Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11](Br)[CH:10]=2)=[O:5])[CH3:2].[CH2:18]([NH:25][C:26]([NH2:28])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:28][C:26]([NH:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:27])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2cc(Br)ccc2c1O
Reactant: NC(=O)NCc1ccccc1
Product: CCOC(=O)c1ncc2cc(NC(=O)NCc3ccccc3)ccc2c1O

Procedure:
7-(3-Benzyl-ureido)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester was prepared from 7-bromo-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester under conditions analogous to Example 116(a) using benzyl urea. The crude product was used in the following steps without purification.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([C:14]([OH:16])=O)=[C:4]([O:17][CH3:18])[CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[N+:26]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33])([O-:28])=[O:27]>ClCCl.CN(C=O)C>[N+:26]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH:33][C:14]([C:5]1[CH:6]=[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]([F:1])=[CH:3][C:4]=1[O:17][CH3:18])=[O:16])([O-:28])=[O:27]
Reactant: COc1cc(F)c(-c2ccccc2)cc1C(=O)O
Reactant: NCc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(F)c(-c2ccccc2)cc1C(=O)NCc1cccc([N+](=O)[O-])c1
Temperature: 40 °C
Yield: 64.8 %

Procedure:
A stirring slurry of 6-fluoro-4-methoxy-biphenyl-3-carboxylic acid (1.0 g, 4.06 mmol) in dichloromethane (8.2 mL, 0.5 M) was treated with oxalyl chloride (1.1 mL, 12.2 mmol) and DMF (1 drop). The mixture was heated to 40° C. until the solution was clear (1-2 h). Next, the mixture was allowed to cool to room temperature, concentrated under reduced pressure, and then diluted with dichloromethane (8.2 mL, 0.5 M). To the stirring mixture at 0° C. was added diisdpropylethyl amine (1.8 mL, 10.2 mmol) followed by 3-nitrobenzylamine hydrochloride salt (1.2 g, 6.1 mmol). Stirring under nitrogen, the solution was gradually warmed to room temperature and stirred overnight. The mixture was then diluted with dichloromethane and washed with 2N HCl (2×50 mL) and saturated aq NaCl (1×100 mL) The organic layer was dried over Na2SO4, filtered, and concentrated to afford a yellow oil. Purification by MPLC (10-100% ethyl acetate in heptane, 23 mL/min, 75 min) provided 6-fluoro-4-methoxy-biphenyl-3-carboxylic acid 3-nitro-benzylamide (1.0 g, 65%) as a yellow solid: Rf 0.33 (50% ethyl acetate in heptane); 1H NMR (DMSO-d6, 300 MHz) δ 8.90 (bd t, J=6.2 Hz, 1H), 8.10 (dd, J1=7.2 Hz, J2=2.4 Hz, 1H), 7.84 (d, J=9.3 Hz, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.52-7.43 (m, 5H), 7.40-7.34 (m, 1H), 7.20 (d, J=12.9 Hz, 1H), 4.61 (d, J=6.0 Hz, 2H), 3.96 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@H:13]([C:15]3[O:22][NH:29][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2cc(Cl)cc(Cl)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(Cl)cc(Cl)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 54.2 %

Procedure:
Trans-methyl 2-(3,5-dichlorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.6 g, 1.49 mmol) (from example 55, step 1) was dissolved in MeOH (6.11 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.393 mL, 1.49 mmol) in water (0.611 mL) was added and the mixture stirred at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.091 mL, 1.49 mmol) was added and stirring continued at −40° C. for 3.5 h. The reaction mixture was then transferred to a preheated 80° C. solution of 6 M hydrogen chloride (7.71 mL, 46.24 mmol) and heating was continued for 20 min. The solvent was then evaporated. DCM and water were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated to yield crude trans-methyl 2-(3,5-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (300 mg, 54%). MS m/z 371 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][NH2:15].S(=O)(=O)(O)O>>[CH3:14][NH:15][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN
Agent: O=S(=O)(O)O
Product: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 97.5 %

