Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(CC)CC>CN(C=O)C.O>[CH2:17]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(N)c1
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cccc(NCc2ccccc2)c1
Reaction time: 48 h
Yield: 30.3 %

Procedure:
A stirred solution of the starting tert-butyl 3-aminobenzylcarbamate (0.925 g, 4.16 mmol, 1 eq, derived from 3-(aminomethyl)aniline (TCI America)) in 10 ml anhydrous DMF under Ar was treated with benzyl bromide (0.54 ml, 0.78 g, 4.58 mmol, 1.1 eq) and Et3N (0.75 ml, 0.55 g, 1.3 eq). After stirring for 48 h the reaction was diluted with water and extracted with EtOAc (×2). The combined organics were washed with water (×4), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.3937 g (1.26 mmol, 30% yield) of tert-butyl 3-(benzylamino)benzylcarbamate.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[CH2:9][NH:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[CH:14]1([C:17](=[O:23])[CH2:18][C:19](OC)=[O:20])[CH2:16][CH2:15]1.N1(C2C=CN=CC=2)CCCC1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[CH2:9][N:8]([C:19](=[O:20])[CH2:18][C:17]([CH:14]3[CH2:16][CH2:15]3)=[O:23])[CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: Cc1cc(Cl)nc2c1CNCC2
Reactant: COC(=O)CC(=O)C1CC1
Agent: Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)nc2c1CN(C(=O)CC(=O)C1CC1)CC2
Temperature: 25 °C
Yield: 52.4 %

Procedure:
Microwave was used to irradiated a suspension of 2-chloro-4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (1.00 g, 4.56 mmol), methyl 3-cyclopropyl-3-oxopropanoate (1.298 g, 9.13 mmol), 4-pyrrolidinopyridine (0.068 g, 0.456 mmol) and DIPEA (1.20 mL, 6.85 mmol) in toluene (10 mL) at 150° C. for 45 min. The mixture was cooled to rt and diluted with 1 M HClaq (10 mL) and EtOAc. The products were extracted twice with EtOAc. The combined organic layer was washed with a mixed solution of 1M HClaq/brine (1 mL/2 mL), dried over Na2SO4, filtered, and concentrated to give crude. The residue was purified by flash column chromatography on 12 g of silica gel (eluent: DCM/EtOAc=90:10 to 0:100) to give crude 1-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-3-cyclopropylpropane-1,3-dione (0.70 g): MS (ESI+) m/z 293.31 (M+H)+. The obtained material was used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:9]([CH3:24])([CH3:23])[CH2:8]2)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([CH:10]2[C:9]([CH3:24])([CH3:23])[CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=3)[NH:11]2)[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(OC)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 83.8 %

Procedure:
To a stirred mixture solution of 2-(3-methoxy-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1.5, 4.6 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was added 50% sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-(3-methoxy-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.2 g, 90%) as a white foam: LC/MS m/e calcd for C19H21NO3 (M+H)+: 312.38, observed: 312.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCl
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccccc1Cl
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A mixture of 51.4 g of o-chlorophenol, 58.8 g of ethyl chloroacetate, 55.3 g of potassium carbonate and 250 ml of acetone was heated under reflux for 7 hours. The mixture was then cooled to room temperature and an insoluble material was filtered off. The filtrate was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography to give 69.0 g of the title compound as an oil, boiling at 134°-137° C./2 mm Hg (267 Pa).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:14][S:15]([O:18][CH3:19])(=[O:17])=[O:16]>>[F:14][S:15]([O-:18])(=[O:17])=[O:16].[CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][N+:10]=1[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccsn2)cc1
Reactant: COS(=O)(=O)F
Product: C[n+]1sccc1OCc1ccccc1
Product: O=S(=O)([O-])F
Yield: 90 %

Procedure:
3-Benzyloxyisothiazole (3.0 g, 0.016 mol) and 5 ml of methyl fluorosulfonate were heated at 60° for 30 min. After cooling, the solid was washed with ether to yield 4.3 g (90%) of 3-benzyloxy-2-methylisothiazolium fluorosulfonate, mp 75°-78° C. (d).
Reaction SMILES: O1CCCC1.[C:6]([C:10]1[C:11]([C:22]([OH:24])=O)=[N:12][C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([Cl:21])[CH:14]=2)([O:8][CH3:9])=[O:7].S(Cl)([Cl:27])=O>>[C:6]([C:10]1[C:11]([C:22]([Cl:27])=[O:24])=[N:12][C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([Cl:21])[CH:14]=2)([O:8][CH3:9])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1c(C(=O)O)nc2cc(Cl)ccc2c1O
Solvent: C1CCOC1
Product: COC(=O)c1c(C(=O)Cl)nc2cc(Cl)ccc2c1O
Temperature: 0 °C

