Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:10][O:9][N:8]=[C:7]([N:11]([CH3:13])[NH2:12])[C:6]=2[CH:14]=1.[CH:15](=O)[CH3:16]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:10][O:9][N:8]=[C:7]([N:11]([CH3:13])[N:12]=[CH:15][CH3:16])[C:6]=2[CH:14]=1
Reactant: CN(N)C1=NOCc2ccc(Cl)cc21
Reactant: CC=O
Solvent: c1ccccc1
Product: CC=NN(C)C1=NOCc2ccc(Cl)cc21
Reaction time: 2 h

Procedure:
To a solution of 3 g. of 6-chloro-4-(1-methylhydrazino)-1H-2,3-benzoxazine in 180 ml. of anhydrous benzene 1 g. of acetaldehyde in 30 ml. of anhydrous benzene is added. The mixture is allowed to stand for 2 hours, then the solvent is distilled off in vacuo and the residue recrystallized from isopropyl ether. Yield 2.4 g. (71.2%) of 6-chloro-4-(2-ethylidene-1-methylhydrazino)-1H-2,3-benzoxazine; m.p. 111°-112° C.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]([CH2:4][C:5]([O:7]C)=O)=[CH2:3].[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17]>CO>[CH3:11][O:10][C:1]([CH:2]1[CH2:4][C:5](=[O:7])[N:17]([CH2:16][C:15]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:14]=2[O:13][CH3:12])[CH2:3]1)=[O:9]
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CO
Product: COC(=O)C1CC(=O)N(Cc2ccc(OC)cc2OC)C1

Procedure:
A solution of dimethyl itaconate (4.08 g, 25.8 mmol) in MeOH (3.2 mL) was added to a solution of 2,4-dimethoxybenzylamine (4.32 g, 25.8 mmol) in MeOH (9.6 mL) via cannula at room temperature. After 18 h at room temperature the reaction was concentrated in vacuo to afford crude 1-(2,4-dimethoxybenzyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3/[C:12](=[CH:19]\[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])/[C:11]([F:26])([F:25])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:29]1([C:35]2[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=2[C:37](O)=[O:38])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OC(=O)C)C.[ClH:50]>C(Cl)(Cl)Cl>[ClH:50].[F:25][C:11]1([F:26])[CH2:10][CH2:9][N:8]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:28][CH:27]=2)=[O:7])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2/[C:12]/1=[CH:19]\[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23]
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: CN(C)CC/C=C1\c2ccccc2N(C(=O)c2ccc(N)cc2)CCC1(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CN(C)CC/C=C1\c2ccccc2N(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)CCC1(F)F

Procedure:
Using 690 mg of (E)-1-(4-aminobenzoyl)-5-(3-dimethylaminopropylidene)-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepine and 430 mg of o-phenylbenzoic acid, 520 mg of free base was synthesized in the same manner as described in Reference Example 8. Next, 340 mg of the free base was dissolved in chloroform, the resulting solution was mixed with 4N hydrochloric acid ethyl acetate solution, and the solvent was evaporated. Then, the resulting residue was mixed with hexane to obtain 111 mg of (E)-4'-[[4,4-difluoro-5-(3-dimethylaminopropylidene)-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl]-2-phenylbenzanilide hydrochloride in the form of colorless amorphous solid.
Reaction SMILES: C(O[C:6]([N:8](C)[C@@H:9]1[CH2:15][CH2:14][CH2:13][C@@H:12]([CH3:16])[N:11]2[C:17](=[O:30])[C:18]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=[C:10]12)=O)(C)(C)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH3:16][C@H:12]1[N:11]2[C:17](=[O:30])[C:18]([O:25][S:26]([CH3:29])(=[O:27])=[O:28])=[C:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=[C:10]2[C@H:9]([NH:8][CH3:6])[CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)c1nc2n(c(=O)c1OS(C)(=O)=O)[C@H](C)CCC[C@H]2N(C)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN[C@@H]1CCC[C@@H](C)n2c1nc(C(=O)OC)c(OS(C)(=O)=O)c2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the methyl trans-rac-10-[(tert-butoxycarbonyl)(methyl)amino]-6-methyl-3-[(methylsulfonyl)oxy]-4-oxo-4,6,7,8,9,10-hexahydropyrimido [1,2-a]azepine-2-carboxylate (3.5 g) in dioxane (25 mL) at 0° C. was added 4M HCl in dioxane (25 mL). After stirring for 30 minutes the reaction mixture was allowed to warm to room temperature and stirred there for 4 hours. The solvent was stripped and the residue dissolved in water and treated with excess sodium carbonate. The resulting mixture was extracted with methylene chloride, then chloroform and dried over sodium sulfate. Filtration and concentration gave the amine as dark brown viscous oil.
Reaction SMILES: [NH3:1].F[CH:3]1[N:8]=[C:7]([F:9])[N:6]=[C:5]([Cl:10])[N:4]1[O:11][CH:12]([F:14])[F:13]>O1CCCC1>[NH2:1][CH:3]1[N:8]=[C:7]([F:9])[N:6]=[C:5]([Cl:10])[N:4]1[O:11][CH:12]([F:14])[F:13]
Reactant: FC1=NC(F)N(OC(F)F)C(Cl)=N1
Reactant: N
Solvent: C1CCOC1
Product: NC1N=C(F)N=C(Cl)N1OC(F)F
Temperature: 22 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
7.8 g (0.46 mol) of ammonia were passed into a mixture of 50.0 g (0.23 mol) of 2,4-difluoro-6-chlorodifluoromethoxy-1,3,5-triazine in 150 ml of tetrahydrofuran in the course of 45 minutes at -70° C., while stirring. Stirring was continued for 2 hours at -70° C. and overnight while warming up to 22° C. The reaction mixture was evaporated down under reduced pressure and the residue was washed with water and dried. The reaction product was then washed onto a silica gel column with methylene chloride and eluted with the same solvent. 21.5 g (43.6% of theory) of 2-amino-4-fluoro-6-chlorodifluoromethoxy-1,3,5-triazine of melting point 131°-133° C. were obtained in fractions 1 to 8.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[NH:6]2.[CH3:29][CH2:30]N(P1(N(C)CCCN1C)=NC(C)(C)C)CC.C(I)C>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[CH2:29][CH3:30]
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)[nH]c12
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Solvent: CCI
Product: CCn1c(=O)[nH]c2c(N)nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 31.2 %

