Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[S-:15][C:16]#[N:17].[NH4+].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1>>[F:29][C:26]([F:27])([F:28])[C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:16]2[S:15][C:2]3[N:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4](=[O:6])[N:17]=2)=[CH:21][CH:22]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: N#C[S-]
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Product: O=c1nc(Nc2ccc(C(F)(F)F)cc2)sc2ncccc12
Yield: 79.6 %

Procedure:
The reaction procedure of Example 6 was followed except that 5.00 g of chloronicotinic acid, 25 ml of thionyl chloride, 2.42 g of ammonium thiocyanate and 5.11 g of 4-aminobenzotrifluoride were used. As a result, 8.16 g of 2-(4-trifluoromethylanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH:3]([OH:13])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1>CO.C(OCC)(=O)C.[Pd]>[CH3:14][CH:2]([CH:3]([OH:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[CH3:1]
Reactant: Cc1ccc(/C=C/C(O)C(C)C)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(CCC(O)C(C)C)cc1
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution of trans-4-methyl-1-p-tolyl-1-penten-3-ol (43.2 g, 0.227 mol) in methanol (35 mL) was added 2 micro-spoon of palladium, 10% on activated carbon and the reaction mixture was hydrogenated overnight at 40 psi. The solution was diluted with ethyl acetate, filtered over celite and evaporated to give 40 g of 2-methyl-5-(p-tolyl)-3-pentanol as a colorless oil and used without further purification in the next step (step g). 1H NMR (300 MHz; CDCl3): 0.90 (d, J=6.9 Hz, 6 H), 1.70 (m, 4 H), 2.31 (s, 3 H), 2.62 (m, 1 H), 2.78 (m, 1 H), 3.39 (m, 1 H), 7.09 (s, 4 H).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-])=[C:4]([CH3:10])[CH:3]=1.C([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)(OC(C)(C)C)=O.C(N(CC)C(C)C)(C)C.Cl.N>S1(CCCC1)(=O)=O.CO>[CH3:10][C:4]1[CH:3]=[C:2]([N:18]2[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]2)[C:7]([CH3:8])=[CH:6][N:5]=1
Reactant: Cc1c[n+]([O-])c(C)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: Cl
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S1(=O)CCCC1
Solvent: CO
Product: Cc1cc(N2CCC(N)CC2)c(C)cn1
Temperature: 220 °C
Reaction time: 18 h
Yield: 34.2 %

Procedure:
A mixture 4-chloro-2,5-dimethyl-pyridine 1-oxide (200 mg, 1.41 mmol), Boc-4-aminopiperidine (311 mg, 1.55 mmol) and N,N-diisopropyl ethyl amine (484 μL, 2.82 mmol) in sulfolane (1 mL) was heated to 160° C. for 30 minutes in a microwave oven followed by heating to 220° C. for 30 minutes. After the addition of aqueous hydrochloric acid (25% in water, 0.5 mL) the mixture was stirred for 18 h at ambient temperature. It was treated with ammonia in methanol and concentrated. Purification by chromatography (SiO2, dichloromethane/methanol/ammonia=95:4.5:0.5 to 90:9:1) afforded the title compound (99 mg, 40%) as a light brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:16][O:17][C:18]1[CH:29]=[CH:28][C:21]([O:22][CH:23](Br)[CH2:24][CH2:25][CH3:26])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:16][O:17][C:18]1[CH:29]=[CH:28][C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][O:1][C:2]2[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=2)[C:6]([O:8][CH3:9])=[O:7])=[CH:20][CH:19]=1
Reactant: CCCC(Br)Oc1ccc(OC)cc1
Reactant: COC(=O)c1ccc(O)cc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCCCCOc2ccc(OC)cc2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 72.1 %

