Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([CH:19]([CH3:21])[CH3:20])[CH:6]=1)(=O)C.[OH-].[Na+].CCCCCCC>O.CO>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][C:7]=1[CH:19]([CH3:21])[CH3:20])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)Oc1ccc(OCc2ccccc2)c(C(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCCC
Solvent: CO
Product: CC(C)c1cc(O)ccc1OCc1ccccc1
Reaction time: 1 h

Procedure:
4-Benzyloxy-3-isopropylphenyl acetate (5.59 kg, 19.7 mol) is added to a solution of sodium hydroxide (1.20 kg, 30.0 mol) in a mixture of water (30 L) and methanol (30 L). This solution is stirred at 24° for 1 hour. A black-colored solution develops. This is concentrated in vacuo (40°,3 Torr) to remove the methanol. This residue is then extracted with ethyl acetate (2×16 L) and the combined organic layers are washed with aqueous sodium hydroxide (1N, 2×10 L) and water (3×12 L). The solvent is stripped in vacuo (500, 3 Torr) to yield an amber oil. This oil is then triturted with heptane (10 L) for 4 hours and the allowed to stand overnight at room temperature at which time the solids are collected by filtration and washed with cold heptane (2×1 L). After air-drying, the product is further dried in vacuo (25°,120 Torr) for 72 hours to give 4-benzyloxy-3-isopropylphenol as a low melting solid, m.p. 39°-40°.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[C:11]([O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]([C:20]([O:22][CH3:23])=[O:21])[C@@H:15]([CH3:24])[CH2:14][CH2:13]4)[CH:7]=[N:6]2)[CH2:2]1.C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:32][C:29]1[CH:28]=[CH:27][C:26]([O:25][C:11]2[C:10]([C:8]3[CH:7]=[N:6][N:5]([CH:3]4[CH2:2][N:1]([CH3:35])[CH2:4]4)[CH:9]=3)=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][C@H:15]([CH3:24])[N:16]3[C:20]([O:22][CH3:23])=[O:21])=[CH:31][CH:30]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CNC4)c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COC(=O)N1c2ccc(-c3cnn(C4CN(C)C4)c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.2 %

Procedure:
Methyl (S)-6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (105 mg, 0.241 mmol) was dissolved in methanol and formaldehyde (179 μL, 2.41 mmol) was added. The reaction was stirred for 4 h at ambient temperature and then cooled to 0° C. Sodium triacetoxyborohydride (0.102 g, 0.481 mmol) was added and the reaction was slowly warmed to ambient temperature. After 16 h the reaction was complete, and the reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford methyl (S)-5-(4-fluorophenoxy)-2-methyl-6-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.086 g, 79%) as a pale orange oil. 1H NMR (300 MHz, CDCl3) δ ppm 1.13 (d, J=6.45 Hz, 3H) 1.18-1.20 (m, 1H) 1.20-1.33 (m, 1H) 1.55 (br dd, J=13.34, 5.42 Hz, 1H) 1.94-2.18 (m, 4H) 2.22-2.49 (m, 1H) 2.49-2.69 (m, 1H) 3.81 (s, 3H) 4.26 (br s, 1H) 4.61-4.89 (m, 2H) 5.13-5.32 (m, 1H) 6.63-6.82 (m, 2H) 6.83-7.01 (m, 2H) 7.40 (d, J=8.79 Hz, 1H) 7.54-7.67 (m, 2H) 7.79-8.02 (m, 1H). MS (ESI, pos. ion) m/z 451 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH2:16][CH3:17])[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH2:16][CH3:17])[C:5]2[N:6]=[C:7]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([N:22]4[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]4)=[CH:31][CH:30]=3)[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: CCn1c(=O)c(Br)cc2cnc(S(C)=O)nc21
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Product: CCn1c(=O)c(Br)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Yield: 40.5 %

