Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:32])[C:5]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[CH:6][N:7]2[CH2:16][CH2:17]SCCC(O)=O.ClC1C=CC=[C:36]([C:40]([O:42]O)=[O:41])[CH:35]=1.[S:44]([O-:47])(O)=[O:45].[Na+]>ClCCl.CO>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:32])[C:5]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)=[CH:6][N:7]2[CH2:16][CH2:17][S:44]([CH2:35][CH2:36][C:40]([OH:42])=[O:41])(=[O:47])=[O:45]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCSCCC(=O)O)c12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCS(=O)(=O)CCC(=O)O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
3-{2-[5-Fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylsulfanyl}propionic acid (2.26 g, 4.92 mmol) was dissolved in a mixed solvent of dichloromethane (100 ml) and methanol (20 ml), m-chloroperbenzoic acid (mCPBA, purity: 70%, 2.55 g, 10.33 mmol) was added thereto, and the mixture was then stirred at room temperature for 1 hour. The resulting reaction mixture was ice-cooled. An aqueous saturated sodium hydrogen sulfite solution (50 ml) was added to the reaction mixture, followed by extraction with dichloromethane. The thus-obtained organic layer was washed with water and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=100:0→100:10). The purified product was concentrated under reduced pressure and subjected to recrystallization from ethyl acetate-n-hexane, giving a pale yellow powder of 3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethanesulfonyl}propionic acid (2.2 g, yield: 91%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][CH2:12]Cl.[OH:14][C:15]([CH3:20])([CH3:19])[C:16](=[O:18])[CH3:17]>ClCCl>[CH3:10][O:11][CH2:12][O:14][C:15]([CH3:20])([CH3:19])[C:16](=[O:18])[CH3:17]
Reactant: CC(=O)C(C)(C)O
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC(C)(C)C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N,N-diisopropylethylamine (131 ml) and chloromethyl methyl ether (57 ml) in dichloromethane (50 ml) was added under ice-cooling to a solution of 3-hydroxy-3-methyl-2-butanone (52.6 ml) in dichloromethane (450 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was washed with an aqueous solution (250 ml×2) of 10% citric acid, a saturated aqueous solution (200 ml) of NaHCO3 and saturated brine (200 ml), and dried over MgSO4. The solvent was distilled away under reduced pressure. The residue was distilled under atmospheric pressure to give 53.6 g of the title compound (bp=155°-165° C.) as a colorless liquid (see Table 5).
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=CC#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:17].[Na+].Cl.[CH2:20]([OH:23])[CH2:21]O>O>[C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:21][C:20]([OH:23])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC=C(c1ccccc1)c1ccccc1
Reactant: OCCO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)C=C(c1ccccc1)c1ccccc1
Yield: 81 %

Procedure:
A mixture of 3,3-diphenylacrylonitrile (5.76 g, 28.1 mmol) and sodium hydroxide (11.2 g) in ethylene glycol (180 mL) and water (1 mL) were refluxed for 3 days. The reaction mixture was diluted with water (100 mL), acidified with 5N HCl to pH˜1, and extracted with ethyl acetate. The organic extract was washed with water, dried over sodium sulfate, and concentrated in vacuo. The crude material was purified by flash column chromatography ethyl acetate/hexanes to give 3,3-diphenylacrylic acid (5.1 g, 81%) as a white powder.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:3][CH2:2]1.C(NC(C)C)(C)C.Cl[C:21](=[O:27])[C:22](OCC)=[O:23].O>ClCCl>[CH:1]1([CH2:4][N:5]2[C:22](=[O:23])[C:21]([OH:27])=[N:12][C:11]3[CH:10]=[CH:9][CH:8]=[N:7][C:6]2=3)[CH2:2][CH2:3]1
Reactant: Nc1cccnc1NCC1CC1
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CC(C)NC(C)C
Product: O=c1c(O)nc2cccnc2n1CC1CC1
Yield: 33 %

Procedure:
To 1.6 g (9.8 mM) of N2-(cyclopropylmethyl)pyridine-2,3-diamine and 1.7 ml (9.8 mM) of diisopropylamine in 20 ml of dichloromethane were added, drop by drop, under stirring; at room temperature, 1.1 ml (9.8 mM) of ethyl chloro(oxo)acetate. The reaction mixture was stirred at room temperature for 16 h and water was added. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layer was washed with water, dried on anhydrous sodium sulfate and the solvent was removed under vacuum. The compound was further purified by silica gel column chromatography using dichloromethane/methanol (95/5) as eluant, which afforded after evaporation 700 mg of 4-(cyclopropylmethyl)-2-hydroxypyrido[2,3-b]pyrazin-3(4H)-one as a solid. Yield: 33%.
Reaction SMILES: CC([N:5]([C@@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:30]=[C:31]3[C:36]([CH:37]([OH:39])[CH3:38])=[CH:35][CH:34]=[CH:33][N:32]3[CH:40]=2)=[CH:25][CH:24]=1)[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])[C:6](=[O:8])[O-])(C)C.Cl.O1CCOCC1.C(N(CC)C(C)C)(C)C.[Cl:57][C:58]1[CH:59]=[C:60]([CH:75]=[CH:76][C:77]=1[O:78][CH:79]([CH3:81])[CH3:80])C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O>O>[Cl:57][C:58]1[CH:59]=[C:60]([CH:75]=[CH:76][C:77]=1[O:78][CH:79]([CH3:81])[CH3:80])[C:6]([NH:5][C@@H:9]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:30]=[C:31]3[C:36]([CH:37]([OH:39])[CH3:38])=[CH:35][CH:34]=[CH:33][N:32]3[CH:40]=2)=[CH:27][CH:28]=1)[CH2:10][N:11]1[C:12](=[O:21])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]1=[O:20])=[O:8]
Reactant: CC(O)c1cccn2cc(-c3ccc(C[C@@H](CN4C(=O)c5ccccc5C4=O)N(C(=O)[O-])C(C)(C)C)cc3)nc12
Reactant: CC(C)Oc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)Oc1ccc(C(=O)N[C@@H](Cc2ccc(-c3cn4cccc(C(C)O)c4n3)cc2)CN2C(=O)c3ccccc3C2=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.6 %

