Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:12]([OH:13])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[N:4]=1)[CH3:2].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:13][C:12]1[C:3]([CH2:1][CH3:2])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]=[CH:7][CH:6]=2
Reactant: CCc1nc2ccncc2cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: CCc1nc2ccncc2cc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 140 °C
Reaction time: 4 h
Yield: 6.3 %

Procedure:
2-Ethyl-[1,6]naphthyridin-3-ol (69 mg), 4-chloro-6,7-dimethoxyquinoline (265 mg), and 4-dimethylaminopyridine (145 mg) were suspended in o-dichlorobenzene (3 ml), and the mixture was stirred at 140° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (9 mg, yield 6%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:20]=[C:14]([O:13][CH3:12])[CH:15]=1)=[O:9]
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: COc1cc(NC(=O)c2cc(Br)ccc2O)cc(C(F)(F)F)c1
Yield: 58.8 %

Procedure:
Using 5-bromosalicylic acid and 3-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22](Cl)[CH3:23])[C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[C:19]=1[C:20]#[N:21].[CH3:25][C:26]1[C:34]2[C:29](=[N:30][CH:31]=[N:32][C:33]=2[NH2:35])[NH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[NH2:35][C:33]1[N:32]=[CH:31][N:30]=[C:29]2[N:28]([CH:22]([C:4]3[C:5]4[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=4[C:19]([C:20]#[N:21])=[C:2]([Cl:1])[CH:3]=3)[CH3:23])[N:27]=[C:26]([CH3:25])[C:34]=12
Reactant: CC(Cl)c1cc(Cl)c(C#N)c2c1OCCN(C(=O)OC(C)(C)C)C2
Reactant: Cc1n[nH]c2ncnc(N)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCN(C(=O)OC(C)(C)C)C3)c2ncnc(N)c12
Temperature: 90 °C

Procedure:
The crude tert-butyl 7-chloro-9-(1-chloroethyl)-6-cyano-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.090 g, 0.26 mmol) was dissolved in N,N-dimethylformamide (3 mL), and 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.076 g, 0.51 mmol) and cesium carbonate (0.17 g, 0.51 mmol) were added. The reaction was heated to 90° C. for 18 hrs and then allowed to cool to room temperature. The reaction was diluted with ethyl acetate and then decanted from the solids. The organic layer was washed with water, brine, dried over magnesium sulfate, and concentrated to give tert-butyl 9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate as an oil. LCMS calculated for C23H27ClN7O3 (M+H)+: m/z=484.1; found: 484.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][N:16]2[N:19]=[C:20]([NH2:33])[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=[C:15]2[N:14]=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:33][C:20]2[C:21]([C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:26][CH:27]=3)=[C:15]3[N:14]=[C:13]([CH3:12])[CH:18]=[CH:17][N:16]3[N:19]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1ccn2nc(N)c(-c3ccc(OC(F)(F)F)cc3)c2n1
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ccn2nc(NC(=O)Cc3ccc(F)cc3)c(-c3ccc(OC(F)(F)F)cc3)c2n1
Reaction time: 40 h