Procedure:
The free base of 4-(trifluoromethoxy)phenyl hydrazine was prepared from thehydrochloride salt by treatment of the suspended salt (400 mg, 1.75 mM) in ethyl acetate (50 mL) with 2N sodium hydroxide(50 mL). The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo to provide the free base of 4-(trifluoromethoxy)phenyl hydrazine (325 mg, 1.69 mK). This material was placed into anhydrous tetrahydrofuran (5 mL) and cooled to 0° C. under a nitrogen atmosphere. Concurrently, 3-carbomethoxy-7-chloro-4-hydroxyquinoline-2-carbonyl chloride was prepared from 3-carbomethoxy-7-chloro-4-hydroxyquinoline-2-carboxylic acid(121 mg, 0.43 mM) by heating to 60° C. in thionyl chloride (4 mL). After 3 hours the crude acid chloride was isolated by distilling away the excess thionyl chloride. The crude3-carbomethoxy-7-chloro-4-hydroxyquinoline-2-carbonyl chloride (130 mg, 0.43 mM) was then placed in anhydrous tetrahydrofuran (3 mL) at ambient temperature and added via cannula to the 4-(trifluoromethoxy)phenyl hydrazine solution. After 30 minutes the reaction mixture was poured into 1.0N hydrochloric acid producing a precipitate. The solid was isolated to yield the title compound (185 mg, 95%) as an off-white solid, mp 346°-350° C.; MS 456 (M+H). 1H NMR 12.67 (s, 1H, exchangeable), 10.79 (s, 1H, exchangeable), 8.37 (br s, 1H, exchangeable), 8.13 (d, J=8.61 Hz, 1H), 7.83 (d, J=1.76 Hz, 1H), 7.48 (dd, J=8.61, 1.76 Hz, 1H), 7.21 (d, J=8.50 Hz, 2H), 6.94 (d,J=8.50 Hz, 2H), 3.70 (s, 3H).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[N:23]=[CH:22][CH:21]=[CH:20][C:8]=1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=[O:10].[H-].[Na+].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1>O.ClCCl>[Cl:6][C:7]1[N:23]=[CH:22][CH:21]=[CH:20][C:8]=1[C:9]([N:11]([CH2:32][C:31]1[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=[O:10]
Reactant: COc1cccc(NC(=O)c2cccnc2Cl)c1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)c2cccnc2Cl)c2cccc(OC)c2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 83.1 %

