Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([N:6]1[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[C:8]([I:15])=[CH:7]1)[CH3:5].CI.[CH3:19]C(C)([O-])C.[K+]>C1COCC1>[I:15][C:8]1[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:14]=2[N:6]([C:4]([CH3:19])([CH3:5])[C:3]([O:2][CH3:1])=[O:16])[CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C(C)n1cc(I)c2cnccc21
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)n1cc(I)c2cnccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
To a solution of 2-(3-iodo-pyrrolo[3,2-c]pyridine-1-yl)-propionic acid methyl ester (Preparation 57, 13.1 g, 39.7 mmol) in THF (15 mL) was added methyl iodide (2.96 mL, 47.6 mmol) followed immediately by a 1M solution of potassium tertbutoxide in THF (5.34 g, 47.6 mmol) and the reaction was stirred at room temperature for 15 minutes. The reaction was quenched with water, and the remaining THF removed in vacuo. The residue was extracted with EtOAc, dried and concentrated in vacuo to afford the title compound as a yellow solid (5.1 g, 37%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:10][OH:11])[CH:7]=[N:8][CH:9]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].O>O1CCCC1>[CH3:12][S:13]([O:11][CH2:10][C:6]1[CH:7]=[N:8][CH:9]=[C:4]([Br:3])[CH:5]=1)(=[O:15])=[O:14]
Reactant: OCc1cncc(Br)c1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)OCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) suspension of sodium hydride (60% dispersion in mineral oil, 0.064 g, 1.60 mmol) in tetrahydrofuran (5 mL) was added a solution of (5-bromopyridin-3-yl)methanol (0.200 g, 1.06 mmol) in tetrahydrofuran (5 mL). After stirring for 1 hour, methanesulfonyl chloride (0.099 mL, 1.28 mmol) was added. The reaction was then warmed to room temperature and stirred until complete. The reaction was then poured into water and extracted with ethyl acetate. The organic extracts were combined, washed with water and saturated aqueous sodium chloride solution, dried, filtered, and concentrated under reduced pressure to provide the title compound: LCMS m/z 267.86 [M+2+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:24]=[CH:23][C:10](/[CH:11]=[N:12]/[C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][O:16][C:17]3=[O:22])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].[CH3:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.[O-:34][CH2:35][CH3:36].[Na+].C(O)C>C(OCC)(=O)CC>[CH2:1]([N:3]([CH2:6][C:7]1[CH:24]=[CH:23][C:10]([CH:11]2[CH:25]([C:26]3[CH:33]=[CH:32][C:29]([CH3:30])=[CH:28][CH:27]=3)[C:35](=[O:34])[C:36]3[C:18]([C:17]([O:16][CH2:15][CH3:14])=[O:22])=[CH:19][CH:20]=[CH:21][C:13]=3[NH:12]2)=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1ccc(/C=N/c2cccc3c2COC3=O)cc1
Reactant: Cc1ccc(C=O)cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C)cc1)C(c1ccc(CN(CC)CC)cc1)N2
Temperature: 0 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
A mixture of (E)-4-(4-((diethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)-one (644 mg, 2 mmol) and 4-methylbenzaldehyde (240 mg, 2 mmol) in ethyl propionate (15 mL) was cooled to 0° C. Then a solution of sodium ethoxide in ethanol (sodium (138 mg, 6 mmol) in ethanol (5 mL)) was added dropwise. After the addition, the mixture was stirred at room temperature for 3 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product, which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:1) to give the title compound (320 mg, yield 34%). LC-MS (ESI) m/z: 471 (M+1)+.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][NH:7][C:8](=[O:17])[C:9]([CH2:14][O:15][CH3:16])([CH3:13])[CH2:10][O:11][CH3:12])C.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(C)=O>[CH3:16][O:15][CH2:14][C:9]([CH2:10][O:11][CH3:12])([CH3:13])[C:8]([NH:7][CH2:6][CH2:5][CH:4]=[O:3])=[O:17]
Reactant: CCOC(CCNC(=O)C(C)(COC)COC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: COCC(C)(COC)C(=O)NCCC=O
