Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH2:18][C@H:19]([CH2:24][OH:25])[CH2:20][CH:21]([CH3:23])[CH3:22].C([O-])([O-])=O.[K+].[K+]>O>[CH3:22][CH:21]([CH3:23])[CH2:20][C@H:19]([NH:18][C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2)[CH2:24][OH:25]
Reactant: CC(C)C[C@H](N)CO
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(N[C@H](CO)CC(C)C)c2nc(-c3ccccc3)cc-2[nH]1
Yield: 56.4 %

Procedure:
This compound was prepared according to the method described in Example 2 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (100 mg, 0.41 mmol), (S)-(+)-leucinol (Aldrich Chemical Company) (0.26 mL, 2.05 mmol) and K2CO3 (0.567 g, 4.1 mmol) in H2O (2.5 mL) to give 75 mg (56%) of the title compound as shiny off-white crystals. Mp: 267-269° C. (dec.). 1H NMR (DMSO-d6; 400 MHz): δ 0.91-0.95 (m, 6), 1.48-1.52 (m, 2), 1.66-1.70 (m, 1), 2.37 (s, 3), 3.50 (br s, 2), 4.39 (br s, 1), 4.90 (br s, 1), 6.65 (d, 1, J=8.4), 6.72 (s, 1), 7.36-7.52 (m, 3), 7.79 (d, 2, J=7.9), 11.35 (br s, 1). MS m/z: 325 (M+1), 323 (M−1). Anal. Calcd for C,19H24N4O: C, 70.34; H, 7.46; N, 17.27. Found: C, 70.14; H, 7.35; N, 17.13.
Reaction SMILES: [F:1][C:2]1[C:3]([C:21]2[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH:22]=2)=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17]C)=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1.O1CCCC1.Cl>O>[F:1][C:2]1[C:3]([C:21]2[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH:22]=2)=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([OH:17])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: COC(=O)c1cn2c3c(c(C4=CC(=O)CCC4)c(F)cc3c1=O)CCN2C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CN1CCc2c(C3=CC(=O)CCC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 25 °C
Reaction time: 96 h
Yield: 38.1 %

Procedure:
120 mg of the compound (171) obtained in Example 48 was added to a mixture solution of 3 ml of tetrahydrofuran, 1 ml of 6N hydrochloric acid and 1 ml of water, and the solution was stirred for four days at room temperature. The deposited solid matter was filtered off and washed with water and ethanol in this order to obtain 44 mg of the subject compound (172).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[C:14]([C:20]([OH:22])=O)[NH:15]3)=[CH:5][CH:4]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][C:27]([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][C@H:36]([OH:39])[C@@H:35]([CH3:40])[CH2:34]2)([OH:30])[CH2:26][CH2:25]1>>[OH:30][C:27]1([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][C@H:36]([OH:39])[C@@H:35]([CH3:40])[CH2:34]2)[CH2:28][CH2:29][CH:24]([NH:23][C:20]([C:14]2[NH:15][C:16]3[C:12]([CH:13]=2)=[C:11]([O:10][CH2:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:19]=[CH:18][CH:17]=3)=[O:22])[CH2:25][CH2:26]1
Reactant: COc1ccc(COc2cccc3[nH]c(C(=O)O)cc23)cn1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: COc1ccc(COc2cccc3[nH]c(C(=O)NC4CCC(O)(CCN5CC[C@H](O)[C@@H](C)C5)CC4)cc23)cn1

Procedure:
This compound is synthesized analogously to example 1 from 4-(6-methoxy-pyridin-3-ylmethoxy)-1H-indole-2-carboxylic acid 16e and amine 14.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2(O)[C:12]1[C:20]([OH:21])=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH:7]2[C:12]1[C:20]([OH:21])=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: O=C1Nc2c(Br)cccc2C1(O)c1cc2c(cc1O)OCO2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2c(Br)cccc2C1c1cc2c(cc1O)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
To a solution of 7-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (9.50 g, 27.3 mmol) in trifluoroacetic acid (24 mL) at 0° C. was added triethyl silane (6.12 g, 52.8 mmol). The mixture was stirred at ambient temperature for 3 h. The reaction was quenched by the addition of hexanes and diethyl ether mixture (2:1, 300 mL). The precipitate was filtered, washed with hexanes and ether mixture (100 mL). The solid was dried under reduced pressure to afford 7-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (8.40 g, 93%) as an off-white powder: 1H NMR (300 MHz, DMSO-d6) δ10.67 (s, 1H), 9.26 (s, 1H), 7.33-7.31 (m, 1H), 6.90-6.78 (m, 2H), 6.68 (s, 1H), 6.38 (s, 1H), 5.91 (d, J=1.0 Hz, 2H), 4.75 (s, 1H); MS (ES+) m/z 347.9 (M+1), 349.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([I:14])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[OH-].[Li+].Cl>CO.CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([I:14])[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(I)cc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: COC(=O)c1cc(I)cc(C(=O)O)c1
Reaction time: 16 h
Yield: 721.6 %