Procedure:
21.0 g (0.1 mol) of dimethyl 4-hydroxyphthalate, 25.9 g (0.1 mol) of p-methoxyphenoxy-l-bromobutane and 100 ml of acetonitrile were put in a 300-ml three-neck flask, and 6.91 g of potassium carbonate was added in three divided portions at two-hour intervals at 70° to 80° C. The reaction system was stirred further for 7 hours under reflux. The system was cooled to room temperature, and the salts formed and acetonitrile were taken out by filtration and distillation, respectively. Ethyl acetate and water were added to the residue, which was then washed well with water. Ethyl acetate was removed by distillation, and the residue was recrystallized from a mixed solvent of hexane/ethyl acetate (6/4, v/v). 28.0 g of the intended product was obtained, having a melting point of 68° C. The yield was 72.0%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:23])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.Cl[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>CC(N(C)C)=O.CS(C)=O>[CH:28]([O:27][C:25](=[O:26])[NH:23][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)([CH3:30])[CH3:29]
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCCOCC1
Reactant: CC(C)OC(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CS(C)=O
Product: CC(C)OC(=O)Nc1ccc(OCCN2CCCOCC2)c(-c2ccnn2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenylamine (0.08 g, 0.253 mmol) in 2.0 mL of DMA was added isopropyl chloroformate (0.034 g, 0.278 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted to 5.0 mL with DMSO and was subjected to purification on RP-HPLC. The proper fractions were collected and lyophilized to afford [3-(2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-carbamic acid isopropyl ester as an off-white semisolid in 80% yield. LCMS m/z (%)=403 (M+H, 100). 1H NMR (400 MH, Acetone-d6) δ: 8.35 (bs. 1H), 7.45 (dd, J=8.4 and 2.6 Hz, 1H), 7.33 (s, 1H), 7.23 (d, J=1.8 Hz, 1H), 6.94 (d, J=8.95 Hz, 1H), 6.05 (d, J=1.82 Hz, 1H), 4.69-4.76, (m, 1H), 4.31 (t, J=4.36 Hz, 2H), 3.52 (s, 3H), 3.41 (t, J=4.93 Hz, 2H), 3.10-3.30 (m, 4H), 2.71-2.80 (m, 4H), 1.05 (d, J=6.12 Hz, 6H).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH:4]([CH3:6])[CH3:5].[NH2:8][C:9](=[S:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(O)C>[CH:4]([C:3]1[N:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:15][CH:2]=1)([CH3:6])[CH3:5]
Reactant: CC(C)C(=O)CBr
Reactant: CCOC(=O)C(N)=S
Solvent: CCO
Product: CCOC(=O)c1nc(C(C)C)cs1
Temperature: 25 °C

Procedure:
1-Bromo-3-methylbutan-2-one (3.72 g) in ethanol (15 mL) was added dropwise over 15 minutes to a refluxing solution of ethyl 2-amino-2-thioxoacetate (3 g) in ethanol (120 mL). The mixture was heated at reflux for 2 hours and then cooled to room temperature. The solvent was evaporated down under reduced pressure to a volume of 30 mL, this solution was added to ice/water (200 mL) and the mixture neutralised by dropwise addition of ‘880’ concentrated aqueous ammonia. The mixture was extracted twice with ethyl acetate, the combined organics were washed with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography eluting with 20% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 2.2 g.
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:22][OH:23].CCN=C=NC[CH2:30][CH2:31]N(C)C.Cl.C1C=CC2N([OH:45])N=NC=2C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.ClCCCl.C(O)(=O)C>[F:1][C:2]1[C:3]([CH2:22][OH:23])=[CH:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:30](=[O:45])[CH3:31])[CH2:18][CH2:17]2)[CH2:10][CH2:9]1
Reactant: OCc1cccc(N2CCC(CCC3CCNCC3)CC2)c1F
Reactant: CCN=C=NCCCN(C)C
Reactant: On1nnc2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CC(=O)N1CCC(CCC2CCN(c3cccc(CO)c3F)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
(2-Fluoro-3-{4-[2-(piperidin-4-yl)ethyl]piperidin-1-yl}phenyl)methanol (200 mg) and acetic acid (63 mg) were mixed with DCE (3 ml), and WSC hydrochloride (220 mg) and HOBt (155 mg) were added thereto, followed by stirring at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution and CHCl3 were added to the reaction mixture, and the organic layer was liquid separation and concentrated under reduced pressure. The obtained residue was mixed with MeOH (3 ml), and a 1 M aqueous NaOH solution (1 ml) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 1-[4-(2-{1-[2-fluoro-3-(hydroxymethyl)phenyl]piperidin-4-yl}ethyl)piperidin-1-yl]ethanone (211 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.CO[C:11](OC)([N:13]([CH3:15])[CH3:14])[CH3:12].COC1CCCC1>>[Cl:1][C:2]1[N:7]=[N:6][C:5](/[N:8]=[C:11](/[N:13]([CH3:15])[CH3:14])\[CH3:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: COC(C)(OC)N(C)C
Solvent: COC1CCCC1
Product: C/C(=N\c1ccc(Cl)nn1)N(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Combine 6-chloropyridazin-3-amine (1.500 kg, 11.58 mol); 1,1-dimethoxy-N,N-dimethylethanamine (2.313 kg, 17.37 mol) and cyclopentyl methyl ether (8.25 L) then heat to 98° C. while distilling off the resulting methanol byproduct. After 4 h, the reaction mixture is cooled to ambient temperature and heptanes (11.2 L) is added to the reaction solution for crystallizing the product. The title compound is collected by filtration and is dried. (1.494 kg, 64.95%; mp=73° C.)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](S(C)(=O)=O)[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:16][CH2:17][CH3:18].[Na+].[CH2:20]([OH:22])[CH3:21]>>[CH2:17]([O:16][C:2]1[CH:3]=[C:4]([O:22][CH2:20][CH3:21])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:18]
Reactant: CCO
Reactant: CC[O-]
Reactant: CS(=O)(=O)c1cc(Cl)nn2c(N)nnc12
Agent: [Na+]
Product: CCOc1cc(OCC)c2nnc(N)n2n1
Temperature: 50 °C