Procedure:
300 g (1.49 mol) of 4-chloro-3-nitrobenzoic acid were suspended in 836 mL of a 25-30% aqueous solution of methylamine. After heating to reflux temperature, an orange solution was obtained. The solution was kept at reflux temperature for 4 hours. The solution was cooled to room temperature, and pH was adjusted to about 2 by addition of 2M aqueous sulphuric acid. Precipitation of an orange solid was observed, which was isolated by filtration. The filtered cake was washed with 1.5 L of water and subsequently with 750 mL of ethanol. The solid was suspended in 1.6 L of ethanol and stirred at reflux temperature for 30 minutes. After cooling to room temperature, the solid was filtered and dried at 60° C. under vacuum to obtain 285 g of 4-(methylamino)-3-nitrobenzoic acid as an orange powder. Yield: 97.5%. Purity (HPLC, method 2): 97.7%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:38])([CH2:35][CH2:36][CH3:37])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:34])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])=[CH:20][C:19]([O:32][CH3:33])=[CH:18][C:17]=12)=[O:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:38])([CH2:35][CH2:36][CH3:37])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:34])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:25]([F:31])=[CH:26][CH:27]=[CH:28][C:29]=3[F:30])=[CH:20][C:19]([O:32][CH3:33])=[CH:18][C:17]=12)=[O:12]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(OC)cc12)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(C)(N)CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(OC)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
A solution of 118 mg (0.157 mmol, 73% purity) of rac-{1-[({7-[(2,6-difluorobenzyl)oxy]-5-methoxy-2-methylpyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]-2-methylpentan-2-yl}carbamic acid tert-butyl ester (Example 164A) in 12 ml of dichloromethane was admixed with 1.5 ml of trifluoroacetic acid. The resulting mixture was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure and the remaining residue was purified by preparative HPLC chromatography (Method 21), which gave 37 mg (53% yield) of product.
Reaction SMILES: I[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Cl:22][C:23]1[CH:28]=[C:27](I)[CH:26]=[CH:25][N:24]=1>>[Cl:22][C:23]1[CH:28]=[C:27]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:26]=[CH:25][N:24]=1
Reactant: Clc1cc(I)ccn1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(I)n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1

Procedure:
The title compound was prepared from 2-iodo-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidine (example A.4) (1.47 g, 3.52 mmol) and commercially available 2-chloro-4-iodo-pyridine [CAS No. 153034-86-7] (860 mg 3.6 mmol) according to the general procedure IVc protocol a. Obtained as a light yellow solid (0.70 g, 49%). MS (ISP) 404.1 [(M+H)+]; mp 144.5° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([O:25]C(=O)C)=[C:8]2[C:16]([CH3:17])=[CH:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+].CO>>[CH2:18]([N:14]1[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5])[C:7]([OH:25])=[C:8]2[C:16]([CH3:17])=[CH:15]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c(C)cn2Cc2ccccc2)c1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cn(Cc2ccccc2)c2c(C#N)nc(C(=O)NCC(=O)O)c(O)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-1-benzyl-7-cyano-3-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 365 (M+H)+.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][O:7][C@@H:8]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)(=[O:3])[CH3:2].C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:28][C:24]1[C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=2)=[C:22]([C@@H:8]([C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[O:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)NCCO[C@@H](c1cccc(F)c1-c1cccc(C)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NCCO[C@@H](c1cccc(F)c1-c1cccc(C)c1)[C@@H]1CCCNC1
Yield: 31.5 %

Procedure:
A solution of (3R)-tert-butyl 3-((R)-(2-acetamidoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)piperidine-1-carboxylate (80 mg) in 20% TFA/CH2Cl2 (5 mL) was stirred at 0° C. for 30 min. The solvent was neutralized by adding satd aq NaHCO3 and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4 and evaporated to give N-(2-((R)-(6-fluoro-3′-methylbiphenyl-2-yl)((R)-piperidin-3-yl)methoxy)ethyl)acetamide (20 mg, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11](Br)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[S:28][CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11]([C:24]3[CH:25]=[CH:26][C:27]([S:28][CH3:29])=[C:22]([F:21])[CH:23]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)COc1c(Br)cnn(-c2cccc(Cl)c2)c1=O
Reactant: CSc1ccc(B(O)O)cc1F
Product: CSc1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2OCC(C)C)cc1F

