Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[S:17][C:16]([S:18]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)(=[O:20])=[O:19])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[S:17][C:16]([S:18]([N:21]3[CH:25]=[CH:24][CH:23]=[CH:22]3)(=[O:19])=[O:20])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)n3cccc3)s2)cc1

Procedure:
N-[5-(4-methoxyphenyl)thiophene-2-sulfonyl]pyrrole was prepared, in the same manner as described in Example 32C, from 4-methoxyphenyl-boronic acid and N-(5-bromothiophene-2-sulfonyl)pyrrole. Recrystallization using hexane/ethyl acetate gave a solid in quantitative yield.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)c1ccc(CBr)cc1

Procedure:
A stirred mixture of 4-methylbenzophenone (15.02 g, 76.6 mmol) and N-bromosuccinimide (14.2 g, 79.8 mmol) in CHCl3 (100 cm3) was heated under gentle reflux for 18 h with a 100 W bulb shining 2 cm from the flask. The reaction mixture was washed with water, dried (MgSO4) and solvent was removed in vacuo). The resulting solid was then washed with Et2O to remove any starting material to leave the product as a white solid (15.07 g, 71.5%, mp 110–112° C. (lit. 110–111°); δH (200 MHz; CDCl3) 4.55 (2 H, s, CH2Br), 7.46–7.70 (5 H, m, ArH), 7.80–7.9 (4 H, m, ArH o- to C═O); m/z 277 ([M81Br+H]+, 25%) and 275 ([M79Br+H]−, 25%), 197 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][NH:11][C:10](=[O:16])[CH:9]=2)[CH:7]=1.Br[CH:21]([CH3:25])[C:22]([OH:24])=[O:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:21]([CH3:25])[C:22]([OH:24])=[O:23])[C:10](=[O:16])[CH:9]=2)[CH:7]=1
Reactant: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(Br)C(=O)O
Product: COc1cn(C(C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
115 mg (purity 85%, 0.35 mmol) of 4-(5-chloro-2-nitrophenyl)-5-methoxypyridin-2(1H)-one and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A at 50° C. Yield: 43 mg (35% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][N:12]=[C:13]=[O:14]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:13]([NH:12][CH3:11])=[O:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)NC(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a stirred solution of (R)-(+)-1-(4-bromophenyl)ethylamine (0.5 g, 2.49 mmol) in anhydrous CH2Cl2 was added methyl isocyanate (0.15 mL, 2.49 mmol). The resulting solution was stirred at 25° C. overnight. CH2Cl2 was evaporate and residue partitioned between EtOAC and 1 N HCl. The organic layer was washed with H2O, brine and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (80% EtOAc in hexanes) to provide the desired product (0.60 g, 94%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9](OC[C@H]3CCCN3C(OC(C)(C)C)=O)[CH:10]=[N:11][C:12]=2[Cl:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[O:29]1[CH2:34][CH2:33]OCC1>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:29][CH2:34][C@H:33]3[CH2:8][CH2:9][CH2:10][NH:11]3)=[N:11][C:12]=2[Cl:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(-c2ccccc2)c1
Agent: Cl
Product: Clc1nc(OC[C@H]2CCCN2)ccc1-c1ccccc1
Reaction time: 40 h

