Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24]([OH:26])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][C@@H:36]([NH2:39])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][C@@H:36]([NH:39][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([O:13][CH3:14])[C:10]([F:12])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[NH:23][CH:22]=2)=[O:26])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1cc(-c2ncnc3c(C(=O)O)c[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Product: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C4)c[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A79) and (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[C:3]([F:15])=[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[C:5]([F:8])=[CH:6][CH:7]=1.C([O-])(=O)C.[K+].[B:21]1(B2OCC(C)(C)CO2)[O:26]CC(C)(C)C[O:22]1>O1CCOCC1>[F:15][C:3]1[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[B:21]([OH:26])[OH:22]
Reactant: Fc1ccc(Br)c(F)c1-c1cccnc1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: OB(O)c1ccc(F)c(-c2cccnc2)c1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
A mixture of 3-(3-bromo-2,6-difluorophenyl)pyridine (2.97 g, 11 mmol), potassium acetate (2.16 g, 22 mmol) and bis(neopentyl glycolato)diboron (2.86 g, 12.7 mmol) in 1,4-dioxane (30 ml) was heated at 90° C. for 16 h. The reaction was cooled, filtered (washing the filter cake with a small quantity of diethyl ether) and the filtrate concentrated in vacuo. The residue was partitioned between diethyl ether (100 ml) and 1M sodium hydroxide (100 ml) and the organics discarded. The aqueous was washed with more diethyl ether and then cooled in an ice-water bath. The pH was adjusted to approximately 6 with 36% hydrochloric acid, and allowed to stand for 1 h. The resulting solid was collected by filtration and dried under vacuum to afford 2,4-difluoro-3-(pyridin-3-yl)benzeneboronic acid (2.2 g, 85%) as a grey solid: m/z (ES+) 236 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([S:17][CH3:18])[N:14]=[C:13]([CH:19]([C:22]#[N:23])[C:20]#[N:21])[CH:12]=2)[CH3:9])=[CH:4][CH:3]=1.[NH2:24][NH2:25].C(O)(=O)C.[CH3:30][CH:31](O)[CH3:32]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([S:17][CH3:18])[N:14]=[C:13]([C:19]3[C:20]([NH2:21])=[N:24][N:25]4[CH:32]=[CH:31][CH:30]=[N:23][C:22]=34)[CH:12]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CSc1nc(N[C@@H](C)c2ccc(F)cc2)cc(C(C#N)C#N)n1
Reactant: CC(C)O
Solvent: CC(=O)O
Product: CSc1nc(N[C@@H](C)c2ccc(F)cc2)cc(-c2c(N)nn3cccnc23)n1
Temperature: 160 °C
Reaction time: 0.17 h

Procedure:
(1(S)-2-(6-(1-(4-Fluorophenyl)ethylamino)-2-(methylthio)pyrimidin-4-yl)malononitrile (16c, 110 mg, 0.33 mmol) was suspended in IPA (6.0 mL). Hydrazine was then added (11.0 mg, 0.34 mmol). The reaction mixture was heated at 160° C. with microwave irradiation. After 10 minutes, the reaction mixture was allowed to cool to rt. LC/MS showed the presence of product (LC/MS (M+1): 360.5). In the same pot, glacial acetic acid (130 mg) was added, followed by N,N-dimethyl acrolein (130 mg, 1.3 mmol). The reaction mixture was heated at 160° C. with microwave irradiation for 10 minutes. The mixture was then allowed to cool down to rt. All volatiles were removed at reduced pressure and the crude residue was purified on a combi-flash system (0-100% Hexane/EtOAc). Yield: 55 mg (45%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C)C(=O)C>O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:8]=1)[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C(=O)c1ccccc1)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 80 °C
Reaction time: 20 h
Yield: 47 %

