Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C@H:2]([C@H:7]([CH2:9]Br)[OH:8])[C:3]([O:5][CH3:6])=[O:4].[C:11]([O-:14])(=[O:13])[CH3:12].[K+]>CN(C)C=O.C(OCC)(=O)C.[I-].[K+]>[C:11]([O:14][CH2:9][C@@H:7]1[O:8][C@@H:2]1[C:3]([O:5][CH3:6])=[O:4])(=[O:13])[CH3:12]
Reactant: CC(=O)[O-]
Reactant: COC(=O)[C@H](Br)[C@@H](O)CBr
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1O[C@H]1COC(C)=O
Temperature: 52.5 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
The general procedure of Manchand, et. al. (Manchand, et al., 1988) is employed. Methyl 2,4-dibromo-2,4-dideoxy-L-threonate (131 g, 474 mmol) is added to a stirred solution of potassium acetate (102 g, 1.04 mol) and potassium iodide (3.94 g, 23.8 mmol) in dimethyl formamide (500 mL). This mixture is stirred under nitrogen gas at 50-55° C. for 4 hours and overnight at room temperature. The reaction mixture is diluted with ethyl acetate (1 L) and filtered. The filter cake is washed with ethyl acetate (250 mL). The combined ethyl acetate portion is washed with saturated sodium bicarbonate solution (500 mL) and saturated brine (2×500 mL) and dried over magnesium sulfate. The solvent is removed to yield the title compound as a dark oil (82.0 g, 99% theoretical yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:12]([N:14]([CH3:21])[S@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Zn](CC)[CH2:23][CH3:24].O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:23]([C:2]1[CH:3]=[C:4]([C@H:12]([N:14]([CH3:21])[S@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[CH3:24]
Reactant: CC[Zn]CC
Reactant: C[C@H](c1cc(Br)cc(C(F)(F)F)c1)N(C)[S@@](=O)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc([C@@H](C)N(C)[S@@](=O)C(C)(C)C)cc(C(F)(F)F)c1
Temperature: 6 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
A mixture of (S)-N-((R)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethyl)-N,2-dimethyl propane-2-sulfinamide (1 g, 2.6 mmol), Pd(PPh3)2Cl2 (182 mg, 0.26 mmol) and Et2Zn (640 mg, 5.2 mmol) in THF (10 mL) under N2 atmosphere was stirred at 6° C. for 16 h. The reaction was poured into water (15 mL) and then extracted with EtOAc (2×30 mL). The combined organic layers were dried over anhydrous Na2SO4 and then concentrated. The residue was purified by silica gel chromatography (PE/EtOAc=10/1 to 1/1) to give the title compound (700 mg, yield: 80.3%); m/z (ES+): 336 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH:9][C:10](=O)C(C)(C)C)[C:6]([CH3:16])=[CH:5][CH:4]=1)[CH3:2].C([Li])(C)(C)C.CN(C)C=O.Cl>C(OCC)C>[CH2:1]([C:3]1[N:8]=[C:7]2[NH:9][CH:10]=[CH:16][C:6]2=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C)c(NC(=O)C(C)(C)C)n1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCc1ccc2cc[nH]c2n1
Temperature: -30 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
A solution of N-(6-ethyl-3-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (17.6 g, 0.080 mol) in diethyl ether (400 mL) is cooled to −78° C. and treated with tert-butyllithium (99 mL 1.7 M in pentane). After stirring for 1 h, the solution is warmed to −30° C. for 4 h and treated with N,N-dimethylformamide (19.8 mL, 0.26 mol). After stirring an additional 10 min, the suppension is carefully added to 6 N HCl, pre-cooled to −20° C., at a rate such that the temperature warms to about 0° C. After the addition is complete, the aqueous layer is subsequently washed with ethyl acetate and heated to a gentle reflux for 36 h. The resulting solution is cooled to 0° C. and basified with aq 6 N NaOH to pH 10-12. The solution is then extracted with dichloromethane, dried over MgSO4 and concentrated. The resulting pale orange solid is passed through a plug of silica gel with 30% ethyl acetate in hexanes and recrystaliztion from heptane to give 6-ethyl-1H-pyrrolo[2,3-b]pyridine (6.76 g, 58%) as an off-white solid. mp 117-120° C.; Rf 0.57 (50% ethyl acetate in hexanes); 1H NMR (DMSO-d6, 300 MHz) δ 11.46 (s, 1 H), 7.80 (d, J=8.1 Hz, 1 H), 7.33 (d, J=2.7 Hz, 1 H), 6.90 (d, J=8.1 Hz, 1 H), 6.34 (d, J=3.0 Hz, 1 H), 2.76 (q, J=7.5 Hz, 2 H), 1.23 (t, J=7.5 Hz, 3 H); LRMS calcd for C9H10N: 146.0; found 146.0 (M)+. Anal. Calcd for C9H10N: C, 73.94; H, 6.89; N, 19.16. Found C, 73.93; H, 6.91; N, 19.23.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([F:25])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>C(OC(=O)C)(=O)C.C(OCC)(OCC)OCC>[C:1]([N:4]1[CH2:5][CH:6]=[C:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:24])[C:18](=[CH:22][O:21][CH2:19][CH3:18])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([F:25])[CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(C2=CCN(C(C)=O)CC2)cc1F
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(C2=CCN(C(C)=O)CC2)cc1F