Procedure:
To the 5-phenyl-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine compound from Example 69b (164 mg) was added HCl in dioxane (3 mL). The mixture was tirred at room temperature for 40 hours. The solvent was removed under vacuum at 50° C., and the residue was triturated with Et2O. The solid was dried under high vacuum to afford the title compound. mp 178-180° C. MS (CI/NH3) m/z 289 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 1.27-2.10 (m, 1H), 2.03-2.18 (m, 2H), 2.22-2.31 (m, 1H), 3.41 (t, J=7.5 Hz, 2H), 4.13 (m, 1H), 4.26 (m, 1H), 4.46 (dd, J=3.4, 10.8 Hz, 1H), 7.54 (m, 6H), 8.12 (d, J=3.0 Hz, 1H). Anal. Calcd for C16H17N2OCl.1.2 HCl: C, 57.79; H, 5.52; N, 8.42. Found: C, 57.73; H, 6.5.58; N, 8.27. [α]25D=−10.94° (c 0.64, MeOH).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.O.CC(C)([O-])C.[K+].Br[CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C>[CH:19]1([CH2:18][O:8][C:6]2[CH:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[CH:7]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1cc(O)cc(O)c1
Reactant: BrCC1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(O)cc(OCC2CCCCC2)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 5-methylbenzene-1,3-diol.H2O (1.0 g, 7.0 mmol) in DMF (15 ml) was added potassium tert-butoxide (0.86 g, 77 mmol). The mixture was stirred at 60° C. for 1 h. To the mixture was added (bromomethyl)cyclohexane (1.2 g, 7.0 mmol). The reaction mixture was stirred at 60° C. for 18 h, concentrated under vacuum, partitioned between water (40 ml) and ethyl acetate (60 ml). Ethyl acetate portion was dried over Na2SO4. Purification by chromatography (10 to 30% EtOAc-hexanes gradient) gave 3-(cyclohexylmethoxy)-5-methylphenol (133) as a light yellow solid. Yield (0.40 g, 26%): 1H NMR (400 MHz, CDCl3) δ 6.31 (s, 1H), 6.20-6.22 (m, 2H), 4.62 (bs, 1H), 3.69 (d, J=6.4 Hz, 2H), 2.50 (s, 3H), 1.64-1.88 (m, 6H), 1.16-1.34 (m, 3H), 0.98-1.08 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:28]=2)=[O:24])[CH:20]=[C:19]([CH3:41])[C:18]=1O.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:18]1[C:19]([CH3:41])=[CH:20][C:21]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][Si:34]([C:37]([CH3:39])([CH3:38])[CH3:40])([CH3:35])[CH3:36])[CH:28]=2)=[O:24])=[CH:22][C:17]=1[Cl:16])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc(Cl)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc(Cl)c1OS(=O)(=O)C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
Trifluoromethanesulfonic anhydride (3 mL, 17.7 mmol) was added to a cooled (−78° C.) solution of 2-chloro-4-[[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]-6-methylphenol (6.00 g, 14.8 mmol) and triethylamine (8.24 mL, 59.1 mmol) in dichloromethane (60 mL). After stirring for 2 h at −78° C., the reaction was quenched with solid ammonium chloride (4 g). The mixture was diluted with ethyl acetate (200 mL) and washed with 1N HCl (100 mL), saturated aqueous sodium bicarbonate and brine. The organic layer was dried (MgSO4), filtered, evaporated and chromatographed (20-30% ethyl acetate/hexanes) to give trifluoromethanesulfonic acid, 2-chloro-4-[[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]-6-methylphenyl ester (5.00 g, 63%) as pale orange oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.Cl.[CH2:10]([N:17]1[CH2:22][CH2:21][O:20][CH:19]([C:23](O)=O)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH4+].[OH-]>O>[C:11]1([CH2:10][N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:7][C:4]4[CH:5]=[CH:6][N:1]=[CH:2][C:3]=4[N:8]=3)[CH2:18]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Reactant: Nc1ccncc1N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CN2CCOC(c3nc4cnccc4[nH]3)C2)cc1
Yield: 21.8 %

Procedure:
A mixture of 3,4-pyridinediamine (1.7 g, 15.58 mmol), 4-benzylmorpholine-2-carboxylic acid hydrochloride (4.82 g, 18.69 mmol) and polyphosphoric acid (40 mL, 15.58 mmol) was refluxed for 12 hours. Then water (70 mL) and NH4OH were added thereto, and the resulting mixture was extracted with CH2Cl2 (10% CH3OH) (3×80 mL). The combined organic solution was washed with brine (2×100 mL), dried, and evaporated in vacuo to afford the title compound (1.0 g). LC-MS (ES) m/z=295 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1.[CH3:32][NH2:33]>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:33][CH3:32])[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1
Reactant: CN
Reactant: COc1cc2c(c(-c3cccc(C)c3C)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Product: CNCC1Cc2cc(OC)cc(-c3cccc(C)c3C)c2O1