Procedure:
200 mg (0.531 mmol) of the compound from example 33 and 146 mg (0.531 mmol) of BEMP were initially charged in 10 ml of dimethylformamide, and a solution of 82 mg (0.531 mmol) of ethyl iodide in 2 ml of dimethylformamide was added dropwise at 0° C. within 10 min The mixture was stirred at 0° C. for 20 min. Subsequently, the reaction solution was concentrated under reduced pressure and the residue was purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 10:90→90:10). 67 mg of the title compound were obtained (31% of theory).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].I[CH3:14]>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:14])[CH:3]=1
Reactant: Brc1c[nH]c2ncccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(Br)c2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Step 1—A solution of commercially available 3-bromo-1H-pyrrolo[2,3-b]pyridine (0.53 g, 2.69 mmol) in 4 mL of DMF was added at 0° C. to a suspension of NaH 60% dispersion in oil (0.14 g, 3.497 mmol) in 4 mL of DMF. The resulting mixture was stirred at RT for 30 minutes before being cooled to 0° C. and adding iodomethane (0.67 mL, 10.759 mmol). The reaction mixture was allowed to reach RT overnight before being quenched by addition of H2O and extracted three times with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. The residue was purified by SiO2 chromatography (hexanes/EtOAc 0-20% EtOAc) to give 0.386 g of 3-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine (68% yield).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1([C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Oc1ccccc1
Product: Oc1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 100 °C
Yield: 75.8 %

Procedure:
75.2 g (0.8 mol) of phenol and 52 g (0.2 mol) of triphenylcarbinol were boiled by heating on an oil bath and the resulting water was gradually removed together with excess phenol. When generation of water stopped, the reaction mixture was cooled to about 100° C. by allowing it to stand. Thereafter 2 g of zinc chloride was added and the mixture was heated to 130° to 140° C. whereupon white crystals rapidly precipitated. After heating for 30 minutes, the mixture was allowed to cool and 100 ml of methanol was added thereto, and the crystals were separated by filtration to obtain 51 g of p-triphenylmethylphenol having a melting point of 293° to 295° C.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:21][CH:20]=[C:19]([CH3:22])[N:7]2[C:8](=[O:18])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])[CH3:3].Br[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2.C(N(CC)C(C)C)(C)C>C(O)C>[F:17][C:11]1[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=1[C:9]1[C:8](=[O:18])[N:7]2[C:19]([CH3:22])=[CH:20][S:21][C:6]2=[N:5][C:4]=1[CH:2]([NH:1][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2)[CH3:3]
Reactant: Brc1ncnc2[nH]cnc12
Reactant: Cc1csc2nc(C(C)N)c(-c3cc(F)ccc3F)c(=O)n12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc2nc(C(C)Nc3ncnc4[nH]cnc34)c(-c3cc(F)ccc3F)c(=O)n12
Temperature: 110 °C

