Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:33][CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH2:33][CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: BrCCCCc1ccccc1
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCCCCc2ccccc2)CCc2ccc(C#N)cc2)cc1

Procedure:
A solution of 200 mg (0.486 mmol) of methyl 4-[(3E)-2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-en-1-yl]benzoate in 5 ml of acetonitrile is mixed with 155 mg (0.73 mmol) of (4-bromobutyl)benzene and 100.76 mg (0.73 mmol) of potassium carbonate and then stirred under reflux for 12 h. After cooling, the potassium carbonate is filtered off and the filtrate is evaporated. 308 mg (0.41 mmol, 85% of theory, content 73%) of the title compound are obtained.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH3:3].[C:17]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18]([CH:23]=O)=[CH:19][CH:20]=[CH:21][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:17]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][N:14]1[CH2:13][CH2:12][N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:2][CH3:3])[CH2:16][CH2:15]1
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: CCOc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: CCOc1ccccc1N1CCN(Cc2ccccc2-c2ccccc2)CC1

Procedure:
112.3 mg of the target compound (0.30 mmol, 36.6%) was obtained using 1-(2-ethoxyphenyl)piperazine hydrochloride (400 mg, 1.65 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][C:18]=4[Cl:25])[CH2:13][C@H:12]3[CH3:26])=[N:10][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1>>[Cl:25][C:18]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]3[NH:8][C:7]4[C:2]([NH:1][C:37](=[O:38])[C:36]5[CH:40]=[CH:41][C:33]([C:32]([F:31])([F:42])[F:43])=[CH:34][CH:35]=5)=[CH:3][C:4]([C:27]([F:30])([F:29])[F:28])=[CH:5][C:6]=4[N:10]=3)[C@H:12]([CH3:26])[CH2:13]2)=[N:22][CH:21]=[C:20]([CH2:23][OH:24])[CH:19]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(N)c2[nH]1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(NC(=O)c3ccc(C(F)(F)F)cc3)c2[nH]1

Procedure:
{6-[(3R)-4-(7-Amino-5-trifluoromethyl-1H-benzoimidazol-2-yl)-3-methyl-piperazin-1-yl]-5-chloro-pyridin-3-yl}-methanol from step (b) above,(221 mg, 0.5 mmol) and 4-trifluoromethyl-benzoic acid (105 mg, 0.55 mmol, Aldrich) reacted under the conditions of Example 65 to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 613 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16].[OH-].[K+].[CH3:20]OS(OC)(=O)=O.[OH-].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: COS(=O)(=O)OC
Reactant: O=[N+]([O-])c1ccccc1Nc1ccccc1Cl
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CN(c1ccccc1Cl)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99.7 %

Procedure:
Compound 1 (1.25 g, 5 mmol) was stirred at room temperature in acetone (16 mL). To this, KOH (1.23 g, 22 mmol) was added. The mixture stirred at reflux for 1 h. To this, Me2SO4 (2.18 mL, 23 mmol) was added dropwise over 10 min. The mixture stirred at reflux for 1 h. The reaction was allowed to cool to room temperature. 10M NaOH was added and the reaction was stirred at room temperature. The mixture was quenched with 10 mL H2O and extracted 3 times with 10 mL dichloromethane. Organic layers were combined and dried over Na2SO4. Solvent was removed under vacuum and the mixture was placed in an 80° C. oil bath under vacuum to remove excess Me2SO4. No further purification was needed to give the product as a black oil (1.31 g, 100% yield). 1H NMR (300 MHz, CDCl3) δ 7.68 (1H, dd, J=8.1, 1.5 Hz), 7.54 (1H, ddd, J=8.7, 7.3, 1.7 Hz), 7.42 (1H, dd, J=7.8, 1.5 Hz), 7.19 (1H, dd, J=7.7, 1.7 Hz), 7.14-7.11 (2H, m), 7.06 (1H, dd, J=7.7, 1.9 Hz), 7.0 (1H, ddd, J=8.2, 7.3, 1.1 Hz); 13C (75 MHz, CDCl3) δ 145.0 (q), 143.0 (q), 133.2 (t), 131.3 (t), 130.9 (q), 128.7 (q), 127.9 (t), 126.7 (t), 126.2 (t), 125.9 (t), 120.8 (t), 120.6 (t), 41.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:51][NH:52][O:53][CH3:54]>ClCCl>[CH3:54][O:53][N:52]([CH3:51])[C:20]([C:17]1[CH:16]=[N:15][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)=[N:19][CH:18]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)cn2)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a suspension of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylic acid (13.8 g, 44.8 mmol), EDCI (12.8 g, 67.2 mmol) and HOBT (7.2 g, 53.7 mmol) in dichloromethane (200 mL) was added triethylamine (25 mL, 179.2 mmol), and the mixture was stirred at RT for 1 h, followed by the addition of N,O-dimethylhydroxylamine (5 g, 53.7 mmol). The reaction was stirred for another 3 h. LCMS showed the reaction was completed. The reaction mixture was washed with water (100 mL), and the organic layer was dried, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:1) to give the title compound (11.2 g, 67%) as a white solid. MS (ES+) C16H25N5O4 requires: 351. found: 296 [M−56+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[O:12][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC(=O)Nc1ccc(Br)c(O)c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(Br)c(OCCN2CCCCC2)c1
Yield: 60.7 %