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a solution of 3 g of N-(3,3-diethoxy-propyl)-3-methoxy-2-methoxymethyl-2-methyl-propionamide in 71 mL of acetone was added 3.91 g of TsOH.H2O. The mixture was stirred over night at rt, quenched with sat.-NaHCO3 and extracted with DCM. The organic phase was washed with brine, dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using Hept/EtOAc from 100/0 to 0/100 as eluant to yield 2.19 g of 3-methoxy-2-methoxymethyl-2-methyl-N-(3-oxo-propyl)-propionamide
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][N:28]3[CH2:33][CH2:32][CH:31]([C:34]([O:36]CC)=[O:35])[CH2:30][CH2:29]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>O1CCCC1.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][N:28]3[CH2:33][CH2:32][CH:31]([C:34]([OH:36])=[O:35])[CH2:30][CH2:29]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)C1CCN(Cc2cn(C)c3c(-c4noc(-c5ccc(OC(C)C)c(Cl)c5)n4)cccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CN5CCC(C(=O)O)CC5)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a solution of ethyl 1-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]methyl}-4-piperidinecarboxylate (D79) (308 mg) in tetrahydrofuran (5 mL) and ethanol (5 mL) stirred at 20° C. was added a solution of sodium hydroxide (60 mg) in water (5 mL) in one charge. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was concentrated and then H2SO4 (0.1 M) solution was added dropwise until no further white precipitate was formed. The solid was filtered and recrystallized from EtOAc to afford 1-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]methyl}-4-piperidinecarboxylic acid (E57) (140 mg). δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 1.49-2.21 (7H, m), 2.84-2.87 (2H, m), 3.65 (5H, s), 4.86-4.93 (1H, m), 7.18 (1H, t), 7.31 (1H, s), 7.44 (1H, dd), 7.46 (1H, d), 7.91 (1H, dd), 8.14 (1H, dd), 8.21 (1H, d), 12.06 (1H, br s). MS (ES): C27H29ClN4O4 requires 508; found 380.1 (M—NC5H9COOH+).
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14](Cl)[C:5]2=[N:4][CH:3]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18].CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[Br:1][C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([NH:20][CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]2=[N:4][CH:3]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: Clc1nc2ccccc2n2c(Br)cnc12
Reactant: CC(C)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)CNc1nc2ccccc2n2c(Br)cnc12
Temperature: 170 °C
Yield: 93.3 %

Procedure:
To a stirred solution of 1-bromo-4-chloro-imidazo[1,2-a]quinoxaline (14.13 g, 50 mmol) in NMP (400 mL) was added isobutylamine (9.94 mL, 100 mmol) and DIPEA (26.13 mL, 150 mmol) at room temperature in a microwave reactor. The solution was heated at 170° C. under microwave irradiation for 60 min. After cooling, water was added to the solution and the precipitate was filtered and the residue was washed with water and dried to give (1-bromo-imidazo[1,2-a]quinoxalin-4-yl)-isobutyl-amine (14.89 g, 93.3%): 1H-NMR (300 MHz, d6-DMSO): δ=9.17 (1H, d), 8.01 (1H, d), 7.92 (1H, s), 7.78 (1H, dd), 7.70 (1H, dd) ppm. UPLC-MS: RT=1.14 min; m/z 284.6 [MH+]; required MW=283.5.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH3:4].[O:17]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:3]([O:5][C:6](=[O:16])[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:10][CH:9]=1)[CH3:4]
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Reactant: BrCCCCCCCCCCCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1ccc(OCCCCCCCCCCCCOc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To a suspension of 0.162 g (4.06 mmol) of 60% sodium hydride on oil in 10 ml of anhydrous DMF was added 0.75 g (3.87 mmol) of 4-hydroxy-alpha-oxobenzeneacetic acid ethyl ester. The reaction mixture was stirred at room temperature under argon for 15 minutes and then 1.4 g (4.06 mmol) of 12-phenoxydodecyl bromide in 20 ml of anhydrous DMF was added. The mixture was stirred and heated at 60° for 24 hours. The usual workup followed by chromatography on 45 g of silica gel gave alpha-oxo-4-[(12-phenoxydodecyl)oxy]benzeneacetic acid ethyl ester (83% yield, mp 58°-59°).