Procedure:
To a mixture of 5-Iodo-isophthalic acid dimethyl ester (9.00 g, 3.12 mmol) in methanol/acetone(3:1, 18 ml) was added 4 N aqueous lithium hydroxide (0.78 ml, 3.12 mmol). This mixture was stirred for 16 hours, neutralized with 1 N hydrochloric acid, extracted with ethyl acetate, dried over magnesium Sulfate and the solvent removed under reduced pressure. The crude was purified by silica gel chromatography to afford 5-iodo-isophthalic acid monomethyl ester (6.89 g, 80% yield) as a white solid. MS: m/z 306.1 (M+H+).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH:28]1([NH:34][C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([NH:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:39][CH:40]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(NC2CCCCC2)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(NC2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-cyclohexyl-p-phenylenediamine Rf value: 0.8 (silica gel, methylene chloride/methanol=10:1) C29H28N2O3
Reaction SMILES: O[CH:2]([C:8]1[N:15]2[C:11]([N:12]([CH3:22])[C:13]3[CH:19]=[C:18]([CH3:20])[C:17]([CH3:21])=[CH:16][C:14]=32)=[N:10][C:9]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4]>ClCCl>[CH3:7][N:5]([CH3:6])[C:3](=[O:4])[CH2:2][C:8]1[N:15]2[C:11]([N:12]([CH3:22])[C:13]3[CH:19]=[C:18]([CH3:20])[C:17]([CH3:21])=[CH:16][C:14]=32)=[N:10][C:9]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cc2c(cc1C)n1c(C(O)C(=O)N(C)C)c(-c3ccccc3)nc1n2C
Solvent: ClCCl
Product: Cc1cc2c(cc1C)n1c(CC(=O)N(C)C)c(-c3ccccc3)nc1n2C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
13.7 g (0.0363 mol) of α-hydroxy-N,N,6,7,9-pentamethyl-2-phenyl-9H-imidazo[1,2-a]benzimidazole-3-acetamide are dissolved in 500 ml of dichloromethane. A slight insoluble matter is removed by filtration. 75 ml of thionyl chloride are added to the filtrate and the mixture is stirred for 3 h, allowed to stand overnight, and again stirred for 6 h. The solvent is evaporated under reduced pressure, as well as the excess thionyl chloride by means of toluene. The residue is dissolved in 500 ml of dichloromethane and 23.5 g of Rongalite® are added to this solution. The mixture is stirred for 48 h. The insoluble matter is removed by filtration, and the organic phase is washed with water, with sodium bicarbonate solution and then with water. It is dried over sodium sulphate and concentrated under reduced pressure. 12.23 g of product are obtained which are washed with ether and then purified by silica gel column chromatography, eluting with a chloroform/acetone 95/5 mixture. 6.16 g of product are obtained, of which 1.32 g are removed for two successive treatments with carbon black in methanol. 1.04 g of product are finally isolated. Melting point: 202°-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:16])[CH:3]=1.[Si]([C:21]([F:24])([F:23])[F:22])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:13]=2[CH:14]([OH:15])[C:21]([F:24])([F:23])[F:22])=[C:4]([F:16])[CH:3]=1
Reactant: O=Cc1cnccc1-c1ccc(Cl)cc1F
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: O
Product: OC(c1cnccc1-c1ccc(Cl)cc1F)C(F)(F)F
Reaction time: 1.5 h
Yield: 75 %