Procedure:
The title compound was prepared (0.064 g, 64%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,3-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.132 g, 0.30 mmol) and methylamine (0.093 g, 3.0 mmol). mp 177-179° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClCCCl>[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]([Br:1])[C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: COC(=O)C(Br)c1ccc(Cl)c(Cl)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 106.9 %

Procedure:
N-bromosuccinimide (116 g, 1.4 equivalent amounts) was added to a 1,2-dichloroethane (320 mL) solution of methyl 2-(3,4-dichlorophenyl)acetate (106.8 g, 0.446 mol) at room temperature, followed by heating to 85° C. To this solution, a 1,2-dichloroethane (22.6 mL) solution of benzoyl peroxide (2.26 g, 2.0 mol %) was dropwise added dividedly 10 times every 10 minutes, followed by stirring at 85° C. for 3 hours. The reaction solution was cooled to room temperature, sequentially washed with a 2M sodium hydroxide aqueous solution, a mixed liquid of water-sodium thiosulfate aqueous solution (2:1, (v/v)), a saturated ammonium chloride aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to give the desired product as a brown oil (142 g, yield: 103%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.[C:15](=O)([O:19]CC)[O:16][CH2:17][CH3:18].[H-].[Na+].Cl>CN(C)C=O>[CH2:13]([O:12][C:10]([CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:15]([O:16][CH2:17][CH3:18])=[O:19])=[O:11])[CH3:14]
Reactant: CCOC(=O)OCC
Reactant: CCOC(=O)Cc1ccc(OC)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc(OC)cc1
Temperature: 0 °C

Procedure:
27.7 g of ethyl 4-methoxyphenylacetate and 34 ml of diethyl carbonate were dissolved in 150 ml of N,N-dimethylformamide, and the solution was subjected to reflux under heating, while gradually adding 6.5 g of sodium hydride for 1 hour. After further refluxing under heating for 2 hours, the resulting reaction solution was poured into a mixture of ice water and hydrochloric acid, followed by extraction with ethyl acetate. The resulting organic layer was washed with water, and then dried to distill off the solvent. The residue thus obtained was purified by silica gel column chromatography using toluene as an eluant, thereby obtaining 26.7 g of ethyl 2-ethoxycarbonyl-2-(4-methoxyphenyl)acetate in the form of light yellow oil.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:10]=[N:11][C:12]([Cl:22])=[CH:13][C:14]=1[C:15]1[C:16]([CH3:21])=[N:17][CH:18]=[CH:19][CH:20]=1)C)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[Cl:22][C:12]1[N:11]=[CH:10][C:9]([NH:7][CH3:6])=[C:14]([C:15]2[C:16]([CH3:21])=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=1
Reactant: Cc1ncccc1-c1cc(Cl)ncc1N(C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cnc(Cl)cc1-c1cccnc1C
Reaction time: 1.5 h

Procedure:
To a solution of the obtained (6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-yl)-methyl-carbamic acid tert-butyl ester in dichloromethane is added 0.40 ml trifluoroacetic acid at room temperature. The reaction mixture is stirred at this temperature for about 1.5 h. After addition of an aqueous sodium hydroxide solution, the mixture is extracted with dichloromethane. The combined organic layers are dried and concentrated to give the compound (6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-yl)-methyl-amine of formula IX.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=2[S:30]([CH3:33])(=[O:32])=[O:31])[NH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43].O>CN(C)C=O>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([CH:4]2[N:3]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:2](=[O:1])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=3)[C:6]3[CH2:18][CH2:19][C:20](=[O:21])[C:5]2=3)=[C:23]([S:30]([CH3:33])(=[O:31])=[O:32])[CH:24]=1)#[N:27]
Reactant: CCOC(=O)CBr
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 25 °C