Procedure:
4-Fluorophenylacetic acid (32 mg, 0.21 mmol) was added to a stirring solution of the product from Example 168A (20 mg, 0.065 mmol) in DMF (0.5 mL) and pyridine (0.5 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (43 mg, 0.22 mmol) was added and stirring was continued at room temperature for 40 h. The reaction mixture was quenched by addition of MeOH (1 mL) and HOAc (0.1 mL) and stirred for 40 minutes. The solution was concentrated under vacuum, and the residue was purified by HPLC (30×100 mm XBridge column eluted with aqueous 0.1 M (NH4)2CO3-MeOH, 60:40-0:100 over 15 min) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.56 (s, 3H), 3.65 (s, 2H), 7.03 (d, J=7.1 Hz, 1H), 7.15 (t, J=8.8 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 7.29-7.40 (m, 2H), 7.76 (d, J=8.8 Hz, 2H), 8.94 (d, J=7.1 Hz, 1H), 10.42 (s, 1H); MS (DCI/NH3) m/z 445 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:21])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[NH:10][C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1.IC.[C:24]([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:21])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[N:10]([CH3:24])[C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Br)cccc1-n1c(=O)[nH]c2ccc(F)cc2c1=O
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(Br)cccc1-n1c(=O)c2cc(F)ccc2n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
A mixture of 3-(3-bromo-2-methylphenyl)-6-fluoroquinazoline-2,4(1H,3H)-dione (742 mg, 2.13 mmol), iodomethane (0.159 mL, 2.55 mmol) and Cs2CO3 (1.039 g, 3.19 mmol) in THF (20 mL) was stirred at room temperature overnight. The mixture was filtered and concentrated. The residue was dissolved in DCM and washed sequentially with saturated aqueous NaHCO3 and water, dried and concentrated to provide 3-(3-bromo-2-methylphenyl)-6-fluoro-1-methylquinazoline-2,4(1H,3H)-dione (742 mg, 96% yield). Mass spectrum m/z 363, 365 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[C:37](Cl)(=[O:42])[CH2:38][CH2:39][CH2:40][CH3:41]>ClCCl>[F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][N:34]([C:37](=[O:42])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=3)[C:7]([CH2:9][O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1
Reactant: CCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCC(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
80 mg of 5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.025 ml pentanoyl chloride (0.2 mmol). After 2 h stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 89 mg yellow solid (93%). MS (ISP) 585.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH:36][CH2:37][CH2:38][OH:39])(=[O:35])=[O:34]>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[C:28]([S:33]([NH:36][CH2:37][CH2:38][OH:39])(=[O:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1
Reactant: O=S(=O)(NCCO)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3ncc(N)nc3C#N)c(F)c2)OC1(C)C
Product: N#Cc1nc(N)cnc1-c1ccc(-c2ccccc2S(=O)(=O)NCCO)cc1F

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile and 2-bromo-N-(2-hydroxyethyl)benzenesulfonamide. MS (ESI): mass calcd. for C19H16FNO53S, 413.10; m/z found, 414.0 [M+H]+. 1H NMR (500 MHz, DMSO-δ6) δ 8.26 (s, 1H), 7.99 (dd, J=7.9, 1.4, 1H), 7.72-7.59 (m, 3H), 7.47-7.41 (m, 2H), 7.41-7.31 (m, 4H), 4.70-4.64 (t, J=5.5, 1H), 3.45-3.27 (m, 2H), 2.85-2.78 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[CH:7]=[C:8]([P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14])[C:9]([CH3:11])=O)([O-:3])=[O:2].[NH2:21]/[C:22](/[CH3:38])=[CH:23]\[C:24]([O:26][CH2:27][CH2:28][N:29]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:30])=[O:25]>C(O)(C)C>[CH3:14][O:13][P:12]([O:15][CH3:16])([C:8]1[CH:7]([C:6]2[CH:18]=[CH:19][CH:20]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:23]([C:24]([O:26][CH2:27][CH2:28][N:29]([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:30])=[O:25])=[C:22]([CH3:38])[NH:21][C:9]=1[CH3:11])=[O:17]
Reactant: C/C(N)=C/C(=O)OCCN(C)Cc1ccccc1
Reactant: COP(=O)(OC)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Solvent: CC(C)O
Product: COP(=O)(OC)C1=C(C)NC(C)=C(C(=O)OCCN(C)Cc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Yield: 21.1 %

