Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CC>C1(C)C=CC=CC=1.ClCCl>[CH2:2]([O:3][CH2:4][C@H:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOC[C@@H](O)CO
Temperature: 25 °C
Yield: 709.4 %

Procedure:
19.4 grams of (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol, 49 grams of powdered KOH and 4.8 grams of hexadecyl bromide were stirred in 500 ml toluene (500 ml) were stirred and refluxed for 6 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 100 ml and the reaction mixture was cooled to room temperature. The cooled reaction mixture was dissolved in 500 ml dichloromethane, washed twice with 200 ml water, and the solvent was removed under reduced pressure. The obtained residue was dissolved in 500 ml of a 90:10:5 (v/v) mixture of methanol:water:concentrated H2SO4, and the resulting solution was refluxed for 30 minutes, cooled to room temperature, and extracted with 500 ml dichloromethane. The extract was washed twice with 100 ml water, 100 ml aqueous 5% sodium carbonate, and again with 100 ml water, until neutral. The solvent was removed under reduced pressure and the crude product was recrystallized from hexane at 4° C., yielding 35.3 grams of pure 1-hexadecyl-sn-glycerol. The yield was 76%.
Reaction SMILES: [Cl:1][SiH:2]([CH3:4])[CH3:3].[C:5]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:10])[CH2:6][CH2:7][CH:8]=[CH2:9]>>[Cl:1][Si:2]([CH3:4])([CH3:3])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: C[SiH](C)Cl
Reactant: C=CCCC(=O)OCc1ccccc1
Product: C[Si](C)(Cl)CCCCC(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a mixture of chlorodimethylsilane (0.730 g; 6.57 mmol) and benzyl pent-4-enoate (1.25 g; 6.57 mmol) under argon was added one drop of Karstedt's catalyst solution (in xylenes; ˜2% Pt). The reaction vessel was sealed and the mixture was heated to 60° C. for 13.5 hours. The crude liquid was used without purification.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([N:9]3[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:11][CH2:10]3)=[C:7]([N+:23]([O-])=O)[CH:6]=[N:5]2)[CH2:3][CH2:2]1.[C:26]([O:30][C:31]([NH:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[N:36][C:35]=1[C:46](O)=[O:47])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[F:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C:37]1[S:38][C:34]([NH:33][C:31](=[O:32])[O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[C:35]([C:46](=[O:47])[NH:23][C:7]2[CH:6]=[N:5][N:4]([CH:1]3[CH2:3][CH2:2]3)[C:8]=2[N:9]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:11][CH2:10]2)[N:36]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Reactant: O=C(N[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2C2CC2)CC1)C(F)(F)F
Product: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)Nc1cnn(C2CC2)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Yield: 76 %

Procedure:
Following the procedure for Example 506 starting with (R)-N-(1-(1-cyclopropyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid gave (R)-tert-butyl 2-(2-fluorophenyl)-4-(1-cyclopropyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a cream solid (370 mg, 76%). 1H-NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 8.69 (s, 1H), 8.12-8.00 (m, 1H), 7.45-7.30 (m, 1H), 7.28-7.15 (m, 3H), 6.40-6.27 (m, 1H), 4.30-4.15 (m, 1H), 3.43-3.15 (m, 5H), 2.25-1.75 (m, 6H), 1.55 (s, 9H), 1.35-1.15 (m, 2H), 1.10-0.95 (m, 2H).
Reaction SMILES: N1C=CC=CC=1N1CC2C(=O)N(CC(F)(F)F)C3C=CC=CC=3C=2N1C1CCCCO1.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[CH:39]=[CH:40][C:41]2[C:42]3[C:43](=[CH:54][N:55](C4CCCCO4)[N:56]=3)[C:44](=[O:53])[N:45]([CH2:48][C:49]([F:52])([F:51])[F:50])[C:46]=2[CH:47]=1.[Cl:63]N1C(=O)CCC1=O>C(O)(=O)C.C(Cl)Cl>[Cl:63][C:39]1[C:38]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=2)=[CH:47][C:46]2[N:45]([CH2:48][C:49]([F:52])([F:51])[F:50])[C:44](=[O:53])[C:43]3[CH:54]=[N:55][NH:56][C:42]=3[C:41]=2[CH:40]=1
Reactant: O=c1c2cn(C3CCCCO3)nc2c2ccc(-c3ccccn3)cc2n1CC(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Agent: O=c1c2c(c3ccccc3n1CC(F)(F)F)N(C1CCCCO1)N(c1ccccn1)C2
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=c1c2cn[nH]c2c2cc(Cl)c(-c3ccccn3)cc2n1CC(F)(F)F
Temperature: 80 °C
Reaction time: 3 h
Yield: 38.4 %

