Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:15]=1)[CH3:10].O>ClCCl>[Br:1][C:13]1[S:12][C:11]([CH2:9][CH3:10])=[N:15][C:14]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1nc(-c2ccc(F)cc2)cs1
Solvent: ClCCl
Solvent: O
Product: CCc1nc(-c2ccc(F)cc2)c(Br)s1
Reaction time: 2 h

Procedure:
At room temperature, 1.72 g (9.64 mmol) of N-bromosuccinimide are added a little at a time to a solution of 2.00 g (9.64 mmol) of 2-ethyl-4-(4-fluorophenyl)-1,3-thiazole in 40 ml of dichloromethane. After 2 h, 50 ml of water are added to the reaction mixture, and the organic phase is separated off, washed with saturated NHCO3 solution, dried over MgSO4 and concentrated under reduced pressure. This gives 2.47 g (85%) of the desired product; 1H-NMR(DMSO-d6) δ: 7.92 (m, 2H), 7.32 (m, 2H), 3.02 (q, 2H), 1.31 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([SH:7])[N:3]=1.[CH:8](O)=[O:9]>>[CH:8]([NH:1][C:2]1[NH:6][N:5]=[C:4]([SH:7])[N:3]=1)=[O:9]
Reactant: Nc1nc(S)n[nH]1
Reactant: O=CO
Product: O=CNc1nc(S)n[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 500 mL, 3-necked flask equipped with a mechanical stirrer, a reflux condenser with nitrogen outlet and a thermometer was charged with 24.4 g (0.2 mole) of 95 percent pure 5-amino-3-mercapto-1,2,4-triazole and 140 mL of formic acid. The mixture was heated to reflux with stirring for 4 hr and allowed to cool to room temperature. The solids present were collected by filtration, washed with water, and dried to obtain 28.2 g (98 percent of theory) of the title compound as a white solid, m.p. 260°-262° C. The infrared spectrum was consistent with the assigned structure, having a carbonyl stretch at 1700 cm-1, as was the mass spectrum, having a parent peak at 144 (M+).
Reaction SMILES: C([C@:4]1([OH:41])[C@@H:9]([CH2:10][OH:11])[O:8][C@:7](C(=O)C)([C:12]2[CH:21]=[C:20]3[C:15]([C:16]([CH3:29])=[C:17]([CH2:23][C:24]([O:26]CC)=[O:25])[C:18](=[O:22])[O:19]3)=[CH:14][CH:13]=2)[C@:6](C(=O)C)([OH:33])[C@@:5]1(C(=O)C)[OH:37])(=O)C.[OH-].[K+].Cl>CO>[C@@H:7]1([C:12]2[CH:21]=[C:20]3[C:15]([C:16]([CH3:29])=[C:17]([CH2:23][C:24]([OH:26])=[O:25])[C:18](=[O:22])[O:19]3)=[CH:14][CH:13]=2)[O:8][C@H:9]([CH2:10][OH:11])[C@H:4]([OH:41])[C@H:5]([OH:37])[C@H:6]1[OH:33]
Reactant: CCOC(=O)Cc1c(C)c2ccc([C@@]3(C(C)=O)O[C@H](CO)[C@@](O)(C(C)=O)[C@@](O)(C(C)=O)[C@]3(O)C(C)=O)cc2oc1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(CC(=O)O)c(=O)oc2cc([C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
To a stirred solution of 7-(tetraacetyl-β-galactosyl)-4-methylcoumarin-3-acetic acid, ethyl ester (3) (422 mg, 0.712 mmol) in methanol was added 6.8M KOH (5 mL) and the solution was stirred overnight at room temperature. The solution was neutralized by the addition of 1N HCl and evaporated to dryness under reduced pressure. The residue was dissolved in water (10 mL) and desalted using C18Sep Pack Cartridges in 10×1 mL portions. The C18Sep Pack Cartridge (Waters Part No. 65910) was washed with methanol (3 mL) and water (3 mL) before the sample was applied in 1 mL. The cartridge was then washed with water (3 mL) to remove any salt followed by metahnol (3 mL) which eluted the desired product as determined by TLC (silica gel, acetone:20 mM NaOAc 9:1). The methanol washes were pooled and evaporated under reduced pressure and the while solid obtained was recrystallized from ethanol/water to give 170 mg (0.43 mmol, 60%) of 4 as white crystals: m.p. 186°-188° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17]>C(Cl)Cl>[C:15]([O:1][CH:2]1[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1)(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: C=C(C)C(=O)Cl
Reactant: OC1CCSCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1CCSCC1
Temperature: 0 °C
Yield: 61.2 %