Procedure:
N-(4-Bromo-3-hydroxyphenyl)acetamide (19.4 g), anhydrous potassium carbonate (25.6 g), 1-(2 chloroethyl)piperidine hydrochloride (15.78 g) and acetone (400 ml) were heated at reflux for 18 h, filtered and evaporated to dryness to give the product as a solid (17.48 g).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[S:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH:13]=[N:14][C:15]([C:16]([O:18]C(C)(C)C)=[O:17])=[C:4]2[CH2:3]1>FC(F)(F)C(O)=O>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[S:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH:13]=[N:14][C:15]([C:16]([OH:18])=[O:17])=[C:4]2[CH2:3]1
Reactant: CN1Cc2c(C(=O)OC(C)(C)C)ncn2-c2ccsc2C1=O
Solvent: O=C(O)C(F)(F)F
Product: CN1Cc2c(C(=O)O)ncn2-c2ccsc2C1=O
Reaction time: 1.5 h
Yield: 112 %

Procedure:
7.2 g of tert.butyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylate are dissolved in 100 ml of trifluoroacetic acid while cooling with ice and left to stand at room temperature for 90 minutes. The solution is then evaporated in vacuo and the residue is crystallized from ethyl acetate and diethyl ether. There are obtained 6.65 g of crude 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:29][C:30]([F:41])([F:40])[O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[C:32]([O:31][C:30]([F:29])([F:40])[F:41])[CH:33]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2cccc(OC(F)(F)F)c2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a cold (−78° C.) solution of ethyl N-tert-butoxycarbonylpiperidine-4-carboxylate (5.16 g, 20.05 mmol) in anhydrous tetrahydrofuran (60 mL), a solution of sodium bis(trimethylsilyl)amide (28 mL, 1M, 28 mmol) was added over a period of 30 min. The resultant mixture was stirred at −78° C. for 1 h, and 3-(trifluoromethoxy)benzyl bromide (5.90 g, 23.14 mmol) was added. The reacting mixture was allowed to warm to room temp. and stirred overnight. The product mixture was concentrated, and the residue was partitioned between water and ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 20% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: F[B-](F)(F)F.[F:6][C:7]1[C:12]2[CH2:13][O:14][CH2:15][O:16][C:11]=2[C:10]([O:17][CH3:18])=[CH:9][C:8]=1[CH:19]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=S)[NH2:42])=[CH:37][CH:36]=1)[C:20]1[NH:24][C:23](=[O:25])[N:22]([C:26]2[N:27]=[CH:28][S:29][C:30]=2[C:31]([NH2:33])=[O:32])[N:21]=1.C(O)(C)C.C[SiH](C)[NH:50][SiH](C)C>C(#N)C>[C:41]([C:38]1[CH:37]=[CH:36][C:35]([NH:34][CH:19]([C:8]2[CH:9]=[C:10]([O:17][CH3:18])[C:11]3[O:16][CH2:15][O:14][CH2:13][C:12]=3[C:7]=2[F:6])[C:20]2[NH:24][C:23](=[O:25])[N:22]([C:26]3[N:27]=[CH:28][S:29][C:30]=3[C:31]([NH2:33])=[O:32])[N:21]=2)=[CH:40][CH:39]=1)(=[NH:42])[NH2:50]
Reactant: C[SiH](C)N[SiH](C)C
Reactant: COc1cc(C(Nc2ccc(C(N)=S)cc2)c2nn(-c3ncsc3C(N)=O)c(=O)[nH]2)c(F)c2c1OCOC2
Agent: F[B-](F)(F)F
Solvent: CC(C)O
Solvent: CC#N
Product: COc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncsc3C(N)=O)c(=O)[nH]2)c(F)c2c1OCOC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After adding 33 mg of Me3O+BF4− to a suspension of 109 mg of 4-{3-[(5-fluoro-8-methoxy-4H-benzo[1,3]dioxin-6-yl)-(4-thiocarbamoylphenylamino)methyl]-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl}thiazole-5-carboxylic acid amide in 1 ml of acetonitrile, the mixture was stirred at room temperature for 30 minutes. Next, 4 ml of isopropanol and 0.055 ml of 1,1,3,3-tetramethyldisilazane were added to the reaction mixture, which was then stirred overnight at 60° C. The reaction mixture was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 4-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxy-4H-benzo[1,3]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl}thiazole-5-carboxylic acid amide (36 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH:11]=O)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Cl.Cl.[CH2:15]([C:19]1([N:25]([CH3:27])[CH3:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH2:16][CH2:17][CH3:18].C(B)#N.[Na].CO.C(Cl)(Cl)Cl>CO.C(O)(=O)C>[CH2:15]([C:19]1([N:25]([CH3:27])[CH3:26])[CH2:24][CH2:23][N:22]([CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:21][CH2:20]1)[CH2:16][CH2:17][CH3:18]
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Reactant: CCCCC1(N(C)C)CCNCC1
Agent: BC#N
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCCCC1(N(C)C)CCN(CCN(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 113 %