Procedure:
A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.20 g, 0.74 mmol), benzoyl chloride (0.44 g, 3.1 mmol) and N,N-dimethylacetamide (10 ml) was stirred at 80° C. for 20 hrs. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was successively washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried. The solvent was evaporated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (1:1, v/v). The obtained crystals were recrystallized from ethyl acetate-hexane to give the titled compound (0.13 g, 38%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]CC)=O)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([Mg]Br)[CH3:25].Cl.O1CC[CH2:31][CH2:30]1>>[CH2:30]([C:19]([OH:21])([CH2:24][CH3:25])[CH2:18][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1)[CH3:31]
Reactant: CCOC(=O)Cc1ccc(NC(=O)OCc2ccccc2)cc1
Reactant: CC[Mg]Br
Reactant: C1CCOC1
Agent: Cl
Product: CCC(O)(CC)Cc1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of ethyl (4-{[(benzyloxy)carbonyl]amino}phenyl)acetate (15.3 g) and tetrahydrofuran (100 mL) was added dropwise 1 M ethyl magnesium bromide (1 M tetrahydrofuran solution, 500 g) at 0° C. The reaction mixture was stirred at room temperature for 15 hrs. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give benzyl 4-(2-ethyl-2-hydroxybutyl)phenylcarbamate as colorless crystals from a fraction eluted with hexane-ethyl acetate (2:1-1:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals (6.86 g, yield 43%). melting point: 99-100° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].[N+:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20])([O-:12])=[O:11].N1C=CC=CC=1>C(Cl)Cl>[N+:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([NH:4][C:3]1[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:2]=1[CH3:1])(=[O:21])=[O:20])([O-:12])=[O:11]
Reactant: Cc1ccc(C)c(N)c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(C)c(NS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
2,5-dimethyl-aniline (2.4 g, 20 mmol) and 2-nitrobenzenesulfonyl chloride (4.4 g, 20 mmol) are dissolved in CH2Cl2 and treated with pyridine (1.8 mL, 22 mmol). The reaction mixture is stirred at room temperature until TLC shows no starting material. The reaction mixture is quenched with dilute HCl, and the organic layer washed with saturated brine. Drying over MgSO4, filtration, and concentration provides a solid that is recrystallized from hot EtOAc/hexanes to provide 2-nitro-N-(2,5-dimethyl-phenyl)-benzenesulfonamide.
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:5])[NH2:4].[OH-:6].[Na+].Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10]>C(Cl)Cl>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:11][C:9]([NH:5][C:3](=[N:4][C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[O:6])[S:2][CH3:1])=[O:10])=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: CSC(=N)N
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: ClCCl
Product: CSC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a clean 3-necked round bottom flask equipped with two addition funnels were added DCM (60 mL), S-methylisothiourea (1 g, 7.18 mmol), and 6.25N NaOH solution (aq, 570 uL). After cooling the resulting mixture to 0° C., a solution of 4-nitrobenzyl chloroformate (3.17 g, 14.73 mmol) in DCM (20 mL) and a solution of sodium hydroxide (aq, 1N, 15 mL) were simultaneously added dropwise using the two addition funnels while maintaining pH 11. The mixture was aged for 16 h with gradual warming to rt. The layers were separated and the organic phase was washed with brine (20 mL) and dried over sodium sulfate. Solvent was removed under vacuum and the resulting white solid recrystallized from ethyl acetate and hexanes to give 132 (2.7 g, 84%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9].[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Br:8][C:4]1[C:3]([CH3:9])=[C:2]([N:11]([CH3:10])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CNc1ccccc1
Reactant: Cc1c(Br)cccc1Br
Solvent: Cc1ccccc1
Product: Cc1c(Br)cccc1N(C)c1ccccc1
Temperature: 85 °C

Procedure:
1,3-Dibromo-2-methylbenzene (5.01 g) and N-methylaniline (1.00 g) were added to toluene (65 mL). The solution was degassed and flushed with nitrogen three times. Cesium carbonate (9.12 g), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.872 g), and palladium (II) acetate (0.314 g) were added. The solution was degassed and flushed with nitrogen and then heated to 85° C. for 72 hours. The solution was cooled, added to 1 M aqueous HCl, and extracted with diethyl ether. The extract was washed with brine, dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude material was purified on silica gel using 2% ethyl acetate in hexanes.
Reaction SMILES: Cl.[CH2:2]([N:5]([CH2:16][CH2:17][CH3:18])[C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:9]([OH:11])=O)[CH2:3][CH3:4].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[NH2:33][C@@H:34]([CH2:48][C:49]1[CH:54]=[C:53]([F:55])[CH:52]=[C:51]([F:56])[CH:50]=1)[C@H:35]([OH:47])[CH2:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH3:46])[CH:40]=1>C1COCC1.C(N(CC)CC)C.ClCCl>[F:55][C:53]1[CH:54]=[C:49]([CH:50]=[C:51]([F:56])[CH:52]=1)[CH2:48][C@H:34]([NH:33][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([CH3:15])[N:14]=[C:6]([N:5]([CH2:2][CH2:3][CH3:4])[CH2:16][CH2:17][CH3:18])[CH:7]=1)[C@H:35]([OH:47])[CH2:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH3:46])[CH:40]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCN(CCC)c1cc(C(=O)O)cc(C)n1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCC)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(C)n1
Reaction time: 1 h
Yield: 18.1 %

