Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:17])[C:9]([O:15]C)=[C:10]([O:13]C)[CH:11]=2)[C:6](=[O:18])[C:5]([C:19]([O:21]CC)=[O:20])=[CH:4]1)[CH3:2].B(Br)(Br)Br>ClCCl.CO>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:17])[C:9]([OH:15])=[C:10]([OH:13])[CH:11]=2)[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2cc(OC)c(OC)c(F)c2c1=O
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CCn1cc(C(=O)O)c(=O)c2c(F)c(O)c(O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of ethyl 1-ethyl-5-fluoro-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (65 g, 201 mmol) in Dichloromethane (DCM) (300 mL) was added BBr3 (95 mL, 1005 mmol) at −78° C. The mixture was allowed to warm up to rt, and stirred at 25° C. overnight. LCMS indicated completion of the reaction. The mixture was diluted with MeOH and concentrated to dryness. The same process was repeated several times to afford 1-ethyl-5-fluoro-6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (48 g, 180 mmol, 89% yield) as yellow solid. The crude product was a mixture of acid and small amount of methyl ester, which was used in next step reaction without further purification. LCMS: (M+H)+: 268.0.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)=[N:12][NH:11][C:10]2=[O:20])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[C:30](Cl)(=[O:33])[CH2:31][CH3:32]>ClCCl>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:16]3)=[N:12][NH:11][C:10]2=[O:20])=[CH:5][CH:4]=1
Reactant: CCC(=O)Cl
Reactant: O=c1[nH]nc(C[C@@H]2CCNC2)n1-c1ccc(Br)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
In a 4 mL screwcap vial was placed 4-(4-bromophenyl)-5-[(3S)-3-pyrrolidinylmethyl]-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride (0.278 mmol). Added to the vial were dichloromethane (2 mL) and N,N-diisopropylethylamine (0.859 mmol). The vial contents were stirred for 1 min, at which point propanoyl chloride (0.319 mmol) was added. The vial was capped and the contents were stirred at room temperature for 2 h. The reaction was quenched with saturated aq NH4Cl (1 mL) and the solution was stirred vigorously for 1 min. The separation of the two layers occurred upon settling of the solution. The organic layer was removed, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (0-10% methanol:ethyl acetate) was utilized to purify the title compound (65 mg, 61% yield). MS(ES)+ m/e 379.1, 380.8 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16]C(C)(C)C)=[O:15])=[CH:12][CH:11]=1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C2Cc3ccccc3O2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(C2Cc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of tert-butyl 4-(2,3-dihydrobenzofuran-2-yl)benzoate (0.03 g, 0.1 mmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was removed in vacuo, and the mixture was dissolved in dichloromethane (50 mL), washed with water (50 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo to give pure product 4-(2,3-dihydrobenzofuran-2-yl)benzoic acid as a white solid (0.02 g, 80%).
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][C@H:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=3)[CH3:19])[C:14]([C:27]([NH2:29])=[O:28])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[CH3:30][O:31][C:32]1[C:37]([NH2:38])=[CH:36][CH:35]=[CH:34][N:33]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@@H:18]([NH:17][C:15]2[C:14]([C:27]([NH2:29])=[O:28])=[CH:13][N:12]=[C:11]([NH:38][C:37]3[C:32]([O:31][CH3:30])=[N:33][CH:34]=[CH:35][CH:36]=3)[N:16]=2)[CH3:19])=[N:21][CH:22]=1
Reactant: COc1ncccc1N
Reactant: C[C@H](Nc1nc(On2nnc3ccccc32)ncc1C(N)=O)c1ccc(F)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ncccc1Nc1ncc(C(N)=O)c(N[C@@H](C)c2ccc(F)cn2)n1
Yield: 68.5 %

