Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=[O:3])C.[O:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH2:6]1.[OH-].[Na+].Cl>C(O)C>[O:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:3])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH2:6]1
Reactant: C1=Cc2ccccc2OC1
Reactant: CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1ccc2c(c1)C=CCO2
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 291.5 %

Procedure:
A solution of the chromene acetate (1.0 g, 2.13 mmol) in ethanol (20 mL) was treated with 2 N NaOH (20 mL) and stirred at 60° C. for 90 min. The reaction mixture was cooled, acidified with 5 N HCl, and the ethanol was removed in vacuo. The resulting aqueous solution was extracted with ether and concentrated to a light yellow oil that was purified by silica gel chromatography eluting with ethyl acetate (15%, v/v) in hexanes. This yielded the desired chromene-6-ol intermediate as a colorless oil (0.92 g, 98%). 1H-NMR (CDCl3/TMS, ppm): 0.87 (m, 12H, 4a′-, 8a′-, 12a′-, 13′-CH3), 1.0-1.6 (m, 24H, 4′-, 8′-, 12′-CH, 2′-, 3′-, 5′-, 6′-, 7′-, 9′-, 10′-, 11′-CH2, 2a-CH3), 2.14, 2.18, 2.19 (3×s, 9H, 5a-, 7a-, 8a-CH3), 5.63, 6.55 (2×d, J=10.0 Hz, 2H, CH); 13C-NMR (CDCl3, ppm): 10.8, 11.6, 12.4 (5a-, 7a-, 8a-CH3), 19.6, 19.7 (CH3), 21.3 (CH2), 22.6, 22.7 (CH3), 24.4, 24.8 (CH2), 25.2 (2a-CH3), 27.9 (CH), 30.9 (3-CH2), 32.7, 32.8 (CH), 37.2, 37.4, 37.5, 39.3, 40.5 (CH2), 50.8 (2-C), 116.2, 117.8, 120.1, 122.3, 123.0, 130.0 (aryl and vinyl C), 144.6, 145.3 (aryl C—O), 169.4 (CO); HRMS (CI, m/z): 428.365275 M+H+, Calc. for C29H48O2 428.365431.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([C@@H:10]2[CH2:12][C@H:11]2[C:13]2[N:17]([CH3:18])[C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[N:14]=2)[CH:4]=1)[NH2:2].[Si:23]([O:30][C@@H:31]([CH3:40])[C:32]([N:34]=[C:35](N(C)C)[CH3:36])=O)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].C(=O)(O)[O-].[Na+]>C(O)(=O)C.COCCOC>[Si:23]([O:30][C@H:31]([C:32]1[N:1]([C:3]2[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([C@@H:10]3[CH2:12][C@H:11]3[C:13]3[N:17]([CH3:18])[C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=4[N:14]=3)[CH:4]=2)[N:2]=[C:35]([CH3:36])[N:34]=1)[CH3:40])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(=NC(=O)[C@H](C)O[Si](C)(C)C(C)(C)C)N(C)C
Reactant: Cc1nc(NN)cc([C@@H]2C[C@H]2c2nc3ccccc3n2C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(=O)O
Product: Cc1nc([C@@H]2C[C@H]2c2nc3ccccc3n2C)cc(-n2nc(C)nc2[C@H](C)O[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of Intermediate 6 (1.8 g, 6.1 mmol) in acetic acid (40 ml) was added Intermediate 13 (4.0 g, 14.7 mmol) as a crude reaction mixture in 1,2-dimethoxyethane (40 mL). The reaction mixture was allowed to stir for 5 minutes at room temperature and then heated at 80° C. for 1 h. The reaction was cooled to room temperature, poured carefully over saturated aqueous sodium bicarbonate solution (200 mL), and the aqueous layer was made basic to pH˜8 by the addition of solid sodium bicarbonate. The solution was extracted with ethyl acetate (200 mL) and the organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-60% EtOAc/hexanes) to afford 13-1 as an oil. MS: m/z=504.4 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[CH:7][CH2:6][CH2:5]2.[C:17]([Cu])#[N:18]>CN1CCCC1=O>[C:17]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[CH:7][CH2:6][CH2:5]2)#[N:18]
Reactant: N#C[Cu]
Reactant: Brc1ccc2c(c1)CCC=C2n1ccnc1
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2c(c1)CCC=C2n1ccnc1

