Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2=[CH:15][N:16]([CH3:18])C)=[O:4].NC1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2=[CH:15][NH:16][C:18]1[CH:25]=[CH:24][C:23]([S:26](=[O:28])(=[O:27])[NH2:29])=[CH:22][CH:21]=1)=[O:4]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: COC(=O)c1ccc2c(c1)C(=CN(C)C)C(=O)N2
Product: COC(=O)c1ccc2c(c1)C(=CNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Yield: 41 %

Procedure:
A solution of 2.66 g (20.0 mmol) of ethyl (methylthio)acetate dissolved in 200 mL of dichloromethane was cooled with stirring to −70° C. and 2.7 g (20.0 mmol) of sulfuryl chloride was added. The reaction was stirred for 30 min. at −70° C., and a solution of 3.0 g (20 mol) of methyl 4-aminobenzoate and 4.3g (20 mmol) of Proton Sponge® in 250 mL of dichloromethane was added dropwise over 1 h. The resulting pink slurry was treated with 2.3 g (23 mmol) of TEA in one portion, and the solution was allowed to warm to rt. The solution was washed with three 250-mL portions of water, dried over MgSO4, and concentrated to give an oil. This was chromatographed on silica gel eluting with hexane:EtOAc (1:1) to yield 2.0 g (42% yield) of 3-methylthio-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester: 1H NMR (DMSO-d6): δ1.97 (s, 3H), 3.35 (s, 3H), 4.67 (s, 1H), 6.97 (d, J=8.2 Hz, 1H), 7.84 (s, 1H), 7.91 (d, J=8.2 Hz, 1H), 10.97 (s, 1H). A solution of 2.0 g (8.4 mmol) of 3-methylthio-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester in 20 mL of acetic acid was treated with 10 g of zinc powder. The reaction mixture was stirred for 2 h at rt, filtered through celite and concentrated to dryness. The residue was chromatographed on silica gel eluting with hexane:EtOAc (1:1) to yield 1.6 g (99% yield) of 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester as a pink solid: 1H NMR (DMSO-d6): δ3.52 (s, 2H), 3.77 (s, 3H), 6.87 (d, J=8.2 Hz, 1H), 7.74 (s, J=1H), 7.80 (d, J=8.2 Hz, 1H), 10.72 (br s, 1H). Conversion to the 3-dimethylaminomethylene-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester (mixture of E and Z isomers) was carried out via Procedure G in 49% yield: 1H NMR (DMSO-d6): δ3.29 Z (s, 6H), 3.31 E (s, 6H), 3.76 Z (s, 3H), 3.76 E (s, 3H), 6.74 Z (d, J=8.1 Hz, 1H), 6.81 E (d, J=8.2 Hz, 1H), 7.47-7.50 Z(m, 1H), 7.50-7.52 E (m, 1H), 7.57 E (dd, J=1.3, 8.2 Hz, 1H), 7.74 Z (s, 1H), 7.89 Z (s, 1H), 7.94 E (s, 1H), 10.33 Z (bs, 1H), 10.43 E (bs, 1H). The title compound was prepared in 41% yield from 3-[(dimethylamino)methylene]oxindole-5-carboxylic acid methyl ester and 4-aminobenzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ3.81 (s, 3H), 6.92 (d, J=8.2 Hz, 1H), 7.26 (s, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.2 Hz, 1H), 7.75 (d, J=8.4 Hz, 2H), 8.29 (s 1H), 8.86 (d, J=12.4 Hz, 1H), 10.80 (d, J=12.4 Hz, 1H), 10.94 (s, 1H); APCI−MS m/z372 (M−1)−. Anal. Calcd for C17H15N3O5S: C, 54.68, H, 4.05; N, 11.25; S 8.59. Found C, 54.65, H, 4.12; N, 11.17; S. 8.49.
Reaction SMILES: [ClH:1].O1CCOCC1.[Br:8][C:9]1[N:25]=[C:12]2[CH:13]=[C:14]([NH:17]C(=O)OC(C)(C)C)[CH:15]=[CH:16][N:11]2[N:10]=1>O1CCOCC1>[ClH:1].[Br:8][C:9]1[N:25]=[C:12]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][N:11]2[N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccn2nc(Br)nc2c1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccn2nc(Br)nc2c1