Procedure:
6-Bromo-8-ethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (4, 600 mg, 1.90 mmol) and 4-(4-methylpiperazino)aniline (363 mg, 1.90 mmol) were stirred at 120° C. for 3 h. The reaction mixture was purified by column chromatography using dichloromethane:methanol (100:3→100:5) to give the title compound (340 mg, 0.77 mmol, 40%) as a yellow solid. ESMS m/z 443 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.47 (s, 1H) 7.92 (s, 1H) 7.51 (d, J=8.8 Hz, 2H) 7.24 (br. s., 1H) 6.96 (d, J=8.8 Hz, 2H) 4.48 (q, J=7.0 Hz, 2H) 3.13-3.29 (m, 4H) 2.53-2.64 (m, 4H) 2.36 (s, 3H) 1.35 (t, J=7.0 Hz, 3H).
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:12]([O:14][C:15]1[CH:20]=[C:19]([CH2:21][C:22]([NH:24][CH:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH2:26][CH2:27][CH3:28])=[O:23])[CH:18]=[CH:17][C:16]=1[CH2:41][CH2:42][C:43]([NH2:45])=O)[CH3:13].C(O)(=O)CC.C(N1C=CN=C1)(N1C=CN=C1)=O.N>O1CCCC1.O.N1C=CC=CC=1>[CH2:12]([O:14][C:15]1[CH:20]=[C:19]([CH2:21][C:22]([NH:24][CH:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH2:26][CH2:27][CH3:28])=[O:23])[CH:18]=[CH:17][C:16]=1[CH2:41][CH2:42][C:43]#[N:45])[CH3:13]
Reactant: CCCC(NC(=O)Cc1ccc(CCC(N)=O)c(OCC)c1)c1ccccc1N1CCCCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCC(=O)O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCC(NC(=O)Cc1ccc(CCC#N)c(OCC)c1)c1ccccc1N1CCCCC1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
At ambient temperature, p-toluenesulphonic acid chloride (45.8 mg, 0.24 mmol) is added to a mixture of 3-[2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenyl]-propionic acid amide, (56 mg, 0.12 mmol) melting point 153-155° C. [prepared from the corresponding propionic acid by reacting with carbonyldiimidazole and then with ammonia in tetrahydrofuran] and absolute pyridine (0.044 ml). The mixture is stirred for 45 minutes at 20° C. and for 2 hours at 50 to 60° C. After cooling, water is added, the mixture is made alkaline with concentrated ammonia and extracted three times with chloroform. The combined chloroform extracts are washed with water, dried over sodium sulphate, filtered and concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/ethyl acetate=9/1).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH2:17][C:18](=[O:27])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:11][C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1)=[O:4].C(N(CC)CC)C.[CH:37]([N:40]([CH:48]([CH3:50])[CH3:49])[P:41](Cl)[O:42][CH2:43][CH2:44][C:45]#[N:46])([CH3:39])[CH3:38].CO>C(Cl)Cl>[CH3:1][C:2]([CH3:29])([CH3:28])[C:3]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH2:17][C:18](=[O:27])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][P:41]([N:40]([CH:48]([CH3:50])[CH3:49])[CH:37]([CH3:38])[CH3:39])[O:42][CH2:43][CH2:44][C:45]#[N:46])=[CH:11][C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1)=[O:4]
Reactant: CC(C)(C)C(=O)Oc1ccc2c(CC(=O)NCCCCCCO)cc(=O)oc2c1
Reactant: CC(C)N(C(C)C)P(Cl)OCCC#N
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(C)N(C(C)C)P(OCCC#N)OCCCCCCNC(=O)Cc1cc(=O)oc2cc(OC(=O)C(C)(C)C)ccc12
Reaction time: 1 h
Yield: 65.2 %

Procedure:
To a solution of 33a (0.6 g, 1.5 mmol) in 10 mL of anhydrous CH2Cl2 was added triethylamine (0.4 mL) followed by 2-cyanoethyl diisopropylchlorophosphoramidite (0.35 mL, 1.6 mmol). The solution was kept at room temperature for 1 h and treated with 0.1 mL of MeOH. The solvent was evaporated and the residue was partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated. The crude product was chromatographed on silica eluting with 5% triethylamine in ethyl acetate. Concentration of the pure product fractions and drying under vacuum afforded 0.59 g (65%) of 34 as a colorless, viscous oil.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][OH:20].C(=O)([O-])O.[K+]>O1CCCC1>[OH:20][CH2:19][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][CH:1]=[O:3]
Reactant: Nc1ccccc1CCO
Reactant: O=CO
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=CNc1ccccc1CCO
Temperature: 60 °C
Reaction time: 2 h