Reaction SMILES: [C:1]([O:7]C)(=O)[CH2:2][C:3]([CH3:5])=O.[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[C:18]1[CH:22]=[N:21][NH:20][C:19]=1[NH2:23].C(O)C>C(O)(=O)C>[CH3:5][C:3]1[NH:23][C:19]2[N:20]([N:21]=[CH:22][C:18]=2[C:11]2[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[CH3:9])[C:1](=[O:7])[CH:2]=1
Reactant: Cc1cc(C)c(-c2cn[nH]c2N)c(C)c1
Reactant: COC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(C)c(-c2cnn3c(=O)cc(C)[nH]c23)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
Methyl acetoacetate (0.7 ml) was added to a solution of 4-(2,4,6-Trimethyl-phenyl)-2H-pyrazol-3-ylamine (1.120 g, 5.57 mmol) in 5 ml of acetic acid and the resulting mixture was heated at reflux for two days. Reaction mixture cooled and a white solid formed. Ethanol (6 ml) was added and stirred at room temperature overnight, filtered to give white solid which was recrystallized from ethanol to give 673 mg(45.2%) of the title compound as white crystals. 1H NMR (DMSO-d6) ä 11.9(s, 1H), 7.7(s, 1H), 6.95(s, 2H), 5.55(s, 1H), 2.25(s, 3H), 2.20(s, 3H), 2.0(s, 6H)ppm.
Reaction SMILES: O[CH:2]([CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10].CCN(S(F)(F)[F:25])CC.CO>O1CCOCC1>[F:25][CH:2]([CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10]
Reactant: CCN(CC)S(F)(F)F
Reactant: O=[N+]([O-])c1nccn1CC(O)CN1CCCCC1
Solvent: C1COCCO1
Solvent: CO
Product: O=[N+]([O-])c1nccn1CC(F)CN1CCCCC1

Procedure:
To a solution of 2.2 g (8.65 mmol) of 1-(2'-hydroxy-3'-piperidylpropyl)-2-nitroimidazole in 20 ml of dry dioxane, 2.5 g (15.5 mmol) of DAST was dropwise added with cooling by ice and reacted for 5 hours at room temperature. After reaction, to the solution, 10 ml of methanol was added to decompose excess DAST. Then, the solution was concentrated and partitioned between chloroform and water. The pH of the aqueous phase was adjusted to 12 by the addition of an aqueous solution of sodium hydroxide and the liquid was again partitioned between chloroform and water. The chloroform phase was dried on magnesium sulfate and filtered. The filtrate was concentrated and subjected to isolation and purification by silica gel chromatography to give 1-(2'-fluoro-3'-piperidylpropyl)-2-nitroimidazole, which was treated with hydrochloric acid to form a hydrochloride and crystallized from ethanol to give 560 mg of crystalline hydrochloride of 1-(2'-fluoro-3'-piperidylpropyl)-2-nitroimidazole.