Procedure:
A stirred solution of 4-(4-chloro-2-fluorophenyl)nicotinaldehyde (1.8 g, 7.64 mmol) (prepared as described in Example 5, Part B) and TMS-CF3 (0.521 mL, 3.52 mmol) in dichloromethane (20 mL) was stirred at 0° C. for 20 min. TBAF (1.0 M in THF) (0.4 mL, 1.528 mmol) was added dropwise slowly and the solution stirred for 90 min. Water was added and the solution extracted with dichloromethane (2×25 mL). The combined organic layers were washed with brine, dried over sodium sulphate, concentrated and purified by Prep. TLC using 25% ethyl acetate in hexane to give 1-(4-(4-chloro-2-fluorophenyl)pyridin-3-yl)-2,2,2-trifluoroethanol (1 g, 2.64 mmol, 35% yield) as a yellow oil. LCMS (ESI) m/e 306.0 [(M+H)+, calcd for C13H9ClF4NO 306.02]; LC/MS retention time (Method C): tR=2.05 min.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[S:8][C:6]=2[N:7]=1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.C1(O)C=CC=CC=1>>[N:23]1([C:2]2[N:3]=[C:4]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:5]3[CH:10]=[C:9]([CH3:11])[S:8][C:6]=3[N:7]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: Cc1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Solvent: Oc1ccccc1
Product: Cc1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3ccnc3)nc2s1
Yield: 184.9 %

Procedure:
A solution of 2-chloro-6-methyl-4-(3,4-methylene dioxybenzylamino)-thieno-[2,3-d]-pyrimidine (1.67 g), imidazole (1.02 g) and phenol (2 g) are heated 5 hours at 150° C. After cooling, the residue is dissolved in C2Cl2. The solvent is removed, and the usual workup yields 2-(imidazol-1-yl)-6-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine (3.38 g) Mp. 162° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:13]([CH3:14])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C@@H:8]([NH2:10])[CH3:9].CC(C)([O-])C.[K+].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>COCCOC>[CH3:14][N:13]1[C:4]2[C:5](=[N:6][C:7]([C@@H:8]([NH2:10])[CH3:9])=[C:2]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:3]=2)[CH:11]=[CH:12]1
Reactant: C1COCCN1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: C[C@H](N)c1nc2ccn(C)c2cc1N1CCOCC1

Procedure:
(S)-1-(6-Bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (1.6 g, 6.30 mmol) was stirred with potassium tert-butoxide (2.83 g, 25.2 mmol) and morpholine (6.58 g, 76 mmol) in DME (50 mL) at 88° C. for 4 hours. The mixture was then concentrated in vacuo. The residue was taken up in acetonitrile and water, and was lyophilized to give the title compound, which was used without further purification. ESI-MS m/z [M+H]+ calc'd for C14H20N4O, 261; found 261.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[C:3]#[C:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1>ClC1C=CC=CC=1Cl>[CH3:1][C:2]1([CH3:20])[CH:3]=[C:4]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=2)[C:19]2[CH:18]=[C:15]([C:16]#[N:17])[CH:14]=[CH:13][C:12]=2[O:11]1
Reactant: CC(C)(C#Cc1cccnc1)Oc1ccc(C#N)cc1
Solvent: Clc1ccccc1Cl
Product: CC1(C)C=C(c2cccnc2)c2cc(C#N)ccc2O1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
11.8 g of 4-[1,1-dimethyl-3-(3-pyridyl)-2-propynyloxy]benzonitrile were heated at reflux in 75 ml of 1,2-dichlorobenzene for 3.5 hours. The reaction mixture was allowed to cool to room temperature and was then evaporated. The residue was chromatographed on silica gel using ethyl acetate for the elution. After recrystallization from cyclohexane there were obtained 6.7 g of 2,2-dimethyl-4-(3-pyridyl)-2H-1-benzopyran-6-carbonitrile of melting point 98°-99° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:11](=O)([O:37]C1C=CC=CC=1)[O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]3[CH:26]=[C:27]([Cl:34])[C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][C:24]=3[N:23]=[C:22]2[CH2:35][CH3:36])=[CH:17][CH:16]=1>>[N:1]1[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11](=[O:37])[O:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[C:25]4[CH:26]=[C:27]([Cl:34])[C:28]([C:30]([F:31])([F:33])[F:32])=[CH:29][C:24]=4[N:23]=[C:22]3[CH2:35][CH3:36])=[CH:19][CH:20]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccncc1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)Oc2ccccc2)cc1
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 243 from 4-pyridinesulfonamide (Comrie, A. M.; et al., J. Chem. Soc., 1958, 3514) and 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 243).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26]>>[C:1]([NH:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[CH3:21])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CN(C)CCCN
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCN(C)C
Temperature: 180 °C