Procedure:
6-bromo-1-(1-imidazolyl)-3,4-dihydronaphthalene (Example 6) is converted by reaction with CuCN in 1-methylpyrrolidone into the title compound, m.p. 152°-153°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:13]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:14]
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CCOC(=O)[C@H](C)N
Product: CCOC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure G' and using 3,5-difluorophenylacetic acid (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared as a solid with a melting point of 93°-95° C. The reaction was monitored by tlc on silica gel (Rf=0.8 in EtOAC) and purification was by chromatography on silica gel using EtOAc as the eluant followed by recrystallization from 1-chlorobutane.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:26]=[C:27]([CH3:28])[C:21]=2[N:20]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:35][OH:36]>C(N=C=O)(C)C>[CH:3]([NH:11][C:35]([N:32]1[CH2:31][CH2:30][N:29]([C:25]2[CH:26]=[C:27]([CH3:28])[C:21]3[N:20]=[C:19]([C:13]4[C:14](=[O:18])[NH:15][CH:16]=[CH:17][C:12]=4[NH:11][C@H:3]([CH2:2][OH:1])[CH2:4][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:23][C:22]=3[CH:24]=2)[CH2:34][CH2:33]1)=[O:36])([CH3:4])[CH3:2]
Reactant: Cc1cc(N2CCNCC2)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Reactant: CO
Agent: CC(C)N=C=O
Product: Cc1cc(N2CCN(C(=O)NC(C)C)CC2)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69 %

Procedure:
To a solution of (S)-4-(1-hydroxymethyl-2-phenyl-ethylamino)-3-(4-methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-pyridin-2-one (30 mg, 0.063 mmol) in methanol (2 mL) was added isopropyl isocyanate (2 drops). The reaction mixture was stirred at room temperature for 5 min. Concentration gave the residue, which was purified by prep. HPLC to yield the title compound (23.8 mg, 69%). 1H NMR (400 MHz, CD3OD) δ 7.55 (1H, s), 7.14–7.28 (7H, m), 6.12 (1H, d, J=7.8 Hz), 4.01–4.03 (1H, m), 3.92 (quintet, J=6.6 Hz), 3.80 (4H, m), 3.76 (1H, dd, J=4.8, 11.2 Hz), 3.70 (1H, dd, J=5.2, 11.2 Hz), 3.61–3.64 (4H, m), 3.09 (11H, dd, J=5.6, 13.7 Hz), 2.91 (1H, dd, J=8.0, 13.7 Hz), 2.64 (3H, s), 1.19 (6H, d, J=6.8 Hz). LCMS (M+H)+ m/z 545 (t=1.99 min.).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Ca+2].[OH-].[C:12](Cl)(=O)[CH2:13][CH2:14]CC>C(Cl)Cl.C(C(C)=O)C>[C:3]([CH2:2][C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH2:5][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(=O)Cl
Reactant: COC(=O)CC(C)=O
Agent: [Ca+2]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CCCCC(=O)CC(=O)OC
Yield: 95.5 %

Procedure:
Under the same conditions as in Example 1, 116 g (1.0 mol) of methyl acetoacetate in a mixture of 520 ml of methylene chloride and 30 ml of methyl ethyl ketone were reacted with 77.8 g (1.05 mol) of calcium hydroxide and 138.7 g (1.15 mol) of valeryl chloride. The pH in this gave 151 g (GC purity 82.5%) of methyl valerylacetate (yield 79.0%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>C(Cl)Cl>[CH2:26]([N:28]([CH2:29][CH3:30])[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[O:3][C:2]([F:1])([F:14])[F:13])[CH3:27]
Reactant: O=C(O)c1ccccc1OC(F)(F)F
Reactant: CCNCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccccc1OC(F)(F)F
Reaction time: 4 h
Yield: 94.1 %