Procedure:
To a suspension of 7-(pyrid-2-yl-1-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 7-(pyrid-2-yl)-2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one [described in Step 1.5] (1.6 g, 3.73 mmol) in 32 mL of acetic acid is added N-chlorosuccinimide (2.49 g, 18.67 mmol). The reaction mixture is stirred for 3 hours at 80° C., cooled to room temperature and concentrated to dryness to give a yellow solid, which is dissolved in DCM. The solution is washed with saturated aqueous NaHCO3 solution and then with saturated aqueous NaCl solution, dried over Na2SO4, filtered and concentrated to give a yellow solid. The solid is taken up in DCM. After filtering off and drying, 542 mg of a white solid are obtained (yield: 35%).
Reaction SMILES: C(OC([O:6][CH:7]1[C:12]2[CH:13]=[CH:14][S:15][C:11]=2[S:10](=[O:17])(=[O:16])[N:9]([CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[CH2:8]1)C)C.C([Li])CCC.[S:29](=[O:31])=[O:30].O.O.O.C([O-])(=O)C.[Na+].[NH2:40]OS(O)(=O)=O>C1COCC1.O>[CH2:22]([O:21][CH2:20][CH2:19][CH2:18][N:9]1[CH2:8][CH:7]([OH:6])[C:12]2[CH:13]=[C:14]([S:29]([NH2:40])(=[O:31])=[O:30])[S:15][C:11]=2[S:10]1(=[O:17])=[O:16])[CH3:23]
Reactant: O=S=O
Reactant: CCOCCCN1CC(OC(C)OCC)c2ccsc2S1(=O)=O
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCCCN1CC(O)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Temperature: -60 °C
Reaction time: 0.75 h
Yield: 86 %

Procedure:
A solution of the product from Step C (13.25 g, 36.5 mmol) in THF (250 mL) was degassed under nitrogen and cooled to -60° C. in a dry-ice/isopropanol bath. n-Butyllithium (16.0 mL of a 2.5M solution, 40 mmol) was added slowly over 5 min and the mixture was stirred at -60° C. for 45 min followed by the introduction of excess sulfur dioxide gas into the flask. The mixture was allowed to warm to room temperature over two hours and the solvent was removed by evaporation. The residue was mixed with water (200 mL) and sodium acetate trihydrate (13.91 g, 102.2 mmol) followed by the addition of hydroxylamine-O-sulfonic acid (6,9 g, 61.32 mmol). The mixture was stirred at room temperature for 18 hr and then extracted with ethyl acetate (5×15 mL). The combined extracts were evaporated and the residue dissolved in THF (150 mL), mixed with 2N HCl (10 mL), warmed gently for 1 hr and then evaporated to a residue. The residue was mixed with ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, washed with saturated aqueous sodium chloride, dried (MgSO4) and evaporated to a residue which was purified by column chromatography (silica, gradient, 3:1 hexane/ethyl acetate to 7:3 methylene chloride/methanol) to provide a pale yellow solid (11.6 g, 86%): mp 140°-145° C. dec. Analysis. Calculated for C11H18N2O6S3 : C, 35.66; H, 4.90; N, 7.56. Found: C, 35.79; H, 4.80; N, 7.47.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:10]1([CH2:16][CH2:17][CH:18]([C:24]([CH3:26])=O)[C:19](OCC)=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>C(O)C>[OH:2][C:1]1[C:9]2[C:24]([CH3:26])=[C:18]([CH2:17][CH2:16][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:19](=[O:20])[O:8][C:7]=2[CH:6]=[C:4]([OH:5])[CH:3]=1
Reactant: Oc1cc(O)cc(O)c1
Reactant: CCOC(=O)C(CCc1ccccc1)C(C)=O
Agent: Cl
Solvent: CCO
Product: Cc1c(CCc2ccccc2)c(=O)oc2cc(O)cc(O)c12