Procedure:
A 300 g (1.05 mol) portion of octadecanoic acid was put into a flask and melted by stirring at 180° C. in an atmosphere of nitrogen. To this was added dropwise 113.1 g (1.11 mol) of N,N-dimethyl-1,3-diaminopropane spending 3 hours, thereby effecting the reaction while evaporating the generated water. After completion of the dropwise addition, this was further stirred at 180° C. for 4 hours in an atmosphere of nitrogen. Thereafter, the unreacted material amine remained in the reaction mixture was evaporated under a reduced pressure to obtain the title compound as a light brown waxy solid (melting point 64-67° C.).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].C(N(CC)CC)C.Cl.[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([NH:26][C:27]3[CH:32]=[C:31]([O:33][C:34]([O:36][CH3:37])=[O:35])[C:30]([CH3:38])=[CH:29][C:28]=3[F:39])=[N:21][CH:22]=[N:23]2)=[CH:18][CH:17]=1>C(Cl)Cl>[F:39][C:28]1[CH:29]=[C:30]([CH3:38])[C:31]([O:33][C:34]([O:36][CH3:37])=[O:35])=[CH:32][C:27]=1[NH:26][C:20]1[C:19]2[C:24](=[CH:25][C:16]([NH:15][C:4](=[O:5])[CH2:3][O:2][CH3:1])=[CH:17][CH:18]=2)[N:23]=[CH:22][N:21]=1
Reactant: COCC(=O)Cl
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(N)ccc23)c(F)cc1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)Nc1ccc2c(Nc3cc(OC(=O)OC)c(C)cc3F)ncnc2c1
Reaction time: 1 h
Yield: 54.8 %

Procedure:
Methoxyacetyl chloride (119 mg, 1.1 mmol) followed by triethylamine (232 mg, 2.3 mmol) were added to a suspension of 7-amino-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazoline hydrochloride (415 mg, 1.1 mmol) in methylene chloride (10 ml) and the mixture stirred for 1 hour. The solvent was removed by evaporation and the residue partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The resulting solid was purified by column chromatography eluting with methylene chloride/acetonitrile 50/50 followed by methylene chloride/acetonitrile/methanol 50/45/5 to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-methoxyacetamidoquinazoline (250 mg, 60%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:5]([CH2:23][CH2:24][CH2:25][CH3:26])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=2)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:27]([C:29]1[C:30](=[C:37]([C:40]#[N:41])[C:38]#[N:39])[O:31][C:32]([CH3:36])([CH3:35])[C:33]=1[CH3:34])#[N:28].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:23]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[CH:34][C:33]3[C:32]([CH3:35])([CH3:36])[O:31][C:30](=[C:37]([C:38]#[N:39])[C:40]#[N:41])[C:29]=3[C:27]#[N:28])=[CH:16][CH:15]=2)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OC)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)s2)c(OC)c1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 74.8 %

Procedure:
In 10 ml of ethanol and 3 ml of tetrahydrofuran were dissolved 300 mg (0.81 mmol) of 5-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]thiophene-2-carboaldehyde and 177 mg (0.89 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene)propanedinitrile. To this mixture was added 63 mg of ammonium acetate, and the mixture was stirred at room temperature for 24 hours and further at 50° C. for 2.5 hours. The solvent was evaporated off and the residue was washed with ethanol to give 335 mg of a brown powdered crystal (yield: 75.1%; mp: 191-192° C.)
Reaction SMILES: [CH3:1][C@@:2]1([CH2:8][CH2:9][C:10]2[N:11]([CH3:16])[C:12](I)=[CH:13][CH:14]=2)[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[CH:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(COC)OC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:1][C@@:2]1([CH2:8][CH2:9][C:10]2([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH2:24][CH2:23][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[CH:31]=3)[CH2:14][CH:13]=[CH:12][N:11]2[CH3:16])[CH2:6][O:5][C:4](=[O:7])[NH:3]1
Reactant: CC1(C)OB(c2cccc(OCCC3CCCCC3)c2)OC1(C)C
Reactant: Cn1c(I)ccc1CC[C@]1(C)COC(=O)N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CN1C=CCC1(CC[C@]1(C)COC(=O)N1)c1cccc(OCCC2CCCCC2)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 10.8 %