Procedure:
To a 200-mL three-necked flask fitted with a stirrer bar coated with Teflon™, were added 5.37 g of 4-hydroxytetrahydrothiopyran (manufactured by SANKYO KASEI Co., Ltd.), 5.08 g of triethyl amine, and 50 mL of dried methylene chloride, and the mixture was stirred under nitrogen atmosphere at 0° C. To the mixture, 5.0 g of methacryloyl chloride was slowly added through a dropping funnel, and the resulted mixture was reacted at 0° C. for 40 minutes, allowed to warm to room temperature, and was further reacted for another 5 hours. After confirming loss of the starting material by a thin layer chromatography (TLC), the reaction solution was poured into a 300-mL separatory funnel, washed with 100 mL of water followed by 100 mL of saturated NaCl solution (brine), and dried with anhydrous sodium sulfate. From the obtained solution, the solvent was removed by an evaporator, to obtain an oily crude product. The crude product was purified by silica gel chromatography using a mixed solution of n-hexane and ethyl acetate to give 5.18 g of tetrahydro-2H-thiopyran-4-yl methacrylate (thiopyran derivative of the following formula 2) (yield: 61.3%).
Reaction SMILES: [C:1]([O:4][C:5]12[CH2:9][C:7]([NH2:10])([CH2:8]1)[CH2:6]2)(=[O:3])[CH3:2].[C:11](Cl)(=[O:13])[CH3:12]>>[C:1]([O:4][C:5]12[CH2:9][C:7]([NH:10][C:11](=[O:13])[CH3:12])([CH2:8]1)[CH2:6]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)OC12CC(N)(C1)C2
Product: CC(=O)NC12CC(OC(C)=O)(C1)C2

Procedure:
The commercially available 3-aminobicyclo[1.1.1]pentane-1-carboxylic acid can be converted to the methyl ketone intermediate by treatment with either methyl lithium or methylmagnesium bromide (Scheme 1). Baeyer-Villagar type oxidation with mCPBA or other peroxycarboxylic acids can give 3-aminobicyclo[1.1.1]pentan-1-yl acetate. The amine can then be coupled with an appropriate carboxylic acid or acid chloride, such as acetyl chloride to give 3-acetamidobicyclo[1.1.1]pentan-1-yl acetate (3). Selective hydrolysis of the ester group with hydroxide ion gives N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1). Alternatively, starting with the commercially available 3-hydroxybicyclo[1.1.1]pentane-1-carboxylic acid and carrying out a Curtius reaction or modified Curtius reaction using diphenylphosphoryl azide gives the amino alcohol intermediate, which can then be treated with acetyl chloride (1 eq) in the presence of base (for example, K2CO3, Na2CO3, TEA, and the like) to give N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1) or with acetyl chloride (>2 eq) in the presence of base (for example, K2CO3, Na2CO3, TEA, and the like) to give 3-acetamidobicyclo[1.1.1]pentan-1-yl acetate (3).
Reaction SMILES: [F:1][C:2]1[C:20]([CH3:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([N+:24]([O-:26])=[O:25])[C:3]=1[C:4]([CH:6](C(OCC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[F:1][C:2]1[C:20]([CH3:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([N+:24]([O-:26])=[O:25])[C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1c(F)c(C)c(F)c(F)c1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CC(=O)c1c(F)c(C)c(F)c(F)c1[N+](=O)[O-]
Yield: 93.3 %