Procedure:
6-Chloro-8-methanesulfonyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.126; 60 mg, 0.24 mmol) was dissolved in ethanol (5 ml), sodium ethoxide (500 μl, 21% in ethanol) was added and the mixture was heated to 50° C. for 5 h. The mixture was concentrated and the residue was purified by flash chromatography (dichloromethane:methanol). Yield: 54 mg LC-MS rt: 0.52 min [M+H]+: 224.1 (met. b)
Reaction SMILES: [O:1]=[C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[C:31](Cl)(=[O:35])[C:32](Cl)=[O:33].[CH3:37][NH2:38]>C1(C)C=CC=CC=1>[CH3:37][NH:38][C:31](=[O:35])[C:32]([N:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:2](=[O:1])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:7][CH2:6]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:33]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccccc2Nc2ccccc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: CNC(=O)C(=O)N(c1ccccc1)c1ccccc1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound prepared in Example 303 (0.100 g) was suspended in toluene (10 mL) and oxalyl chloride (0.085 mL) added. The reaction mixture was stirred at room temperature for 2 hours. Methylamine solution (2 mol/L; 3.672 mL) was added and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was then partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude material (0.173 g), which was used without further purification possessing the following physical data.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:12].C(N(CC)CC)C.[CH3:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>ClCCl>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[CH3:20]
Reactant: Oc1ccc2c(c1Br)CCCC2
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Oc1ccc2c(c1Br)CCCC2
Reaction time: 1 h

Procedure:
To a solution of 1-bromo-5,6,7,8-tetrahydro-2-naphthol (6.81 g) and triethylamine (4.2 ml) in dichloromethane (60 ml) was added 2-methylbenzoyl chloride (4.62 g) dropwise with ice-cooling. The mixture was stirred under ice cooling for 1 hour, after which it was washed with water and dried (MgSO4). The solvent was then distilled off to give 1-bromo-2-(2-methylbenzoyloxy)-5,6,7,8-tetrahydronaphthalene as oil in quantitative yield.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH2:4][CH:5]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7](F)[N:6]1[O:13][CH:14]([F:16])[F:15]>C(OCC)C>[NH2:4][CH:5]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7]([N:2]([CH3:3])[CH3:1])[N:6]1[O:13][CH:14]([F:16])[F:15]
Reactant: CNC
Reactant: NC1N=C(Cl)N=C(F)N1OC(F)F
Solvent: CCOCC
Product: CN(C)C1=NC(Cl)=NC(N)N1OC(F)F
Reaction time: 8 h

Procedure:
4.2 g (0.093 mol) of dimethylamine were passed into a solution of 10 g (0.047 mol) of 2-amino-4-chlorodifluoromethoxy-6-fluoro-1,3,5-triazine in 150 ml of diethyl ether in the course of 20 minutes at 0° C. while stirring. Stirring was continued for one hour at 0° C. and overnight at 22° C. Washing with water, drying and evaporating down gave 9.8 g (87.8% of theory) of the title compound of melting point 130°-133° C. (decomposition).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[N:13]=[C:12]2[C:19]1[N:24]=[C:23]2[C:25]([C:47]([O-:49])=[O:48])=[CH:26][N:27]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:22]2=[N:21][CH:20]=1)(C(C)(C)C)(C)C.[CH3:50]CCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[N:13]=[C:12]2[C:19]1[N:24]=[C:23]2[C:25]([C:47]([O:49][CH3:50])=[O:48])=[CH:26][N:27]([C:28]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:22]2=[N:21][CH:20]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)[O-])cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(C)c4ccc(O)cc34)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 115.5 %

