Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:10])[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][C:3]=1[C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1.O[C:30]1[CH:39]=[CH:38][C:33]([O:34][CH:35]([OH:37])[CH3:36])=[CH:32][CH:31]=1>CN(C)C1C=CN=CC=1.ClCCl>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:10])[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][C:3]=1[C:20]1[CH:28]=[CH:27][C:23]([C:24]([O:26][C:30]2[CH:39]=[CH:38][C:33]([O:34][CH:35]([OH:37])[CH3:36])=[CH:32][CH:31]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: CC(O)Oc1ccc(O)cc1
Reactant: CCCCCC[C@H](C)Oc1cc(N)c(-c2ccc(C(=O)O)cc2)cc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCC[C@H](C)Oc1cc(N)c(-c2ccc(C(=O)Oc3ccc(OC(C)O)cc3)cc2)cc1[N+](=O)[O-]

Procedure:
0.6 g of 4-[4-(2-amino-5-nitro-4-[(S)-2-octyloxy]phenyl)benzoic acid and 0.2 g of (4-hydroxyphenoxy)ethanol, 0.04 g of 4-dimethylaminopyridine, 0.4 g of N,N'-dicyclodicyclohexyldicarbodimide and 50 ml of dichloromethane are reacted in an analogous manner to Example 1 to give 0.4 g of (4-[4-(2-amino-5-nitro-4-[(S)-2-octyloxy]phenyl)benzoyloxy]phenoxy)ethanol.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[CH:11]([NH:13][NH:14][C:15]1[CH:16]=[CH:17][C:18]([O:26][CH3:27])=[C:19]([CH2:21][CH2:22][C:23]([OH:25])=O)[CH:20]=1)=[O:12].[NH2:28][C:29]1[CH:37]=[CH:36][C:32]2[NH:33][N:34]=[N:35][C:31]=2[CH:30]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH:33]1[C:32]2[CH:36]=[CH:37][C:29]([NH:28][C:23](=[O:25])[CH2:22][CH2:21][C:19]3[CH:20]=[C:15]([NH:14][NH:13][CH:11]=[O:12])[CH:16]=[CH:17][C:18]=3[O:26][CH3:27])=[CH:30][C:31]=2[N:35]=[N:34]1
Reactant: COc1ccc(NNC=O)cc1CCC(=O)O
Reactant: Nc1ccc2[nH]nnc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc(NNC=O)cc1CCC(=O)Nc1ccc2[nH]nnc2c1

Procedure:
Anhydrous N-hydroxybenzotriazole (1.3 g) was added to a cooled solution of 3-[5-(2-formylhydrazino)-2-methoxyphenyl]propionic acid (1.2 g) and 5-aminobenzotriazole (0.67 g, 0.005 mole) in dry dimethylformamide (10 ml). A solution of dicyclohexylcarbodi-imide (1.1 g) was added dropwise to the solution of reactants at such a rate that the temperature was kept at 0°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH2:11][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:14][CH:15]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:3]=1.C(N(CC)CC)C.Cl[C:47](Cl)([O:49]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:4]2[CH:5]=[C:6]([C:10]3[CH2:11][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:14][CH:15]=3)[C:7]3[CH2:8][O:9][C:47](=[O:49])[NH:1][C:2]=3[N:3]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(COc2ccccc2-c2cc(C3=CCCN(C(=O)OC(C)(C)C)C3)c(CO)c(N)n2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(COc2ccccc2-c2cc(C3=CCCN(C(=O)OC(C)(C)C)C3)c3c(n2)NC(=O)OC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 2′-amino-3′-(hydroxymethyl)-6′-{2-[(4-methoxybenzyl)oxy]phenyl}-5,6-dihydro-3,4′-bipyridine-1(2H)-carboxylate (25.0 mg, 0.05 mmol), which was obtained in the step (2) of Example 11-4, and triethylamine (0.02 mL, 0.14 mmol) in THF (3.0 mL) was added a solution of triphosgene (5.7 mg, 0.02 mmol) in THF (3.0 mL), and the stirring was continued for 30 min. The reaction mixture was allowed to warm to room temperature. The reaction was cooled to 0° C. and then quenched by an addition of saturated aqueous NaHCO3 solution, extracted with ethyl acetate. The separated organic phase was washed with brine, dried over MgSO4, filtered and evaporated. The crude product was purified by preparative silica gel TLC (10% acetone in chloroform) to give tert-butyl 5-(7-{2-[(4-methoxybenzyl)oxy]phenyl}-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate as a white solid. (21.7 mg, yield 83%)
Reaction SMILES: [CH:1]1([CH2:10][C:11]([N:13]2[CH2:20][CH2:19][CH2:18][C@H:14]2[C:15]([OH:17])=[O:16])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.O[N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]1=[O:28].C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1>[CH:1]1([CH2:10][C:11]([N:13]2[CH2:20][CH2:19][CH2:18][C@H:14]2[C:15]([O:17][CH:24]2[CH2:25][C:26](=[O:27])[NH:22][C:23]2=[O:28])=[O:16])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CC1CCc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C1CC(OC(=O)[C@@H]2CCCN2C(=O)CC2CCc3ccccc32)C(=O)N1
Yield: 64.8 %