Procedure:
To a mixture of 3.42 grams of dimethyl 1-(3-nitrobenzylidene)-acetonylphosphonate and 3.13 grams of 2-(N-benzyl-N-methylamino)-ethyl 3-aminocrotonate was added 50 ml of isopropanol and the mixture was heated to reflux for four hours with stirring. The reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate, to this was added 5% hydrochloric acid solution followed by separation, chloroform was added the lower layer followed by separation, the chloroform layer was washed with 5% calcium carbonate solution and then with water, and dried. Chloroform was evaporated in vacuo, the residue was purified by subjecting to silica gel column chromatography (100 grams of silica gel being used; eluting solution is ethyl acetate), and the resulting crystals were recrystallized from a mixture of ethyl acetate and ether to give 1.28 grams (yield 20%) of 2-(N-benzyl-N-methylamino)-ethyl 5-dimethoxyphosphinyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate, pale yellow crystals, melting point 101°-3° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:16])([F:15])[CH2:12][CH2:13]I.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[F:10][C:11]([F:16])([F:15])[CH2:12][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: FC(F)(F)CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCC(F)(F)F)cc1
Temperature: 85 °C
Reaction time: 24 h
Yield: 1.8 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (740 mg, 6.0 mmol) and (3,3,3-trifluoro)-1-iodopropane (2.67 g, 12.0 mmol) in 10 mL dimethylformamide was added cesium carbonate (4.0 g, 12.3 mmol) and the resulting slurry stirred vigorously at 85° C. for 24 h. After cooling to room temperature the reaction mixture was poured into 100 mL water. Organics were extracted with ether (3×75 mL), dried over magnesium sulfate, filtered and concentrated. The residue was subjected to chromatography on silica gel (30% ethyl acetate in hexanes) to give 4-(3,3,3-trifluoropropoxyl)benzaldehyde (24 mg, 2%). Used without further characterization.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](=[S:8])[NH:6][CH:7]=1.C(N(CC)CC)C.[CH2:16](Br)[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>CCO>[CH2:16]([S:8][C:5]1[N:6]=[CH:7][C:2]([Br:1])=[CH:3][N:4]=1)[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]
Reactant: S=c1ncc(Br)c[nH]1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(CSc1ncc(Br)cn1)c1ccccc1
Reaction time: 1 h
Yield: 71 %

Procedure:
5-Bromopyrimidine-2-thione (10.5 mmol) was added to a solution of triethylamine (11.6 mmol) in EtOH (130 ml) and the mixture stirred for 15 min before addition of phenacyl bromide (10.5 mmol). The reaction mixture was stirred for 1 h before the solvent was removed at reduced pressure, the residue extracted with chloroform and the chloroform solution chromatographed on alumina (100 g, activity I); yield 71%, m.p. 107°-109° C. (iPrOH). 1H NMR (CDCl3): δ4.60 (CH2), 7.5-8.0 (Ph), 8.46 (H-4, H-6).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([C:17]([O:30][CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([O:15]C)=[O:14])[N:4]=1.[OH-].[K+]>O1CCOCC1.O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][CH:12]([C:17]([O:30][CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:13]([OH:15])=[O:14])[N:6]=1
Reactant: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(OC)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(OC)nc(OC(C(=O)O)C(OC)(c2ccccc2)c2ccccc2)n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2.12 g (5 mmol) of methyl 2-(4,6-dimethoxy-pyrimidin-2-yl-oxy)-3-methoxy-3,3-diphenylpropionate were dissolved in 50 ml of dioxane, 10 ml of 1 N KOH solution were added, and the mixture was stirred at 100° C. for 3 h. The solution was diluted with 300 ml of water and extracted with ethyl acetate to remove unreacted ester. The aqueous phase was then adjusted to pH 1–2 with dilute hydrochloric acid and extracted with ethyl acetate. After drying over magnesium sulfate and removal of the solvent by distillation, the residue was mixed with an ether/hexane mixture, and the precipitate which formed was filtered off with suction. After drying, 1.85 g (90%) of a white powder remained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]SNC1C=CC=CC=1.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[C:18]#[CH:19]>C(OCC)(=O)C.CCCCCC>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH:19]=[C:18]1[C:17]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Nc1ccccc1SSNc1ccccc1
Reactant: C#CC(=O)OCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C1=CNc2ccccc2S1
Temperature: 150 °C
Yield: 22.6 %