Procedure:
A solution of 3.95 g (11.25 mmol) ethyl 4-(1-acetyl-1,2,3,6-tetrahydro-4-pyridyl)-2,5-difluoro-β-oxobenzenepropionate in 25 ml of acetic anhydride and 2.8 ml of trietyl orthoformate was refluxed 1.5 hours. The title compound was isolated as a syrup after evaporation under vacuum in an oil bath at 80° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](O)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2].[NH2:37][C@@H:38]1[CH2:41][C@H:40]([C:42]([N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:43])[C:39]1([CH3:51])[CH3:50]>C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:31])[NH:37][C@@H:38]4[CH2:41][C@H:40]([C:42]([N:44]5[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]5)=[O:43])[C:39]4([CH3:51])[CH3:50])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)[C@H](N)C[C@@H]1C(=O)N1CCCCC1
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.410 g, 0.823 mmol) (Prepared as described in J. Med. Chem. 2009. 52, 3248-3258) in DCM (1 ml) Oxolyl chloride (0.71 ml, 8.232 mmol) in DCM (3.42 ml) was added at 0° C. and stirred at room temperature for about 3 hours and completion of the reaction was monitored by TLC, then the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (4 ml), which was added to a stirred solution of ((1S,3R)-3-amino-2,2-dimethylcyclobutyl)(piperidin-1-yl)methanone (step 2, 0.328 g, 1.56 mmol) at 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with aqueous 1N HCl, then washed with water and brine, and dried over Na2SO4 then the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.400 g; Yield: 71.9%; 1H NMR (300 MHz, CDCl3): δ 5.85 (d, 1H), 4.72 (s, 1H), 4.58 (s, 1H), 4.50-4.41 (m, 1H), 4.18-4.07 (m, 1H), 3.78-3.67 (m, 1H), 2.50-2.30 (m, 3H), 3.19-3.07 (m, 1H), 2.88 (t, 1H, J=8.1 Hz), 2.54-2.13 (m, 3H), 2.04 (s, 3H), 2.00-1.86 (m, 2H), 1.80-1.11 (m, 33H), 0.95, 0.93, 0.87, 0.83, 0.81 (s, 18H); Mass: [M+H]+ 691 (100%), [M+Na]+ 713 (25%); IR (KBr, cm−1): 3395, 2943, 2864, 1736, 1734, 1624, 1444, 1370, 1248, 1192, 1154, 1024, 979, 884; M.R: 140.2° C.-145.8° C.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)([O-:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:13]1[CH:14]=[CH:15][N:16]=[C:12]1[N+:9]([O-:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: O=[N+]([O-])c1ncc[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1nccn1Cc1ccccc1
Temperature: 25 °C
Yield: 50.4 %