Procedure:
A solution of phloroglucinol (0.87 g) and ethyl 2-(2-phenylethyl)acetoacetate (1.62 g) in ethanol (30 ml) was treated with dry HCl as described in example 1a. Yield: 1.77 g (87%). Melting point 248-252° C.
Reaction SMILES: C(O)(=O)C.Cl.[C:6]1([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20]N)=[CH:16][CH:15]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][C:29](=O)[CH2:28]1)=[O:26])[CH3:23]>O>[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][C:30]2[NH:20][C:17]3[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)=[CH:19][C:18]=3[C:29]=2[CH2:28]1)=[O:26])[CH3:23]
Reactant: NNc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C1CCC(=O)C1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1Cc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To 250 ml of 80% acetic acid in water, were added 4-phenylmethoxyphenylhydrazine hydrochloride (30 g, 0.12 mole) and 3-oxocyclopentane carboxylic acid ethyl ester (20 g, 0.13 mole). After stirring at ambient temperature for one hour and then at 100° C. for four hours, the mixture was cooled and poured into one liter of water. After stirring for five minutes, the mixture was extracted with ethyl acetate (3×). The organic layer was washed successively with water (2×) and saturated sodium chloride solution, and thereafter dried over anhydrous MgSO4. After filtering, the solution was concentrated to a dark oil (~48 g), which was eluted on a silica gel column with 5% ethyl acetate/dichloromethane via HPLC. The desired fractions were combined and concentrated to give the product as a thick brown oil (24.1 g).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=S)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:18]C1C=CC([Te](C2C=CC(OC)=CC=2)=O)=CC=1>CO>[C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C(Nc1ccccc1)Nc1ccccc1
Reactant: COc1ccc([Te](=O)c2ccc(OC)cc2)cc1
Solvent: CO
Product: O=C(Nc1ccccc1)Nc1ccccc1
Yield: 68 %

Procedure:
1,3-Diphenylthiourea (114 mg, 0,5 mmol) was reacted with bis-(p-methoxyphenyl)-telluroxide for 16 h (methanol as solvent), the methanol was evaporated off under vacuum, the residue triturated with benzene and filtered to afford 1,3-diphenylurea as a white solid (72 mg, 68%), m.p. 234° (lit., 238°-239°).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]=1[CH2:29][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:8].[CH3:39][I:40]>CC(C)=O>[I-:40].[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]=1[CH2:29][N+:30]1([CH3:39])[CH2:31][CH2:32][CH2:33][CH2:34]1)=[O:8]
Reactant: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(CN3CCCC3)n(Cc3ccccn3)c2c1
Reactant: CI
Solvent: CC(C)=O
Product: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C[N+]3(C)CCCC3)n(Cc3ccccn3)c2c1
Product: [I-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-(3,4-difluorobenzyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-2-(pyrrolidin-1-ylmethyl)-1H-indole-3-carboxamide (Compound 175, 17 mg, 0.033 mmol) in acetone (1 ml) was added MeI (0.1 ml, 1.6 mmol). The reaction was stirred at room temperature for 16 h and the solvent was removed in vacuo. The residue was purified by PTLC on silica gel (10% MeOH-EtOAc) to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][C:17]([O:19]CC)=[O:18])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[Li+].[OH-]>C1COCC1.CO.O.Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][C:17]([OH:19])=[O:18])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3
Reactant: CCOC(=O)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of the product of Step 1 (41.1 mg, 0.1 mmol, 1 equiv) in THF-methanol-water (3:2:1, total 1.2 mL) was added LiOH (12.0 mg, 0.5 mmol, 5 equiv). The mixture was stirred at room temperature for 1 hour. The reaction was diluted with 1M HCl (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with water (10 mL) twice and dried with MgSO4 to afford 38.3 mg white solid as product, yield 99%. 1H NMR (CDCl3, 400 MHz) δ=5.02 (s, 2H) 7.22 (d, J=8.8 Hz, 2H) 7.58 (dd, J=8.7, 1.2 Hz, 2H) 8.16 (d, J=1.6 Hz, 2H). ESI (m/z): 379.6 (M−H+).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4][C:3]1=[N:10][OH:11].[CH3:12][N:13]([S:17][C:18]([CH3:25])([C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH3:19])[C:14](Cl)=[O:15].C(N(CC)CC)C.C(OC(C)C)(C)C>O1CCOCC1>[CH3:12][N:13]([S:17][C:18]([CH3:19])([C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[CH3:25])[C:14]([O:11][N:10]=[C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4]1)=[O:15]
Reactant: CC(C)C(=O)C(C)(C)SN(C)C(=O)Cl
Reactant: CN1C(=O)C(C)(C)SC1=NO
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: CC(C)C(=O)C(C)(C)SN(C)C(=O)ON=C1SC(C)(C)C(=O)N1C
Yield: 39.6 %