Procedure:
A solution of (S)-2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(1-(5-fluoropyridin-2-yl) ethyl amino)pyrimidine-5-carboxamide (Preparation 5c, 30 mg, 0.08 mmol), 2-methoxy pyridin-3-amine (14 mg, 0.11 mmol) and p-toluenesulfonic acid hydrate (15 mg, 0.08 mmol) in 1,4-dioxane (3 mL) was heated at 120° C. for 4 hours. The solvent was evaporated under reduced pressure and the resulting residue was purified by reverse phase chromatography (C-18 silica from Waters©, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give the title compound (21 mg, 72%) as a solid.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([F:24])=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1>O1CCOCC1.C(Cl)Cl>[C:1]1([C@H:7]([NH:9][C:11]2[C:20]3[C:15](=[CH:16][C:17]([F:24])=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1F
Reactant: C[C@@H](N)c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H](Nc1ncnc2cc(F)c([N+](=O)[O-])cc12)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 74 ml of (R)-1-phenyl-ethylamine in 100 ml of dioxane is added dropwise to 108.8 g of 4-chloro-6-nitro-7-fluoro-quinazoline in 800 ml of methylene chloride while cooling with an ice bath. The reaction mixture is stirred overnight at ambient temperature. For working up it is extracted with water. The organic phase is dried over magnesium sulphate and evaporated down. The residue is purified by chromatography through a silica gel column with petroleum ether/ethyl acetate (1:1) as eluant.
Reaction SMILES: [CH:1]1([N:7]([CH2:13][CH3:14])[C:8](=[O:12])[O:9][CH2:10]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:15][C@@H:16]([C@H:18]1[C:38](=[O:39])[N:20]2[C:21]([C:35]([O-:37])=[O:36])=[C:22]([S:25]/[CH:26]=[CH:27]\[C:28]3[S:32][CH:31]=[N:30][C:29]=3[CH2:33][OH:34])[C@H:23]([CH3:24])[C@H:19]12)[CH3:17].[Na+]>>[OH:15][C@@H:16]([C@H:18]1[C:38](=[O:39])[N:20]2[C:21]([C:35]([O:37][CH2:10][O:9][C:8]([N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:13][CH3:14])=[O:12])=[O:36])=[C:22]([S:25]/[CH:26]=[CH:27]\[C:28]3[S:32][CH:31]=[N:30][C:29]=3[CH2:33][OH:34])[C@H:23]([CH3:24])[C@H:19]12)[CH3:17]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CCN(C(=O)OCCl)C1CCCCC1
Agent: [Na+]
Product: CCN(C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12)C1CCCCC1
Yield: 67.9 %

Procedure:
In the same manner as in step b) in Example 125, 285 mg of the title compound was prepared from 190 mg of chloromethyl N-cyclohexyl-N-ethylcarbamate and 300 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethyl-thiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:13][C:12]([O:14][CH3:15])=[N:11][C:10]([CH3:16])=[C:9]2[C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:23]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:13]([C:22]([O:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:23])[C:12]([O:14][CH3:15])=[N:11][C:10]([CH3:16])=[C:9]2[C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(C)N=C(OC)NC1c1ccc(F)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1=C(C)N=C(OC)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 6-(4-fluorophenyl)-2-methoxy-4-methyl-1,6-dihydro-5-pyrimidinecarboxylate (1.76 g, 6.34 mmol) and 4-dimethylaminopyridine (12.7 mmol, 1.55 g) in anhydrous CH2Cl2 (20.0 mL) was added solution of 4-nitrophenyl chloroformate (4.47 g, 22.2 mmol) in CH2Cl2 (20.0 mL) at 23° C. The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was diluted with CH2Cl2 (50 mL), washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (hexanesiethyl acetate 4:1). The product was obtained as yellow syrup, which upon trituration with hexanes became a white powder (2.40 g, 84.3%). The crude product was used in next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)(=O)C.S(Cl)([Cl:19])(=O)=O>C(OCC)C>[NH2:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([Cl:19])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: Nc1c(O)cccc1C(=O)O
Solvent: CC(=O)O
Solvent: CCOCC
Product: Nc1c(O)cc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.7 %