Procedure:
N,N-Dimethylformamide was added to the compound (972.4 mg, 3.1736 mmol) prepared in step 1 and the mixture was cooled to 0° C. Sodium hydride (380 mg, 9.52 mmol) was slowly added and the resulting mixture stirred at 0° C. for 20 minutes. p-Methoxybenzyl chloride (0.646 ml, 4.76 mmol) was added at 0° C. and the mixture stirred for 3 hours at room temperature. Once the reaction was completed, dichloromethane and water was added, the organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate=2.5:1) to obtain the title compound (1.01 g, yield: 84%, ivory oil).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([N:13]1[C@H:17]([CH3:18])[C@H:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:15][C:14]1=[O:25])=[O:12].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O([CH2:44][CH3:45])S(C(F)(F)F)(=O)=O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C@H:10]([CH2:44][CH3:45])[C:11]([N:13]1[C@H:17]([CH3:18])[C@H:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:15][C:14]1=[O:25])=[O:12]
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)CCc1ccc(F)cc1F
Reactant: CCOS(=O)(=O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H](Cc1ccc(F)cc1F)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
A flask was charged with 54 g (156 mmol) of (4R,5S)-3-[3-(2,4-difluoro-phenyl)-propionyl]-4-methyl-5-phenyl-oxazolidin-2-one and 300 mL of dry THF, and the solution was cooled to −78° C. To this solution was added 172 mL (172 mmol) of 1 M NaHMDS in THF, and the mixture was stirred cold for 1 hour. Then 30.6 g (172 mmol) of ethyl triflate was added dropwise to the enolate solution, and the reaction mixture was warmed to −40° C. to −30° C. and stirred for 1.5 hour. The reaction mixture was quenched by the addition of aqueous brine. The THF was removed under reduced pressure and the residue was partitioned between EtOAc and water. The organics were collected, and EtOAc was removed under reduced pressure. The resulting crude oil was purified by column chromatography (3:1 hexanes/EtOAc eluent) to get 29.5 g of an impure oil that was used without further purification.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[NH2:11][CH2:12][CH:13]([OH:15])[CH3:14].C(N(CC)CC)C>ClCCl>[OH:15][CH:13]([CH3:14])[CH2:12][NH:11][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: CC(O)CN
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(O)CNC(=O)c1ccncc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
289 g isonicotinoyl chloride hydrochloride was added to 128 g 1-amino-propan-2-ol and 549 mL triethylamine in 2 L dichlormethane at 0° C. The reaction was stirred for 30 min. at 0° C. and then the solvent was removed. The residue was suspended in ethyl acetate and the precipitate was filtered. The filtrate was recrystallized from ethyl acetate to give 154 g of the desired product. Rf: 0.4 (DCM/MeOH=20/1), (M+H)+: 181
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[I:12]Cl>C(O)(=O)C.C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[I:12]
Reactant: ClI
Reactant: COC(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(O)c(I)c1
Temperature: 45 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a 500 mL 3-necked flask equipped with a magnetic stirrer, a thermometer, and a condenser were added 10.0 g of methyl 4-hydroxybenzoate (Aldrich) and 30 mL of glacial acetic acid. To this suspension was added a solution of 11.74 g of iodine monochloride in 30 mL of glacial acetic acid via addition funnel. The solution was heated at 80° C. for 1 h, 45° C. for 18 h, and 90° C. for an additional 4 h. Cooling to RT afforded a thick red-orange suspension which was transferred to a 1 L separatory funnel and dissolved in 500 mL of CHCl3 by shaking vigorously. The dark purple solution was washed with water (2×100 mL), saturated aqueous sodium thiosulfate (2×100 mL), and 5% aqueous NaHCO3 (2×100 mL). A light yellow solution resulted which was dried over MgSO4, and concentrated in vacuo to give a white solid. This material was recrystallized from water-MeOH to afford 14.92 g (82%) of methyl 4-hydroxy-3-iodobenzoate as a white crystalline solid, m.p. 145-146° C.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[N:4]([CH3:15])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].ClC1C=CC=C(C(OO)=[O:29])C=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:20][C:18]1[CH:17]=[CH:16][C:3]([N:4]([CH3:15])[S:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)(=[O:7])=[O:6])=[C:2]([N:1]=[O:29])[CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2N=O)cc1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
To a solution of 2′-amino-4′-chloro-N-methyl-p-toluenesulfonanilide (1.50 g (4.83 mmol)) in chloroform (20.0 ml), 70% mCPBA (m-chloro-perbenzoic acid) (2.38 g) was added with stirring at room temperature. After being stirred for 3 days at room temperature, saturated aqueous solution of sodium bicarbonate was added to the reaction mixture and the resulting mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:6) as eluent to give 1.15 g (73%) of the title compound as blue-green crystals.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[C:16]([CH3:21])[N:15]=1>>[Cl:13][C:14]1[N:15]=[C:16]([CH3:21])[CH:17]=[C:18]([O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)[N:19]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: Cc1cc(Cl)nc(Cl)n1
Product: Cc1cc(Oc2ccc(OC(F)(F)F)cc2)nc(Cl)n1
Yield: 60 %

Procedure:
Prepared in analogy to example 81a) from 4-trifluoromethoxyphenol and 2,4-dichloro-6-methylpyrimidine in a yield of 60%. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.28 (d, 2H), 7.18 (d, 2H), 6.65 (s, 1H), 2.50 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]([CH:13]=[CH:14][CH:15]([OH:27])[CH2:16][CH:17]([OH:26])[CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[C:11]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].CO.[OH-].[Na+:38]>O>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:27])[CH2:16][CH:17]([OH:26])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:38]
Reactant: CC(C)n1c(C=CC(O)CC(O)CC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 35 °C
Reaction time: 4.5 h
Yield: 31.6 %