Procedure:
A suspension of 4 N hydrochloric acid-1,4-dioxane (8 ml) and 1,4-dioxane (8 ml) containing the tert-butyl (2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamate (400 mg) obtained in (Example 3.15) <Step 4> was heated to reflux for 40 minutes. Thereafter, the precipitated solid was collected by filtration, and was then washed with 1,4-dioxane (15 ml). The obtained solid was dried to obtain the title compound (279 mg) in the form of a white solid.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][CH2:11][C:12]([F:16])([F:15])[CH2:13][CH3:14])[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4].O.[OH-].[Li+]>C1COCC1.O>[C:20]([O:19][C:17]([N:6]1[CH2:7][CH:8]([CH2:10][CH2:11][C:12]([F:15])([F:16])[CH2:13][CH3:14])[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])=[O:18])([CH3:21])([CH3:22])[CH3:23]
Reactant: CCC(F)(F)CCC1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(F)(F)CCC1CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To a solution of 4-(3,3-difluoro-pentyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (106 mg, 0.26 mmol, 1 equiv) in THF (2.4 mL) and water (0.8 mL) was added lithium hydroxide monohydrate (54 mg, 1.29 mmol, 5 equiv). The reaction mixture was stirred at rt overnight. THF was removed under vacuum. The residue was diluted with water (10 mL), washed with ether (20 mL). The aqueous layer was taken up in ethyl acetate (50 mL), partitioned with 10% citric acid (25 mL). The organic layer was washed with water (1×), brine (1×), dried and concentrated to give 4-(3,3-difluoro-pentyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester as a clear oil (82.1 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:29]2[CH2:33][C@H:32]([O:34][Si](C(C)(C)C)(C)C)[CH2:31][C@H:30]2[C:42]([O:44][CH3:45])=[O:43])=[N:4][CH:5]=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[C:15]([CH2:26][O:27][CH3:28])[CH:14]=3)[O:10][N:9]=2)[CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(Cl)Cl.O>[Cl:1][C:2]1[C:3]([N:29]2[CH2:33][C@H:32]([OH:34])[CH2:31][C@H:30]2[C:42]([O:44][CH3:45])=[O:43])=[N:4][CH:5]=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[C:15]([CH2:26][O:27][CH3:28])[CH:14]=3)[O:10][N:9]=2)[CH:7]=1
Reactant: COCc1cc(-c2nc(-c3cnc(N4C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]4C(=O)OC)c(Cl)c3)no2)ccc1-c1ccccc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COCc1cc(-c2nc(-c3cnc(N4C[C@H](O)C[C@H]4C(=O)OC)c(Cl)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.3 %

Procedure:
To a solution of methyl (2S,4R)-1-(3-chloro-5-(5-(2-(methoxymethyl)-2′-methylbiphenyl-4-yl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-4-(tert-butyldimethylsilyloxy)-pyrrolidine-2-carboxylate (0.118 g; 0.18 mmol) in THF (2 mL) was added a solution of tetrabutylammonium fluoride (1.0 M in THF; 0.36 mL; 0.36 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The mixture was diluted with DCM and water and poured through a hydrophobic frit. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica, eluting with iso-hexane/EtOAc (100% iso-hexane to 50%/50% iso-hexane/EtOAc) to afford the title product (0.085 g; 88%). 1H NMR (CDCl3, 400 MHz) δ 8.81 (1H, d, J=2 Hz), 8.40 (1H, d, J=1.2 Hz), 8.26 (1H, d, J=1.6 Hz), 8.15-8.13 (1H, m), 7.34-7.24 (4H, m), 7.14-7.12 (1H, m), 5.01 (1H, t, J=8 Hz), 4.66 (1H, s), 4.34-4.30 (1H, m), 4.22-4.21 (2H, m), 4.02-3.99 (1H, m), 3.74 (3H, s), 3.33 (3H, s), 2.38 (1H, m), 2.21-2.14 (1H, m), 2.08 (3H, s), 1.76 (1H, d, J=3.6 Hz).
Reaction SMILES: C1(C)C=CC(S(O[N:11]=[C:12]([NH:14][C:15]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][NH:17][N:16]=2)[CH3:13])(=O)=O)=CC=1.N1C=CC=CC=1>C(O)C>[CH3:13][C:12]1[NH:14][C:15]2[N:16]([N:17]=[CH:18][C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:11]=1
Reactant: CCOC(=O)c1c[nH]nc1NC(C)=NOS(=O)(=O)c1ccc(C)cc1
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1cnn2nc(C)[nH]c12
Yield: 45.3 %