Procedure:
The title compound was prepared according to the method of Example 6, starting with 2-(3-chlorophenyl)-4-(2-methylpropoxy)-5-bromo-3(2H)-pyridazinone in place of 2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone and substituting 3-fluoro-4-(methylthio)benzeneboronic acid (Example 72D) in place of 4-fluorobenzeneboronic acid.
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.CC(N(C)C)=O>CO>[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:2]2[C:3]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:25][CH:24]=1
Reactant: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1ccccc1
Reactant: Nc1ccc(F)cc1
Solvent: CC(=O)N(C)C
Solvent: CO
Product: O=S(=O)(Nc1nc2ccccc2nc1Nc1ccc(F)cc1)c1ccccc1
Temperature: 120 °C
Yield: 61.8 %

Procedure:
A CEM microwave reaction vessel was charged with N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (52 mg, 0.16 mmol), prepared using procedures similar to those described in the above step, 4-fluoroaniline (36 mg, 0.32 mmol), and 0.8 mL of dimethylacetamide. The vessel was sealed and the reaction mixture was heated under microwave radiation for 25 m at 120° C. in a CEM Discover microwave instrument. Methanol (1 mL) was added to the reaction mixture and after 20 minutes the product precipitated out of the solution. Filtration yielded N-(3-(4-fluorophenylamino)quinoxalin-2-yl)benzenesulfonamide (39 mg, 62%). 1H-NMR (400 MHz, d6-DMSO): δ 12.30 (s, 1H), 9.11 (s, 1H), 8.16-8.10 (d, 2H), 8.02-7.90 (m, 3H), 7.68-7.58 (m, 3H), 7.55-7.51 (m, 1H), 7.41-7.32 (m, 2H), 7.25-7.16 (m, 2H); MS (EI) m/z C20H15FN4O2S: 395.0 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:13][CH3:14])[CH2:8][NH:7][CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.[CH3:15][C:16]1[S:17][C:18]([C:27](O)=[O:28])=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=1>>[CH3:1][O:2][C:3]1([O:13][CH3:14])[CH2:8][N:7]([C:27]([C:18]2[S:17][C:16]([CH3:15])=[N:20][C:19]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:28])[CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1
Reactant: Cc1nc(-c2ccccc2)c(C(=O)O)s1
Reactant: COC(=O)C1CCC(OC)(OC)CN1
Product: COC(=O)C1CCC(OC)(OC)CN1C(=O)c1sc(C)nc1-c1ccccc1

Procedure:
Methyl 5,5-dimethoxy-1-(2-methyl-4-phenylthiazole-5-carbonyl)piperidine-2-carboxylate was prepared according to general procedure A using methyl 5,5-dimethoxypiperidine-2-carboxylate and 2-methyl-4-phenylthiazole-5-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].I[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH2:14][CH2:13][CH2:12][CH2:1][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ncccc1C(=O)O
Reactant: ICCCc1ccccc1
Product: O=C(O)c1cccnc1CCCCc1ccccc1
Yield: 75.3 %

Procedure:
Starting from 2.1 g (15.0 mmol) of 2-methyl-nicotinic acid and 5.5 g (22.5 mmol) of 1-iodo-3-phenyl-propane, 2.9 g (11.3 mmol, 75%) of 2-(4-phenylbutyl)nicotinic acid were obtained according to the process described in precursor VB006.
Reaction SMILES: [ClH:1].[CH:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([C:14]=2[C:16]([OH:18])=O)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[ClH:21].[CH:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([C:14]=2[C:16]([Cl:1])=[O:18])=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1c2ccccc2nc2ccccc12
Reactant: O=S(Cl)Cl
Agent: Cl
Product: O=C(Cl)c1c2ccccc2nc2ccccc12
Temperature: 110 °C