Procedure:
12.6 ml of formic acid were added dropwise at 0° C. to 15 ml of acetic anhydride, and the mixture was then stirred for 2 hours at 60° C. After cooling to 20° C., the mixture was diluted with 140 ml of tetrahydrofuran, cooled to −4° C., and at this temperature a solution of 18.4 g of 2-(2-aminophenyl)ethanol in 185 ml of tetrahydrofuran was added dropwise. After stirring for 3 hours at −6° C. the mixture was neutralised with aqueous potassium hydrogen carbonate solution (25% KHCO3) and extracted four times with 300 ml of ethyl acetate each time. The combined extracts were dried over sodium sulfate and concentrated by evaporation in vacuo. 18.4 g (94% of theory) of the title compound were thereby obtained in the form of yellowish crystals that melted at 49–54° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH2:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.CCN(CC)CC.[C:20](Cl)(=[O:23])[CH2:21][CH3:22].O>C(Cl)Cl>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:20](=[O:23])[CH2:21][CH3:22])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: NC1CCCc2c(Br)cncc21
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCC(=O)NC1CCCc2c(Br)cncc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
To a solution of (rac)-4-bromo-5,6,7,8-tetrahydro-isoquinolin-8-ylamine (intermediate A-2 [D]) (3.7 g, 16.3 mmol) and Et3N (3.3 g, 32.6 mmol) in DCM (50 mL) was added propionyl chloride (2.25 g, 24.4 mmol) at 0° C. The resulting reaction mixture was stirred for 3 hr before it was warmed up to room temperature and poured into water (50 mL) and extracted with DCM (2×50 mL). The combined organic layers were then dried over anhy. Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography and afforded the title compound (4.29 g, 93% yield) as a white solid. MS: 283.0 (M+H+).
Reaction SMILES: Cl[C:2]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([CH3:22])=[N:19][CH:18]=4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[N:9][N:10]=[C:3]12.[F:30][C:31]1[CH:32]=[C:33]([OH:38])[CH:34]=[CH:35][C:36]=1[F:37].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O.C(OCC)(=O)C>[F:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][C:36]=1[F:37])[O:38][C:2]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([CH3:22])=[N:19][CH:18]=4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[N:9][N:10]=[C:3]12
Reactant: Oc1ccc(F)c(F)c1
Reactant: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(Oc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
A mixture of ethyl 8-chloro-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (2000 mg), 3,4-difluorophenol (655 mg), potassium carbonate (1989 mg) and DMF (10 mL) was stirred at 90° C. for 30 min, and the mixture was allowed to cool to room temperature. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1240 mg).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[CH:15]=1)(=[O:4])=[O:3].[OH-].[NH4+:17]>O1CCCC1>[NH2:17][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[CH:15]=1)(=[O:4])=[O:3]
Reactant: [NH4+]
Reactant: CC1(C)Cc2cc(S(=O)(=O)Cl)ccc2O1
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(S(N)(=O)=O)ccc2O1

Procedure:
In a manner similar to Step B of Example 9, the reaction of 9.0 g (0.036 mole) of 5-chlorosulfonyl-2,3-dihydro-2,2-dimethylbenzofuran with 60 mL of an aqueous 29% ammonium hydroxide solution in 70 mL of tetrahydrofuran produced 8.0 g of 5-aminosulfonyl-2,3-dihydro-2,2-dimethylbenzofuran as a solid (mp 157°-160° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:5]2[CH3:16].[H-].[Na+].Cl.Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)=[CH:24][CH:23]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)=[CH:26][CH:27]=1)[C:6]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:5]2[CH3:16]
Reactant: ClCc1ccc(-n2ccnc2)cc1
Reactant: Cc1c(CCC(=O)O)[nH]c2ccc(F)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CCC(=O)O)n(Cc2ccc(-n3ccnc3)cc2)c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 10.4 %