Procedure:
A 25-mL round bottomed flask equipped with a magnetic stirrer was charged with 2-amino-3-hydroxybenzoic acid (0.852 g, 5.59 mmol), acetic acid (0.4 mL) and diethyl ether (0.4 mL). After cooling to 0° C. sulfuryl chloride (0.754 g, 5.59 mmol) was added and the reaction stirred at ambient temperature for 4 h. Dilution with ether (15 mL), filtration and purification by preparative HPLC afforded 0.500 g (48% yield) of 2-amino-5-chloro-3-hydroxybenzoic acid as a white solid: 1H NMR (500 MHz, CD3OD) δ 7.29 (d, J=9.5 Hz, 1H), 6.76 (d, 1H, J=9.5 Hz, 1H) MS (ESI) m/z 186 (M−H).
Reaction SMILES: [F:1][C:2]([F:55])([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[C@H:11]([C:25](N1[C@@H](C(C)C)C(C2C=CC=CC=2)(C2C=CC=CC=2)SC1=O)=[O:26])[C@@:12]([OH:24])([CH2:20][CH2:21][O:22][CH3:23])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:56][C@@H:57]([CH2:62][C:63]1[CH:68]=[CH:67][C:66]([O:69][CH2:70][CH2:71][CH2:72][CH3:73])=[CH:65][CH:64]=1)[C:58]([O:60][CH3:61])=[O:59]>ClCCl>[CH2:70]([O:69][C:66]1[CH:65]=[CH:64][C:63]([CH2:62][C@H:57]([NH:56][C:25]([C@@H:11](/[CH:10]=[CH:9]/[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:55])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C@@:12]([OH:24])([CH2:20][CH2:21][O:22][CH3:23])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:26])[C:58]([O:60][CH3:61])=[O:59])=[CH:68][CH:67]=1)[CH2:71][CH2:72][CH3:73]
Reactant: CCCCOc1ccc(C[C@H](N)C(=O)OC)cc1
Reactant: CCCCCCCC(F)(F)CCCCCC/C=C/[C@H](C(=O)N1C(=O)SC(c2ccccc2)(c2ccccc2)[C@@H]1C(C)C)[C@@](O)(CCOC)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCCCCCCC(F)(F)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)OC)[C@@](O)(CCOC)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 60 h
Yield: 87 %

Procedure:
tert-Butyl (E)-(2S,3S)-12,12-difluoro-2-hydroxy-3-((S)-4-isopropyl-2-oxo-5,5-diphenyl-thiazolidine-3-carbonyl)-2-(2-methoxy-ethyl)-nonadec-4-enoate (No. 5552816; 17.0 mg, 0.0216 mmol) and methyl (S)-2-amino-3-(4-butoxy-phenyl)-propionate (8.2 mg, 0.0324 mmol) were dissolved in dichloromethane and the solvent was distilled off. The resulting mixture was stirred at 50° C. for 2.5 days, cooled to room temperature, and subsequently the residue was purified by preparative TLC (33% ethyl acetate/n-hexane, Rf=0.6) to obtain tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoate (No. 5552820; 13.9 mg, 87% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[C:7](=[CH2:16])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1.C12BC(CCC1)CCC2.C1C[O:31]CC1>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH:7]([CH2:16][OH:31])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: C1CCOC1
Reactant: C=C1c2ccccc2C=Cc2cc(OC)ccc21
Agent: B1C2CCCC1CCC2
Product: COc1ccc2c(c1)C=Cc1ccccc1C2CO
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-methoxy-5-methylene-dibenzo [a,d]cycloheptene (12.8 g) in dry THF (50 ml), under an inert atmosphere, was added 9-borabicyclo[3,3,1]nonane (116 ml of a 0.5 molar solution in THF) at ambient temperature, and the reaction mixture was then refluxed for 3h. After cooling in an ice bath the reaction was quenched by the slow addition of 2N sodium hydroxide solution (150 ml) and 30% hydrogen peroxide (30 ml). After stirring vigorously at 0° C. for 45 minutes the reaction mixture was allowed to warm to room temperature over a period of 2h then extracted with diethyl ether (3×200 ml). The combined organic layers were washed with brine (1×300 ml), dried (Na2SO4), filtered and concentrated in vacuo to leave a residue, which was purified by chromatography on flash silica with 30% ethyl acetate in hexane as eluent, to give the title compound (10.9 g) as an oil. δ(360 MHz, CDCl3) 3.77-3.81 (2H, d, J=8.1 Hz, CH2), 3.80 (3H, s, OCH3), 4.16 (1H, t. J=8.1 Hz, CH--CH2OH), 6.79 (1H, d, J=11.9 Hz, ArCHA =CHB --Ar), 6.33 (1H, d, J=2.6 Hz, CH=C(OCH3)--CH), 6.85 (1H, d, J=11.9 Hz, Ar--CHA =CHB --Ar), 6.89 (1H, dd, J=8.3 and 2.6 Hz, CH=C(OCH3)CH) and 7.23-7.33 (5H, m, aromatics). m/e (CI+) 253 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][S:8][CH2:9]2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:23][C:24]([F:33])([F:32])[C:25](C1NC=CN=1)=[O:26].Cl>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH:7]([C:25](=[O:26])[C:24]([F:33])([F:32])[F:23])[S:8][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(c1ncc[nH]1)C(F)(F)F
Reactant: O=C1CSCc2cc(Cl)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2ccc(Cl)cc2CSC1C(=O)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
7-Chloroisothiochroman-4-one from Step 3 (0.3 g, 1.5 mmol) was dissolved in tetrahydrofuran (15 mL) and cooled to -78° C. A solution of sodium bistrimethylsilyl amide (1.5 mL of a 1.0M tetrahydrofuran solution) was added and the reaction stirred for 0.5 hours at -78° C. Trifluoroacetyl imidazole (0.21 mL, 1.8 mmol) was added and the reaction was warmed to room temperature and stirred under a nitrogen atmosphere for 16 hours. 1N Hydrochloric acid (100 mL) was added to the reaction followed by extraction with ether (150 mL). The organics were washed with brine (75 mL), dried over MgSO4 and concentrated in vacuo. The resulting yellow oil was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[CH2:7]2)[CH2:3][CH2:2]1.[CH2:16]=O>C(O)=O>[CH3:16][N:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[CH2:7]2)[CH2:3][CH2:2]1
Reactant: O=C1CC2(CCNCC2)c2ccccc21
Reactant: C=O
Solvent: O=CO
Product: CN1CCC2(CC1)CC(=O)c1ccccc12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To the product of Example 138A were added formic acid (88% sol, 0.64 g) and formaldehyde (36% sol, 0.45 g) and stirred at 120° C. overnight. The crude product was used in the next step.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Cl[CH2:13][CH2:14][CH2:15][O:16][CH3:17]>>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=[C:5]([O:11][CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH:6]=1
Reactant: COCCCCl
Reactant: COc1cc(O)cc(CO)c1
Product: COCCCOc1cc(CO)cc(OC)c1