Procedure:
To 2-(dipropylamino)-6-methylisonicotinic acid hydrochloride (approx. 0.4 mmol) in THF (3 mL) was added triethylamine (0.17 mL), followed by dichloromethane (2 mL) and then CDI (0.071 g, 0.44 mmol). After stirring for 1 h, a mixture of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride (0.163 g, 0.400 mmol), triethylamine (0.11 mL), and dichloromethane (approx. 2 mL) was added to the CDI mixture. The mixture was allowed to stir overnight, after which an additional 0.12 mL of triethylamine and 0.045 g of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride was added. After stirring for several more hours, the mixture was partitioned between dichloromethane and aq. sodium bicarbonate. The organic layer was dried with sodium sulfate, concentrated, and the residue was chromatographed on silica gel using MeOH-dichloromethane (5/95) to give 0.04 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[C@@H:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH3:24])=[CH:17][CH:16]=3)[CH2:13][O:12][C:11]2=[O:25])[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[CH:26](OCC)(OCC)OCC>>[CH3:9][C:6]1[C:7]2[NH:8][CH:26]=[N:1][C:2]=2[CH:3]=[C:4]([N:10]2[C@@H:14]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH3:24])=[CH:19][CH:20]=3)[CH2:13][O:12][C:11]2=[O:25])[CH:5]=1
Reactant: CCCOc1ccc([C@H]2COC(=O)N2c2cc(C)c(N)c(N)c2)cc1
Reactant: CCOC(OCC)OCC
Product: CCCOc1ccc([C@H]2COC(=O)N2c2cc(C)c3[nH]cnc3c2)cc1

Procedure:
The (S)-3-(3,4-diamino-5-methylphenyl)-4-(4-propoxyphenyl)oxazolidin-2-one was dissolved in triethyl orthoformate and was refluxed for 30 minutes. After cooling the excess of triethyl orthoformate was removed under reduced pressure. The final product was purified via FPLC using a chloroform-methanol gradient (0→10%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:25])[C:15]=2[N:14]=[C:13]1[CH2:26][CH2:27][CH2:28][CH3:29].[CH2:30]([N:34]=[C:35]=[O:36])[CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[NH2:25][C:16]1[C:15]2[N:14]=[C:13]([CH2:26][CH2:27][CH2:28][CH3:29])[N:12]([CH2:11][CH2:10][CH2:9][NH:8][C:35]([NH:34][CH2:30][CH2:31][CH2:32][CH3:33])=[O:36])[C:24]=2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: CCCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCCNC(=O)NCCCn1c(CCCC)nc2c(N)nc3ccccc3c21
Yield: 40 %

Procedure:
Triethylamine (765 mg, 7.56 mmol) was added to a solution of 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 5.04 mmol) in 1-methyl-2-pyrrolidinone (100 mL). Butyl isocyanate (549 mg, 5.55 mmol) was added dropwise with stirring. The reaction mixture was allowed to stir overnight and then it was poured into water (500 mL). The pH was adjusted to 10 using solid potassium carbonate. The resulting precipitate was isolated by filtration, washed with water and then purified by column chromatography (silica gel eluting with 5% methanol in dichloromethane and then with 10% methanol in dichloromethane. The purified material was recrystallized from acetonitrile to provide 800 mg of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-butylurea as a white solid, m.p. 185.5-186.4° C. Analysis: Calculated for C22H32N6O: % C, 66.64; % H, 8.13; % N, 21.29. Found: % C, 66.38; % H, 8.19; % N, 21.10.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=[O:2].[CH2:12]([OH:16])[CH2:13][CH2:14][CH3:15].O.[C:18]1(C)[CH:23]=CC(S(O)(=O)=O)=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH2:23]([O:7][CH:6]([O:16][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:18][CH2:19][CH3:20]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CCCCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOC(OCCCC)c1ccccc1[N+](=O)[O-]