Procedure:
To a stirring solution of 2-trifluoromethoxybenzoic acid (3.6 g, 17.5 mmol, Avocado) in dry CH2Cl2 (150 mL) with DMF (0.5 mL) was added a 2M solution of oxalyl chloride in CH2Cl2 (17.5 mL) dropwise over 30 min. The reaction was stirred for 4 h and then conc. in vacuo to a white solid. The solid was dissolved in CH2Cl2 (150 mL) and reacted with diethylamine (3.2 g, 43.8 mmol, Aldrich) the reaction was stirred for 16 h and then conc. in vacuo to a yellow solid. The solid was purified by radial chromatography (SiO2, 1:5, EtOAc:hexanes) to yield 4.3 grams (94%) of the product as a colorless oil. MS (ESI) 262 (M+H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH2:7][CH2:8][C:9]1([OH:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Cl:1][CH2:2][C:3]([NH:6][CH2:7][CH2:8][C:9]1([OH:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][CH2:10]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CCN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(O)(CCNC(=O)CCl)CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Chloroacetyl chloride (0.483 mL) was added dropwise over 10 minutes to a vigorously stirred mixture at 0° C. of tert-butyl 4-(2-aminoethyl)-4-hydroxypiperidine-1-carboxylate (example 89, step b) (1.1 g) in ethyl acetate (25 mL) and potassium carbonate (1.77 g) dissolved in water (20 mL). The mixture was then stirred at 0° C. for 45 minutes before being extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography eluting with ethyl acetate. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.9 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18].[C:20]1(C)C=C(C)C=C(C)C=1Cl>CN(C=O)C>[OH:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9](=[O:19])[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:20][O:1]2)=[CH:4][CH:5]=1
Reactant: COc1ccccc1CC(=O)c1ccc(O)cc1O
Reactant: Cc1cc(C)c(Cl)c(C)c1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1coc2cc(O)ccc2c1=O
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
BF3—OEt2 complex (14 ml, 112 mmol) was gradually added to a solution of 1-(2,4-dihydroxy-phenyl)-2-(2-methoxy-phenyl)-ethanone (7.2 gm, 28 mmol) in DMF at 0° C. The resulting solution was stirred for 30 min. Mesityl chloride (6.5 ml, 84 mmol) was then gradually added to it at 50° C. The solution was then heated up to 110° C. for 5 hours. The mixture was then concentrated. The residue was treated with ice and the solid obtained was purified with silica gel column chromatography using hexane-chloroform as the eluent to give 7-hydroxy-3-(2-methoxy-phenyl)-chromen-4-one (5.6 gm, 75%) as white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:25][C:13]([F:12])([F:24])[C:14]1[CH:15]=[CH:16][C:17]([S:20]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH:10]=[O:11])=[CH:2]2)(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=Cc1cn(S(=O)(=O)c2ccc(C(F)(F)F)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of 1H-indole-3-carboxaldehyde (0.290 g, 2.00 mmol) in methylene chloride (4 mL) was added with 4-(trifluoromethyl)phenylsulfonyl chloride (0.587 g, 2.40 mmol) and diisopropylethylamine (0.310 g, 2.40 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate to terminate the reaction, and then extracted three times with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 1-[4′ (trifluoromethyl)phenylsulfonyl]-1H-indole-3-carboxaldehyde (0.650 g, 92%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.C(N(CC)C(C)C)(C)C.Cl[C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1>CN1C(=O)CCC1>[NH:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=[C:31]1[NH:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:4]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c(CNc2nc3ccccc3[nH]2)cn(-c2ccccc2)c2cc(Cl)ccc12
Temperature: 115 °C