Procedure:
2-(2-Aminophenyl)disulfanylaniline (1.0 g, 4.0 mmol) and ethyl prop-2-ynoate (790 mg, 816 μL, 8.05 mmol) were combined in a microwave tube and heated at 150° C. for 30 min. The reaction was concentrated in vacuo. Silcia gel chromatography (10-35% ethyl acetate/hexane) provided ethyl 4H-1,4-benzothiazine-2-carboxylate as an orange solid (200 mg, 23% yield). LC/MS m/z 222.0 [M+H]+. 1H NMR (400.0 MHz, CDCl3) δ 7.11 (d, J=6.6 Hz, 1H), 6.86-6.82 (m, 1H), 6.79-6.74 (m, 2H), 6.27 (d, J=7.9 Hz, 1H), 5.68 (br d, J=4.2 Hz, 1H), 4.19 (q, J=7.2 Hz, 2H), 1.28 (t, J=7.1 Hz, 3H)
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:18])[C:11](=[CH:16][CH:17]=1)[C:12](OC)=[O:13].Cl>CO>[Cl:7][C:8]1[CH:9]=[C:10]([OH:18])[C:11](=[CH:16][CH:17]=1)[C:12]([NH:2][OH:3])=[O:13]
Reactant: NO
Reactant: COC(=O)c1ccc(Cl)cc1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(NO)c1ccc(Cl)cc1O

Procedure:
Hydroxylamine hydrochloride (20.65 g, 0.297 mol) is added to a mixture of sodium methoxide (53 g, 0.99 mol) in methanol while maintaining the temperature below 10° C. A mixture of methyl 4-chlorosalicylate (46.2 g, 0.248 mol) in methanol is then added to the reaction mixture and the resultant mixture is stirred at room temperature for 10 days, acidified with concentrated hydrochloric acid (pH3) and filtered to give the title product as an off-white solid which is identified by NMR spectral analyses.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[H+].[B-](F)(F)(F)F.CCOCC.[Br:24]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([Br:24])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(=O)c1ccc(O)c(Br)c1
Temperature: -15 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
This procedure is modified from the work of Oberhauser (J. Org. Chem, 1997, 62, 4504). To a solution of 4-hydroxybenzoic acid ethyl ester (57.8 g, 348 mmol) in 480 mL of dry acetonitrile was added HBF4 Et2O (54% in Et2O, 32.9 mL). The solution was cooled to −15° C. with an ice/methanol bath. N-bromosuccinimide (67.2 g, 378 mmol) was added portionwise at a rate where the temperature would not rise above −10° C. After addition was complete, the cooling bath was removed and the reaction mixture was allowed to stir overnight at room temperature. Worked up by pouring the reaction mixture into aqueous sodium bisulfite (38%, 200 mL) and extracting four times with ethyl acetate. The organic layers were combined, washed with water, saturated brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo to give a white solid. Recrystallization from ethyl acetate/hexane gave 3-bromo-4-hydroxybenzoic acid ethyl ester (70.7 g, 83%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.39 (t, J=6.7 Hz, 3H, —CO2CH2CH3), 4.34 (t, J=6.7 Hz, 2H, —CO2CH2CH3), 7.02 (d, 1H, arom), 7.91 (dd, 1H, arom), 8.19 (d, 1H, arom).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C@@H:12]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:34]1C=CC2N(O)N=NC=2[CH:39]=1.CCN=C=NCCCN(C)C.Cl>C(O)C>[CH2:34]([O:14][C:13](=[O:15])[C@H:12]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:39]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
In ethanol (60 ml), 5-t-butoxycarbonylamino-(2R)-(9H-fluoren-9-ylmethoxycarbonylamino)-pentanoic acid (1.9914 g) was dissolved. The solution was added with HOBt (770.2 mg) and WSCI hydrochloride (1.0927 g) and the whole was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with 1 mol/l hydrochloric acid, a 1 mol/l sodium hydroxide aqueous solution, and a saturated saline solution, followed by drying with magnesium sulfate. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (1.9846 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)O1.O1CCOCC1>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>[C:28]([O:27][C:25]([N:22]1[CH2:21][CH:20]=[C:19]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:24][CH2:23]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 48.7 %