Procedure:
A solution of ethyl 3-[1-(p-toluenesulfonyloxyimino)-ethyl]amino-1H-pyrazole-4-carboxylate (1.00 g) and pyridine (240 mg) in ethanol (20 ml) was refluxed for 3 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with water. The solution was adjusted to pH 4 with 1N hydrochloric acid. The formed precipitate was collected by vacuum filtration to give ethyl 2-methyl-1H-pyrazolo[1,5-b][1,2,4]triazole-7-carboxylate (240 mg).
Reaction SMILES: Cl[O-:2].[Na+].[O:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])C)=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CC(C)=O>[O:4]([C:11]1[CH:12]=[CH:13][C:14]([C:17]([OH:19])=[O:2])=[CH:15][CH:16]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)c1ccc(Oc2ccccc2)cc1
Reactant: [O-]Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)c1ccc(Oc2ccccc2)cc1

Procedure:
In each case a 5.25% sodium hypochlorite solution (85.1 g.: 0.060 mole) was added slowly in portions to a solution of 3.18 g. (0.0150 mole) the p-phenoxyacetophenone sample while heating from 40° to 100° C. The resulting solution was concentrated at 100° C., producing a crystalline precipitate. Acetone was then added to consume excess sodium hypochlorite followed by boiling, acidification with some excess concentrated hydrochloric acid (10 ml of 12N), stirring, filtration, water wash and then drying at 70° C./under vacuum for about 1 hr. The p-phenoxybenzoic acid obtained from the p-phenoxyacetephenone produced in the presence of hydrogen fluoride was white with a melting point of 159°-162° C. In contrast, the p-phenoxybenzoic acid produced in the presence of aluminum trichloride had a yellow (or light beige) discoloration and a strongly depressed melting point of 137°-149° C., indicating presence of considerable impurities.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C-]#N.[K+].[OH2:13]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[O:7])[CH:6]([C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[OH:13])=[CH:4][CH:3]=1
Reactant: O
Reactant: O=Cc1ccc(Cl)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Product: O=C(c1ccc(Cl)cc1)C(O)c1ccc(Cl)cc1

Procedure:
42.2 g of 4-chlorobenzaldehyde and 5 g of KCN were heated under reflux in 300 ml of a 1:1 mixture of ethanol and water for 6 hours. After cooling, the ethanol was stripped off, the residue was cooled in an ice bath and the supernatant aqueous phase was decanted off. The product was recrystallized from ethanol/petroleum ether and dried. 22 g of the compound Z1 mentioned in the title were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:27]3[CH2:28][CH2:29][NH:30][CH2:31][C:26]=3[S:25][C:10]=2[N:11]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12](=[O:16])[CH:13]([OH:15])[N:14]=1.C(N(CC)CC)C.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([N:47]=[C:48]=[S:49])=[C:43]([N+:50]([O-:52])=[O:51])[CH:42]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:27]3[CH2:28][CH2:29][N:30]([C:48](=[S:49])[NH:47][C:44]4[CH:45]=[CH:46][C:41]([O:40][CH3:39])=[CH:42][C:43]=4[N+:50]([O-:52])=[O:51])[CH2:31][C:26]=3[S:25][C:10]=2[N:11]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12](=[O:16])[CH:13]([OH:15])[N:14]=1
Reactant: O=C1C(O)N=C(c2ccccc2Cl)c2c(sc3c2CCNC3)N1CCc1ccccc1
Reactant: COc1ccc(N=C=S)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=S)N2CCc3c(sc4c3C(c3ccccc3Cl)=NC(O)C(=O)N4CCc3ccccc3)C2)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
5-(2-chlorophenyl)-1,2,3,6,7,9-hexahydro-3-hydroxy-1-(2-phenylethyl)-8H-pyrido[4′,3′:4,5]thieno[2,3-e]-1,4-diazepine-2-one (0.167 g, 0.29 mmol) is dissolved in dichloromethane (2 ml). Triethylamine (0.06 ml, 0.44 mmol) then 4-methoxy 2-nitrophenylisothiocyanate (0.062 g, 0.29 mmol) are added. After agitation at 23° C. for 2 hours, the solvent is evaporated off. After purification by chromatography on a silica column (eluent: dichloromehane-methanol: 98-2), the fractions contining only the product are evaporated. The solid is taken up in ether and a drop of dichloromethame and a drop of acetone are added. After filtration on flit and washing the solid with ether, the desired product is obtained in the form of a yellow powder (0.08 g, 41%).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:18]/[C:19](/[CH3:26])=[CH:20]/C(OCC)=O)C>>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10](/[C:13](/[CH3:14])=[CH:20]/[C:19](=[O:18])[CH3:26])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C(\C)OCC
Reactant: CC(=O)c1ccc(C2CCCCC2)cc1
Product: CC(=O)/C=C(\C)c1ccc(C2CCCCC2)cc1
Yield: 55 %