Procedure:
Analogously to Method F, 3.15 g of 3-hydroxymethyl-5-methoxyphenol are reacted with 1-chloro-3-methoxypropane. The title compound is obtained as a slightly yellowish oil. Rf=0.27 (1:1 EtOAc-heptane). Rt=3.23.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[Br-:13].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.O>[C:1]([C:5]1[CH:10]=[C:9]([Br:13])[CH:8]=[CH:7][C:6]=1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1C(C)(C)C
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a solution of 2-(t-butyl)anisole (16.38 g, 0.0997 mol) in CH2Cl2 (350 mL) was added pyridinium tribromide (35.09 g, 0.110 mol). The resulting mixture was allowed to stir at RT overnight. The mixture was diluted with CH2Cl2 and H2O and the layers were separated, the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were washed with H2O, brine and dried with MgSO4. The mixture was filtered and the solvents evaporated to give 2-(t-butyl)-4-bromoanisole as an oil (23.16 g, 95%). 1H NMR (300 MHz, CDCl3): δ 1.35 (s, 9H), 3.82 (s, 3H), 6.74 (d, J=8.7 Hz, 1H), 7.28 (dd, J1=8.7 Hz, J2=2.4 Hz, 1H), 7.35 (d, J=2.4 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11](Cl)=[O:12].[CH2:15]([OH:17])[CH3:16]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:17][CH2:15][CH3:16])=[O:12]
Reactant: CCO
Reactant: COC(=O)/C=C/[C@H]1[C@@H](C(=O)Cl)C1(C)C
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)[C@@H]1[C@H](/C=C/C(=O)OC)C1(C)C

Procedure:
Using the procedure of Example 3, 1.51 g of (1R,cis) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylic acid chloride in 10 ml of benzene and 0.465 ml of ethanol were reacted to obtain 0.837 g of ethyl (1R,cis) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =-21°±1.5° (c=1% in chloroform).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[C:3]1=[O:12].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:30][C:31]1[CH:36]=[CH:35][C:34]([Pb+3])=[C:33]([CH2:38][CH3:39])[CH:32]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([CH:6]2[C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[C:3](=[O:12])[C:2]([CH3:13])([CH3:1])[C:7]2=[O:8])=[C:33]([CH2:38][CH3:39])[CH:32]=1
Reactant: CC1(C)C(=O)CC(=O)C(C)(C)C1=O
Reactant: CCc1cc(Br)ccc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1cc(Br)ccc1C1C(=O)C(C)(C)C(=O)C(C)(C)C1=O
Temperature: 80 °C
Yield: 35.5 %