Procedure:
(4R)-4-Methyl-4-[2-(5-iodo-1-methylpyrrol-2-yl)ethyl]-1,3-oxazolidin-2-one (0.3101 g, 0.92 mmol) obtained in Example (40a), 2-[3-(2-cyclohexylethyloxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.4646 g, 1.41 mmol), dichlorobis(triphenylphosphine)palladium(II) (63.1 mg, 0.09 mmol) and cesium carbonate (0.6006 g, 1.81 mmol) were suspended in a mixed solvent of dimethoxyethane (8 ml) and water (2 ml) and stirred at 80° C. for 6 hours. After cooling, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:2) as the eluent to afford the crude product. Furthermore, the crude product thus obtained was purified using a preparative reversed phase HPLC column [Inertsil ODS-3 (2.0 cm×25 cm), GL Science, mobile phase: acetonitrile/water (75:25), flow rate: 10 ml/min] to afford the title compound (41.1 mg, yield: 11%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24]([CH2:28][C:29](Cl)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:29](=[O:30])[CH2:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: CC(C)(C)CC(=O)Cl
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)CC(C)(C)C)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-3,3-dimethyl-butyramide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and tert-butylacetyl chloride (123 μl, 0.89 mmol). The title compound was obtained as brown powder (142 mg, 43%).
Reaction SMILES: [CH2:1](O)[CH2:2]O.C(O)COCCO.[C:12]1(=O)O[C:15](=O)[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>O>[CH2:20]1[CH:15]2[CH:2]3[CH:1]=[CH:12][CH:13]([CH:14]2[CH:18]=[CH:19]1)[CH2:21]3
Reactant: O=C1OC(=O)c2ccccc21
Reactant: OCCO
Solvent: OCCOCCO
Solvent: O
Product: C1=CC2C3C=CC(C3)C2C1
Temperature: 120 °C

Procedure:
The reaction product was added by 184 g (2.95 mol) of ethylene glycol (EG), 85 g (0.8 mol) of diethylene glycol (DEG) and 30 g (0.2 mol) of phthalic anhydride (PA), and then esterified by heating to 200° C. with removing water distillated from the reaction product. When the acid value of the esterified product reached 22, it was cooled to 120° C. to obtain a dicyclopentadiene-modified unsaturated polyester (second step).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:29][C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([F:25])[CH:27]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1cccc(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cccc(C=C(Br)Br)c1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred cooled (ice/salt, 0°) solution of carbon tetrabromide (48.82 g) in anhydrous CH2Cl2 (200 ml) was added portionwise over 3 minutes, triphenylphosphine (77.1 g), maintaining the temperature below 10°. The resulting orange suspension was stirred at 0° for 1 hour before adding to it, 3-fluorobenzaldehyde (7.8 ml). After the addition was complete, the suspension was stirred at 0° for 1 hour then quenched by the addition of water (75 ml). The organic phase was separated and washed with brine (75 ml), dried (Na2SO4) and evaporated to dryness. The residual gum was poured into cyclohexane (1L) and stirred for 30 minutes. The organic phase was decanted and the residue taken up into CH2Cl2 and poured into cyclohexane (1L). This procedure was repeated twice more and the combined organic phases concentrated to ˜100 ml and passed through silica gel. The filtrate was concentrated to give the title compound as a mobile yellow oil (24 g, 100%).
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]([OH:19])=O)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O>C1(C)C(C)=CC=CC=1>[CH2:1]([C:7]1[CH:8]=[C:9]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:17](=[O:19])[CH2:16][CH2:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc(CCC(=O)O)ccc1OC
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCCCc1cc2c(cc1OC)C(=O)CC2
Temperature: 80 °C

Procedure:
18.5 g (69.9 mmol) of 3-(3-hexyl-4-methoxyphenyl)propanoic acid dissolved in 100 ml of xylene are added to a mixture of 100 g of polyphosphoric acid and 100 ml of xylene heated to 80° C. The mixture is then heated at 135° C. for 1 hour 30 minutes. The mixture is poured into water and extracted with ethyl acetate. The organic phase is washed with sodium bicarbonate solution. The solvents of the organic phase are dried (Na2SO4) and evaporated off, and the residue is purified by flash chromatography (9 g; 52%).