Procedure:
(E)-4-(4-cyclohexyl-phenyl)-3-pentene-2-one was prepared analogous to Example 52 from 4'-cyclohexyl-acetophenone and ethyl (E)-3-ethoxy-crotonate with a yield of 55% of theory. B.p. 148°-151°C at 0.4 mm Hg; m.p. 49°-50°C (after recrystallization from methanol and petroleum ether). Characteristic signals in NMR (CDCl3): τ 3.50 (1H-q; /J/=1.2 ± 0.1 Hz); τ 7.50 (3H-d; /J/=1.2 ± 0.1 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13]C(C)(C)C)=[O:12])=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O1CCCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C1CC1c1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CC1c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 102.3 %

Procedure:
In a round bottom flask, mixed the tert-butyl 2-(4-bromophenyl)cyclopropanecarboxylate 2 (3.7 g, 12.0 mmol) in methanol/tetrahydrofuran (1:1, 30 mL) and heated to 50° C. Separately dissolved lithium hydroxide (1.4 g, 60 mmol) in water (15 mL) and then added to the solution of 2. Increased the heat to 65° C., and monitored by HPLC for reaction completion (<1% pA of 2, ˜3 h). The reaction mixture was then cooled to room temperature and distilled to ½ volume. Cooled the suspension to <20° C. and acidified (exothermic addition) the product mixture to pH<2 with 2N HCl (˜30 mL) to precipitate the product. Stirred the resulting suspension at 20° C. for NLT 0.5 h. Filtered the suspension and washed the wetcake with water (˜20 mL). Dried the wetcake at 45° C. under vacuum. Isolated 2.96 g of an off-white solid (98% pA, 97 wt %=99% wt-adjusted yield). 1H NMR (400 MHz, CDCl3) δ 1.35-1.40 (m, 1H), 1.65-1.69 (m, 1H), 1.85-1.89 (m, 1H), 2.53-2.58 (m, 1H), 6.97 (d, 2H, J=8.37), 7.40 (d, 2H, J=8.37). 13C NMR (100 MHz, CDCl3) δ 17.7, 24.2, 26.7, 120.2, 127.7, 131.3, 138.1 & 178.9 with 2 peaks overlapping.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18]Br)[CH2:14][CH2:13]1)[CH3:11].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:18][C@H:15]1[CH2:16][CH2:17][C@H:12]([CH2:10][CH3:11])[CH2:13][CH2:14]1
Reactant: CC[C@H]1CC[C@H](CBr)CC1
Reactant: Oc1cccc(F)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC[C@H]1CC[C@H](COc2cccc(F)c2F)CC1
Temperature: 105 °C
Reaction time: 1 h

Procedure:
30 g of 2,3-difluorophenol was dissolved in 300 ml of DMF, and 56.8 g of (trans-4-ethylcyclohexyl)methyl bromide and 73.4 g of tripotassium phosphate were added thereto, and then stirred for 1 hours at 100 to 110° C. Water and toluene were added thereto, and the organic layer was fractioned while the aqueous layer was extracted with toluene. The organic layers were combined, washed with saturated saline, and then subjected to column chromatography. Then, the solvent was evaporated under reduced pressure. The residue was purified by recrystallization, to thereby obtain 37 g of 2,3-difluoro-1-(trans-4-ethylcyclohexyl)methoxybenzene.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:2].[P:12]([O-:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>>[CH2:14]([O:13][P:12]([O:16][CH2:17][CH3:18])([C:5]([OH:11])([CH2:4][CH2:3][C:1]#[N:2])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:19])[CH3:15]
Reactant: CCOP([O-])OCC
Reactant: CCOC(=O)C(=O)CCC#N
Product: CCOC(=O)C(O)(CCC#N)P(=O)(OCC)OCC
Reaction time: 84 h