Procedure:
A solution of 4.73 g (1 eq) tert-butyl methyl(2-oxoethyl)carbamate in 20 ml methanol was added to a solution of 7 g (1 eq) 4-butyl-N,N-dimethylpiperidin-4-amine bis hydrochloride in 50 ml methanol at room temperature and the reaction mixture obtained was stirred for 50 min at room temperature. 3.43 g (2 eq) sodium cyanoboron hydride were added in portions to this reaction mixture and it was then stirred for 12 h at room temperature. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCl3). Once the conversion was complete, the reaction mixture was cooled to 0° C. and adjusted to a pH of ˜5 with acetic acid. 2 g tert-butyl formylmethyl methylcarbamate and 1.7 g sodium cyanoboron hydride were again added and the reaction mixture was stirred for a further 60 min at room temperature. The methanol was then distilled off, 100 ml saturated NaHCO3 solution were added and the mixture obtained was extracted with ethyl acetate (2×200 ml) and the combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, 10.5 g of crude product were obtained in the form of a pale yellow oil.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:26][CH2:27][CH2:28][S:29][CH3:30])(=[O:5])[CH2:2][CH2:3][CH3:4].[OH2:31].[O-]Cl.[Na+]>C(Cl)Cl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:26][CH2:27][CH2:28][S:29]([CH3:30])=[O:31])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O
Reactant: CCCC(=O)c1cnc2c(OCCCSC)cccc2c1Nc1ccccc1OC
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(OCCCS(C)=O)cccc2c1Nc1ccccc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 4.6 %

Procedure:
3-butyryl-4-(2-methoxyphenylamino)-8-(3-methylthiopropoxy)quinoline (0.30 g, 0.70 mmol) was dissolved in methylene chloride (10 ml), 5 ml water was added and then a solution of 1.5 ml (1.09 mmol) of 5% NaOCl in 10 ml methylene chloride was added. The mixture was stirred for 4 h at room temperature. The organic phase was separated and evaporated. Chromatography with methylene chloride: methanol 95:5 as the eluent gave 14 mg (4.6%) of the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C@@H:10]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11][OH:12])[C:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][C:19]=2[O:28][CH3:29])=[C:5]([CH3:30])[N:4]=1.[C:31]([O-])(O)=O.[Na+]>CO>[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C@@H:10]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11][OH:12])[C:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH3:31])=[O:26])=[CH:20][C:19]=2[O:28][CH3:29])=[C:5]([CH3:30])[N:4]=1
Reactant: CCCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1OC
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)OC)cc1OC
Temperature: 70 °C