Procedure:
Benzyl chloride (1.8 mL, 15.4 mmol, 1.2 equiv) was added to a solution of 2-nitroimidazole (1.45 g, 12.8 mmol) and triethylamine (3.6 mL, 25.7 mmol, 2 equiv) in DCM (40 mL). The reaction mixture was stirred at reflux for 72 h, allowed to cool to rt, diluted with DCM, washed with H2O and brine, dried (sodium sulfate), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc, 7:3) to afford 1.31 g of the title compound as a white solid: ES-MS: 204.0 [M+H]+; tR=3.72 min (System 1); TLC: Rf=0.22 (Hex/EtOAc, 7:3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][C:11]=1[C:18]1[C@@:19]2([CH3:27])[C:24]([CH3:26])([CH3:25])[C@@H:22]([CH:23]=1)[CH2:21][CH2:20]2.S(Cl)([Cl:30])=O>C(Cl)Cl.CN(C=O)C>[CH3:9][O:8][C:5]1[CH:4]=[C:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][Cl:30])=[CH:12][C:11]=2[C:18]2[C@@:19]3([CH3:27])[C:24]([CH3:26])([CH3:25])[C@@H:22]([CH:23]=2)[CH2:21][CH2:20]3)[C:2]([F:1])=[CH:7][CH:6]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2=C[C@H]3CC[C@]2(C)C3(C)C)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CCl)cc2C2=C[C@H]3CC[C@]2(C)C3(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a stirred solution of 66.15F (0.035 g, 0.10 mmol) in DCM (2.00 mL) and DMF (0.01 mL) at 0° C. was added thionyl chloride (0.01 g, 0.10 mmol). The reaction was then stirred at room temperature for 2 hours and was then concentrated in vacuo. The resulting product was then purified on silica gel (0-10% EtOAc in hexanes) to yield 66.15G as a colorless oil (0.035 g, 95% yield).
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][S:5]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH2:19]O)=[C:9]1[CH3:21])(=[O:7])=[O:6]>CS(C)=O.O1CCCC1>[CH3:4][S:5]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH2:19][C:1]#[N:2])=[C:9]1[CH3:21])(=[O:7])=[O:6]
Reactant: [C-]#N
Reactant: COc1ccc2c(c1)c(CO)c(C)n2S(C)(=O)=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1ccc2c(c1)c(CC#N)c(C)n2S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of potassium cyanide (3.0 g, 46.1 mmol) in methyl sulfoxide (16 ml) and tetrahydrofuran (4 ml) at 0° C. was added a solution of (1-methanesulfonyl-5-methoxy-2-methyl-1H-indol-3-yl)-methanol (0.26 g,) in tetrahydrofuran (20 ml) at 0° C. The reaction mixture was stirred at room temperature for 8 hours and then kept at 4° C. for 72 hours. The mixture was partitioned between ethyl acetate and water, and the organic extract was washed with brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 50 to 70% ethyl acetate in hexane) to give (1-methanesulfonyl-5-methoxy-2-methyl-1H-indol-3-yl)-acetonitrile as a white solid, (0.2 g, 13% in 2 steps). 1H NMR (CDCl3) δ: 2.58 (s, 3H), 3.03 (s, 3H), 3.71 (s, 2H), 3.88 (s, 3H), 6.93-6.99 (m, 2H), 7.91 (dd, 1H, J=8.9 Hz, 0.6 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH:13]([OH:15])[CH3:14])=[CH:5][NH:6]2.[C:16]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=O)[CH2:17][CH2:18][CH3:19].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:16]1([CH2:17][CH2:18][CH3:19])[C:5]2[NH:6][C:7]3[C:3]([C:4]=2[CH2:12][CH:13]([CH3:14])[O:15]1)=[C:2]([Br:1])[CH:10]=[CH:9][C:8]=3[F:11])[CH3:26]
Reactant: CC(O)Cc1c[nH]c2c(F)ccc(Br)c12
Reactant: CCCC(=O)CC(=O)OCC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCC1(CC(=O)OCC)OC(C)Cc2c1[nH]c1c(F)ccc(Br)c21
Reaction time: 3 h

Procedure:
To a solution of 1-(4-bromo-7-fluoro-1H-indol-3-yl)-propan-2-ol (155 mg, 0.570 mmol) and ethyl butyrylacetate (0.137 mL, 0.854 mmol) in CH2Cl2 (3 mL) was added BF3.OEt2 (0.11 mL, 0.854 mmol) dropwise at room temperature. After stirring for 3 hours, the mixture was diluted with CH2Cl2 (15 mL) and then washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 10% EtOAc in hexanes) to give (5-bromo-8-fluoro-3-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as a pale yellow solid (this sample contains ethyl butyrylacetate).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.C([O-])([O-])=O.[Na+].[Na+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](OB(O)O)=[CH:22][CH:21]=1>O1CCOCC1.CO>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)=[CH:22][CH:21]=1
Reactant: O=c1ccc2cc(Br)ccc2[nH]1
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O=c1ccc2cc(-c3ccc(Cl)cc3)ccc2[nH]1
Temperature: 110 °C