Procedure:
A solution comprising 2-nitrobenzaldehyde (4.53 g, 30.0 mmol), 1-butanol (13.7 ml, 150 mmol) and toluene (60 ml) was added with p-toluene sulfonic acid monohydrate (57 mg, 0.300 mmol) and molecular sieves-4A (1 g), and refluxed for two days. The mixture was filtered through celite, washed with saturated sodium bicarbonate and saturated sodium chloride water, and then dried with anhydrous magnesium sulfate. The solution was concentrated to obtain Step 1 compound (8.43 g, quant) as a brown oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[NH2:15][C:16]1[C:24]2[O:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.[NH:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH:36]=O)=[CH:35][C:30]=2[N:29]=[CH:28]1>>[NH:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][NH:1][C:4]3[C:5]4[CH:6]=[CH:7][C:8]([NH:15][C:16]5[C:24]6[O:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20]=6[CH:19]=[CH:18][CH:17]=5)=[N:9][C:10]=4[CH:11]=[CH:12][CH:13]=3)=[CH:35][C:30]=2[N:29]=[CH:28]1
Reactant: O=Cc1ccc2[nH]cnc2c1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: CC1(C)Cc2cccc(N)c2O1
Product: CC1(C)Cc2cccc(Nc3ccc4c(NCc5ccc6[nH]cnc6c5)cccc4n3)c2O1

Procedure:
The title compound, MS: m/e=436.1 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 7-amino-2,3-dihydro-2,2-dimethylbenzofuran (CAS 68298-46-4) and 1H-benzimidazole-5-carbaldehyde as described in example 26.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][NH:11][CH2:12][CH:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[OH:14].[Cl:21][C:22]1[CH:44]=[CH:43][C:25]([CH2:26][NH:27][C:28]([C:30]2[C:31](=[O:42])[C:32]3[CH:39]=[C:38]([CH2:40]Cl)[O:37][C:33]=3[N:34]([CH3:36])[CH:35]=2)=[O:29])=[CH:24][CH:23]=1.O>CN(C=O)C>[Cl:21][C:22]1[CH:44]=[CH:43][C:25]([CH2:26][NH:27][C:28]([C:30]2[C:31](=[O:42])[C:32]3[CH:39]=[C:38]([CH2:40][N:11]([CH2:12][CH:13]([OH:14])[C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH3:10])[O:37][C:33]=3[N:34]([CH3:36])[CH:35]=2)=[O:29])=[CH:24][CH:23]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Reactant: CNCC(O)c1cccnc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)c1cccnc1
Temperature: 90 °C
Yield: 37.5 %

Procedure:
N,N-Diisopropylethylamine (0.11 mL) and 2-(methylamino)-1-pyridin-3-ylethanol (Preparation 39, 0.094 g) were added to a suspension of N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2, 0.150 g) in DMF (10 mL). The reaction mixture was heated to 90° C. for 1 h. The mixture was allowed to cool to room temperature, poured into water (25 mL), and was extracted with CH2Cl2 (4×25 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The resulting solid was purified by column chromatography (CH2Cl2/methanol; 98/2, 97/3, 96/4, 95/5) followed by recrystallization from ethyl acetate to yield 0.074 g of the title compound as a pale yellow solid. Physical characteristics. M.p. 145-149° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.64, 8.54, 8.50, 8.40-8.39, 7.69-7.67, 7.41-7.33, 7.29-7.25, 6.83, 5.33, 4.77-4.73, 4.55, 3.88, 3.71, 2.67-2.55, 2.32; MS (ESI+) m/z 481 (M+H)+.
Reaction SMILES: [CH:1]1[N:9]2[C:4]([C:5]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[CH:3][CH:2]=1.[OH:19][S:20]([OH:23])(=[O:22])=[O:21].[C:24](I)([F:27])([F:26])[F:25].OO>CS(C)=O>[S:20]([OH:23])([OH:22])(=[O:21])=[O:19].[F:25][C:24]([F:27])([F:26])[C:1]1[N:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:4]2=[CH:3][CH:2]=1
Reactant: FC(F)(F)I
Reactant: c1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CS(C)=O
Product: FC(F)(F)c1ccc2n1-c1ccccc1OC21CCNCC1
Reaction time: 0.25 h
Yield: 33 %