Procedure:
A mixture of 7-(1-aminoethyl)-6-(2,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.045 g, 0.14 mmol), 6-bromo-9H-purine (0.042 g, 0.21 mmol), and N,N-diisopropylethylamine (0.049 mL, 0.28 mmol) in ethanol (0.3 mL) was heated at 110° C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.05% TFA), to give the desired product as a mixture of two diastereomers (TFA salts). LCMS calculated for C20H16F2N7OS (M+H)+: m/z=440.1. Found: 440.1. 1H NMR (DMSO-d6, 400 MHz) δ 8.64 (1H, br s), 8.38 (1H, s), 8.36 (1H, s), 7.34˜7.19 (3H, m), 7.08 (1H, m), 5.06 (1H, m), 2.60 (3H, s), 1.46 (1.5H, d, J=6.8 Hz), 1.33 (1.5H, d, J=6.8 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) δ −117.8, −119.4, −119.8, −119.9 ppm.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].[CH2:17](O)[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][CH3:18])[CH:14]=2)[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CC(=O)NCCC1CCc2ccc(O)cc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1ccc2c(c1)C(CCNC(C)=O)CC2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1-[2-(acetylamino)ethyl]-6-hydroxyindan (1.00 g, 4.56 mmol), ethanol (0.32 ml, 5.47 mmol) and triphenylphosphine (1.32 g, 5.02 mmol) in THF (20 ml) was added dropwise, under ice-cooling, diethyl azodicarboxylate (0.87 g, 5.02 mmol). The mixture was stirred for 15 hours at room temperature. The reaction mixture was concentrated under reduced pressure. To the concentrate was added water, and the mixture was subjected to extraction with ethyl acetate. The extract solution was washed with brine, which was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography (ethyl acetate→ethyl acetate/methanol, 95:5) to give 1-[2-(acetylamino)ethyl]-6-ethoxyindan. To this compound was added hydrazine hydrate (20 ml). The mixture was heated under reflux for 15 hours under argon atmosphere. The reaction mixture was cooled, to which was added water. The mixture was subjected to extraction with ethyl acetate. The extract solution was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 0.34 g (yield 36%) of the above-titled compound as an oily product.
Reaction SMILES: [CH:1]1[CH:15]=[C:14]2[C:4]([CH:5](O)[C:6]3[C:11]([CH:12]=[CH:13]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:3][CH:2]=1.C(O)(=O)[CH2:18][C:19]([OH:21])=[O:20]>>[CH:15]1[C:14]2[CH:13]=[CH:12][C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[CH:5]([CH2:18][C:19]([OH:21])=[O:20])[C:4]=2[CH:3]=[CH:2][CH:1]=1
Reactant: O=C(O)CC(=O)O
Reactant: OC1c2ccccc2C=Cc2ccccc21
Product: O=C(O)CC1c2ccccc2C=Cc2ccccc21
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
A round bottom flask, equipped with a distillation apparatus, is charged with dibenzosuberenol (10.0 g, 48.01 mmol) and malonic acid (25.0 g, 240.08 mmol). The mixture is heated in a 160° C. oil bath. The solids melt. Gas bubbles form and water and acetic acid are distilled through the condenser. After 1.5 hours, the mixture is cooled to room temperature and dissolved in ethyl acetate. The organic solution is washed with brine and dried over MgSO4. The solvent is removed in vacuo to give an off white solid, which is recrystallized from hexane-ethyl acetate-(AcOEt)/1:1 to yield the title compound as white crystals, 10.2 g; mp167 °-168° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([CH3:17])=[CH:4][C:3]=1[OH:18].Br[CH2:20][CH2:21][CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:28][C:23]([CH3:29])([CH2:22][CH2:21][CH2:20][O:18][C:3]1[CH:4]=[C:5]([CH3:17])[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([CH3:8])[C:2]=1[CH3:1])[C:24]([O:26][CH3:27])=[O:25]
Reactant: Cc1cc(O)c(C)c(C)c1OCc1ccccc1
Reactant: COC(=O)C(C)(C)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)(C)CCCOc1cc(C)c(OCc2ccccc2)c(C)c1C
Yield: 1007.8 %