Procedure:
A mixture of 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (40 mg, 0.140 mmol), N,N-diisopropylethylamine (74.0 mg, 100 μL, 0.570 mmol) and 2-chlorobenzimidazole (29 mg, 0.186 mmol) in NMP (500 μL) was heated at 115° C. in a sealed tube overnight. After this time, very little desired product was observed via LC/MS. Additional 2-chlorobenzimidazole (30 mg, 0.196 mmol), N,N-diisopropylethylamine (74.0 mg, 100 μL, 0.570 mmol), and NMP (0.2 mL) were added, and the reaction mixture was transferred to a small microwave tube. The mixture was heated via microwave irradiation at 180° C. for 2 hr. The reaction mixture was concentrated under a stream of nitrogen, and the crude product was purified by preparative reverse-phase HPLC. The product 3-[(1H-Benzoimidazol-2-ylamino)-methyl]-7-chloro-1-phenyl-1H-quinolin-4-one (4 mg, 6.8%) was obtained as an off-white solid. MS calcd. for C23H17ClN4O [(M+H)+] 401.1, obsd. 401.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1.CCN(C(C)C)C(C)C.Cl.[N:24]1([C:29](N)=[NH:30])C=CC=N1>CN(C=O)C>[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:29]([NH2:30])=[NH:24])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNC(=N)N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
The mixture of 4-Aminomethyl-benzoic acid methyl ester HCl (15.7 g, 77.8 mmol) in DMF (85.6 mL) and DIPEA (29.5 mL, 171.2 mmol) was stirred at rt for 10 min. Pyrazole-1-carboxamidine HCl (12.55 g, 85.6 mmol) was added to the reaction mixture and then stirred at rt for 4 h to give clear solution. The reaction mixture was evaporated to dryness under vacuum. Saturated NaHCO3 solution (35 mL) was added to give nice suspension. The suspension was filtered and the filter cake was washed with cold water. The mother liquid was evaporated to dryness and then filtered. The two solids were combined and re-suspended over distilled H2O (50 ml). The filter cake was then washed with minimum quantities of cold H2O and ether to give 12.32 g white crystalline solid intermediate 1 (77% yield, M+1: 208 on MS).
Reaction SMILES: CS[C:3]1[S:4][CH2:5][CH2:6][CH2:7][N:8]=1.[N+:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])([O-:11])=[O:10].C(O)(C)C>[Cl-].[Zn+2].[Cl-].CCOCC>[N+:9]([C:12](=[C:3]1[NH:8][CH2:7][CH2:6][CH2:5][S:4]1)[C:13]([O:15][CH3:16])=[O:14])([O-:11])=[O:10]
Reactant: CSC1=NCCCS1
Reactant: COC(=O)C[N+](=O)[O-]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Solvent: CCOCC
Product: COC(=O)C(=C1NCCCS1)[N+](=O)[O-]

Procedure:
To a mixture of 221 g of 5,6-dihydro-2-(methylthio)-4H-1,3-thiazine (A. F. McKay et al., J. Am. Chem. Soc., 80, 3339 (1950) and 1 g of zinc chloride at about 100°, 202 g of methyl nitroacetate (S. Zen et al., Kogyo Kagaku Zasshi, 74, 70 (1971)) was added dropwise over a 30-minute period. The resulting mixture was heated for 4 hours at 95°-105°. 200 ml of isopropyl alcohol then was added to the hot mixture, then 400 ml of ether was added. The resulting mixture was filtered to give methyl nitro(tetrahydro-2H-1,3-thiazin-2-ylidene)-acetate (1A), as a pale yellow solid, m.p.: 107°-108° C.
Reaction SMILES: C[Li].[C:3]([O:11][CH3:12])(=[O:10])[C:4]#[C:5][CH2:6][CH2:7][CH:8]=[CH2:9].[CH2:13](O)C>C1COCC1.CCOCC.[Cu]I>[CH3:13]/[C:5](/[CH2:6][CH2:7][CH:8]=[CH2:9])=[CH:4]/[C:3]([O:11][CH3:12])=[O:10]
Reactant: C=CCCC#CC(=O)OC
Reactant: CCO
Agent: [Cu]I
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC/C(C)=C\C(=O)OC
Temperature: -20 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A suspension of copper(I) iodide (12.38 g, 65 mmol) in 150 mL of dry THF under a nitrogen atmosphere was cooled to −20° C., and methyllithium (1.6 M in ether, 81.5 mL, 130 mmol) was added dropwise over 15 min. The solution was cooled to −78° C., and 4.49 g (32.5 mmol) of the compound from Example 19 in 15 mL of dry THF was added gradually, keeping the temperature below −70° C. After 1 h, 40 mL of ethanol was added cautiously, and the mixture was allowed to warm to room temperature. The mixture was diluted with ether, and washed with satd aq NH4Cl (200 mL), 5N NH3 (4×250 mL), water (200 mL), and brine (200 mL), dried, and the bulk of the solvent was evaporated to give the title compound (6.8 g, 100%) as an oil. The material had only minor solvent contamination and was adequate for use in the next reaction.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][CH2:12][CH:13]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:14]([OH:16])=[O:15].[C:22]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:22][O:20][C:19]([CH2:18][CH2:17][CH:13]([CH2:12][S:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:14]([OH:16])=[O:15])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CCC(CSc1ccc2ccccc2c1)C(=O)O
Solvent: CO
Product: COC(=O)CCC(CSc1ccc2ccccc2c1)C(=O)O
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 1646.6 %

