Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10](O)=[O:11])[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].C(Cl)(=O)C([Cl:23])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([Cl:23])=[O:11])[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCc1cc(C(=O)Cl)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Intermediate 28 (2 g; 7.80 mmol) in DCM (40 mL) was added oxalyl chloride (1.98 mL; 23.41 mmol) followed by DMF (60 μL) under vigorous stirring at RT. After 2 h, solvents were removed under vacuum to give 2-(methoxymethyl)-2′-methylbiphenyl-4-carbonyl chloride as a yellow oil that was dried under vacuum. To a solution of Intermediate 62 (150 mg; 0.49 mmol) in CH3CN (1.50 mL) and DI EA (0.33 mL) was added a solution of 2-(methoxymethyl)-2′-methylbiphenyl-4-carbonyl chloride (134.07 mg; 0.49 mmol) in CH3CN (1.50 mL). Reaction mixture was stirred at RT for 1 h 30 after which it was heated to 150° C., 30 min under microwave irradiations. Reaction mixture was concentrated under vacuum, dissolved in DCM and purified by column chromatography (EtOAc:cHex from 10:90 to 80:20) to give the title compound as a colorless oil. LC/MS (Method B): 528.5 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:23][CH:24](C)[CH2:25][CH2:26][OH:27]>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: CC(N)CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCCCO
Temperature: 0 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 7-bromo-4-chloro-3-nitroquinoline (10.00 g, 34.78 mmol) in dichloromethane (140 mL) was added triethylamine (10.2 mL, 73.1 mmol). The solution was cooled to 0° C., and 3-amino-1-butanol (2.80 mL, 36.5 mmol) was added. The solution was stirred overnight at ambient temperature and then filtered to collect a precipitate. The precipitate was washed with dichloromethane and water. The filtrate was washed with saturated aqueous sodium bicarbonate and then added to the precipitate. The mixture was concentrated under reduced pressure. Methanol and toluene were added several times and removed under reduced pressure. The resulting solid was dried under high vacuum to provide 11.34 g of 3-[(7-bromo-3-nitroquinolin-4-yl)amino]propan-1-ol as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]([Cl:18])[CH:10]=2)=[C:4]([Cl:19])[CH:3]=1.C1C(=O)N([Cl:27])C(=O)C1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]([Cl:18])[C:10]=2[Cl:27])=[C:4]([Cl:19])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)c1cnc(Cl)cc1Nc1ccc(Br)cc1Cl
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.9 %

Procedure:
To a thick suspension of 4-(4-bromo-2-chlorophenylamino)-6-chloronicotinic acid (13.25 g, 36.8 mmol) in 350 ml DMF was added NCS (4.94 g, 37 mmol) and the suspension was stirred at room temperature for 3 days. Since the reaction did not go to completion (NMR control), an additional 1.987 g NCS was added and the mixture was stirred for 18 h, upon which the reaction went to completion. The mixture was poured into a solution of 20 g sodium metabisulfite in H2O (1 l) and the thick suspension was rest for 30 min. It was filtered, and the precipitate was washed with water, then with hexanes and it was dried in oil pump vacuo at 50° C. for 24 hours to obtain the desired compound as a white solid (13.11 g, 90%). 1H-NMR (500 MHz, DMSO-D6): δ=9.90 (s, br, 1H), 8.63 (s, 1H), 7.74 (s, 1H), 7.43-7.42 (dd, 1H), 6.99-6.97 (dd, 1H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH3:14])=[CH:6][CH:5]=1.CNCC1C=CC2C(=CC=CC=2)C=1CCC.Cl.[O:32]=[C:33]1[NH:42][C:41]2[N:40]=[CH:39][C:38](/[CH:43]=[CH:44]/[C:45](O)=[O:46])=[CH:37][C:36]=2[CH2:35][CH2:34]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[CH3:1][N:2]([CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH3:14])=[CH:6][CH:5]=1)[C:45](=[O:46])/[CH:44]=[CH:43]/[C:38]1[CH:39]=[N:40][C:41]2[NH:42][C:33](=[O:32])[CH2:34][CH2:35][C:36]=2[CH:37]=1
Reactant: CNCc1ccc(C)c2ccccc12
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1ccc(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)c2ccccc12
Yield: 76 %