Procedure:
To spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (5.20 g, 21.6 mmol) in DMSO (104 mL) was added H2SO4 (1.27 mL, 23.8 mmol) (note: exothermic), ferrous sulfate heptahydrate (6.5 mL of 1.0 M, 6.5 mmol) followed by CF3I (4.24 g, 21.6 mmol) by slow bubbling through the solution and taking weight difference of cannister. The mixture cooled with a ice-water bath before H2O2 (2.45 mL of 30% w/v, 21.6 mmol) was added drop-wise over 10 min keeping temperature <23° C. The mixture was allowed to stir for 15 min before it was poured onto ice (250 g) producing a white precipitate. The slurry was stirred for 5 min and then the solid was collected via filtration. The off-white solid was taken up in acetonitrile (150 mL) and was heated at reflux of 1 h. The solvent was removed and the solid was recrystallized from EtOH (15 mL/g) and water (5 mL/g). The solid was collected and dried to give 1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] sulfate (2.9 g, 33%). ESI-MS m/z calc. 308.1, found 309.1 (M+1)+; Retention time: 1.23 minutes (3 min run).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1>>[Cl-:17].[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S+:8]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)c2ccc(C)cc2)cc1
Product: Cc1ccc([S+](c2ccc(C)cc2)c2ccc(C)cc2)cc1
Product: [Cl-]

Procedure:
The end compound was synthesized as in Synthesis Example 2 except that bis(4-methylphenyl) sulfoxide was used instead of the phenyl sulfoxide in Synthesis Example 2, 4-chlorotoluene was used instead of the chlorobenzene, and the quantity of water for extraction was increased.
Reaction SMILES: [F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([B:11]([OH:13])[OH:12])[C:4]=2[O:3]1.[Li][CH:16](CC)C.C1CCCCC1.CI>C1COCC1>[F:14][C:2]1([F:1])[O:6][C:5]2[C:7]([CH3:16])=[CH:8][CH:9]=[C:10]([B:11]([OH:13])[OH:12])[C:4]=2[O:3]1
Reactant: OB(O)c1cccc2c1OC(F)(F)O2
Reactant: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CI
Product: Cc1ccc(B(O)O)c2c1OC(F)(F)O2
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
(2,2-difluoro-1,3-benzodioxol-4-yl)boronic acid (Intermediate 35, crude material) was dissolved in THF (20 mL) and the resulting solution cooled down to −78° C. sec-BuLi 1.4M solution in cyclohexane (17.4 ml, 24.36 mmol) was added dropwise and the reaction mixture was stirred for 1.5 hours at −78° C. Methyl iodide (4.6 ml, 73 mmol) was then added and the reaction mixture was stirred for 2 hours while the temperature was allowed to reach room temperature. The reaction was quenched by addition of an aqueous 2N solution of HCl and diluted with ethyl acetate. The organic layer was collected and then washed twice with brine, dried over Na2SO4 and evaporated to dryness. Crystallization from n-heptane afforded the title compound (150 mg) as white solid.
Reaction SMILES: Br[Mg][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29]([CH:30]=[O:31])=[C:28]([CH:32]([CH3:34])[CH3:33])[CH:27]=[C:26]3[C:21]=2[C:22](=[O:37])[CH2:23][C:24]([CH3:36])([CH3:35])[O:25]3)=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29]([CH:30]([OH:31])[C:3]3[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=3)=[C:28]([CH:32]([CH3:33])[CH3:34])[CH:27]=[C:26]3[C:21]=2[C:22](=[O:37])[CH2:23][C:24]([CH3:35])([CH3:36])[O:25]3)=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1ccc([Mg]Br)cc1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C=O)C(=O)CC(C)(C)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reaction time: 0.75 h

Procedure:
At −78° C., 2.29 ml (1.15 mmol) of a freshly prepared 0.5 M solution of bromo[4-(trifluoromethyl)phenyl]magnesium in tetrahydrofuran are slowly added dropwise to a solution of 300 mg (881 μmol) of 5-(4-fluorophenyl)-7-isopropyl-2,2-dimethyl-4-oxochroman-6-carbaldehyde (Example 20A) in 7 ml of tetrahydrofuran. The mixture is then allowed to thaw slowly to −20° C. and stirred at this temperature for 45 min. A 10% strength sodium bicarbonate solution is then added, the mixture is extracted three times with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. The organic phases are dried over magnesium sulfate, the solvent is then removed under reduced pressure and the residue is purified by column chromatography on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 10:1).