Reaction SMILES: Br.C(O)(=O)C.C(O[C:11]([N:13]([C:15]1[CH:39]=[CH:38][C:18]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:31][CH2:30][C:28]3=[O:29])[CH2:23][CH2:22]2)=[O:20])=[CH:17][CH:16]=1)C)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:11][NH:13][C:15]1[CH:16]=[CH:17][C:18]([C:19]([N:21]2[CH2:22][CH2:23][CH:24]([N:27]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:31][CH2:30][C:28]3=[O:29])[CH2:25][CH2:26]2)=[O:20])=[CH:38][CH:39]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CNc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture (5 ml) of hydrobromic acid and acetic acid (35 % solution) is added to 1-{1-[4-(N-t-butoxycarbonyl-N-methylamino)benzoyl]-4-piperidinyl}-3,4-dihyrocarbostyril (1.8 g) and the mixture is stirred at room temperature overnight. The reaction mixture is poured into water and the pH value thereof is adjusted to pH 12-14 by adding potassium carbonate. The mixture is extracted with chloroform, dried with sodium carbonate and then purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=1:1). The resultant is recrystallized from n-hexane/ethanol to give 1-{1-[4-(N-methylamino)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1.2 g), as white powder, m.p. 184°-186° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:17])(O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Br:15])[CH:2]=1.C[O:19][CH:20](OC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1.C1(C)C=CC=CC=1>[C:21]1([CH:20]2[O:17][CH:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Br:15])[O:19]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OC(O)(Cc1ccccc1Br)c1cccnc1
Reactant: COC(OC)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1
Product: Brc1ccccc1C1OC(c2ccccc2)OC1c1cccnc1

Procedure:
37 g (0.1258 mol) of 1-(pyrid-3-yl)-2-(2-bromophenyl)-ethanediol and 38.5 g (0.2516 mol) of benzaldehyde dimethyl acetal were refluxed together in 440 ml of 10:1 chlorobenzene/toluene with 1 g of p-toluenesulfonic acid. The resulting methanol was distilled off as an azeotrope with toluene. After the end of the reaction, the chlorobenzene was distilled off under reduced pressure and the product wa purified by chromatography over silica gel.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][CH:11]([CH3:18])[CH2:12]/[CH:13]=[CH:14]/[C:15](=[O:17])[CH3:16].[CH3:19][CH2:20][O:21][C:22]([CH2:24][N+:25]([O-:27])=[O:26])=[O:23].Cl>C(#N)C>[CH2:12]([CH:13]([CH2:14][C:15](=[O:17])[CH3:16])[CH:24]([N+:25]([O-:27])=[O:26])[C:22]([O:21][CH2:20][CH3:19])=[O:23])[CH:11]([CH3:18])[CH3:10]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: CC(=O)/C=C/CC(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(C(CC(C)=O)CC(C)C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diisopropylethylamine (7.9 mL) was added to the acetonitrile solution (50 mL) of (3E)-6-methylhept-3-en-2-one (6.25 g) and nitro ethyl acetate (5 mL) under argon gas atmosphere, and the reaction mixture was stirred at room temperature overnight. 1N hydrochloric acid was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed by water and a saturated aqueous solution of sodium chloride, and dried with anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=95/5→75/25) to obtain the title compound (9.88 g) having the following physical data.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:30][CH2:31][CH3:32])[CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C@H:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19][CH2:18]3)=[N:8][CH:9]=1)=[S:3].Br[CH:34]([CH3:38])[C:35](=O)[CH3:36]>C(O)C>[CH3:38][C:34]1[N:1]=[C:2]([C:4]2[CH:5]=[CH:6][C:7]([N:10]([CH2:30][CH2:31][CH3:32])[CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C@H:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19][CH2:18]4)=[N:8][CH:9]=2)[S:3][C:35]=1[CH3:36]
Reactant: CC(=O)C(C)Br
Reactant: CCCN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC)c1ccc(C(N)=S)cn1
Solvent: CCO
Product: CCCN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC)c1ccc(-c2nc(C)c(C)s2)cn1
Temperature: 80 °C
Yield: 98.5 %

Procedure:
A mixture of ethyl ((1S)-5-{3-[[5-(aminocarbonothioyl)-2-pyridinyl]-(propyl)-amino]-propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 266) (90 mg, 0.20 mmol) and 3-bromo-2-butanone (40 mg, 0.26 mmol) in ethanol (9 mL) was heated under argon at 80° C. for 18 h. The solution was then concentrated and the residue purified by column chromatography (2:1 hexanes/EtOAc) to provide the title compound (0.1 g, 100%). 1H NMR (400 MHz, CD2Cl2) δ 8.54 (d, 1H), 7.89 (d, 1H), 7.06 (d, 1H), 6.79 (d, 1H), 6.71 (dd, 1H), 6.56 (d, 1H), 4.16 (q, 2H), 4.01 (t, 2H), 3.74 (t, 2H), 3.55-3.45 (m, 3H), 2.95-2.78 (m, 2H), 2.76-2.68 (m, 1H), 2.46-2.30 (m, 8H), 2.11 (qt, 2H), 1.72-1.62 (m, 3H), 1.28 (t, 3H), 0.97 (t, 3H).