Procedure:
According to the procedure of Example 1 (a), except substituting methyl-(4-methyl-naphthalen-1ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.410 g, 76%) was prepared as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.67-10.62 (m, 1H), 8.38-8.29 (m, 1H), 8.15-7.94 (m, 3H), 7.60-3H), 7.36-7.02 (m, 3H), 5.30-5.06 (m, 2H), 3.04-2.73 (m, 5H), 2.65-2.45 (m, 5H); MS (ESI) m/e 386 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-])=O)=[CH:4][CH:3]=1>C(O)(=O)C.CO.[Zn]>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(Cl)nc1N
Reaction time: 18 h

Procedure:
Add zinc (4.0 g) to a solution of 6-chloro-3-nitropyridin-2-yl-amine (1.0 g, 5.76 mmol) in acetic acid (1.5 mL) and methanol (40 mL). Stir the resulting mixture is at room temperature for 18 hours, and filter through a pad of celite. Evaporate the filtrate to dryness under reduced pressure. Treat the resulting residue with 1N aqueous NaOH and extract with EtOAc. Wash the EtOAc extract with water and saturated aqueous NaCl. Separate the organic layer, dry over Na2SO4, filter and concentrate. Purify by flash column chromatography (50% EtOAc-hexane) to obtain 6-chloro-pyridine-2,3-diamine. C. 5-Chloro-1,3-dihydro-imidazole[4,5-b]pyridin-2-one
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].O.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][N:12]([C:24](=[O:27])[CH:25]=[CH2:26])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:6][CH:7]=1
Reactant: C=CC(=O)Cl
Reactant: Clc1ccc(C2CNc3ccccc3S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)N1CC(c2ccc(Cl)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a mixture of 2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (9.62 g), sodium hydrogen carbonate (6.0 g), methylene chloride (100 ml) and water (50 ml) is added dropwise with stirring a solution of acryloyl chloride (5.0 g) in methylene chloride (20 ml) under ice cooling over a period of about 30 minutes. The mixture is stirred at room temperature for 3 hours, and the organic layer is washed and dried. After the solvent is distilled off, the resulting crystals are washed with n-hexane to give 2-(4-chlorophenyl)-4-acryloyl-3,4-dihyro-2H-1,4-benzothiazine (10.76 g, yield 93%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:10]=[O:11])=[C:7]([OH:9])[CH:8]=1)[CH3:2].CS(O[CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][O:19]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:10]=[O:11])=[C:7]([O:9][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][O:19]2)[CH:8]=1)[CH3:2]
Reactant: CS(=O)(=O)OCC1CCOCO1
Reactant: CCc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(C=O)c(OCC2CCOCO2)c1
Temperature: 80 °C
Yield: 55.3 %

Procedure:
A stirred solution of 3.8 grams (0.026 mole) of 5-ethyl-2-formylphenol, 5.0 grams (0.026 mole) of 4-methylsulfonyloxymethyl-1,3-dioxane, and 7.0 grams (0.051 mole) of potassium carbonate in 150 mL of N,N-dimethylformamide was heated at 80° C. for about 18 hours. Analysis by thin layer chromatography (TLC) indicated the reaction was not complete. An additional 2.5 grams (0.013 mole) of 4-methylsulfonyloxymethyl-1,3-dioxane was added, and the reaction mixture was heated at 80° C. for an additional five hours. After this time the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with aqueous 10% lithium chloride, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, yielding 3.6 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH:12]([Si:15]([Cl:18])([Cl:17])[Cl:16])[CH2:13]Cl>>[C:1]1([CH:13]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][Si:15]([Cl:18])([Cl:17])[Cl:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCC(Cl)[Si](Cl)(Cl)Cl
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cl[Si](Cl)(Cl)CC(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 54.1 %