Procedure:
A solution of 22.7 g (0.101 mol) 6-bromo-1H-quinolin-2-one in 380 mL 1,4-dioxane and 380 mL MeOH is combined with 141.5 ml (0.283 ml) 2 M Na2CO3 solution and saturated with argon. Then 3.735 g (3.23 mmol) tetrakis-triphenyl-phosphane-palladium and 4-chlorophenylboric acid are added successively. The reaction mixture is heated to 110° C. for four hours and then evaporated down to a volume of 300 mL. 1.2 L water are added and the precipitate is filtered off. The solid is dried at 55° C. in the drying cupboard, washed with diisopropylether and dried again.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([NH:17][CH2:18][CH2:19][OH:20])([CH3:16])([CH3:15])[CH3:14]>C(O)C>[CH2:1]([O:8][CH2:9][CH:10]([OH:11])[CH2:12][N:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:18][CH2:19][OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)NCCO
Reactant: c1ccc(COCC2CO2)cc1
Solvent: CCO
Product: CC(C)(C)N(CCO)CC(O)COCc1ccccc1
Reaction time: 8 h
Yield: 83.5 %

Procedure:
A solution of 2-[(benzyloxy)methyl]oxirane (350 mg) and 2-(tert-butylamino)ethanol (500 mg) in ethanol (20 mL) was heated to reflux temperature and left at this temperature overnight. The solution was concentrated at reduced pressure. The residue was purified by filtration through a short pad of silica eluting with 20% methanol in dichloromethane. This gave the title compound as a colourless oil (501 mg)
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]1[C:34](Cl)=[N:35][CH:36]=[C:37]([CH:43]=1)[C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:34]2[C:33]([Cl:32])=[CH:43][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][N:35]=2)[CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)[CH3:22])=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Reactant: COc1cccc([C@@H](C)N(CC2CCNCC2c2ccccc2)C(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cnc(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc(OC)c3)C(c3ccccc3)C2)c(Cl)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
To a mixture of 119 mg of the crude tert-butyl[(1R)-1-(3-methoxyphenyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate, 62 mg of ethyl 5,6-dichloronicotinate, and 39 mg of potassium carbonate was added 1.0 mL of DMSO at room temperature, and the mixed solution was stirred at 100° C. overnight. After cooling to room temperature, to the reaction mixture was added water, followed by extraction with ethyl acetate, and the organic layer was then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 132 mg of ethyl 6-[4-({(tert-butoxycarbonyl)[(1R)-1-(3-methoxyphenyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-5-chloronicotinate as a colorless foamy substance. FAB+: 608
Reaction SMILES: [C:1]([Cu])#[N:2].Br[C:5]1[CH:6]=[N:7][CH:8]=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11]>CN(C=O)C>[CH3:13][O:12][C:10](=[O:11])[C:9]1[CH:14]=[C:5]([C:1]#[N:2])[CH:6]=[N:7][CH:8]=1
Reactant: N#C[Cu]
Reactant: COC(=O)c1cncc(Br)c1
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(C#N)c1
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 59.9 %

Procedure:
CuCN (5.22 g, 58.3 mmol) was added to a solution of methyl 5-bromonicotinate (6 g, 27.8 mmol) in dry DMF (150 mL). The solution was purged with argon and heated to 160° C. for 12 h under argon atmosphere. The reaction mixture was cooled to room temperature and then quenched with saturated NH4Cl solution. Further EtOAc was added and the reaction mixture was stirred for 10 min. The reaction mixture was filtered through a Celite plug, the organic layer was separated, washed with water and brine, and dried over anhydrous Na2SO4. Solvent was evaporated under reduced pressure to get methyl-5-cyano-nicotinate as greenish-white solid (2.7 g, yield 60%): 1H NMR (300 MHz, DMSO-d6) δ 9.29-9.27 (m, 2H), 8.77 (s, 1H), 3.91 (s, 3H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([C:25](=[O:27])[CH3:26])[C:12]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23]Br)=[CH:13][CH:14]=2)[CH:9]=1.[OH:29][C:30]1[C:35]([CH2:36][CH2:37][CH3:38])=[C:34]([OH:39])[CH:33]=[CH:32][C:31]=1[C:40](=[O:42])[CH3:41].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([C:25](=[O:27])[CH3:26])[C:12]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:39][C:34]3[CH:33]=[CH:32][C:31]([C:40](=[O:42])[CH3:41])=[C:30]([OH:29])[C:35]=3[CH2:36][CH2:37][CH3:38])=[CH:13][CH:14]=2)[CH:9]=1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: COC(=O)CCCOc1ccc2ccc(OCCOCCBr)c(C(C)=O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCOCCOc2ccc3ccc(OCCCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Yield: 86 %