Procedure:
To a solution of 2-(5-(tert-butyldimethylsilyloxy)-1-methyl-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (3.4 g, 4.9 mmol) in THF (25 mL) was added TBAF (6.42 mL, 12.85 mmol) at 0° C., after the addition was completed, the reaction mixture was warmed to room temperature and stirred for 0.5 hour, then H2O (25 mL) was added to the mixture extracted with EtOAc (100 mL), the organic layer was washed with H2O (100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give methyl 2-(5-hydroxy-1-methyl-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (3.2 g, >100%) as a yellow solid. LCMS: (M+H)+=566; (M+Na)+=588.
Reaction SMILES: C([Al](CC(C)C)CC(C)C)C(C)C.[NH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][NH:19]2.C(OC)(=O)[C:25]1[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)[OH:27].Cl>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.C(Cl)Cl>[NH:19]1[C:20]2[C:16](=[C:15]([NH:14][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[OH:27])[CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:18]1
Reactant: Nc1cccc2[nH]ccc12
Reactant: COC(=O)c1ccccc1O
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Oc1ccccc1Nc1cccc2[nH]ccc12
Temperature: 25 °C

Procedure:
92 ml of a 1.1 mole/liter solution of triisobutylaluminum in toluene were added with stirring under an inert atmosphere to a solution of 6.6 g of 4-amino indole in 250 ml of chloroform and then 9.6 ml of methyl salicylate were added. The mixture was refluxed for 20 hours and then cooled to ambient temperature. 300 ml of N hydrochloric acid and 300 ml of methylene chloride were added, followed by washing with water, drying over a desiccant, filtering, evaporating to dryness under reduced pressure at 50° C., triturating with ether, filtering and drying at 60° C. under reduced pressure to obtain 9.4 g of 2-[N-(1H-indol-4-yl)amino]phenol melting at ≃232° C.
Reaction SMILES: [C:1]([C:3](=[CH:9][CH:10]1[CH2:12][CH2:11]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH3:13][Mg]Br>[Cu]I.C(OCC)C>[C:1]([CH:3]([CH:9]([CH:10]1[CH2:11][CH2:12]1)[CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=CC1CC1
Reactant: C[Mg]Br
Agent: [Cu]I
Solvent: CCOCC
Product: CCOC(=O)C(C#N)C(C)C1CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.4 %

Procedure:
7.3 g (44 mmol) of ethyl 2-cyano-3-cyclopropyl-2-propenoate and 0.15 g of copper(I) iodide were introduced into 100 ml of dry diethyl ether. 16.9 ml of etheric 3 M methylmagnesium bromide solution (51 mmol) was then added dropwise at reflux temperature, and the mixture was subsequently stirred for 14 hours at room temperature. For working-up, the mixture was poured into 300 ml of ice-water and stirred for 10 minutes. The aqueous phase was separated off and washed with ether. The combined organic phase [sic] were washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated. The residue was subjected to fractional distillation in vacuo. This gave 4.9 g (yield 61%) of ethyl 2-cyano-3-cyclopropylbutanoate (b.p. 90° C./2 mbar).
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9]CC)=[O:8])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1>[OH-].[Na+]>[Br:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1c[nH]c(Br)c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c[nH]c(Br)c1-c1ccc(Cl)cc1