Reaction SMILES: [S:1]1[C:5]([NH:6][S:7]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=3[C:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH:31]=3)[CH2:11]2)(=[O:9])=[O:8])=[N:4][CH:3]=[N:2]1.[ClH:43].O1CCOCC1>C(OCC)C>[ClH:43].[NH:33]1[CH2:32][CH:31]=[C:30]([C:21]2[CH:22]=[C:23]([C:26]([F:28])([F:29])[F:27])[CH:24]=[CH:25][C:20]=2[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:17]=2[CH2:18][CH2:19][N:10]([S:7]([NH:6][C:5]2[S:1][N:2]=[CH:3][N:4]=2)(=[O:8])=[O:9])[CH2:11]3)[CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2-c2cccc3c2CCN(S(=O)(=O)Nc2ncns2)C3)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=S(=O)(Nc1ncns1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2C2=CCNCC2)C1
Temperature: 80 °C

Procedure:
A vial charged with tert-butyl 4-(2-(2-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.305 g, 0.491 mmol) was treated with HCl 4N in dioxane (3.07 ml, 12.26 mmol) then was heated to 80° C. for one hour. The reaction mixture was cooled to room temperature and was diluted with diethyl ether. The resulting white solid was filtered off and dried yielding 5-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride (0.242 g, 0.434 mmol). [M+H]+=522.0. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.81 (br. s., 2H), 8.35-8.44 (m, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.60 (d, J=1.3 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.18-7.28 (m, 2H), 7.02 (d, J=6.6 Hz, 1H), 5.72 (br. s., 1H), 4.22-4.36 (m, 2H), 3.31-3.52 (m, 4H), 3.26 (m, 2H), 2.83-3.08 (m, 2H), 1.91-2.20 (m, 2H)
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C1O[C:10]2([CH2:19][CH2:18][C:13]3([NH:17][CH2:16][CH2:15][CH2:14]3)[CH2:12][CH2:11]2)[O:9]C1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[N:17]1([C:2]([O:4][CH2:5][CH3:6])=[O:3])[C:13]2([CH2:18][CH2:19][C:10](=[O:9])[CH2:11][CH2:12]2)[CH2:14][CH2:15][CH2:16]1
Reactant: CCOC(=O)Cl
Reactant: C1CNC2(C1)CCC1(CC2)OCCO1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCCC12CCC(=O)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
Ethyl chloroformate (1.90 mL, 2.16 g, 19.9 mmol) was added drop-wise to a cold (0° C.), stirred solution of 1-azaspiro[4.5]decan-8-one ethylene ketal (3.00 g, 15.2 mmol), triethylamine (3.20 mL, 2.32 g, 23.0 mmol) and catalytic 4-(dimethylamino)pyridine (10 mg) in dry dichloromethane (25 mL) under a nitrogen atmosphere. The ice bath was removed and the reaction was stirred 4 h at ambient temperature and poured into saturated aqueous sodium bicarbonate (10 mL). The mixture was shaken and the organic layer drawn off. The aqueous layer was extracted with dichloromethane (25 mL), and the combined dichloromethane extracts were dried (Na2SO4) and concentrated by rotary evaporation. The residue (3.5 g) was combined with 2% aqueous sulfuric acid (50 mL) and stirred 3 h at ambient temperature. The mixture was extracted with ethyl acetate (4×20 mL), and the combined extracts were washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride (10 mL each) and dried (Na2SO4). The residue from concentration of the dried extracts was dissolved dichloromethane (100 mL) and stirred for 1 h with silica gel (5 g). The silica gel was then removed by filtration, and the filtrate was concentrated, leaving 2.35 g (68.7%) of viscous colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.II.