Procedure:
Into a 4 ml of tetrahydrofuran were dissolved 0.82 g of 1-(2-indanylacetyl)-L-proline and 0.35 g of N-hydroxysuccinimide. To the solution was dropwise added a solution of 0.74 g of DCC in 2 ml of tetrahydrofuran at room temperature with stirring. After stirring for a further 17 hours at the same temperature, insoluble components were removed by filtration. From the filtrate the solvent was evaporated under reduced pressure. The oily residue thus obtained was washed with n-hexane, dissolved in 5 ml of benzene, and treated with activated carbon. Benzene was evaporated under reduced pressure to produce 0.72 g of 1-(2-indanylacetyl)-L-prolyloxysuccinimide as coloress amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:13][O:12]1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[S:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1>CCO.O>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:12])[CH2:13][NH:15][C:16]1[CH:17]=[CH:18][C:19]2[S:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Reactant: CC(C)(C)OC(=O)NCCCC1CO1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCC(O)CNc1ccc2c(c1)NC(=O)CS2
Yield: 37.7 %

Procedure:
A solution of ((rac)-3-oxiranyl-propyl)-carbamic acid tert-butyl ester (1.08 g, 5.34 mmol) and 6-amino-4H-benzo[1,4]thiazin-3-one (1.01 g, 5.61 mmol) in 9:1 EtOH/H2O (20 mL) was heated at 70° C. overnight. After cooling the mixture was concentrated in vacuo and chromatographed on SiO2 (DCM-MeOH—NH4OH: 1000:50:4) to afford the title intermediate as beige foam (767 mg, 38% yield).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=1>CC(N(C)C)=O>[O:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1ccccc1
Reactant: CC(C)(C)C(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)C(=O)c1ccc(COc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6.73 g. sodium hydride (57% suspension in mineral oil-0.165 mole) in 200 ml. dry dimethylacetamide, there is added dropwise 14.1 g. (0.15 mole) of phenol in 50 ml. dimethylacetamide maintaining the temperature below 25°C. After the addition is complete, the resulting mixture is stirred for 1 1/2 hours at room temperature. A solution of 38.3 g. (0.15 mole) α-bromo-p-pivaloyl toluene in 50 ml. dimethylacetamide is then added dropwise at room temperature and the resulting mixture is stirred for 18 hours at room temperature. The mixture is then treated with 10 ml. of methanol and the solvent removed in vacuo. The resulting residue is partitioned between ether and water, and the ether layer is washed twice with 200 ml. of 2N sodium hydroxide, once with water and once with brine. The organic layers are combined and dried over anhydrous magnesium sulfate, decolorized and evaporated. The resulting solid is triturated with petroleum ether to give p-(phenoxymethyl)pivalophenone, m.p. 79.5° to 80°C.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([CH2:9][NH2:10])=[O:8].C(=O)(O)[O-].[Na+].[C:16](Cl)(=[O:20])[CH:17]([CH3:19])[CH3:18]>>[C:16]([NH:10][CH2:9][C:7]([C:3]1[O:2][CH:6]=[CH:5][CH:4]=1)=[O:8])(=[O:20])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)C(=O)Cl
Reactant: NCC(=O)c1ccco1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)C(=O)NCC(=O)c1ccco1
Yield: 67.3 %