Procedure:
Prepared as in Example I by reacting 2.94 g (0.0169 m) of 3,5,5-trimethyl-2-oximino-thiazolidin-4-one, 4.0 g (0.0169 m) of N-methyl-N-(2,4-dimethyl-3-oxo-2-pentanesulfenyl)carbamoyl chloride and 1.7 g (0.0169 m) of triethylamine in 200 ml of dioxane. The productcrystallized from isopropyl ether to yield 2.5 g of a white solid, m.p. 112°-114° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].[CH:19](OCC)=[O:20].[H-].[Na+].O>CCOCC>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH:19]=[O:20])[C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccccc1-c1ccccc1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(C=O)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 24 g biphenylacetic acid ethyl ester and 8.2 g ethyl formate is added dropwise while stirring to a suspension of 2.4 g sodium hydride in 250 ml ether. The reaction mixture is stirred for 2 hours at room temperature and cold water is carefully added. The aqueous phase is acidified to pH 2 and the product is extracted with ether. The extract is dried and concentrated by evaporation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[S:16][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:27]([N:29]([CH2:33][CH3:34])[C:30](Cl)=[O:31])[CH3:28].CO>N1C=CC=CC=1>[CH2:27]([N:29]([CH2:33][CH3:34])[C:30](=[O:31])[O:26][CH:23]1[CH2:22][CH2:21][N:20]([C:17]2[S:16][C:15](/[CH:14]=[C:11](\[C:12]#[N:13])/[C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:19][CH:18]=2)[CH2:25][CH2:24]1)[CH3:28]
Reactant: CCN(CC)C(=O)Cl
Reactant: COc1ccc(/C(C#N)=C/c2ccc(N3CCC(O)CC3)s2)cc1OC
Solvent: c1ccncc1
Solvent: CO
Product: CCN(CC)C(=O)OC1CCN(c2ccc(/C=C(\C#N)c3ccc(OC)c(OC)c3)s2)CC1
Yield: 21.4 %

Procedure:
Compound 6 (150 mg) was dissolved in pyridine (1 mL), and diethylcarbamoyl chloride (55 mg) was added to the solution, followed by stirring under reflux for 2 hours. After completion of reaction, methanol was added to the reaction mixture, followed by stirring for 30 minutes. The solvent was evaporated to dryness, and the residue was extracted with chloroform and purified water. The organic layer was dried over sodium sulfate anhydrate, and the solvent was evaporated to dryness. The residue was recrystallized from ethyl acetate, to thereby yield the target product (yield: 40.6 mg, 21.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)[NH:10][CH3:11].[C:17](OCC)(OCC)(OCC)[CH2:18]C.[C:29](O)(=O)C>>[CH2:17]([C:11]1[N:10]([CH3:29])[CH:9]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[CH3:18]
Reactant: CCOC(CC)(OCC)OCC
Reactant: CNC(Cc1ccccc1N)c1ccsc1
Reactant: CC(=O)O
Product: CCC1=Nc2ccccc2CC(c2ccsc2)N1C