Procedure:
Concentrated hydrochloric acid (1 mL) was added to a stirred solution of the product from step (i) (0.1 g) in MeOH (2 mL) and the mixture was heated at 70° C. for 2 h. The mixture was allowed to cool and then poured into saturated aqueous NaHCO3 solution (5 mL). The mixture was adjusted to pH ˜7 by adding NaHCO3 and the aqueous was extracted with EtOAc. The combined organic phase was dried, filtered and evaporated. The crude product was purified by RPHPLC to give the title compound, 0.014 g.
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9]C)=[CH:7][CH:6]=[CH:5][C:4]=1[Br:11].[Al+3].[Cl-].[Cl-].[Cl-].O>C1(C)C=CC=CC=1>[OH:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[Br:11]
Reactant: COc1cccc(Br)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: Oc1cccc(Br)c1O
Yield: 7.2 %

Procedure:
To 2,3-dimethoxy-bromobenzene (8.2 g, 0.45 moles) in 50 mL of toluene was added AlCl3 (22.1 g, 0.178 moles). The reaction mixture was refluxed for 3 hours, cooled, poured into 800 mL of water, and extracted with 800 mL of ether. The ether extracts were dried over magnesium sulfate, filter and the solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluted with methylene chloride and the fraction were combined and evaporated under reduced pressure to yield 2,3-dihydroxy-bromobenzene (6.1 g, 73% yield).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)[C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)=[O:7])=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.B(Br)(Br)Br.O.CCOC(C)=O>C(Cl)Cl>[F:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:7])=[C:4]([C:27]([F:28])([F:29])[F:30])[CH:3]=1
Reactant: COc1ccc(N(C(=O)c2ccc(F)cc2C(F)(F)F)c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(F)cc1C(F)(F)F)N(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Yield: 92.5 %

Procedure:
Compound 4-fluoro-N,N-bis(4-methoxyphenyl)-2-(trifluoromethyl)benzamide (2e) (1.00 g, 2.38 mmol) was dissolved in dry CH2Cl2 (30 mL) at room temperature. BBr3 (10 mL of 1.0 M CH2Cl2 solution, 10.0 mmol) was added dropwise with stirring via a syringe at room temperature. The reaction solution was allowed to stir overnight at room temperature. The mixture was cooled to 0° C. in an ice bath and hydrolyzed by adding water. EtOAc was added to partition the solution. The organic layer was separated; the aqueous layer was extracted with EtOAc twice. The organic layers were combined, washed with brine and dried over anhydrous MgSO4. The solvent was removed under vacuum. The residue was purified by flash column chromatography using silica-gel with CH3OH/CH2Cl2 (1/9 v/v) to afford the pure desired phenolic compound as a white solid, 0.86 g, 92.5% yield. 1H NMR (DMSO-d6, 300 MHz) δ 9.55 (s, 1H), 9.53 (s, 1H), 7.69-7.58 (m, 2H), 7.46-7.39 (m, 1H), 7.18 (d, 2H, J=8.7 Hz), 6.93 (d, 4H, J=8.7 Hz), 7.03 (d, 2H, J=8.4 Hz), 6.78 (d, 2H, J=8.7 Hz), 6.57 (d, 2H, J=8.7 Hz). MS m/z 392.1(M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([OH:29])=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[Cl:15].[CH3:30][C:31]([N:34](CCBr)C(=O)[O-])(C)C.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C(=O)C.CO.O1CCOCC1>[ClH:8].[NH2:34][CH2:31][CH2:30][O:29][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([NH:16][C:11]3[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([Cl:8])[CH:10]=3)=[N:18][CH:19]=[N:20]2)=[CH:25][C:24]=1[O:27][CH3:28]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Reactant: CC(C)(C)N(CCBr)C(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCCN
Temperature: 100 °C
Yield: 170.3 %