Procedure:
In the same apparatus and procedures as EXAMPLE 2 above, 25.2 ml (282 mmol) of benzene and 0.80 g (6.0 m) of aluminum chloride were alkylated with 6.60 g (28.2 mmol) of (1,2-dichloroethyl)trichlorosilane for 20 min at 70° C. The aluminum chloride catalyst was quenched with POCl3 and then stirred for another 1 hour to complete the deactivation. Freshly distilled hexane(50 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic soultion. After hexane and benzene were distilled, the reaction products were vacuum distilled to give 4.82 g of (2,2-diphenylethyl)trichlorosilane (bp; 117° C./0.5 torr, yield; 54%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[N:19]1([CH2:25][CH2:26][NH2:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:27][CH2:26][CH2:25][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:14]
Reactant: NCCN1CCCCC1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NCCN1CCCCC1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-(2-piperidin-1-ylethyl)isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 2.5 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 4.0 mmol of 2-piperidin-1-ylethylamine. LC/MS [5.40 min; 469 (M+1)]
Reaction SMILES: O.[C@@H]1([N:11]2[C:21]3[N:20]=[C:18]([NH2:19])[NH:17][C:15](=[O:16])[C:14]=3[N:13]=[CH:12]2)O[C@H](CO)[C@@H](O)[C@H]1O.[C:22]([C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br)#[N:23].Cl>CS(C)=O>[NH2:19][C:18]1[NH:17][C:15](=[O:16])[C:14]2[N:13]([CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[C:22]#[N:23])[CH:12]=[N:11][C:21]=2[N:20]=1
Reactant: N#Cc1ccccc1CBr
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccccc1Cn1cnc2nc(N)[nH]c(=O)c21

Procedure:
Prepared by reacting 20.00 g of guanosine-hydrate with 22.54 g of 2-cyano-benzylbromide in dimethylsulphoxide at 60° C. and subsequent treatment with 57 ml of conc. hydrochloric acid.
Reaction SMILES: O1CCCC1.C[Si]([C:10]#[C:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([C:31]2[CH:36]=[CH:35][C:34]([C:37]#[C:38][Si](C)(C)C)=[CH:33][CH:32]=2)[C:19]2[CH:24]=[CH:23][C:22]([C:25]#[C:26][Si](C)(C)C)=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)(C)C.[F-].[K+]>CO>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([N:18]([C:15]2[CH:14]=[CH:13][C:12]([C:11]#[CH:10])=[CH:17][CH:16]=2)[C:31]2[CH:36]=[CH:35][C:34]([C:37]#[CH:38])=[CH:33][CH:32]=2)=[CH:24][CH:23]=1)#[CH:26]
Reactant: C[Si](C)(C)C#Cc1ccc(N(c2ccc(C#C[Si](C)(C)C)cc2)c2ccc(C#C[Si](C)(C)C)cc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1ccc(N(c2ccc(C#C)cc2)c2ccc(C#C)cc2)cc1
Temperature: 50 °C
Yield: 74.9 %

Procedure:
To a mixture of 180 ml of tetrahydrofuran (THF) and 240 ml of methanol were added 13.84 g (0.026 mol) of tri(4-trimethylsilylethynylphenyl)amine and 4.53 g (0.078 mol) of potassium fluoride. The reaction mixture was heated at 50° C. for 5 h, cooled down to room temperature, and solvent was removed under the reduced pressure. The residue was extracted with ether and the ether layer was washed with distilled water. The washed ether layer was concentrated to give crude product. The crude product was purified by column chromatography on silica gel by eluting with hexane to give 6.182 g (75%) of tri(4-ethynylphenyl)amine of which NMR spectrum was shown in FIG. 9 and mp was 115° C.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].S(Cl)([Cl:19])=O>N1C=CC=CC=1>[CH2:1]([O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:19])=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCCOc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: C=CCCCCOc1ccc(C(=O)Cl)cc1

Procedure:
The 4-(5-hexenyloxy)benzoic acid 10 g (0.046 mol) was reflux with thionyl chloride (5.4 mL, 0.069 mol) and several drops of pyridine for 8 hours. The excess thionyl chloride was removed in vacuo leaving 4-(5-hexenyl-oxy)benzoyl chloride as a clear liquid at 25° C. This acid chloride was used without further purification.
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[F:23][C:24]1[C:25]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([I:43])=[CH:39][C:38]=2[F:44])=[C:26]([CH:30]=[C:31]([CH:34]=O)[C:32]=1[F:33])[C:27]([OH:29])=[O:28]>C(#N)C>[C:4]([O:3][C:1]([NH:2][CH2:34][C:31]1[C:32]([F:33])=[C:24]([F:23])[C:25]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([I:43])=[CH:39][C:38]=2[F:44])=[C:26]([CH:30]=1)[C:27]([OH:29])=[O:28])=[O:8])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(N)=O
Reactant: O=Cc1cc(C(=O)O)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCc1cc(C(=O)O)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 120 h