Procedure:
A mixture of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 10, 1.78 g, 3.74 mmol) and cesium carbonate (1.83 g, 5.62 mmol) in N,N-dimethylformamide (25.0 mL) is treated with ethyl bromoacetate (0.50 mL, 4.50 mml), and the mixture is stirred at room temperature over night. Water (30 ml) is added, and the precipitate is filtered and dried. Yield: 1.80 g; ESI mass spectrum: [M+H]+=562; Retention time HPLC: 1.05 min (Z018_S04).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(C(C)C)CC)(C)C>ClCCl>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[N:4]=[C:10]=[S:11]
Reactant: S=C(Cl)Cl
Reactant: Nc1c(F)cccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Fc1cccc(F)c1N=C=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
1,3-Difluoro-2-isothiocyanato-benzene was synthesized as follows, according to scheme 1. A solution of 2,6-difluoro aniline (0.13 g, 1.01 mmol) in dichloromethane (10.00 ml) was treated with thiophosgene (0.12 g, 1.06 mmol) and diisopropylethylamine (0.26 g, 2.01 mmol). The mixture was stirred for 1 h at room temperature. The solvent was then evaporated, leaving 1,3-difluoro-2-isothiocyanato-benzene (0.17 g, 99%) as a light brown gum, which was used crude.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][C:16]1[NH:17][CH:18]=[CH:19][N:20]=1>CO.C(Cl)Cl>[CH3:15][C:16]1[N:17]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH:18]=[CH:19][N:20]=1
Reactant: O=[N+]([O-])c1ccc(Br)c(C(F)(F)F)c1
Reactant: Cc1ncc[nH]1
Solvent: CO
Solvent: ClCCl
Product: Cc1nccn1-c1ccc([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound is prepared by hearing 1-bromo-4-nitro-2-trifluoromethyl-benzene and 2-methyl-imidazole between 100-150° C. during 15 h: M+H=272.0; Rf (MeOH/CH2Cl2=1:5): 0.60.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[S:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1ccc(S)cc1
Product: COc1ccc(Sc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 109.3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (50 mg) and commercially available 4-methoxybenzenethiol (63 mg) were mixed and stirred at 150° C. for 5 minutes. Purification was carried out in the same manner as described in Example 18, and further crystallization with chloroform gave 80 mg of the title compound (yield: 100%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[CH3:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2>CCOCC>[CH3:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:1](=[O:5])[C:2]([Cl:4])=[O:3]
Reactant: Cc1ccc2[nH]ccc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: Cc1ccc2[nH]cc(C(=O)C(=O)Cl)c2c1

Procedure:
Oxalyl chloride (0.76 ml) was slowly added to a stirred solution of 1 g of 5-methylindole in 20 ml of anhydrous ether at 0° C. The precipitate which formed was filtered off and dried at 80° C. to give 5-methyl-3-indolylglyoxylyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:8][C:9]=2[CH3:11])[N:4]([CH3:19])[N:3]=1.O.[Li+].[OH-]>O1CCOCC1>[Cl:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][C:9]=2[CH3:11])[N:4]([CH3:19])[N:3]=1
Reactant: CCOC(=O)COc1cc(C)c2c(Cl)nn(C)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(OCC(=O)O)nc2c1c(Cl)nn2C
Reaction time: 2 h