Procedure:
16.0 g of (2-furylcarbonyl)methylamine hydrochloride, 20.5 g of sodium bicarbonate and 11.4 g of isobutyryl chloride are treated in the same manner as described in Preparation 1-(1). 13.0 g of N-isobutyryl-(2-furylcarbonyl)methylamine are thereby obtained. Yield: 67.0%
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]#[N:13])[N:9]=[CH:8]1.[CH3:16][CH2:17][Mg+].[Br-].O>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2([NH2:13])[CH2:17][CH2:16]2)[N:9]=[CH:8]1
Reactant: CC[Mg+]
Reactant: C[Si](C)(C)CCOCn1cnc(C#N)c1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1cnc(C2(N)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
To a round bottom flask was added 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile (310 mg, 3.19 mmol) in THF (10 ml), followed by the addition Ti(OiPr)4 (0.9 ml, 3.05 mmol) Next, EtMgBr (3.0 M in ether) (1.85 ml, 5.55 mmol) was added slowly. The clear solution changed to dark and gas evolved was found. The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was added with water (10 ml). The solid precipitate was filtered through celite. The filter cake was washed with THF (10 ml), EtOAc (10 ml). The combined solvent was concentrated to afford 400 mg of 1-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-cyclopropylamine, m/z 254.6 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]2)[CH:4]=1.[ClH:25]>ClCCl>[ClH:25].[ClH:25].[F:24][C:2]([F:1])([F:23])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)[CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(C(F)(F)F)ncn2)CC1
Agent: Cl
Solvent: ClCCl
Product: NC1CCN(c2cc(C(F)(F)F)ncn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.1 %

Procedure:
To a solution of tert-butyl 1-(6-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-ylcarbamate (1.42 g, 4.1 mmol) in dichloromethane (20 mL) was added HCl (2 M in diethylether, 10.2 mL, 20.5 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The mixture was filtered and the white precipitate was washed with dichloromethane and diethylether and dried to afford the title compound (1.27 g, 97%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:23][C:24]([C:26]2[C:27]([CH3:38])=[N:28][N:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:30]=2)=[O:25])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([O:15][Si](C(C)(C)C)(C)C)[CH2:11][CH2:10]1)#[N:2].[H-].[Na+].Br[CH2:42][C:43]([O:45]CC)=[O:44].O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([N:23]([C:24]([C:26]2[C:27]([CH3:38])=[N:28][N:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:30]=2)=[O:25])[CH2:42][C:43]([OH:45])=[O:44])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:10][CH2:11][CH:12]([OH:15])[CH2:13][CH2:14]1)#[N:2]
Reactant: Cc1nn(-c2ccc(F)cc2)cc1C(=O)Nc1ccc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)c(C#N)c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccc(F)cc2)cc1C(=O)N(CC(=O)O)c1ccc(N2CCC(O)CC2)c(C#N)c1
Temperature: 25 °C
Yield: 10.6 %

Procedure:
N-(3-Cyano-4-(4-tert-butyldimethylsilyloxypiperidin-1-yl)phenyl)-1-(4-fluorophenyl)-3-methylpyrazole-4-carboxamide (2.1 g) and sodium hydride (60% content, 0.2 g) were reacted in dimethylformamide (30 ml) under ice-cooling for 1 h. Dimethylformamide solution (10 ml) containing ethyl bromoacetate (1.0 g) was added and the mixture was stirred under ice-cooling for 1 h and, after allowed to warm to room temperature, stirred for another 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. To the residue were added tetrabutylammonium fluoride (2.0 g), tetrahydrofuran (20 ml) and acetonitrile (20 ml) and the mixture was stirred at 80° C. for 1 h. The solvent was evaporated under reduced pressure. To the residue was added dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. A mixed solvent of toluene-ethyl acetate was added to the residue to allow crystallization. The crystals were recrystallized from hydrous isopropanol to give the title compound (0.2 g), melting point: 124–125° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:16]2[CH:21]=[C:20]([Cl:22])[N:19]=[C:18]([C:23](=[O:35])[NH:24][CH2:25][C:26]3[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=3[CH3:32])[C:17]=2[Cl:36])[CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:22].[Cl:36][C:17]1[C:18]([C:23]([NH:24][CH2:25][C:26]2[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=2[CH3:32])=[O:35])=[N:19][C:20]([Cl:22])=[CH:21][C:16]=1[N:14]([CH3:15])[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: Cc1cc(C)c(CNC(=O)c2nc(Cl)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2Cl)c(=O)[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2nc(Cl)cc(N(C)C3CCNCC3)c2Cl)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.2 %