Procedure:
tert-Butyl carbamate (commercially available, 187 mg, 1.602 mmol), trifluoroacetic acid (123 μL, 1.602 mmol), and triethylsilane (255 μL, 1.602 mmol) were added sequentially to a suspension of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-benzoic acid (225 mg, 0.534 mmol) obtained in Step A of Example 5 in acetonitrile (anhydrous, 20 mL). The mixture was stirred at room temperature for 5 days. After completion of the reaction, the reaction mixture was evaporated under reduced pressure, and the resultant residue was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resultant crude product was purified by silica gel flash chromatography (Mega Bond Elut, Varian, 5% methanol/methylene chloride as an eluent) to give 5-(tert-butoxycarbonylamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid. [LC/MS m/z 523 (M+1)]. Then, trifluoroacetic acid (0.5 mL) was added to a solution of the resultant product in methylene chloride (20 mL), and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, the reaction mixture was evaporated under reduced pressure, and the resultant residue was recrystallized from a mixed solvent of diethyl ether:hexane (1:1) to give 5-aminomethyl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid trifluoroacetate (285 mg, 99% in 2 steps) as white crystals.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5]Cl)[CH3:3].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:18]=3[C:19]=2[C:20](=[O:28])[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[CH:11][CH:10]=1>>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:18]=3[C:19]=2[C:20](=[O:28])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])=[CH:23][CH:22]=2)=[CH:11][CH:10]=1
Reactant: COc1ccc(-c2oc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: CN(C)CCCl
Product: COc1ccc(-c2oc3cc(OC)ccc3c2C(=O)c2ccc(OCCN(C)C)cc2)cc1

Procedure:
The title compound was prepared essentially as described in Example 24, supra, except that 2-(N,N-dimethylamino)ethyl chloride was reacted with 2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)-6-methoxybenzofuran instead of the 2-(N,N-diisopropylamino)ethyl chloride employed in that example.
Reaction SMILES: [C:1]([BH3-])#N.[Na+].[CH:5]1([C:11]2[C:12]3[CH:13]=[CH:14][C:15]([C:44]([NH:46][S:47]([CH:50]4[CH2:52][CH2:51]4)(=[O:49])=[O:48])=[O:45])=[CH:16][C:17]=3[N:18]3[CH2:24][CH:23]([C:25]([N:27]4[CH2:34][C:33]56[CH2:35][NH:36][CH2:37][C:29]5([CH2:30][O:31][CH2:32]6)[CH2:28]4)=[O:26])[CH2:22][C:21]4[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=[CH:41][C:20]=4[C:19]=23)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C=O>CO>[CH:5]1([C:11]2[C:12]3[CH:13]=[CH:14][C:15]([C:44]([NH:46][S:47]([CH:50]4[CH2:52][CH2:51]4)(=[O:48])=[O:49])=[O:45])=[CH:16][C:17]=3[N:18]3[CH2:24][CH:23]([C:25]([N:27]4[CH2:34][C:33]56[CH2:35][N:36]([CH3:1])[CH2:37][C:29]5([CH2:30][O:31][CH2:32]6)[CH2:28]4)=[O:26])[CH2:22][C:21]4[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=[CH:41][C:20]=4[C:19]=23)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: [BH3-]C#N
Reactant: COc1ccc2c(c1)CC(C(=O)N1CC34CNCC3(COC4)C1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CC(C(=O)N1CC34COCC3(CN(C)C4)C1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
A 1M solution of sodium cyanoborohydride in THE (0.16 mL, 0.16 mmol) was added to a solution of 13-cyclohexyl-N-(cyclopropylsulfonyl)-3-methoxy-6-(3-oxa-7,10-diazatricyclo[3.3.3.01,5]undec-7-ylcarbonyl)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxamide (Example 24A) (11 mg, 0.016 mmol) and formaldehyde (37 wt. % in water) (0.01 mL, 0.1 mmol) in MeOH (1 mL) and the mixture was stirred at rt for 16 h. The reaction was concentrated, dissolved into MeOH, filtered and purified by preparative HPLC (H2O-MeOH with 0.1% TFA buffer) to yield 13-cyclohexyl-N-(cyclopropylsulfonyl)-3-methoxy-6-((10-methyl-3-oxa-7,10-diazatricyclo[3.3.3.01,5]undec-7-yl)carbonyl)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxamide (12 mg, 0.013 mmol, 82% yield) as a yellow solid. LCMS: m/e 687 (M+H)+. LCMS retention time: 2.47 min. (Column: Phenomenex-Luna 3.0×50 mm S10. Solvent A=90% Water: 10% Methanol: 0.1% TFA. Solvent B=10% Water: 90% Methanol: 0.1% TFA. Start % B=0. Final % B=100. Gradient Time=3 min. Flow Rate=4 mL/min).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH2:16][NH:17][O:18][CH3:19]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:17]([CH2:16][C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=2[F:13])[O:18][CH3:19])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CONCc1ccccc1F
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(Cc1ccccc1F)C(=O)C=C1OC(C)(C)OC1=O
Yield: 84 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(2-fluorobenzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as a white solid (84% yield): mp 109-111° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.72 (3H, s, OCH3), 4.92 (2H, s, NCH2), 6.40 (1H, s, CH), 7.03-7.12 (2H, m, aromatics), 7.24-7.30 (1H, m, aromatic), 7.4 (1H, m, aromatic). Anal. calcd. for C15H16FNO5: C, 58.25; H, 5.21; N, 4.52. Found: C, 58.47; H, 5.16; N, 4.66.
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: O
Solvent: OCCOCCO
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: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Br:32][C:33]1[CH:44]=[CH:43][CH:42]=[CH:41][C:34]=1[C:35](N(OC)C)=[O:36]>C1COCC1>[Br:32][C:33]1[CH:44]=[CH:43][CH:42]=[CH:41][C:34]=1[C:35]([C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:21])([F:22])[F:20])[CH:13]=2)(=[O:10])=[O:11])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1)=[O:36]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CON(C)C(=O)c1ccccc1Br
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60.2 %