Procedure:
A solution of 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol trifluoroacetate (salt) (1.00 g, 2.15 mmol), 1,1-dimethylethyl(2-bromoethyl)carbamate (0.480 g, 2.15 mmol), and potassium carbonate (1.78 g, 12.9 mmol) in N,N-dimethylacetamide (2.2 mL) was heated to 100° C. for 2.5 h. An additional 0.23 g (1.03 mmol) of 1,1-dimethylethyl(2-bromoethyl)carbamate was added and the reaction mixture was further heated to 100° C. for a total of 7 h. The crude reaction mixture was partitioned between water and ethyl acetate and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography (SiO2, 3:2 hexanes:acetone) gave N-Boc product, which was then taken up in methanol and treated with 4M hydrogen chloride in dioxane while heating. Dilution with ethyl ether precipitated a pale yellow solid, which was collected by filtration and dried to give 0.761 g (94%) of 7-[(2-aminoethyl)oxy]-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine hydrochloride. 1H NMR (400 MHz, d6-DMSO): 12.01 (s, 1H), 8.94 (s, 1H), 8.67 (s, 1H), 8.35 (broad s, 2H), 8.21 (s, 1H), 7.90 (dd, 1H), 7.75 (d, 1H), 7.53 (s, 1H), 4.43 (t, 2H), 4.08 (s, 3H), 3.36 (m, 2H).
Reaction SMILES: ClC[C:3]([N:5]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]#[N:22])[CH:15]=1)[CH2:6][CH2:7][NH:8][C:9](=O)[O-])=[O:4].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][N:5]2[CH2:6][CH2:7][NH:8][CH2:9][C:3]2=[O:4])=[CH:15][C:16]=1[C:21]#[N:22]
Reactant: N#Cc1cc(CCN(CCNC(=O)[O-])C(=O)CCl)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(CCN2CCNCC2=O)ccc1F
Temperature: 25 °C

Procedure:
A solution of (2-{(chloroacetyl) [2-(3-cyano-4-fluorophenyl)ethyl]amino}ethyl)carbamate (0.12 g, 0.31 mmol) and TFA in 5 mL of DCM was stirred at room temperature for 1 h. The solvent was evaporated. The residue was dissolved in 40 mL of ethanol and K2CO3 (0.13 g, 0.93 mmol) was added. The resulting mixture was refluxed under N2 overnight, cooled to room temperature, and filtered. The filtrate was evaporated and the residue was purified with preprep-HPLC to give 2-Fluoro-5-[2-(2-oxopiperazin-1-yl)ethyl]benzonitrile. 1H-NMR (400 MHz, CDCl3) δ: 7.41˜7.44 (m, 2H), 7.07˜7.12 (m, 1H), 3.51˜3.53 (m, 4H), 3.18˜3.22 (m, 2H), 2.99˜3.04 (m, 2H), 2.75˜2.86 (m, 2H).
Reaction SMILES: C(O)(C)C.FC(F)(F)C([NH:9][CH:10]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[C:11]([CH3:14])([OH:13])[CH3:12])=O.[OH-].[K+]>C(O)C>[NH2:9][CH:10]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[C:11]([CH3:14])([OH:13])[CH3:12]
Reactant: CC(C)(O)C(NC(=O)C(F)(F)F)c1cccc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)O
Product: CC(C)(O)C(N)c1cccc2ccccc12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
180 mL of isopropanol and 180 mL of ethanol were added to 36.0 g of the 1-(trifluoroacetylamino)-1-(1-naphthyl)-2-methyl-2-propanol obtained, and 63 g of an aqueous solution of 22% by weight of potassium hydroxide was added dropwise thereto over 30 minutes at room temperature. The inner temperature of the mixture was raised to 50° C. and, at the same temperature, the mixture was stirred for 2 hours to effect reaction. The reaction mixture was concentrated, and 500 mL of chloroform and 180 mL of water were added to the resulting concentrated residue to carry out extraction treatment. The organic layer obtained was washed with 100 mL of water and the organic layer obtained was dried over dehydrated sodium sulfate and then concentrated. The resulting concentrated residue was dried at an inner temperature of 30° C. under reduced pressure to obtain 28.0 g of brown, viscous and oily 1-amino-1-(1-naphthyl)-2-methyl-2-propanol
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][CH2:29][O:30][C:23]=3[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][CH2:29][O:30][C:23]=4[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-nitro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-nitro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.