Procedure:
A mixture of 7.75 g (0.05 mole) of ethyl 4-cyano-2-oxo-butanoate in 31 g (0.225 mole) of diethyl phosphite is stirred at 20°-30° for 3-4 days. The excess diethyl phosphite is removed on a rotary evaporator under high vacuum at a bath temperature of 50°-700 to yield the crude product as an oil. This is purified by chromatography on silica gel.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH2:13][C@@H:12]([C:14](OC)=[O:15])[C@H:11]([C:18](OC)=[O:19])[CH2:10][C:9]=1[CH3:22].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[OH:15][CH2:14][C@H:12]1[C@H:11]([CH2:18][OH:19])[CH2:10][C:9]([CH3:22])=[C:8]([CH3:7])[CH2:13]1
Reactant: COC(=O)[C@@H]1CC(C)=C(C)C[C@H]1C(=O)OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC1=C(C)C[C@@H](CO)[C@H](CO)C1
Yield: 36 %

Procedure:
To a suspension of lithium aluminium hydride (1.52 g, 0.04 mol) in dry THF (60 ml) at 0° C. was added trans-dimethyl 1,2-dimethylcyclohex-1-ene-4,5-dicarboxylate (2.26 g, 0.01 mol) in dry THF (40 ml) over 30 min. The resultant suspension was stirred for another hour at 0° C., and then saturated sodium sulphate solution (5 ml) was added dropwise. The solution was filtered and the filtrate evaporated to give an oil, which on purification gave the title compound in 36% yield. N.m.r: δH (90 MHz, CDCl3) 3.70 (m,4H), 3.55 (bs,2H), 2.02 (m,4H), 1.96 (m,2H), 1.64 ppm (s,6H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.Cl.[NH2:23][CH2:24][C:25]1([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:23][CH2:24][C:25]1([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: CCOC(=O)C1(CN)CCCCC1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(CNc2c([N+](=O)[O-])cnc3ccccc23)CCCCC1
Reaction time: 4 h
Yield: 62.5 %

Procedure:
A solution of 4-chloro-3-nitroquinoline (10.96 g, 52.5 mmol) in dichloromethane (200 mL) was cooled to approximately 0° C., and triethylamine (22.0 mL, 158 mmol) and a solution of ethyl 1-(aminomethyl)cyclohexanecarboxylate hydrochloride (11.65 g, 52.5 mmol) in dichloromethane (30 mL) were sequentially added. The reaction was stirred for four hours, and the solvent was removed under reduced pressure. The residue was stirred in deionized water (50 mL) for one hour, and the mixture was extracted several times with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting orange oil was purified by chromatography on silica gel (eluting with 3-5% methanol in dichloromethane) to provide 11.72 g of ethyl 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclohexanecarboxylate as art orange oil that solidified upon standing.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C@H:18]([C:31]([O:33]CC2C=CC=CC=2)=[O:32])[CH2:19][CH2:20][C:21]([O:23]CC2C=CC=CC=2)=[O:22])=[O:16])=[CH:10][C:9]=1[Cl:41])[CH2:5][CH2:6][Cl:7]>C(OCC)(=O)C.[Pd]>[Cl:7][CH2:6][CH2:5][N:4]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C@H:18]([C:31]([OH:33])=[O:32])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:16])=[CH:10][C:9]=1[Cl:41])[CH2:3][CH2:2][Cl:1]
Reactant: O=C(Nc1ccc(N(CCCl)CCCl)c(Cl)c1)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)CC[C@H](NC(=O)Nc1ccc(N(CCCl)CCCl)c(Cl)c1)C(=O)O
Reaction time: 1 h