Procedure:
A 2-1, 3 neck, round bottom flask equipped with an overhead stirrer is charged with 29.4 g (12mmol) of 2,3,5-trimethyl-4-(phenylmethoxy)phenol (Example C), 29.8 g (1.1×12.1 mmol) of 5-bromo-2,2-dimethylvaleric acid, methyl ester (U.S. Pat. No. 4,665,226), 20.1 g (1.2×121 mmol) of anhydrous potassium carbonate and 300 mL of acetonitrile. The heterogeneous mixture is stirred at reflux for 96 hours. The solid is removed and the reaction flask and filtered solids are washed with fresh acetonitrile, the solvent removed and the residue taken up in 500 mL of hexane. On standing the product crystallizes partially and a seed crystal is retained. The solution is diluted to 700 mL with hexane and warmed to dissolve the product. After washing with 2×75 mL of 2N potassium hydroxide solution, and brine the solution is dried and evaporated leaving 46.5 g of a pale yellow solid. This crystallizes from 500 mL of hexane in the presence of charcoal and the solution is cooled to 0° C. and seeded to afford 41.4 g of the title compound as a colorless solid; mp 67°-68° C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C@@H:10]2[CH2:14][NH:13][C:12](=[O:15])[CH2:11]2)[C:5]([Br:9])=[CH:6][C:7]=1[Cl:8].C(OCC)(=O)C.O.N([O-])=O.[Na+]>S(=O)(=O)(O)O>[Br:9][C:5]1[CH:6]=[C:7]([Cl:8])[CH:2]=[CH:3][C:4]=1[C@@H:10]1[CH2:14][NH:13][C:12](=[O:15])[CH2:11]1
Reactant: Nc1cc([C@@H]2CNC(=O)C2)c(Br)cc1Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1C[C@H](c2ccc(Cl)cc2Br)CN1
Temperature: 55 °C
Yield: 55 %

Procedure:
(4R)-4-(3-Amino-6-bromo-4-chlorophenyl)pyrrolidin-2-one was dissolved in 32 mL of sulfuric acid aqueous solution (1M) and the heated at 55° C. for 20 min. The reaction mixture was cooled to 0° C. and 160 mL ethyl acetate/water added. To this mixture, 1.5 equivalent of NaNO2 was added portion wise. The reaction was monitored by LCMS. After the starting material was consumed, the mixture was diluted with water and extracted with dichloromethane. The combined organic phases were washed with water and brine, and dried over sodium sulfate. The solvent was removed to provide the title compound as an off-white solid (4.7 g, 55% yield). 1H-NMR (400 MHz, CD3OD): δ 2.38-2.44 (dd, J=17.2, 4.0 Hz, 1H), 2.73-2.80 (dd, J=17.2, 9.2 Hz, 1H), 3.33-3.37 (dd, J=10.0, 6 Hz, 5.6 Hz, 1H), 3.78-3.83 (dd, J=10.0, 8.0 Hz, 1H), 4.06-4.13 (m, 1H), 7.64-7.65 (m, 1H), 7.38 (m, 2H); MS (ESI) m/z 275.89 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[OH:6][CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[Br:1][CH2:2][C:3]([O:6][CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)=[O:4]
Reactant: OCc1cccs1
Reactant: O=C(Cl)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(CBr)OCc1cccs1
Yield: 48 %

Procedure:
A solution of bromoacetyl chloride (60 mmol) and 2-hydroxymethylthiophene (60 mmol) in benzene (100 ml) was heated under reflux for 90 min, the cold solution shaken with saturated NaHCO3 aq., the dried (MgSO4) solution evaporated and the residue fractionally distilled; yield 48%, b.p. 96° C./0.05 mmHg. 1H NMR (CDCl3) δ3.80 (CH2), 5.30 (OCH2), 7.00 and 7.26 (thiophene).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[N:11]=1>C(#N)C>[Br:1][C:15]1[C:10]([F:9])=[N:11][C:12]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][CH:14]=1
Reactant: CC(C)(C)COc1cccc(F)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)COc1ccc(Br)c(F)n1
Temperature: 70 °C
Yield: 51.8 %