Procedure:
A solution of 6.00 g of 2-amino-N-methyl-α-(3-thienyl)benzeneethanamine and 10 ml of triethyl orthopropionate, was treated with 8 ml of glacial acetic acid. After refluxing for eight hours, the volatile components were removed at 70° C. on a rotary evaporator. The residual oil was decanted into an ice-water mixture and basified with 10% sodium hydroxide solution. The aqueous mixture was extracted with dichloromethane and the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to provide 4,5-dihydro-2-ethyl-3-methyl-4-(3-thienyl)-3H-1,3-benzodiazepine as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[C:9]([C:25]([O:27]CC)=[O:26])[N:8]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:7]=12.CCO.O.[Li+].[OH-]>C1COCC1>[C:33]([O:32][C:30]([N:8]1[C:7]2=[C:2]([Cl:1])[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:16][CH:15]=2)=[C:9]1[C:25]([OH:27])=[O:26])=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCOC(=O)c1c(CCOc2ccc(OC(F)(F)F)cc2)c2ccnc(Cl)c2n1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)n1c(C(=O)O)c(CCOc2ccc(OC(F)(F)F)cc2)c2ccnc(Cl)c21
Reaction time: 2.5 h
Yield: 99.8 %

Procedure:
To a solution of 1-tert-butyl 2-ethyl 7-chloro-3-{2-[4-(trifluoromethoxy)phenoxy]ethyl}-1H-pyrrolo[2,3-c]pyridine-1,2-dicarboxylate (33 mg, 0.06 mmol) in THF (1 mL) was added EtOH (0.2 mL)m and water (0.2 mL). Solid LiOH (30 mg, 1.2 mmol) was then added in a single portion. After 2.5 h, quenched with 5% potassium bisulfate until acidic (˜pH 3) and extracted with Et2O and then EtOAc. The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo to yield the title compound (30 mg). LRMS (ESI) calc (M+H)+=501.1. found 501.2.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>C(O)C>[Br:13][C:14]1[CH:15]=[C:16]([NH:17][C:4]2[C:5](=[O:12])[C:6](=[O:11])[C:7]=2[O:8][CH2:9][CH3:10])[CH:18]=[CH:19][CH:20]=1
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1cccc(Br)c1
Solvent: CCO
Product: CCOc1c(Nc2cccc(Br)c2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.7 g of 3,4-diethoxy-3-cyclobuten-1,2-dione in 25 mL of absolute ethyl alcohol was added 1.7g of 3-bromoaniline, the reaction mixture was stirred at room temperature for 20 hours, then 0.4 g of 3-bromoaniline was added and the reaction mixture was stirred for 48 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:16][CH:15]=1)=[CH:9][CH:8]=[C:7]([Br:29])[CH:6]=2.C(N(CC)CC)C.[CH2:37]([O:39][CH2:40][C:41](Cl)=O)[CH3:38]>ClCCl>[C:22]([O:21][C:20](=[O:26])[NH:19][CH2:18][C:17]1[CH:27]=[CH:28][C:14]([CH2:13][N:12]2[C:11]3[C:10]4[CH:9]=[CH:8][C:7]([Br:29])=[CH:6][C:5]=4[N:4]=[CH:3][C:2]=3[N:1]=[C:38]2[CH2:37][O:39][CH2:40][CH3:41])=[CH:15][CH:16]=1)([CH3:24])([CH3:25])[CH3:23]
Reactant: CCOCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNc2c(N)cnc3cc(Br)ccc23)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2cnc3cc(Br)ccc3c2n1Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35 %