Procedure:
A solution of 198 mg of 5-fluoro-3-methyl-1H-indole-2-propanoic acid in 20 ml of dry DMF is cooled at 0° C., and treated with 155 mg of 55% NaH. The reaction mixture is stirred for 60 minutes at 0° C., then 307 mg of 1-[4-(chloro-methyl)phenyl]-1H-imidazole hydrochloride are added portionwise under nitrogen at 0° C. After stirring at room temperature for 16 hours the mixture is poured into water and washed with methylene chloride. The aqueous solution is neutralized with diluted HCl and extracted with methylene chloride. The organic layer is dried over sodium sulfate and evaporated to dryness. The residue, taken up with acetone, filtered and dried, yields 35 mg of the title compound (m.p. 222° C.)
Reaction SMILES: [CH3:1][C:2]1[C:6](/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:13])[NH:4][N:3]=1.[H-].[Na+].[CH2:16](Br)[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:16]([N:4]1[C:5]([CH3:13])=[C:6](/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])[C:2]([CH3:1])=[N:3]1)[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCC=Cc1ccccc1
Reactant: COC(=O)/C=C/c1c(C)n[nH]c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1c(C)nn(CC=Cc2ccccc2)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
(E)-methyl 3-(3,5-dimethyl-1H-pyrazol-4-yl)acrylate (360 mg, 2 mmol) was dissolved in DMF (6 mL). Sodium hydride, (NaH 60% dispersion, 80 mg, 1 equiv) was added in small portions while maintaining the temperature at 0° C. The mixture was then stirred at room temperature for 1 h. The mixture was cooled to 0° C. and cinnamyl bromide (394 mg, 1 equiv) was added. The mixture was then stirred overnight at room temperature. It was quenched with aqueous ammonium chloride, diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography using a gradient of hexane/EtOAc (10:1 to 0:100 v/v). Fractions containing pure product were combined and the solvents were removed under reduced pressure to yield (E)-methyl 3-(1-cinnamyl-3,5-dimethyl-1H-pyrazol-4-yl)acrylate (401 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br[CH2:25][C:26]([C:28]1[CH:33]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)c1ccnc(C(=O)CBr)c1
Product: COC(=O)Cc1c(C(=O)c2cc(C(C)(C)C)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-bromoacetyl-4-tert-butylpyridine*.
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC1C=CC(OC)=CC=1)=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:8]([O:7][P:5]([O:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:9]=[CH2:10]
Reactant: C=CCOP(=O)(OCC=C)OCCCC(=O)OCc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Product: C=CCOP(=O)(OCC=C)OCCCC(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 4-methoxybenzyl 4-[[bis(allyloxy)phosphoryl]oxy]butyrate (700 mg, 1.82 mmol) obtained from Example 13-(1) and anisole (0.7 ml) was added trifluoroacetic acid (3 ml) at room temperature. The mixture was stirred at room temperature for 15 minutes, then diluted with toluene, and the solvent was distilled off under reduced pressure. The residue was redissolved in toluene, and the solvent was distilled off under reduced pressure to give crude 4-[[bis(allyloxy)phosphoryl]oxy]butanoic acid as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].C[O-].[Na+].Cl[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:13]#[N:14].O>CO.CN(C=O)C>[NH2:14][C:13]1[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:3][C:2]=1[C:1]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)CS
Reactant: N#CC=C(Cl)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COC(=O)c1sc(-c2ccccc2)cc1N
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
To a solution of methyl thioglycolate (1 g, 9.43 mmol) in methanol (5 mL) was added a solution of sodium methoxide (0.5 g, 9.43 mmol) in methanol (5 mL) and stirred for 0.5 h. To the above mixture, a solution of 3-chloro-3-phenylprop-2-enenitrile (1.22 g, 7.5 mmol) in DMF (3.5 mL) was added dropwise for 10 min at rt and stirred the mixture at 60° C. for 2 h. Then, a solution of sodium methoxide (1 g, 18.6 mmol) in methanol (10 mL) was added dropwise at rt and stirring was continued for 2 h at 60° C. The mixture was allowed to rt and poured into cold water and stirred for 15 min. The solution was extracted with chloroform (3×100 mL) and the combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel using hexane-ethyl acetate (92:8) as eluent to give the product as a pale yellow color solid (1.1 g, 50%), mp 130-132° C. 1H NMR (400 MHz, DMSO-d6): δ 7.62-7.65 (2H, m), 7.38-7.48 (3H, m), 7.00 (1H, s), 4.29 (2H, br s), 3.74 (3H, s); LC-MS (positive ion mode): m/z 234 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C@@H:18]([C:27]#[C:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@:19]([NH2:26])([O:24][CH3:25])[C:20]([O:22]C)=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.COC1C=CC(B(O)O)=CC=1.CCO.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.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.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([C@@H:18]([C:27]#[C:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@:19]([NH2:26])([O:24][CH3:25])[C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)[C@@](N)(OC)[C@H](C#Cc1ccccc1)S(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccc(S(=O)(=O)[C@@H](C#Cc3ccccc3)[C@](N)(OC)C(=O)O)cc2)cc1
Temperature: 25 °C