Procedure:
A 100 ml round bottom flask was loaded with fluvastatin tert-butyl ester (4.0 g, 8.56 mmole), MeOH (24 ml) and NaOH (0.31 g) in water (2 ml). The mixture was heated to 35° C. and stirred for 4.5 h then water (10 ml) was added and the MeOH was evaporated. The volume of the water was completed to 8 vol. and the mixture was extracted with EtOAc (25 ml). The aqueous solution was evaporated to contain ca. 1 vol. water and ACN (60 ml) was added. The solution was stirred at room temperature over night. The product was isolated by filtration under nitrogen, washed with ACN and dried at 40° C. in a vacuum oven for 24 h to obtain 1.06 g (28.6%) of fluvastatin sodium crystal form XIV, having a peak at 12.4±0.2 degrees two-theta in the XRD pattern.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.[F:24]C1C=CC(NC(OCC=C)=O)=CC=1C(OC)=O.ClC1N=C(C)C=CN=1>>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][C:16]=2[F:24])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1ccc(F)c(C(=O)OC)c1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1
Agent: Cc1ccnc(Cl)n1
Product: C=CCOC(=O)Nc1ccc(F)c(C(=O)Cc2ccnc(Cl)n2)c1
Yield: 69.9 %

Procedure:
Using multiple iterations of a procedure analogous to the procedure described in Intermediate 11 using methyl 2-fluoro-5-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (104 g, 411 mmol) and 2-chloro-4-methylpyrimidine (59 g, 493 mmol), the title compound of Step B was obtained (100 g, 69.9% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.67-13.75 (br, 1H), 8.50-8.53 (m, 0.3H), 8.31-8.38 (m, 1H), 7.50-7.82 (m, 2.6H), 6.56-7.20 (m, 3.5H), 6.20-6.25 (m, 1H), 5.82-6.01 (1.3H), 5.20-5.40 (m, 2.6H), 4.50-4.61 (m, 2.6H), 4.31-4.41 (m, 0.9H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3]1.[Br:22]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)(Cl)Cl>[Br:22][C:9]1[C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[C:6]2=[N:7][C:8]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCc1cc(C)c2c(n1)N(C)CC2
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCc1nc2c(c(C)c1Br)CCN2C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 286 mg (0.99 mmol) of 1,4-dimethyl-6-decyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine in 4 mL of chloroform was added 143 mg (0.50 mmol) of 1,3-dibromo-5,5-dimethylhydantoin in portions at 0° C. The reaction mixture was stirred at 0° C. for 30 min. The reaction was quenched by the addition of 5 mL of sat aq NaHCO3. The mixture was extracted with chloroform and the combined organic layer was washed with brine and dried over MgSO4. The concentrated residue was purified by flash chromatography on a silica gel column (20 1.7 cm). Elution with 100:1 hexanes/ethyl acetate gave the product as a yellow oil: yield 342 mg (94%); silica gel TLC Rf 0.7 (8:1:1 hexanes/ethyl acetate/methanol); 1H NMR (CDCl3) δ 0.87 (t, 3H, J=6.8 Hz), 1.25-1.39 (m, 16H), 1.66 (quint, 2H, J=7.2 Hz), 2.17 (s, 3H), 2.77 (t, 2H, J=8.0 Hz), 2.83-2.87 (m, 5H) and 3.40 (t, 2H, J=8.0 Hz); 13C NMR (CDCl3) δ 14.1, 19.5, 22.7, 25.2, 28.7, 29.4, 29.54, 29.59, 29.64, 29.64, 31.9, 33.0, 38.1, 52.4, 110.9, 120.4, 141.1, 156.8 and 161.8; mass spectrum, m/z 366.2 and 268.2 (M)+ (theoretical 366.2 and 368.2); mass spectrum (APCI), m/z 367.1747 and 369.1673 (M+H)+ (C19H32N2Br requires 367.1749 and 369.1728).
Reaction SMILES: [Cl-:1].[Cl-].[CH3:3][Al+2:4].[CH3:5][Al:6]([Cl:8])[CH3:7].[CH3:9][Al](Cl)[Cl:11]>>[Cl-:8].[CH3:5][Al+:6][CH3:7].[Cl-:11].[Cl-:1].[CH2:3]([Al+2:4])[CH3:9]
Reactant: C[Al](C)Cl
Reactant: C[Al+2]
Reactant: C[Al](Cl)Cl
Agent: [Cl-]
Product: CC[Al+2]
Product: C[Al+]C