Procedure:
N-bromosuccinimide (8.29 g, 46.6 mmol) was added to a solution of 2-fluoro-6-(neopentyloxy)pyridine (7.11 g, 38.8 mmol) in acetonitrile (80 mL) at rt. The reaction mixture was heated to 70° C. overnight. The reaction mixture was cooled to rt and the solvent was removed under reduced pressure. The residue was dissolved in DCM and washed with water. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (100% hexanes) to obtain 3-bromo-2-fluoro-6-(neopentyloxy)pyridine (5.27 g, 20.11 mmol) as a white solid.
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[N+:11]([O-])([OH:13])=[O:12]>CCOCC>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[OH:10]
Reactant: COc1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CCOCC
Product: COc1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 50 ml of water, 150 ml of ether and 15.0 g of 2-methoxyphenol was added dropwise 12.7 ml of 61% nitric acid, and the mixture was stirred at room temperature for 15 minutes. The ether layer was separated from the aqueous layer and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by silica-gel column-chromatography using Wakogel® C-200 [eluent: chloroform-n-hexane (1:1)] to give 4.72 g of 2-methoxy-6-nitrophenol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:44][CH3:45])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[O:20][CH:21]1[CH2:38][CH:37]2[N:23]([C:24](=[O:43])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]3[C:34]([C:40]([OH:42])=O)([NH:35][C:36]2=[O:39])[CH2:33]3)[CH2:22]1.C(C1N=C(C2C=C(OC3CC4N(C(=O)CCCCCCC=CC5C(C([NH:87][S:88]([CH:91]6[CH2:93][CH2:92]6)(=[O:90])=[O:89])=O)(NC4=O)C5)C3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[Cl:1][C:2]1[C:3]([O:44][CH3:45])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[O:20][CH:21]1[CH2:38][CH:37]2[N:23]([C:24](=[O:43])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]3[C:34]([C:40]([NH:87][S:88]([CH:91]4[CH2:93][CH2:92]4)(=[O:90])=[O:89])=[O:42])([NH:35][C:36]2=[O:39])[CH2:33]3)[CH2:22]1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl

Procedure:
The title compound was prepared from 17-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-2,14-dioxo-3,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (56) following the procedure reported for synthesis of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl](cyclopropyl)sulfonamide 11: m/z=756 (M+H)+. 1H NMR (CDCl3): 0.90-0.98 (m, 1H), 1.05-2.0 (m, 2H), 1.3-1.4 (m, 9H), 1.5-1.6 (m, 2H), 1.6-1.65 (m, 1H), 1.75-1.9 (m, 5H), 2.2-2.3 (m, 1H), 2.3-2.4 (m, 1H), 2.45-2.55 (m, 2H), 2.6-2.7 (m, 1H), 2.75-2.85 (m, 1H), 3.15-3.25 (m, 1H), 3.8 (d, J=11.2 Hz, 1H), 4.15 (s, 3H), 3.25 (dd, J=11.15 Hz, J=4.5 Hz, 1H), 4.7 (t, J=7.1 Hz, 1H), 5.2 (t, J=10.4 Hz, 1H), 5.5 (br s, 1H), 5.6-5.7 (m, 1H), 6.9 (br s, 1H), 7.1 (s, 1H), 7.21 (d, J=9.5 Hz, 1H), 7.6 (s, 1H), 8 (d, J=9.5 Hz, 1H), 10.8 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][CH3:9].Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl>>[CH3:9][N:8]1[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[NH:1][C:11]1=[O:13]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNc1ccncc1N
Product: Cn1c(=O)[nH]c2cnccc21
Reaction time: 1 h

Procedure:
To a stirred suspension of 3-amino-4-methylaminopyridine [U.S. Pat. No. 5,371,086 (1993)](190 mg, 1.54 mmol) in CH3 CN (10 mL) was added triphosgene (458 mg, 1.54 mmol) portionwise. After 1 h, the mixture was concentrated in vacuo and the residue was converted to the free base by ion exchange chromatography on a SCX cartridge, eluting with 2 M NH3 in MeOH to give the title compound. MS: m/z=150 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21](=[O:22])[N:20]([CH3:23])[C:11]3[N:12]([CH3:19])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[Br:24][CH2:25][C:26](Cl)=[O:27]>>[Br:24][CH2:25][C:26]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:19])[C:11]1[N:20]([CH3:23])[C:21](=[O:22])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][C:10]2=1)=[O:27]
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3ccccc3n(C)c21
Reactant: O=C(Cl)CBr
Product: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(C(=O)CBr)ccc3n(C)c21

Procedure:
The process is carried out as in preparation 1.1 above, using compound from Example 72A, 3-(4-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and bromoacetyl chloride.
Reaction SMILES: I[C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:23]([O:22][C:18](/[CH:19]=[CH:20]/[C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)C1=Cc2cccc(I)c2OCC1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)/C=C/c1cccc2c1OCCC(C(=O)OCC)=C2
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of ethyl 2,3-dihydro-9-iodo-1-benzoxepin-4-carboxylate (0.34 g), ethyl acrylate (0.13 ml), palladium(II) acetate (2.2 mg), tri-o-tolylphosphine (6.0 mg), and triethylamine (0.15 ml) in acetonitrile (1 ml) was stirred at 100° C. under nitrogen atmosphere for 5 hours and partitioned between ethyl acetate and water. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was triturated in n-hexane to give a solid of ethyl 2,3-dihydro-9-[(E)-(2-ethoxycarbonylvinyl)]-1-benzoxepin-4-carboxylate (0.14 g).