Procedure:
Tert-butyl4-[(3,6-dichloro-2-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]carbamoyl}pyridin-4-yl)(methyl)amino]piperidine-1-carboxylate (310 mg, 1.29 mmol) was dissolved in 4M HCl in dioxane solution (3 ml) and stirred at room temperature for 16 h after which the solvent was evaporated and the compound purified by preparative HPLC to afford the title compound as a beige powder (13 mg, 14%). LC-MS 100%, 2.41 min (7 minute LC-MS method), m/z=438.1/439.8, 1H NMR (500 MHz, Methanol-d4) δ 7.12 (s, 1H), 6.11 (s, 1H), 4.46 (s, 2H), 4.01-3.81 (m, 1H), 3.45 (d, J=12.9 Hz, 2H), 3.12-2.97 (m, 2H), 2.82 (s, 3H), 2.35 (s, 3H), 2.22 (s, 3H), 2.13-1.93 (m, 4H).
Reaction SMILES: [C:1]([S:5]([NH:7][C:8]1([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH2:11][O:10][CH2:9]1)=[O:6])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)=[O:20]>>[C:1]([S:5]([NH:7][C:8]1([CH:12]([CH3:16])[C:13]([O:15][CH2:18][C:19](=[O:20])[C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=2)=[O:14])[CH2:9][O:10][CH2:11]1)=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C(=O)O)C1(NS(=O)C(C)(C)C)COC1
Product: CC(C(=O)OCC(=O)c1ccc(OC(F)(F)F)cc1)C1(NS(=O)C(C)(C)C)COC1
Yield: 66.1 %

Procedure:
Prepared by Method E using 2-{3-[(tert-butylsulfinyl)amino]oxetan-3-yl}propanoic acid (Preparation 26, 1.18 g, 4.733 mmol) and 2-bromo-1-[4-(trifluoromethoxy)phenyl]-ethanone (1.47 g, 5.21 mmol). The residue was purified by silica gel column chromatography to afford the title compound (1.413 g, 66% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([OH:43])=[C:19]([CH:42]=2)[C:20]([NH:22][C:23]2[CH:35]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:33]=[CH:32][C:24]=2[C:25]([O:27]C(C)(C)C)=[O:26])=[O:21])[CH:12]=[CH:11][CH:10]=1>>[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([OH:43])=[C:19]([CH:42]=2)[C:20]([NH:22][C:23]2[CH:35]=[C:34]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:33]=[CH:32][C:24]=2[C:25]([OH:27])=[O:26])=[O:21])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2cccc(N)n2)ccc1O
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(-c2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.7 %

Procedure:
Trifluoroacetic acid (5 mL) was added to the obtained tert-butyl 2-(5-(6-aminopyridin-2-yl)-2-hydroxybenzamido)-4-phenylbenzoate (0.032 g), followed by stirring at room temperature for 12 hours. The solvent was evaporated under reduced pressure, and water and ethyl acetate were added thereto. After adjusting the pH to 6 with a saturated aqueous solution of sodium bicarbonate, the solid substance was collected by filtration. Carbon dioxide gas was introduced into a solution mixture of water (1 mL), methanol (0.5 mL), and dioxane (0.5 mL) containing the obtained solid substance, and the solid substance was collected by filtration to obtain 0.018 g of 2-(5-(6-aminopyridin-2-yl)-2-hydroxybenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[S:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:6][C:7]1[S:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(NCc2ccc(OC)cc2OC)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc([N+](=O)[O-])c(N)s1
Yield: 100 %

Procedure:
A solution of methyl 5-(2,4-dimethoxybenzylamino)-4-nitrothiophene-2-carboxylate 86 (40.3 mmol, 14.2 g) in CH2Cl2 (100 mL) and TFA (10 mL) was stirred overnight at rt. Reaction mixture was poured on ice and the precipitate was collected to give methyl 5-amino-4-nitrothiophene-2-carboxylate 87 (8.15 g, 100%). NMR (400 MHz, DMSO-d6) 3.77 (s, 3H), 7.75 (s, 1H), 9.06 (br s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[C:4]([F:15])[CH:3]=1.C[Al](C)C.N#N.[NH:22](/[C:26](/[CH3:32])=[CH:27]\[C:28](OC)=[O:29])[C:23]([CH3:25])=O>C(Cl)Cl>[F:15][C:4]1[CH:3]=[C:2]([N:1]2[C:28](=[O:29])[CH:27]=[C:26]([CH3:32])[N:22]=[C:23]2[CH3:25])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1
Reactant: Nc1ccc(N2CCC(O)CC2)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Agent: N#N
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCC(O)CC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
To a solution of 1-(4-amino-2-fluorophenyl)piperidin-4-ol (1.68 g, 8.00 mmol) in CH2Cl2 (20 mL) was added trimethylaluminium (32 mL, 64 mmol, 2 M in heptane) carefully under N2. The mixture was stirred at rt for 30 min, followed by the addition of a solution of methyl 3-acetaminocrotonate (1.40 g, 8.90 mol) in CH2Cl2 (5 mL). The reaction mixture was stirred at rt for another 5 h, then quenched with saturated NH4Cl aqueous solution (100 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by recrystallized from EtOAc to give the title compound as a yellow solid (1.25 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11]C)[C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C.Cl.N1C=CC=CC=1.Cl>>[OH:11][C:7]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([OH:19])=[O:3]
Reactant: CCOC(=O)c1cccc(OC)c1-c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)c1cccc(O)c1-c1ccccc1
Temperature: 180 °C
Yield: 56.4 %