Procedure:
A mixture of 2-(2-naphthylthiomethyl)glutaric acid (28.8 g), methanol (300 ml), and p-toluenesulfonic acid (0.9 g) was stirred at 40° C. for 2.5 hours. The reaction mixture was concentrated in vacuo, and water was added to the resulting residue. The mixture was extracted with ethyl acetate, washed with water, dried over MgSO4, and concentrated in vacuo. The residue was recrystallized from isopropyl ether to give 27.4 g of 2-(2-methoxycarbonylethyl)-3-(2-naphthylthio)propionic acid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].CN(C=O)C.[CH2:19]([O:21][C:22]([C@@H:24]1[CH2:33][C@@H:32]2[C@@H:27]([CH2:28][CH2:29][C@H:30]([CH2:34]OS(C3C=CC=C([N+]([O-])=O)C=3)(=O)=O)[CH2:31]2)[CH2:26][N:25]1[C:48]([O:50][CH3:51])=[O:49])=[O:23])[CH3:20]>C1COCC1>[CH2:19]([O:21][C:22]([C@@H:24]1[CH2:33][C@@H:32]2[C@@H:27]([CH2:28][CH2:29][C@H:30]([CH2:34][N:5]3[C:4]([CH3:3])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]=[CH:6]3)[CH2:31]2)[CH2:26][N:25]1[C:48]([O:50][CH3:51])=[O:49])=[O:23])[CH3:20]
Reactant: CCOC(=O)c1[nH]cnc1C
Reactant: CCOC(=O)[C@@H]1C[C@H]2C[C@@H](COS(=O)(=O)c3cccc([N+](=O)[O-])c3)CC[C@H]2CN1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn(C[C@H]2CC[C@H]3CN(C(=O)OC)[C@H](C(=O)OCC)C[C@H]3C2)c1C
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 49.9 %

Procedure:
Sodium hydride (0.24 g, 1.2 eq) was washed with hexanes (3×10 ml) and suspended in dry THF (10 ml). To this was added a solution of 0.848 g of ethyl 4-methyl-5-imidazolecarboxylate in THF (5 ml) dropwise. The reaction mixture was stirred at 20° C. for 1.5 h and DMF (10 ml) was added. To the resulting solution was slowly added a solution of 2.43 g of [3S,4aR,6S,8aR]-ethyl-6-((3-nitrophenylsulfonyloxy)methyl)-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate in THF (10 ml). The reaction was stirred at ambient temperature over night under N2. The reaction was quenched with saturated aqueous sodium bicarbonate. The resulting white solid was removed by filtration and the filtrate was extracted with ethyl acetate (3×10 ml). The combined organic extract was washed with brine, dried (MgSO4), filtered, and evaporated to a light brown oil. The crude product was chromatographed over silica gel eluting with ethyl acetate to give 1.09 g of the intermediate title compound: MS m/z: 456.3 (m++1);
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][N+:15]([O-])=[CH:14][C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)([Br:22])=O>C(#N)C.O1CCOCC1>[C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([Br:22])[C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=S(=O)(c1ccccc1)n1ccc2c[n+]([O-])ccc21
Solvent: CC#N
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)nccc21
Temperature: 70 °C
Reaction time: 18 h
Yield: 71.8 %