Procedure:
In a 500 mL round-bottomed flask, 5-bromo-2-nitropyridine (6.56 g, 32.3 mmol, Eq: 1) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (10 g, 32.3 mmol, Eq: 1.00) were combined with dioxane (160 ml) to give a light yellow solution. Cs2 CO3 (21.1 g, 64.7 mmol, Eq: 2) and water (6 ml) were added. The reaction mixture was degassed with argon before bis(triphenylphosphine)palladium(II) dichloride (2.27 g, 3.23 mmol, Eq: 0.1) was added. The reaction mixture was heated to 80° C. and stirred for 15 h. The reaction mixture was poured into 500 mL H2O and extracted with EtOAc (3×200 mL). The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 220 g, 10% to 40% EtOAc in hexanes) to afford a pink solid. The resulting solid was triturated with ether to afford the desired product as a solid (4.8 g). The filtrate from the trituration and mixed fractions from the first chromatography were combined and purified by flash chromatography (silica gel, 220 g, 20% to 40% EtOAc in hexanes) affording additional product (2.2 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.52 (s, 9 H) 2.59 (d, J=1.52 Hz, 2 H) 3.72 (t, J=5.56 Hz, 2 H) 4.19 (d, J=3.03 Hz, 2 H) 6.35 (br. s., 1 H) 7.97 (dd, J=8.46, 2.40 Hz, 1 H) 8.27 (d, J=8.34 Hz, 1 H) 8.67 (d, J=2.27 Hz, 1 H).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)=[CH2:2].[CH3:10][SiH:11]([CH3:13])[Cl:12]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH:7]12[CH2:9][CH:4]([CH:3]([CH2:1][CH2:2][Si:11]([CH3:13])([CH3:10])[Cl:12])[CH2:8]1)[CH:5]=[CH:6]2
Reactant: C=CC1CC2C=CC1C2
Reactant: C[SiH](C)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: C[Si](C)(Cl)CCC1CC2C=CC1C2
Temperature: 70 °C

Procedure:
To a flask equipped with a dropping funnel were charged 150 parts of 2-vinyl-5-norbornene and 0.1 part of a solution of chloroplatinic acid in isopropanol (containing 2% as a platinum atom) were charged. While heating to 70° C., 136 parts of dimethylchlorosilane were added dropwise to the mixture and reacted at 70° C. for an hour. Distillation was performed under reduced pressure to give 195 parts of 2-(5-norbornenyl)ethyldimethylchlorosilane.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH3:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)Sc1sc3c(c1C(=O)N2)CCCC3
Reactant: CN1CCNCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1ccc2c(c1)Sc1sc3c(c1C(N1CCN(C)CC1)=N2)CCCC3

Procedure:
In the same manner as in Example 80 and using 1,2,3,4-tetrahydro-8-methyl-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 1,2,3,4-tetrahydro-8-methyl-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzothiazepine is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH2:17][F:18])[N:3]=1.NC1N=C(N)C(C2C=C([Cl:33])C=C(Cl)C=2Cl)=C(CO)N=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([Cl:33])[CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH2:17][F:18])[N:3]=1
Reactant: Nc1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)c(CO)n1
Reactant: Nc1nc(N)c(-c2cccc(Cl)c2Cl)c(CF)n1
Product: Nc1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)c(CF)n1

Procedure:
This compound was prepared in an analogous manner to the compound of Example 18 from 2,4-diamino-5-(2,3,5-trichlorophenyl )-6-hydroxymethylpyrimidine, mp. 215°-217° C.