Procedure:
To a solution of N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (250 mg, 0.50 mmol) in 4.0 ml of THF under nitrogen atmosphere at 0° C. was added drop-wise 0.6 mLl (1.2 mmol) of isopropylmagnesium chloride. The mixture was then stirred for 20 min at 0° C. followed by addition of a solution of 2-Bromo-N-methoxy-N-methyl-benzamide (244 mg, 1.0 mmol) in 1 mL of THF. The mixture was stirred at room temperature overnight, quenched with saturated ammonium chloride and extracted with ethyl acetate. After concentration of the solvent the residue was purified by flash chromatograph (20% ethyl acetate in hexane) to afford 180 mg of title compound as an off white solid. MS: (M+Na)/z=621.2, (M−32)/z=567.0.
Reaction SMILES: CO[CH:3](OC)[CH2:4][Br:5].Br.O.[Br:10][C:11]1[C:12]([NH2:18])=[N:13][CH:14]=[C:15](Br)[N:16]=1>CN(C=O)C>[Br:5][C:4]1[N:16]=[C:11]([Br:10])[C:12]2[N:18]([CH:15]=[CH:14][N:13]=2)[CH:3]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: COC(CBr)OC
Agent: Br
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cn2ccnc2c(Br)n1
Reaction time: 12 h
Yield: 81.3 %

Procedure:
A mixture of 5.0 g (30 mmol) of bromoacetaldehyde dimethyl acetal 1.0 ml of concentrated aqueous HBr solution and 4.0 ml of distilled water was brought to reflux for 1 h. After reaction, the mixture was alkalinized and extracted with ether. This organic phase was added to a solution of 1.0 g (4.0 mmol) of 3,5-dibromopyrazin-2-amine in 2 ml of DMF. The ether was removed and the mixture was stirred under a stream of nitrogen for 12 h. After reaction, the DMF was removed and the residue was dissolved in 5 ml of anhydrous ethanol and then it was brought to reflux for 1 h. The alcohol was then removed and the residue was dissolved in water, alkalinized with Na2CO3 and extracted with dichloromethane. After chromatography with alumina column (eluted with ether), 900 mg (yield: 82%) of 6,8-dibromoimidazo[1,2-a]pyrazine was obtained. ESI-MS (M+H+): 278.