Procedure:
To a solution of Ethyl 2-((3-chloro-1,4-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)oxy)acetate in dioxane (5 ml) were added H2O (2.5 ml) and LiOH (111 mg, 4.65 mmol). After 2 h, more water was added and the mixture extracted with CH2Cl2. Then, the aqueous phase was acidified by drop wise addition of conc. HCl until the product precipitated. The title compound (580 mg, 98%) was filtered off and dried under reduced pressure. [1H-NMR (DMSO-d6, 400 MHz) δ 6.62 (s, 1H), 4.98 (s, 2H) 3.84 (s, 3H), 2.61 (s, 3H); HPLC-MS RtJ=0.81 min; [M+H]+=255.9, 258.0]
Reaction SMILES: [C:1](SCC)(=[S:3])[CH3:2].[NH2:7][CH2:8][C@@H:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH2:23][C:24](=[O:27])[NH:25][N:26]=3)=[C:17]([F:28])[CH:16]=2)[CH2:10]1.C(N(CC)CC)C>CN(C=O)C>[F:28][C:17]1[CH:16]=[C:15]([N:11]2[CH2:10][C@H:9]([CH2:8][NH:7][C:1](=[S:3])[CH3:2])[O:13][C:12]2=[O:14])[CH:20]=[CH:19][C:18]=1[C:21]1[S:22][CH2:23][C:24](=[O:27])[NH:25][N:26]=1
Reactant: CCSC(C)=S
Reactant: NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=S)NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Ethyl dithioacetate (0.0708 ml, 0.747 mmol) is added to 2-[4-(5(S)-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluorophenyl]-4H-[1,3,4]thiadiazin-5-one (0.200 g, 0.617 mmol) and triethylamine (0.0946 ml, 0.679 mmol) in DMF (3 ml) and is stirred at room temperature overnight. The reaction mixture is evaporated to dryness and the residue is purified by PTLC (10% MeOH/DCM) to give a white solid (0.21 g, 90%); 1HNMR (300 MHz, DMSO-d6) δ 2.43 (s, 3H), 3.59 (s, 2H), overlapping 3.84 (dd, J=6.6, 9.1, 2H) and 3.92 (t, J=4.7 Hz, 2H), 4.19 (t, J=9.1 Hz, 1H), 4.92-5.05 (m, 1H), 7.43 (dd, J=2.2, 8.5 Hz, 1H), 7.58 (dd, J=2.2, 14, 1H), 7.69 (t, J=8.5, 1H), 10.4 (t, J=5.8 Hz, 1H), 11.6 (s, 1H); mp 182-3; MS (m/z): [M+H]+=383.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:9](=[O:12])[NH:10][N:11]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.CO>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:8]2[C:7](=[O:20])[C:6]([C:4]([OH:5])=[O:3])=[N:11][NH:10][C:9]2=[O:12])=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1n[nH]c(=O)n(-c2ccc(F)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1n[nH]c(=O)n(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(4-Fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid ethyl ester (300 mg, 1 mmol) in THF (3 mL) and MeOH (7 mL) was added 5M NaOH (2 mL, 2 mmol). The mixture was stirred at rt for 1 h and was concentrated. Water was added and the mixture was extracted with ether. The aq. layer was made acidic with HCl at 0° C. and was extracted with EtOAc and concentrated. LCMS m/z=274 (M+Na); 1H NMR (DMSO) δ: 13.03 (s, 1H), 7.35-7.30 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]=[C:19]=[O:20])[CH:13]=1.[ClH:21]>ClCCl.C(O)C>[ClH:21].[CH3:11][N:6]1[C:7]2[C:3](=[C:2]([NH:1][C:19]([NH:18][C:14]3[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=3)=[O:20])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: Cn1ccc2c(N)cccc21
Reactant: O=C=Nc1cccnc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: Cn1ccc2c(NC(=O)Nc3cccnc3)cccc21
Reaction time: 17 h

Procedure:
A solution of the aminoindole (D10) (0.44 g; 3.01 mM) in dichloromethane (10 ml) was added dropwise to a solution of 3-pyridyl isocyanate (D4) (prepared from 3-pyridine carbonyl azide (0.51 g; 3.4 mM) in toluene) at room temperature. The reaction mixture was stirred for 17 h, then cooled and the precipitate filtered off to give the crude product (1 g; 100%). This was dissolved in hot ethanol and ethereal hydrogen chloride added to afford the title compound as its hydrochloride salt (0.74 g; 81%), m.p 238° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([O:15][N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][C:21](F)=[C:22]([F:27])[CH:23]=2)[N:18]([CH2:29][CH3:30])[C:17]1=[O:31])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:8]([O:15][N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][C:21]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[C:22]([F:27])[CH:23]=2)[N:18]([CH2:29][CH3:30])[C:17]1=[O:31])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(F)cc21
Reactant: CN1CCNCC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCN(C)CC3)cc21
Yield: 84.9 %

Procedure:
4-Methylpiperazine (0.08 mL, 0.72 mmol) was added to a solution of 3-benzyloxy-1-ethyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example C, 0.2 g, 0.6 mmol) and DBU (0.09 mL, 0.6 mmol) in 30 mL of acetonitrile. The solution was warmed to reflux for 100 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform washed with water, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.21 g of a solid. The solid was purified by column chromatography (chloroform/methanol 99:1). The appropriate fractions were combined to give 0.14 g of the title compound as a solid, mp 134-136° C.