Procedure:
A mixture of 45.3 g of diethyl (2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)malonate, 30 mg of p-toluenesulfonic acid, and 120 ml of water was heated under reflux for 50 minutes. After cooling, the reaction mixture was extracted with diethyl ether, and the extract was washed with brine, and then dried and concentrated to give 34.2 g of brown oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH3:12])[N:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]3)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH3:12])[N:3]=[C:2]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]4)[C:10]=12
Reactant: CC(C)(C)OC(=O)N1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Cn1nc(Br)c2c(N)ncnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)OC(C)(C)C)c2c(N)ncnc21
Temperature: 120 °C
Yield: 70.9 %

Procedure:
To a 25 mL pressure tube was charged 3-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (670 mg, 2.94 mmol), 1,1-dimethylethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole-1-carboxylate (1014 mg, 2.94 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (120 mg, 0.147 mmol), and sodium carbonate (494 mg, 5.88 mmol) followed by dioxane (8 mL), and water (2 mL). The reaction was heated at 120° C. for 40 minutes in a microwave reactor. LCMS showed no more SM. The reaction was cooled to room temperature, the mixture was transferred into a 100 mL Erlenmeyer flask, rinsed by EtOAc, with the water layer and black greasy solid stayed in tube (total 50 mL of EtOAc was added to the mixture). White solid was formed in brown solution. The solid was filtered to give titled product (764 mg).
Reaction SMILES: [F:1][C:2]1([F:56])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH:42]=[O:43])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)[CH2:4][CH2:3]1.[BH4-].[Na+]>C(O)C.O1CCCC1>[F:56][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][OH:43])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:46]=[CH:47][C:48]([C:51]([F:52])([F:54])[F:53])=[CH:49][CH:50]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(C=O)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(CO)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reaction time: 0.83 h
Yield: 103.8 %

Procedure:
To a solution of 500 mg (0.64 mmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-formyl pyrimidin-2-yl)piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 16, in a mixture of 5 ml ethanol and 5 ml tetrahydrofuran, 12 mg (0.32 mmol) of sodium borohydride was added under ice cooling, and the reaction solution was stirred under ice cooling conditions for 0.83 hour. After completion of the reaction, the solvent was distilled off under reduced pressure and 1 N hydrochloric acid and 1 N sodium hydroxide aqueous solution were added in order, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to provide 0.52 g of the title compound as a white foam (yield: quantitative).
Reaction SMILES: Br[C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=1.[C:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])[CH3:14]>>[C:13]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=2)=[CH:18][CH:17]=1)(=[O:15])[CH3:14]
Reactant: NC(=O)c1cc(Br)sc1[N+](=O)[O-]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: CC(=O)c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cc1

Procedure:
The title compound was prepared according to the general procedure in Intermediate 10 Step 5 using 5-bromo-2-nitrothiophene-3-carboxamide (Intermediate 10, Step 4) (0.5 g, 1.992 mmol) and (4-acetylphenyl)boronic acid (0.392 g, 2.390 mmol) as the starting materials.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[N:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:11]=2)[CH2:6][CH2:5]1.Br[CH2:28][CH:29]([O:32][CH3:33])[O:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O1CCOCC1>[Cl:19][C:15]1[CH:14]=[C:13]2[C:18]([C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:29]([O:32][CH3:33])([O:30][CH3:31])[CH3:28])[CH2:5][CH2:6]3)=[CH:11][N:12]2[C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[CH:17][CH:16]=1
Reactant: NCCN1CCC(c2cn(-c3ccc(F)cc3)c3cc(Cl)ccc23)CC1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(C)(NCCN1CCC(c2cn(-c3ccc(F)cc3)c3cc(Cl)ccc23)CC1)OC