Procedure:
A mixture of acridine-9-carboxylic acid hydrochloride (74 mg, 0.33 mmol) in thionyl chloride (3 ml, 41.1 mmol) was refluxed at 110° C. under nitrogen for 2 hours. After cooling, the solution was evaporated under reduced pressure to dryness. The solid was washed with anhydrous diethyl ether (5 ml) to give acridine-9-carbonyl chloride hydrochloride. This acid chloride was dissolved in anhydrous pyridine (4 ml), followed by addition of benzyl 3,5-diisopropyl-4-hydroxy-benzoate (102 mg, 0.33 mmol) and 4-N,N-dimethylamino-pyridine (16 mg, 0.13 mmol). After 16 hours of stirring at 25° C. under nitrogen, the solution was evaporated under reduced pressure to dryness. The residue was purified on a Chromatotron plate (1 mm silica gel) by elution with 20% diethyl ether/hexane to yield (4-benzyloxycarbonyl-2,6-diisopropyl)phenyl acridine-9-carboxylate (64 mg, 38%). Rf 0.6 (silica gel, 20% ethyl acetate/toluene). MS(EI): m/z 517(M).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[Br:12]N1C(=O)CCC1=O>C(#N)C>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([Br:12])[C:3]=1[O:10][CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(OC)c1Br
Solvent: CC#N
Product: COc1ccc(Br)c(OC)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
17.9 g of 1-bromo-2,6-dimethoxybenzene and 200 mL of acetonitrile were placed in a flask, and the resulting mixture was cooled on ice. Then, 14.7 g of N-bromosuccinimide was added. Then, while heating the reaction solution to room temperature, stirring was conducted for 8 hours. 2.39 g of N-bromosuccinimide was further added, and stirring was conducted at room temperature for 7 hours. After completion of the stirring, the solvent was distilled off under reduced pressure. Residues were dissolved in dichloromethane, and washed sequentially with sodium thiosulfate and saturated saline. An organic phase was dried with magnesium sulfate and concentrated. Residues were purified by means of silica gel column chromatography, whereby 23.2 g (yield: 95%) of colorless oil of 1,3-bromo-2,6-dimethoxybenzene was obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([Cl:16])=[CH:9][N+:8]=1[O-].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([Cl:16])=[CH:9][N:8]=1
Reactant: O=[N+]([O-])c1cc(Cl)[n+]([O-])cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(Cl)ncc1Cl
Yield: 105.5 %

Procedure:
To a solution of phosphorus oxychloride (6.40 μL, 73.21 mmol) in chloroform (61.2 mL) was added 2,5-dichloro-4-nitropyridine 1-oxide (3.06 g, 14.64 mmol), and the mixture was stirred under reflux overnight. The reaction solution was poured into ice, adjusted by saturated aqueous sodium hydrogen carbonate solution to pH7 to 8, and extracted with chloroform three times. The organic layer was combined, filtered through Phase-separator (Varian Inc.), and then concentrated under reduced pressure to give a crude 2,5-dichloro-4-nitropyridine (2.98 g, quant.) as a yellow oil. (2) To a solution of vinylmagnesium bromide (54.04 mmol) in tetrahydrofuran (104 mL) was added a solution of the above crude compound (2.98 g, 15.44 mmol) in tetrahydrofuran (100 mL) at 0° C. over 40 minutes, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate three times. The organic layer was combined, filtered through Phase-separator (Varian Inc.), and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20→50:50) to give 4,7-dichloro-1H-pyrrolo[3,2-c]pyridine (0.74 g, 27%) as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:14]N1C(=O)CCC1=O.ClCCl>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:14][CH2:12][C:10]1[C:9]([F:13])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1
Reactant: COC(=O)c1cc(F)c(C)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(F)c(CBr)cc1F
Temperature: 85 °C
Yield: 104.9 %