Procedure:
Methyl (2R)-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-amino-(3S)-methoxy-5-phenylpent-4ynoate: The starting sulfonamide 63f (510 mg, 1.02 mmol) and 4-methoxyphenylboronic acid (230 mg, 1.53 mmol) are taken up in 10 mL of benzene, 1.5 mL of EtOH and 1.5 mL of water in the presence of Pd(PPh3)4 (35 mg, 0.03 mmol) and 200 mg of Na2CO3 and brought to reflux for 18 hr. The mixture is cooled to room temperature, poured into water, and extracted with methylene chloride. The organic layer is dried over MgSO4, filtered and evaporated. The crude product is purified by silica gel chromatography using 9:1 hexane:EtOAc to give the desired product as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.[CH3:11][N:12]([CH3:35])[C:13]1(C#N)[CH2:18][CH2:17][CH:16]([CH:19]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]1.O.[Cl-].[NH4+]>O1CCCC1>[CH2:31]([O:30][CH:28]([O:27][CH:19]([CH:16]1[CH2:17][CH2:18][C:13]([N:12]([CH3:35])[CH3:11])([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:14][CH2:15]1)[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:29])[CH3:32]
Reactant: COc1cccc([Mg]Br)c1
Reactant: CCOC(C)OC(Cc1ccccc1)C1CCC(C#N)(N(C)C)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(C)OC(Cc1ccccc1)C1CCC(c2cccc(OC)c2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 1 M solution of 3-methoxyphenylmagnesium bromide in tetrahydrofuran (9.25 ml, 9.25 mmol) was added dropwise to a solution of 1-dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclohexanecarbonitrile (1.06 g, 3.1 mmol) in tetrahydrofuran (15 ml), while cooling with ice and under an argon atmosphere. The mixture was stirred at room temperature for 48 h and thereafter water and saturated ammonium chloride solution (10 ml of each) were added. The phases were separated and the aqueous phase was extracted with diethyl ether (3×10 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:14](=[O:15])[CH2:13][CH:12]([NH:16][CH2:17][CH2:18]Cl)[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CN(C)C=O>[CH2:3]([N:10]1[C:14](=[O:15])[CH:13]2[CH:12]([NH:16][CH2:17][CH2:18]2)[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CC(NCCCl)C(=O)N1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C2CCNC2C(=O)N1Cc1ccccc1
Reaction time: 8 h
Yield: 55.7 %

Procedure:
17.4 g (0.58 mmol) of sodium hydride suspension are reacted with 119 g (0.45 mol) of 1-benzyl-3-(2-chloroethylamino)-pyrrolidine-2,5-dione in 550 ml of absolute dimethylformamide in accordance with the working instructions of Example Ib. After the mixture has been left to stand overnight, it is worked up under aqueous conditions. On purification by chromatography, impurities are first eluted with ethyl acetate and the product is then eluted with ethyl acetate:methanol (3:1) (RF value 0.55). 57.7 g of product (56% of theory) are isolated.