Procedure:
A mixture of 1.6 g of 4-[[8-acetyl-7-[2-(2-bromoethoxy)ethoxy]-2-naphthalenyl]oxy]butanoic acid methyl ester, 0.82 g of 1-(2,4-dihydroxy-3-propylphenyl)-ethanone and 0.73 g of anhydrous potassium carbonate in 33 ml of anhydrous acetone and 11 ml of anhydrous dimethylformamide was stirred at reflux for 16 hours. The mixture was filtered and filtrate was concentrated to an oil. The oil was purified by high pressure liquid chromatography using 50% ethyl acetate-hexane to give 1.72 g (86%) of 4-[[8-acetyl-7-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-naphthalenyl)oxy]butanoic acid methyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:12][C:13](N)=[O:14]>>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:3]2[C:2]=1[N:1]=[C:13]([OH:14])[N:12]=[CH:4]2
Reactant: COc1cccc(C=O)c1N
Reactant: NC(N)=O
Product: COc1cccc2cnc(O)nc12
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Solid 2-amino-3-methoxybenzaldehyde (37.2 g, 0.246 mole), urea (158 g, 2.5 mole) and catalytic NH4OAc (1 g) were thoroughly mixed together in a roundbottom flask. The solid mixture was heated in a 160° C. bath. The solids quickly melted and stirring was commenced. After about 15 minutes, solids start to precipitate from the hot solution. After adding NMP (150 mL) to dissolve the solids, the reaction was heated with stirring for an additional 30-45 minutes until complete as judged by LCMS. The hot reaction mixture was poured into vigorously stirred water (400 mL). The reaction flask was washed out with water (3×100 mL) and EtOAc (4×50 mL). After stirring ca. 30 minutes, mixture was filtered to collect the light solid precipitate. The solid filter cake was washed with portions of water and EtOAc to give a white solid. The solid was dried on the frit and in vacuo to give the product in 99% purity and 95% yield (41 g, 233 mmole).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]1([NH:10]C(OC(C)(C)C)=O)[CH2:7][C@H:6]1[CH:8]=[CH2:9])=[O:4].[ClH:18].CO>O1CCOCC1>[ClH:18].[CH3:1][O:2][C:3]([C@@:5]1([NH2:10])[CH2:7][C@H:6]1[CH:8]=[CH2:9])=[O:4]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C=C[C@@H]1C[C@]1(N)C(=O)OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 76 %

Procedure:
Compound 20a (39.96 g, 165.7 mmol) was dissolved in dioxane (25 mL) and the solution added dropwise with stirring to 4 N HCl in dioxane (Aldrich, 250 mL). After 45 min, TLC analysis indicated complete deprotection. Volatiles were removed under reduced pressure, and the residue co-evaporated twice with MeOH (2×100 mL). Ether (300 mL) and MeOH (10 mL) were added to the brown, oily residue and the mixture stirred overnight at room temperature resulting in the precipitation of a semi-solid. Additional MeOH (15 mL) was added and stirring continued for 6 h, at which point a yellowish solid was collected by filtration. The product was washed with 5% MeOH in ether (50 mL) and ether (2×50 mL), and dried in vacuo to give compound 20b as a yellowish solid (22.60 g, 76% yield). Filtrates (including washings) were evaporated in vacuum to give additional 20b as a brown oil (7.82 g, 26% yield). Both fractions were pure enough for use in the synthesis of HCV protease inhibitors: [α]D25+38.2° (c 1.0, MeOH).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][C@@H:14]([CH3:18])[C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:23]=2[N:24]=1.[CH3:33][NH:34][CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:33][N:34]([CH3:35])[C:15]([C@@H:14]([NH:13][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:19][C:20]3[S:21][C:22]4[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[CH:25][C:23]=4[N:24]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])[CH3:18])=[O:16]
Reactant: CNC
Reactant: C[C@H](NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C)C(=O)N(C)C

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((S)-1-dimethylcarbamoyl-ethyl)-amide (25 mg) was prepared by following General Procedure F starting from (S)-2-{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionic acid (100 mg), dimethylamine (119 uL, 2 M in THF), HBTU (98 mg), and DIEA (57 uL), with a modification of General Procedure F where DIEA was slowly added to the reaction mixture as the last reagent. LC/MS: m/z 490.6. 1H NMR (DMSO-d6, 400 MHz): δ 8.56 (d, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 7.84 (d, 1H), 7.71 (d, 2H), 7.53 (d, 1H), 5.00-4.87 (m, 1H), 3.70 (s, 3H), 3.07 (s, 3H), 2.86 (s, 3H), 1.32 (d, 3H), —NH proton signal was not observed.