Procedure:
A solution of methyl 2,5-difluoro-4-methylbenzoate (Preparation 2, 500 mg, 2.69 mmol), N-bromosuccinimide (526 mg, 2.96 mmol) and dibenzoyl peroxide (20 mg, 0.08 mmol) dissolved in carbon tetrachloride (10 mL) was heated to reflux at 85° C. for 18 hours. The mixture was cooled to room temperature, dichloromethane (20 mL) added and the mixture poured into a separating funnel. The resulting organic layer was separated and washed successively with water (20 mL) and aqueous sodium thiosulphate solution (20 mL). The organic layer was dried over magnesium sulphate and filtered. The solvent was removed under reduced pressure to give an oil (748 mg). The crude product was purified by flash column chromatography (Biotage™ 50 g silica cartridge) eluting with 10% ethyl acetate in heptane to give the title compound (479 mg, 67%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[CH3:17][NH2:18]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH:18][CH3:17])=[O:11])[CH2:7]1
Reactant: CN
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 5.6 g (0.02 mole) of 3-(3,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was stirred while 5 ml (0.06 mole) of 40% aqueous methylamine was added slowly, stirring was continued for 18 hr. The reaction mixture was diluted with 200 ml of ice water, and the solid which formed was collected by filtration, 6.9 g. The crude wet solid was recrystallized from ethanol/water to yield 3.65 g (66.3%) of greenish-gray plate-like crystals, m.p. 158°-159° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:12]=[C:11]([OH:13])[C:10]2[C:5](=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:33][C:31]1([CH3:34])[C:30]([CH3:35])([CH3:36])[O:29][B:28]([C:25]2[CH:24]=[CH:23][C:22]([CH2:21][O:13][C:11]3[C:10]4[C:5](=[C:6]([C:14]([F:15])([F:16])[F:17])[CH:7]=[CH:8][CH:9]=4)[N:4]=[C:3]([C:2]([F:18])([F:1])[F:19])[CH:12]=3)=[CH:27][CH:26]=2)[O:32]1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: Oc1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(COc3cc(C(F)(F)F)nc4c(C(F)(F)F)cccc34)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
Step 2A [Intermediate 4, G9591-157-1]: To a solution of 2,8-Bis-trifluoromethyl-quinolin-4-ol (3.85 g, 13.7 mmol, 1.1 equiv.) in DMF (40 mL) was added 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (3.7 g, 12.5 mmol, 1.0 equiv.) and K2CO3 (3.45 g, 24.92 mmol, 2.2 equiv.) under N2 atmosphere. The reaction mixture was stirred at room temperature overnight. The reaction was complete as determined by TLC. The reaction mixture was poured into cold water, the white precipitate formed was collected by filtration, washed with water, dried under vacuum to yield 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-2,8-bis-trifluoromethyl-quinoline in 73% yield (4.95 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8](=[O:12])[C:7]2([CH3:14])[CH3:13].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2/[CH:17]=[CH:16]/[C:15]([O:19][CH2:20][CH3:21])=[O:18])[C:7]([CH3:14])([CH3:13])[C:8]1=[O:12]
Reactant: CN1C(=O)C(C)(C)c2cccc(Br)c21
Reactant: C=CC(=O)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cccc2c1N(C)C(=O)C2(C)C
Temperature: 180 °C

Procedure:
A mixture of 7-bromo-1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one from Step A (112 mg, 0.44 mmol), ethyl acrylate (0.238 mL, 2.20 mmol), triethylamine (0.124 mL, 0.88 mmol), and (PPh3)4Pd (51 mg, 0.044 mmol) in DMF (1.5 mL) was heated at 180° C. in a microwave reactor for 4 h. The reaction mixture was partitioned between CH2Cl2 (50 mL) and saturated aqueous NaHCO3 (50 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 60:40, to give the title compound. MS: m/z=274 (M+1).