Procedure:
This example illustrates the use of a high Cl/Al atomic ratio. Dimethylaluminum chloride and ethylaluminum dichloride were prepared by a process similar to Reaction (1) above, except that methylaluminum dichloride was used as a starting material in place of methylaluminum sesquichloride. Hence, the reaction was as follows, with a starting mixture having a Cl/Al ratio of 1.75:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])[N:9]=2)[CH2:4]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35]>CN(C=O)C>[CH3:40][O:39][CH2:38][CH2:37][O:36][C:34](=[O:35])[NH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])[N:9]=2)[CH2:4]1
Reactant: Cc1ccc2c(N3CC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Reactant: COCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCOC(=O)NC[C@@H]1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
A solution of 2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (0.12 g, 0.35 mmol) and triethylamine (98 μL, 0.7 mmol) in anhydrous DMF (4.0 mL) was cooled in an ice bath. 2-Methoxyethyl chloroformate (40 mL, 0.35 mmol) was added, and the ice bath was removed. The solution was stirred at room temperature overnight. Purification via silica gel chromatography using 0-10% MeOH in CH2Cl2 gave 2-methoxyethyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate (0.12 g, 80%). LC/MS: m/z 437.5 (M+H)+ at 2.20 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH2:19]S(C(F)(F)F)(=O)=O)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH:30]([N:32]1[CH:36]=[N:35][CH:34]=[N:33]1)=C>>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH:19]=[CH:30][N:32]3[CH:36]=[N:35][CH:34]=[N:33]3)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cn1cncn1
Reactant: CC(C)(Cc1c[nH]c2c(CS(=O)(=O)C(F)(F)F)cccc12)NC(=O)OC(C)(C)C
Product: CC(C)(Cc1c[nH]c2c(C=Cn3cncn3)cccc12)NC(=O)OC(C)(C)C

Procedure:
{1,1-Dimethyl-2-[7-(2-[1,2,4]triazol-1-yl-vinyl)-1H-indol-3-yl]-ethyl}-carbamic acid tert-butyl ester is prepared from [1,1-dimethyl-2-(7-trifluoromethanesulfonylmethyl-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester and 1-vinyl-1,2,4-triazole as described for the preparation of Amine 23 (93%). FDMS m/e=381.2 (M++1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:9]1=[O:10]>>[OH:8][C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:12][CH2:11][C:9]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:10]
Reactant: CN1CCNCC1
Reactant: O=C1CCc2ccccc2O1
Product: CN1CCN(C(=O)CCc2ccccc2O)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 103.4 %

Procedure:
N-Methylpiperazine (1.23 g) was added to 3,4-dihydrocoumarine (1.80 g) and stirred for 2 hours at 80° C., thereby yielding the entitled compound (3.12 g) as pale brown solid.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12]([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]#C>CN(C=O)C>[CH3:12][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH2:7][C:18]#[CH:19]
Reactant: C#CCBr
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C=O)ccc1O
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(C=O)ccc1OC
Temperature: 80 °C
Yield: 79.4 %

Procedure:
A mixture of vanillin 17 (0.76 g, 4.90 mmol), K2CO3 (1.37 g, 9.90 mmol) and propargyl bromide (1.19 g, 6.90 mmol) in DMF (30 mL) was refluxed at 80° C. for 1 hr. Reaction mixture was cooled to 0° C. in ice bath and filtered through a short bed of celite. Ethyl acetate (50 mL) was added and the mixture was washed with 1N HCl (20 mL), extracted with ethyl acetate (100 mL). The organic phase was combined and washed with brine and dried over anhydrous Na2SO4. After filtration, solvent was removed under reduced pressure and the crude residue was purified by flash chromatography (hexane/ethyl acetate: 8/2) to afford 18 as white solid (0.74 g, 80%). 1HNMR (400 MHz, CDCl3) δ 2.57 (t, 1H), 3.94 (s, 3H), 4.85-4.86 (d, J=2.44 Hz, 2H), 7.13-7.15 (d, J=8.16 Hz, 1H), 7.43-7.47 (m, 2H), 9.87 (s, 1H); 13CNMR (100 MHz, CDCl3) δ 56.06, 56.65, 109.58, 112.71, 126.21, 131.00, 150.11, 152.17, 190.85.