Procedure:
A 250 mL round-bottomed flask, under nitrogen, fitted with a thermometer probe and a condenser/inert gas bubbler (via a Claisen head), was charged with a solution of 1-benzenesulfonyl-1H-pyrrolo[3,2-c]pyridine 5-oxide (3.5 g, 12.8 mmol) in acetonitrile (50 mL) and dioxane (50 mL). To this solution was added dropwise phosphorus oxybromide (12 g, 40.9 mmol) and the resulting mixture was stirred at 70° C. for 18 h. The precipitate formed was removed by filtration and washed several times with dioxane. The solution was concentrated in vacuo and partitioned between DCM, water and brine. The organic layer was isolated then dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PCC, 0-20% EtOAc in cyclohexane) to give the desired product (3.1 g, 72%). 1H NMR (CDCl3, 300 MHz): δ 8.23 (d, J=5.7 Hz, 1 H); 7.94-7.85 (m, 3 H); 7.67-7.59 (m, 2 H); 7.55-7.48 (m, 2 H); 6.75 (dd, J=3.7, 0.8 Hz, 1 H).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:4].Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1>CCCCCC.O1CCCC1>[C:3]([CH2:5][C:6]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1)([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:4]
Reactant: CCOC(=O)C(CC#N)C(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(CC#N)(C(=O)OCC)c1ccc([N+](=O)[O-])cn1
Reaction time: 0.25 h

Procedure:
Sodium hydride (53% dispersion in oil) (5.17 g, 0.1 mole) was washed by decantation with hexane (2×150 ml), tetrahydrofuran (THF) (150 ml) and was finally suspended in THF (150 ml). Diethyl 2-(cyanomethyl)malonate (26.4 g, 0.11 mole) in THF (20 ml) was added dropwise over 45 minutes keeping the internal temperature at 18° C. to 22° C. (with ice bath cooling). The resulting suspension cleared over 15 minutes when 2-chloro-5-nitropyridine (14.22 g, 0.09 mole) was added to give a deep magenta solution. The resulting solution was refluxed for 3 hours and the solvent was removed on the rotary evaporator. The resulting oil was partitioned between water (200 ml) and chloroform (200 ml), the pH was adjusted to ~7 (concentrated hydrochloric acid), and the chloroform was run off. The aqueous layer was extracted with a further (2×250 ml) chloroform, the extracts were combined, dried over magnesium sulphate and the solvent was removed to give the title compound as an amber oil. Ether (25 ml) was added and the solution was allowed to crystallise to give the title compound (18.48 g). m.p. 66°-68° C.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([O:4][C:5]([NH:7][C@@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]1[OH:17])=[O:6])[CH3:3].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:3][C:2]([CH3:18])([O:4][C:5]([NH:7][C@@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]1[O:17][S:27]([CH3:26])(=[O:29])=[O:28])=[O:6])[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.7 %

Procedure:
Cis-1-[(1,1-Dimethylethoxy)carbonylamino]-2-hydroxyindan (Method 5; 14.0 g, 56.2 mmol) was dissolved in DCM (200 ml) and triethylamine (11.8 ml, 84.3 mmol). Methanesulfonyl chloride (7.1 g, 61.9 mmol) dissolved in DCM (20 ml) was added and the mixture stirred at room temperature for 3 hours. The mixture was evaporated and EtOAc (250 ml) added. After washing with water and drying over magnesium sulphate the organic solution was evaporated to yield Cis-1-[(1,1-dimethylethoxy)carbonylamino]-2-methanesulphonyloxyindan (9.7 g, 98%) as a white solid.