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[C:8]([CH3:11])[CH:7]=3)[N:1]=2)=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1ccc(N)c(C(N)=O)c1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2nc(-c3ccc(F)cc3)[nH]c(=O)c2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
A mixture of 2-amino-5-methylbenzamide (1.0 g, 6.7 mmol), 4-fluorobenzaldehyde (0.83 g, 6.7 mmol), iodine (2.03 g, 8.0 mmol), and potassium carbonate (1.38 g, 10 mmol) in DMF (50 mL) was stirred at 80° C. for 16 hours. The reaction mixture was cooled to 20° C. and poured into icy water. The solid was collected by filtration, washed with water, and air dried to give 2-(4-fluoro-phenyl)-6-methyl-3H-quinazolin-4-one (1.41 g, 83%). A solution of 2-(4-fluoro-phenyl)-6-methyl-3H-quinazolin-4-one (1.4 g, 5.5 mmol), NBS (0.98 g, 5.6 mmol), and benzoyl peroxide (67.0 mg, 0.276 mmol) in AcOH (150 mL) and chloroform (150 mL) was stirred at 80° C. for 5 hours with light shedding on. The reaction mixture was cooled to 20° C. and concentrated using a rotary evaporator to yield the crude bromide. A solution of the above crude bromide in DMF (20 mL) and 1,4-dioxane (100 mL) was mixed with morpholine (10 mL) and stirred at 80° C. for 4 hours. The reaction was quenched by adding water (200 mL), extracted with dichloromethane (3×100 mL), and concentrated using a rotary evaporator. The residue was further purified by column (SiO2, Hexanes/EtOAc/MeOH=4:3:1) to yield 2-4-fluoro-phenyl)-6-morpholin-4-ylmethyl-3H-quinazolin-4-one (0.89 g, 48% over two steps). A solution of 2-(4-fluoro-phenyl)-6-morpholin-4-ylmethyl-3H-quinazolin-4-one (0.89 g, 2.62 mmol) in dichloromethane (100 mL) and MeOH (50 mL) was mixed with HCl in ether (8 mL, 16 mmol) and stirred for 1 hour. The reaction was concentrated using a rotary evaporator. The solid was rinsed with DCM (50 mL) and MeOH (5 mL), collected by filtration, washed with DCM-MeOH (10:1) to afford 2-(4-fluorophenyl)-6-(morpholinomethyl)quinazolin-4(3H)-one (0.82 g, 76%) as an off-white solid; MS (ES) m/z: 340 (M+1); MP 321.8-323.3° C.
Reaction SMILES: O1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH2:21]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][N:21]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[NH:10][CH:11]=[N:12][C:8]=2[CH:7]=1
Reactant: c1nc2ccc(-c3nnco3)cc2[nH]1
Reactant: COc1ccc(CN)cc1OC
Product: COc1ccc(Cn2cnnc2-c2ccc3[nH]cnc3c2)cc1OC

Procedure:
The compound was synthesized starting from 5-(1,3,4-oxadiazol-2-yl)benzimidazole (186 mg, 1 mmol) and 3,4-Dimethoxybenzylamine (0.5 ml) as described above; yield: 0.087 g (25.9%); MS m/z: 336.3 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.55 (s, 3H); 3.65 (s, 3H); 5.27 (s, 2H); 6.50 (dd, 1H, 4J=2.1 Hz, 3J=8.3 Hz); 6.64 (d, 1H, 4J=2.1 Hz); 6.81 (d, 1H, 3J=8.3 Hz), 7.62 (dd, 1H, 4J=1.2 Hz, 3J=8.7 Hz); 7.83 (d, 1H, 3J=8.7 Hz); 7.92 (br s, 1H); 8.76 (s, 1H); 8.98 (s, 1H); HPLC (METHOD [A]): rt 7.36 min (100%)