Procedure:
tert-Butyl {4-[(3-amino-7-bromoquinolin-4-ylamino)methyl]benzyl}carbamate (8.46 g, 18.5 mmol), triethylamine (2.25 mL) and dichloromethane (92 mL) were combined. Ethoxyacetyl chloride (2.92 g, 24 mmol) was added dropwise to the mixture. The reaction was stirred for an additional 1.5 hours and then concentrated under reduced pressure. Ethanol (92 mL) and triethylamine (10.31 mL) were added to the residue and the reaction was heated at reflux temperature for 1.5 hours. A precipitate formed. The reaction was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed sequentially with water and saturated aqueous sodium chloride. The organic fraction was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. An initial purification by flash column chromatography eluting with a gradient of CMA in chloroform (2–10%) was followed by recrystallization from acetonitrile to provide 3.4 g of tert-butyl[4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-ylmethyl)benzyl]carbamate as yellow-orange crystals.
Reaction SMILES: [N+:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][NH:6][C:5]1=[O:11])([O-:3])=[O:2].N1CCC[CH2:14][CH2:13]1>C(O)C>[CH:13]([C:8]1[C:9](=[O:10])[N:4]([N+:1]([O-:3])=[O:2])[C:5](=[O:11])[NH:6][CH:7]=1)=[CH2:14]
Reactant: C1CCNCC1
Reactant: O=c1cc[nH]c(=O)n1[N+](=O)[O-]
Solvent: CCO
Product: C=Cc1c[nH]c(=O)n([N+](=O)[O-])c1=O

Procedure:
As shown in Scheme 1, a suitable nitro-uracil precursor, (1), is mixed with an appropriate aldehyde, (2), and piperidine, in a suitable solvent such as ethanol. The solution is heated to reflux for approximately 10-20 hours. After reflux, the mixture is concentrated and purified using conventional methods, such as thin layer chromatography, to produce the vinyl-nitro-uracil (3).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[C:6]([NH:8][NH:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)=[O:7])#[N:2].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].C(OCC)(=O)C.ClCCl>ClC(Cl)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:7][C:23](=[O:24])[N:9]([C:10]3[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=3)[N:8]=2)[CH:20]=[CH:21][CH:22]=1)#[N:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1ccc(NNC(=O)c2cccc(C#N)c2)cc1
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2nc(-c3cccc(C#N)c3)oc2=O)cc1
Yield: 98 %

Procedure:
Methyl 4-[2-(3-cyanobenzoyl)hydrazino]benzoate (0.59 g, 2.0 mmol) and carbonyldiimidazole (0.49 g, 3.0 mmol) are stirred at 80° C. in dichloroethane (20 mL) overnight, and the mixture is then subjected to chromatography directly (silica gel, 1:9 ethyl acetate-dichloromethane) to provide methyl 4-[5-(3-cyanophenyl)-2-oxo-1,3,4-oxadiazol-3(2H)-yl]benzoate (0.63 g, 98%). MS (ES+) m/z: 322.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH:8]([C:10]1[N:11]=[N:12][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:14]([CH3:16])[N:15]=1)[NH2:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][C:14]1[N:15]=[C:10]([NH:8][NH:9][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][CH3:1])[N:11]=[N:12][C:13]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Reactant: CCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)NNc1nnc(-c2ccccc2)c(C)n1
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
A solution of n-valeryl chloride (1.93 g) in methylene chloride (3 ml) was added dropwise to a stirred solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3.224 g) and triethylamine (1.784 g) in methylene chloride (40 ml) under ice cooling, and the stirring was continued for 30 minutes. The reaction mixture was evaporated and the resultant residue was extracted with ethyl acetate after addition of water. The extract was washed successively with 5% hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate and water, dried over magnesium sulfate, and then concentrated to a small volume under reduced pressure. The resultant residue was crystallized from diethyl ether, collected by filtration, washed with diethyl ether and dried to give 5-methyl-6-phenyl-3-(2-valerylhydrazino)-1,2,4-triazine (3.406 g).