Procedure:
3-methoxy-2-phenylbenzoic acid ethyl ester (0.53 g) and pyridine hydrochloride (6 g) were combined under nitrogen, then heated to 180° C. for 1 hour. The melt was poured into dilute aqueous hydrochloric acid and extracted with ethyl acetate. Purification by silica gel chromatography, eluting with hexane/acetone (2:1) with 0.5% acetic acid, gave 3-hydroxy-2-phenylbenzoic acid as a white solid (0.25 g, 58%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[N:4]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].O.O.P([O-])(O)(O)=[O:25].[Na+].Cl([O-])=O.[Na+].C(OCC)(=O)C>C(#N)C.O.OO>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:25])=[O:12])[CH:9]=2)[N:4]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=P([O-])(O)O
Reactant: CCOC(=O)c1c(Br)c2cc(C=O)ccc2n1CC(C)C
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1c(Br)c2cc(C(=O)O)ccc2n1CC(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
In 7 ml of acetonitrile is dissolved 0.65 g of ethyl 3-bromo-5-formyl-1-isobutyl-1H-indole-2-carboxylate. To the solution are successively added at ambient temperature 1.56 g of sodium dihydrogen-phosphate dihydrate dissolved in 22 ml of water and 0.64 ml of 30% aqueous hydrogen peroxide. Then, 0.68 g of sodium chlorite dissolved in 20 ml of water is dropwise added thereto at 5-10° C. The mixture thus obtained is stirred at 60° C. for one hour. Ethyl acetate and water are added to the reaction mixture, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Thus, 0.37 g of 3-bromo-2-(ethoxycarbonyl)-1-isobutyl-1H-indole-5-carboxylic acid is obtained as a yellow solid product.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=O)=[C:9]1[Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO.[C:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:24].C(N(CC)CC)C>O>[C:23]([C:25](=[CH:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]=1[Cl:19])[C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:24]
Reactant: CCOC(=O)CC#N
Reactant: O=Cc1c(Cl)n(Cc2ccccc2)c2ccccc12
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)=Cc1c(Cl)n(Cc2ccccc2)c2ccccc12
Reaction time: 96 h

Procedure:
To 5.83 g of 1-benzyl-2-chloroindole-3-carbaldehyde, dissolved in 200 ml of abs. EtOH, was added 6.1 g of ethyl 2-cyanoacetate and 6.6 g of triethylamine. After 4 days with stirring, the solution was added to water, and the precipitate collected by filtration and dried to give (1a). Yield 6.72 g of (1a), m.p. 130°-131° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([NH:9][CH3:10])[C:6]([N+:11]([O-])=O)=[CH:5][N:4]=1.[ClH:14]>CCO.[Pd]>[ClH:14].[CH3:1][NH:2][C:3]1[N:8]=[C:7]([NH:9][CH3:10])[C:6]([NH2:11])=[CH:5][N:4]=1
Reactant: CNc1ncc([N+](=O)[O-])c(NC)n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNc1ncc(N)c(NC)n1
Yield: 210.9 %

Procedure:
To a solution of N2,N4-dimethyl-5-nitropyrimidine-2,4-diamine (4 g, 21.8 mmol) in EtOH was added 10% Pd/C (0.5 g) and 1 N aq HCl solution (10 mL, 10 mmol). The mixture was hydrogenated (30 psi) for 2 h. The reaction mixture was filtered and the filtrate was concentrated to give N2,N4-dimethylpyrimidine-2,4,5-triamine HCl (4 g, 97% yield). 1H NMR (400 MHz, CD3OD): δ 9.00 (s, 1 H), 3.45 (s, 3 H), 3.35 (s, 3 H).