Procedure:
Ethyl 5-bromo-4-(p-chlorophenyl)pyrrole-3carboxylate (15 g., 0.045 mmol) is added to 200 mL of 10% sodium hydroxide and the slurry heated to reflux. After everything appears to dissolve the mixture is refluxed an additional 40 minutes. The mixture is cooled, filtered and the filtrate acidified. The white precipitate (80 g, 58%) is collected and dried. The solid has m.p. >205° C. and an NMR (d6 -DMSO) which showed a pyrrole proton at 7.52 (d). The mass spectrum is also consistent for a monobrominated compound.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:12]([C:13](O)=O)=C[NH:10][C:7]2=N[CH:9]=1)([O-])=O.C[N:17](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.N1C2C(=CC=CN=2)C=C1>CN(C=O)C>[NH:17]1[C:12]2[C:6](=[CH:5][CH:4]=[CH:9][CH:13]=2)[CH:7]=[N:10]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1c[nH]c2ncc([N+](=O)[O-])cc12
Agent: F[B-](F)(F)F
Agent: c1cnc2[nH]ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To the resin (1.5 g, 0.77 mmol/g, 1.16 mmol) of example 7 in anhydrous DMF (15 ml), it was added 5-nitro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (0.359 g, 1.73 mmol), TBTU (0.556 g, 1.73 mmol) and DIPEA (0.44 g, 3.48 mmol). The reaction mixture was shaken at room temperature for 20 hours and then the resin was isolated by filtration. The resin was washed sequentially with DMF (25 ml), DCM (25 ml), DMF (25 ml), DCM (25 ml), MeOH (25 ml), DCM (25 ml), MeOH (25 ml), DCM (25 ml), MeOH (25 ml), TBME (25 ml×2) and dried in vacuo to give the resin bound 7-azaindole (1.70 g).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)=[S:4].C(OCC)(=O)C.[CH3:20][N:21]=[C:22]=[O:23].C(N(CC)CC)C>CCCCCC>[CH3:1][N:2]([CH3:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:22](=[O:23])[NH:21][CH3:20])[CH:7]=1)=[S:4]
Reactant: CN=C=O
Reactant: CN(C)C(=S)Nc1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CNC(=O)Oc1cccc(NC(=S)N(C)C)c1
Temperature: 20 °C

Procedure:
1,1-dimethyl-3-(meta-methylcarbamoyloxyphenyl)-2 -thiourea is prepared by charging to a suitable equipped reaction vessel about 32.7 parts by weight of 1,1-dimethyl-3-(meta-hydroxyphenyl)-2-thiourea, about 100 parts by weight of ethyl acetate, about 12 parts by weight of methyl isocyanate and about 1 part by weight triethylamine, refluxing for about 1 hour with stirring, diluting the resulting slurry with about 100 parts by weight of hexane, cooling to about 20° C., recovering the precipitate from the remainder by filtration, washing the recovered solid with ethyl acetate and hexane and air drying.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.O[C:15]1C=CC(C(=O)C)=C(C)C=1.C(=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:13][O:12][C:3]1[CH:2]=[CH:10][C:6]([C:7](=[O:9])[CH3:15])=[C:5]([CH3:11])[CH:4]=1
Reactant: CC(=O)c1ccc(O)cc1C
Reactant: COc1cc(C)c(C(=O)O)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C(C)=O)c(C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Alternatively, 5-bromo-4-methoxy-2-methylbenzoic acid can be synthesized from 4′-hydroxy-2′-methylacetophenone as a starting material. Potassium carbonate (0.720 mg, 5.21 mmol) and methyl iodide (0.542 g, 3.82 mmol) were added to an acetone (10 mL) solution of 4′-hydroxy-2′-methylacetophenone (0.552 g, 3.47 mmol) and stirred at room temperature for 12 hours. Methyl iodide (0.24 g, 1.73 mmol) was further added, and the mixture was heated to reflux for two hours. After cooled to room temperature, the solvent was evaporated under reduced pressure. After chloroform was added to the residue, insolubles were filtered off and the filtrate was concentrated to obtain 4′-methoxy-2′-methylacetophenone (0.57 g). Then, oxone (0.79 g, 1.27 mmol) and NaBr (0.13 g, 1.27 mmol) were added to an acetone (4 mL) water (4 mL) solution of 4′-methoxy-2′-methylacetophenone (0.21 g, 1.27 mmol), and stirred at room temperature for one hour. After water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with water, a saturated sodium carbonate aqueous solution and brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was evaporated under reduced pressure to obtain 4:1 mixture (0.28 g) of 5′-bromo-4′-methoxy-2′-methylacetophenone and 3′-bromo-4′-methoxy-2′-methylacetophenone. Then, 4:1 mixture (0.26 g) of 5′-bromo-4′-methoxy-2′-methylacetophenone and 3′-bromo-4′-methoxy-2′-methylacetophenone was added with 5% NaOCl solution (3 mL) and potassium hydroxide (0.92 g) and heated to reflux for 2.5 hours. After cooled to room temperature, the reaction mixture was made acidic with 2M HCl. After the mixture was extracted with ethyl acetate, the organic phase was washed with 1M HCl, brine and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was washed with methanol to obtain 5-bromo-4-methoxy-2-methylbenzoic acid (112 mg) as a colorless powder.