)c(N)c2c1Br
Reactant: CC(C)C(=O)Nc1nc(C=O)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2oc(C(=O)C=Cc3csc(NC(=O)C(C)C)n3)c(N)c2c1Br
Temperature: 0 °C
Yield: 61.5 %

Procedure:
A mixture of 12G (2 g, 7 mmol), 11D (2.8 g, 14.5 mmol) in THF (20 mL) was cooled to 0° C. To the mixture was added NaOH (2 g). The reaction mixture was reacted at room temperature overnight. TLC monitored the reaction. After reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 16A (2 g, 61% yield).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCOCC3)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (76 mg, 0.20 mmol), morpholine (44 uL, 44 mg, 0.50 mmol) and DMAP (82 mg, 0.67 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 43 mg (50% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.47-1.62 (m, 4 H), 1.65 (s, 9 H), 2.28-2.43 (m, 1 H), 2.92-3.04 (m, 4 H), 3.29-3.40 (m, 2 H), 3.64-3.74 (m, 4 H), 3.88-3.98 (m, 2 H), 4.51 (d, J=7.42 Hz, 2 H), 7.83 (dd, J=8.79, 1.76 Hz, 1 H), 8.03 (d, J=8.79 Hz, 1 H), 8.08 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=422.0; Anal. Calcd for C21H31N3O4S+0.90 TFA+0.20 EtOAc+0.80H2O (556.22): C, 50.96; H, 6.36; N, 7.55. Found: C, 50.94; H, 6.46; N, 7.51.
Reaction SMILES: [C:1]12([C:11]([OH:13])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:14][CH2:15][CH2:16][CH:17]([OH:19])[CH3:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:19][CH:17]([CH3:18])[CH2:16][CH2:15][NH:14][C:11]([C:1]12[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2)=[O:13]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: CC(O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(O)CCNC(=O)C12CC3CC(CC(C3)C1)C2
Reaction time: 8 h
Yield: 30.2 %

Procedure:
Adamantane-1-carboxylic acid (404 mg, 2.24 mmol), 4-amino-butan-2-ol (200 mg, 2.24 mmol), EDCI (885 mg, 4.48 mmol) and HOBt (605 mg, 4.48 mmol) were dissolved in anhydrous CH2Cl2. DIEA (1.444 g, 11.2 mmol) was added to the above mixture at 0° C. under nitrogen. The mixture was stirred overnight and concentrated to give a residue, which was purified by preparative TLC to provide N-(3-hydroxybutyl)adamantane-1-carboxamide (170 mg, 30%). 1H NMR (MeOD, 400 MHz): δ=1.20 (d, 3H), 1.66˜2.04 (m, 17H), 2.87 (m, 2H), 3.79(m, 1H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[F:16][C:12]1[C:13]([F:15])=[CH:14][C:6]2[NH:5][C:1](=[O:2])[O:9][C:8](=[O:10])[C:7]=2[CH:11]=1
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Reactant: O=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(F)c(F)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of phosgene (45 g) in toluene (160 ml) was added during 20 minutes to a stirred solution of 2-amino-4,5-difluorobenzoic acid (26 g) in aqueous sodium carbonate (20.7 g anhydrous sodium carbonate in 350 ml water), keeping the temperature below 40°. The mixture was stirred at room temperature for 15 hours. The solid product was collected by filtration, washed with water and dried to give the novel compound 6,7-difluoro-1H-3,1-benzoxazine-2,4-dione, m.p. 223°-226° (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].N1C=CC=CC=1.Cl.[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39](Cl)=[O:40])[CH2:35][CH2:34]1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:39]([N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)=[O:40])[CH:17]=1)[C:10]([CH3:23])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)N3CCN(C)CC3)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
To a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (441 mg, 1.36 mmol) in dichloromethane (5 mL) and pyridine (1.1 mL, 13.6 mmol) was added 4-methyl-piperazine-1-carbonyl chloride hydrochloride (297 mg, 1.49 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was extracted with dichloromethane (2×50 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3,3-dimethyl-2-{3-[(4-methyl-piperazine-1-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (612 mg, 100%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C26H34N4O3 (M+H)+: 451.59, observed: 451.2.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:12]I>>[CH3:12][N:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[C:1]1=[O:11]
Reactant: CI
Reactant: Oc1nccc2cnccc12
Product: Cn1ccc2cnccc2c1=O

Procedure:
A method for preparing compounds of Formula (III) is provided in Scheme 6. 2,6-Naphthyridin-1-ol (6-1) is subjected to alkylation with methyl iodide under basic conditions to provide 2-methyl-2,6-naphthyridin-1(2H)-one (6-2). Chlorination of 6-2 with N-chlorosuccinimide provides chloro compound 6-3. Treatment of 6-3 under palladium-catalyzed cross coupling conditions with a suitable halide provides compound 6-4. Selective reduction of the 2,6-naphthyridinone derivative provides the 5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one derivative 6-5.