Procedure:
2,2,6,6-Tetramethylcyclohexane-1,3,5-trione (5 g, 0.027 mol) and 4-dimethylamino-pyridine (16.47 g, 0.135 mol) are added to a mixture of chloroform (100 ml) and toluene (25 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4-Bromo-2-ethylphenyllead triacetate (17.16 g, 0.03 mol) is added in one portion and the reaction mixture is stirred and heated to 80° C. (pre-heated oil bath) under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The organic phase is collected, and the aqueous phase is extracted with dichloromethane (2×75 ml). the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-(4-bromo-2-ethylphenyl)-2,2,6,6-tetramethyl-cyclohexane-1,3,5-trione as a white solid (3.5 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24](Br)[N:23]=2)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.O.[CH3:36][N:37](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:36]#[N:37])[N:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N(c2ccc(F)c(Cl)c2)c2cccc(Br)n2)C1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](N(c2ccc(F)c(Cl)c2)c2cccc(C#N)n2)C1
Temperature: 110 °C
Reaction time: 9 h

Procedure:
3(S)-[(6-bromopyridin-2-yl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 1.06 mmol), zinc cyanide (250 mg, 2.12 mmol) and tetrakis(triphenylphosphine)palladium (122 mg, 0.106 mmol) were suspended in 8 ml of dimethylformamide (DMF), followed by stirring under a nitrogen atmosphere at 110° C. for 9 hours. After cooling to room temperature, ethyl acetate and water were added to the reaction solution to separate the solution into layers. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1→3:1). The solvent was distilled off from the purified product under reduced pressure to thereby obtain 398 mg of oily colorless 3(S)-((3-chloro-4-fluorophenyl)-(6-cyanopyridin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@:9]23[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:23][C:24]([CH3:28])=[CH:25][CH2:26]Br.O>CN(C)C=O>[CH3:23][C:24]([CH3:28])=[CH:25][CH2:26][N:12]1[C:11](=[O:20])[CH2:10][C@@:9]2([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[C:13]1=[O:19]
Reactant: COc1cccc([C@@]23CCCC[C@H]2C(=O)NC(=O)C3)c1
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc([C@@]23CCCC[C@@H]2C(=O)N(CC=C(C)C)C(=O)C3)c1
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A solution of 4 g (14.7 mmoles) of 4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline in 50 ml of anhydrous dimethylformamide was added dropwise to 700 mg of a 55% suspension of sodium hydride in mineral oil in 50 ml of dimethylformamide at 70°. The reaction mixture was heated for 1 hour after the addition was complete and then cooled to 25°. 3,3-Dimethylallyl bromide (2.37 g, 15.8 mmoles) in 10 ml of dimethylformamide was added dropwise and the solution stirred overnight at 25°. After heating at 80° for 1 hour it was poured into water and extracted with ether to yield 4.74 g of N-(3,3-dimethylallyl)-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline (oil), which was evaporatively distilled, bp 225° (0.005 mm).
Reaction SMILES: [Li+].[BH4-].C([O:5][C:6](=O)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([O:16][CH3:17])[CH:9]=1)C.O>C1COCC1>[OH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([O:16][CH3:17])[CH:9]=1
Reactant: CCOC(=O)Cc1ccc(C#N)c(OC)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CCO)ccc1C#N
Reaction time: 12 h

Procedure:
LiBH4 (1.7 mL, 3.4 mmol, 2 M in THF) was added to a stirred solution of ethyl(4-cyano-3-methoxyphenyl)acetate (0.50 g, 2.4 mmol) in THF (25 mL) at 0° C. The resulting solution was stirred for 12 h. Water (15 ml) was added, and the resulting solution was extracted with dichloromethane (2×50 ml). The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography eluting with EtOAc-Hexanes (7:3→1:1) to give 4-(2-hydroxyethyl)-2-methoxybenzonitrile. 1H NMR (500 MHz, CDCl3) δ 7.52 (d, 1H, J=7.0 Hz), 6.91 (d, 1H, J=7.8 Hz), 6.88 (s, 1H), 3.95 (s, 3H), 3.92 (t, 2H, J=6.4 Hz), 2.93 (t, 2H, J=6.4 Hz); LCMS: [(M+1)]+=178.3; tR=2.1 min.