Procedure:
To a solution of 3-[1-(2-aminoethyl)-4-piperidyl]-6-chloro-1-(4-fluorophenyl)-1H-indole 7b (11 g) in dioxan (100 ml) were added 2-bromo-1,1-dimethoxyethane (5.6 g), potassium carbonate (5 g) and a potassium iodide crystal. The mixture was refluxed for 16 hours. After cooling, inorganic salts were filtered off and dioxan evaporated leaving crude 6-chloro-3-[1-[N-(1,1-dimethoxyethyl)-aminoethyl]-4-piperidyl]-1-(4-fluorophenyl)-1H-indole as an oil. The crude product was purified by column chromatography on silica gel (eluted with ethyl acetate/methanol 1:1). Yield: 6 g as an oil. The thus obtained alkylated aminoderivative (6 g) was dissolved in dichloromethane (100 ml) and 2-propylisocyanate (1.1 g) was added. After refluxing for 2 hours dichloromethane was evaporated and the title compound 16a was purified by column chromatography on silica gel (eluted with ethyl acetate/methanol 1:1). Yield: 4.9 g as an oil.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][CH:3]=1.O.[NH2:13][NH2:14].O>C(O)C>[I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:13][NH2:14])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(I)cc1
Temperature: 25 °C

Procedure:
To Methyl 4-iodobenzoate (30.0 g, 114 mmol) in ethanol (180.0 ml) was added hydrazine hydrate (30.0 g, 599 mmol). The reaction mixture was reflux for 22.5 hours. Heating was stopped and then water (300.0 ml) was added. After cooling down to room temperature, white solid was appeared. The white product solid was collected by filtration. The product was washed with water and dried under vacuum. Final white pure product was obtained in 26.0 g (86.7%). 1H NMR (400 MHz, DMSO-d6, δ): 9.84 (s, 1H, NH), 7.82 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 4.50 (s, 2H, NH2).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[N:30]1([C:36]2[CH:41]=[C:40](B(O)O)[CH:39]=[CH:38][N:37]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:40]3[CH:39]=[CH:38][N:37]=[C:36]([N:30]4[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]4)[CH:41]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: OB(O)c1ccnc(N2CCNCC2)c1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
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: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCNCC4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (106.5 mg, 0.214 mmol), 2-(1-piperazinyl)-pyridine-4-boronic acid, pinacol ester (93 mg, 0.322 mmol), Pd(PPh3)4 (25 mg, 0.02147 mmol) and 2M potassium carbonate (0.321 mL, 0.642 mmol) in anhydrous dioxane (1.0 mL) was sparged with nitrogen for 5 minutes, then heated in microwave for 1 h at 100° C. Reaction mixture was diluted with ethyl acetate, washed with brine, dried (MgSO4), filtered, concentrated and used in next step without further purification. LCMS-ESI+: calc'd for C36H36ClN4O3S: 579.2 (M+H+); Found: 579.1 (M+H+).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH3:17])=[CH:11]2.Cl[NH2:19].CCOCC>CN(C=O)C>[F:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([NH2:19])[C:12]([CH3:17])=[CH:11]2
Reactant: NCl
Reactant: Cc1cc2cc(F)ccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cc2cc(F)ccc2n1N
Temperature: 23 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
A solution of potassium tert-butoxide (1.84 g, 16.43 mmol) and 5-fluoro-2-methylindole (1.21 g, 8.09 mmol) in DMF (20 mL) is stirred under N2 at rt for 60 min. A solution of monochloroamine in ether (65 mL, 9.75 mmol) is added via an addition funnel over 10 min. The resulting mixture is stirred at 23° C. for 2 hours, and then concentrated in vacuo. The residue is partitioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10% EtOAc in heptane to afford 5-fluoro-2-methyl-indol-1-ylamine (290 mg, 22%) as a solid. MS: 165 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.24-7.19 (m, 1H), 7.12 (dd, 1H), 6.92 (dt, 1H), 6.12 (s, 1H), 4.23 (br s, 2 H), 2.39 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[S:20][C:19]([NH2:21])=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.[NH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][OH:28]>>[NH2:21][C:19]1[S:20][C:3]2[C:2]([NH:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][OH:28])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[N:5][C:4]=2[N:18]=1
Reactant: NCCOCCO
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Product: Nc1nc2nc(SCc3cccc(F)c3F)nc(NCCOCCO)c2s1

Procedure:
Prepared by the method of example 2 step a), using the product of example 4, step b) and 2-(2-aminoethoxy)-ethanol.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)([O-])=[O:2].C=O.CO.[H][H]>[Pd].O1CCCC1>[OH:2][N:1]=[CH:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(C=C[N+](=O)[O-])cc1
Agent: [Pd]
Agent: C=O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC=NO)cc1
Yield: 20.7 %