Procedure:
A solution of dibenzyl N-((4[N,N-bis-(2-chloroethyl)amino]3-chlorophenylcarbamoyl))-L-glutamate (350 mg) in ethyl acetate (30ml) containing 30% palladium on carbon 70mg (50% moist) was stirred under an atmosphere of hydrogen for 1 hour. After filtration of the catalyst the filtrate was evaporated to dryness and the residue triturated with ether/ethyl acetate to obtain N-(4-[N,N-bis (2-chloroethyl)amino]-3-chlorophenylcarbamoyl)-L glutamic acid as an oil. NMR: 8.7 (s) 1H; 7.6 (s) 1H; 7.1-7.4 (m) 2H; 6.5 (d) 1H; 4.2 (m) 1H; 3.3-3.6 (m) 8H; 1.7-2.4 (m) 4H.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6](I)[CH:5]=[CH:4][N:3]=1.[CH2:11]([O:13][C:14]([Sn](CCCC)(CCCC)CCCC)=[CH2:15])[CH3:12].[F-].[K+]>O1CCOCC1.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>[CH2:14]([O:13][C:11]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[C:7]=1[CH:8]=[O:9])=[CH2:12])[CH3:15]
Reactant: O=Cc1c(I)ccnc1F
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=C(OCC)c1ccnc(F)c1C=O

Procedure:
There are mixed in succession 8 g (31.9 mmol) of 2-fluoro4-iodo-3-pyridinecarbaldehyde (described in J.O.C, 1993, 58, pp. 7832), 12.7 g (35.96 mmol) of 1-ethoxyvinyltributyltin and 740 mg of tetrakis(triphenylphosphine)palladium (2% molar) in 280 ml of dioxane. The reaction mixture is heated at reflux until the starting material has disappeared completely. After returning to room temperature, a solution of potassium fluoride is added to the reaction mixture. Vigorous stirring is maintained for 10 minutes in order to cause precipitation of the tributyltin fluoride, which is filtered off. The filtrate is plunged into a sodium chloride solution. The aqueous phase is extracted 3 times with dichloromethane and then the organic phases are combined, dried over magnesium sulphate, concentrated and purified by chromatography over a silica column, using a dichloromethane/cyclohexane mixture (95/5) as eluant to yield the expected product.
Reaction SMILES: COP([CH2:7][C:8](=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:14]=1)(=O)OC.[CH3:30][C:31]1[N:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][N:32]=1.[OH-].[Na+]>C1COCC1>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][C:15]2[N:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][C:8](=[O:29])[CH:7]=[CH:37][C:34]3[CH:33]=[N:32][C:31]([CH3:30])=[N:36][CH:35]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:26][CH:25]=1
Reactant: Cc1ncc(C=O)cn1
Reactant: COc1ccc(CNc2cccc(CCCCC(=O)CP(=O)(OC)OC)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(CNc2cccc(CCCCC(=O)C=Cc3cnc(C)nc3)n2)cc1
Reaction time: 0.17 h
Yield: 65.2 %

Procedure:
To a solution of 6-7 (42.8 g, 102 mmol) and 2-methyl-pyrimidine-5-carbaldehyde (12.45 g, 102 mmol) in THF (250 mL) at 0° was added 4M NaOH (26.7 mL, 107 mmol) dropwise. After 15 minutes the ice bath was removed and the mixture stirred for an additional 10 minutes. The solution was diluted with water, extracted with ethyl acetate, and dried (Na2SO4). Following concentration, the residue was triturated with ether to give 27.7 g (61%) of 16-1 as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[N:18]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:17]3=[O:32])[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>C(Cl)Cl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[N:18]([CH2:24][C:25]([OH:27])=[O:26])[C:17]3=[O:32])[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N(CCN3CCOCC3)S(C)(=O)=O)cc2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N(CCN1CCOCC1)c1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Yield: 64 %

Procedure:
To a solution of tert-butyl 2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (570 mg, 1.219 mmol) in DCM (15 ml), trifluoroacetic acid (939 μl, 12.19 mmol) was added, and the mixture was reacted for 1 hour at room temperature. The solvent was evaporated and crude 2-(5-(N-(2-morpholinoethyl)-methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid 2,2,2-trifluoroacetic acid salt was obtained (408 mg, 0.776 mmol, 64% yield).MS/ESI+ 411.8 [MH]+) and used without purification.