Procedure:
A mixture of methyl 4-(2-nitrovinyl)benzoate (18.6 g, 90 mmol), paraformaldehyde (3.2 g, 108 mmol) and 10% Pd/C (0.9 g) in the mixture of methanol (220 mL) and tetrahydrofuran (220 mL) was stirred at room temperature over 1 atm of hydrogen for 3 h. Then the mixture was filtered and evaporated, purified by column chromatography (silica gel, petroleum ether/ethyl acetate 15:1 to 8:1) to obtain methyl 4-(2-(hydroxyimino)ethyl)benzoate (3.6 g, yield 21%) as yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.55-3.56 (d, J=6.0 Hz, 0.5H), 3.69-3.71 (d, J=5.2 Hz, 1.5H), 3.84 (s, 3H), 6.84-6.87 (t, J=5.6 Hz, 0.75H), 7.45-7.47 (t, J=6.2 Hz, 0.25H), 7.37-7.41 (m, 2H), 7.90-7.91 (m, 2H), 10.68 (s, 0.25H), 11.14 (s, 0.75H); LC-MS (ESI) m/z: 194 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH3:24].C(N(CC)C(C)C)(C)C.[CH3:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38]>C(Cl)Cl>[CH:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:37](=[O:38])[C:36]4[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=4[CH3:34])=[C:3]([CH3:24])[CH:4]=3)=[O:7])[CH2:9][C:10]=12
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1NC(=O)c1ccccc1C
Yield: 65.9 %

Procedure:
A solution of 0.83 g of 10,11-dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo[2,1-c](1,4]benzodiazepine, 0.5 g of N,N-diisopropylethylamine and 0.6 g of 2-methylbenzoyl chloride in 50 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water, the organic layer dried with Na2SO4 and passed through a pad of hydrous magnesium silicate. Hexane is added at the boil to give 0.75 g of a solid which is crystallized from methylene chloride-hexane to give 0.61 g of the desired product, m.p. 125-130° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:34].O>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N+:8]([O-:34])=[CH:7][C:6]=2[N:15]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1nc2cnc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
A solution of tert-butyl 2-[2-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (13.78 g 35.8 mmol) in 175 mL of CHCl3 was treated with 3-chloroperoxybenzoic acid (MCPBA, 70%, 10.28 g, 41.7 mmol). After stirring for 3 h, the reaction mixture was treated with water (100 mL) and CHCl3 (50 mL) and the layers were separated. The organic portion was washed with 1% Na2CO3 solution (2×), water and brine then dried over Na2SO4 and concentrated to give 14.35 g tert-butyl 2-[2-(2-ethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a sticky tan solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][NH:8][C:9]([NH:11][N:12]([CH2:19][C:20]([O:22]C)=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].Cl>C(C(C)=O)C(C)C>[CH3:7][N:8]1[C:20](=[O:22])[CH2:19][N:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:11][C:9]1=[O:10]
Reactant: CNC(=O)NN(CC(=O)OC)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CN1C(=O)CN(c2ccccc2)NC1=O
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
Potassium t-butoxide (11.33 g) was added over 12 min. to a stirred suspension of methyl [2-[(methylamino)carbonyl]-1-phenylhydrazino]-acetate (20.0 g) in methyl isobutyl ketone (200 ml) under nitrogen at 24°-31°. After stirring for 30 min., 1M hydrochloric acid (200 ml) was added at 15°-20°. The resultant suspension was cooled to 0°-5° for 30 min., and the solid was filtered off, washed with water (100 ml) followed by methyl isobutyl ketone (100 ml) and dried in vacuo to give the title compound (13.86 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[N:30]=[C:31]=[O:32]>>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[NH:30][C:31]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:32]
Reactant: COC(=O)C(Cc1ccc(OC)c(CCO)c1)C(=O)OC
Reactant: O=C=Nc1ccc(F)cc1F
Product: COC(=O)C(Cc1ccc(OC)c(CCOC(=O)Nc2ccc(F)cc2F)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)-4-methoxybenzyl]-malonate and 2,4-difluorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b)