Procedure:
A mixture of 1,1-dimethylethyl[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]carbamate (1.79 g, 3.31 mmol) and 4 M HCl in 1,4-dioxane (20 mL, 80 mmol) was stirred at room temperature for 45 minutes. The reaction was concentrated to dryness and redissolved in DMF (30 mL). To this solution was added N,N-diisopropylethylamine (2.14 g, 16.55 mmol) and pentafluorophenyl 3-chloro-4[(1-methylethyl)oxy]benzoate (1.36 g, 3.31 mmol). The mixture was stirred overnight at room temperature, diluted with water, and extracted into ethyl acetate. The extracts were washed with water, dried (Na2SO4), and concentrated in vacuo to give the title compound (2.10 g, 100%) as a tan solid. MS (ES+) m/e 637 [M+H]+.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:16][CH2:17][C@H:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:16]([CH2:17][C@H:18]([OH:20])[CH3:19])[C:5]=32)=[CH:10][CH:9]=1
Reactant: Cc1ccc2c(c1)C(=O)C(CC=O)C2
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2
Reaction time: 0.75 h
Yield: 79.3 %

Procedure:
A solution of 2.82 g of (RS)-2-(2-oxoethyl)-6-methyl-1-indanone and 100 mg of p-toluenesulfonic acid in 100 ml of anhydrous toluene was heated on a water separator. A solution of 4.51 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 2.7 g (79%) of (R)-1-(7-methyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown-green oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[CH2:5].C[O-].[Na+].[CH3:17][CH:18]([SH:20])[CH3:19].Cl>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[CH:4]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:5][S:20][CH:18]([CH3:19])[CH3:17]
Reactant: CC(C)S
Reactant: C=C(Cc1ccccc1)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C(CSC(C)C)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of methyl-2-benzylacrylate (20 gm. 0.113 mol) in methanol (100 ml) at room temperature was added a solution of sodium methoxide (2N, 17 ml) followed by isopropylthiol (12.56 ml). TLC (4:1, Hexanes: ethyl acetate) showed reaction to be complete after 30 min. The reaction mixture was made acidic with 1N HCl and extracted three times with ethyl acetate. The combined organic fractions were dried over NaSO4, filtered and evaporated in vacuo. The crude product was purified by chromatography (silica 4:1, hexanes: ethyl acetate to give methyl-3-isopropylthio-2-benzylpropionate.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.[CH3:18][NH:19][CH2:20][C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[CH:25]=1.CC1NC2C(C=1CNC)=CC=CC=2>>[O:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[CH:25]=[C:21]1[CH2:20][N:19]([CH3:18])[C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]1[CH:9]=[N:10][C:11]2[NH:12][C:3](=[O:2])[CH2:4][CH2:5][C:6]=2[CH:7]=1
Reactant: CNCc1cc2ccccc2o1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CNCc1c(C)[nH]c2ccccc12
Agent: Cl
Product: CN(Cc1cc2ccccc2o1)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 87.8 %

Procedure:
According to the procedure of Example 4, except substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride salt (1.60 g, 6.3 mmole) for the (E)-3-(2-oxo[2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloride salt, and substituting 2-(methylaminomethyl)benzofuran (1.20 g, 6.9 mmole) for the 2-methyl-3-(methylaminomethyl)indole, the title compound (2.0 g, 90%) was prepared as a tan solid: MS (ES) m/e 363 (M+H)+.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:3].[C:23]([NH:31][CH:32]1[C:38](=[O:39])[N:37]2[CH:40]([C:44]([NH:46][CH:47]([CH:56]([OH:68])[CH2:57][O:58][CH2:59][C:60]3[C:65]([Cl:66])=[CH:64][CH:63]=[CH:62][C:61]=3[Cl:67])[CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:45])[CH2:41][CH2:42][CH2:43][N:36]2[C:35](=[O:69])[CH2:34][CH2:33]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl.CCOC(C)=O>[C:23]([NH:31][CH:32]1[C:38](=[O:39])[N:37]2[CH:40]([C:44]([NH:46][CH:47]([C:56](=[O:68])[CH2:57][O:58][C:59](=[O:3])[C:60]3[C:65]([Cl:66])=[CH:64][CH:63]=[CH:62][C:61]=3[Cl:67])[CH2:48][C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])=[O:45])[CH2:41][CH2:42][CH2:43][N:36]2[C:35](=[O:69])[CH2:34][CH2:33]1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(O)COCc1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(=O)COC(=O)c1c(Cl)cccc1Cl
Reaction time: 1 h
Yield: 69.5 %

Procedure:
Dess-Martin reagent (3.82 g; 9.0 mmol) was added to a stirred solution of the alcohol 215e (3.17 g; 4.5 mmol) in CH2Cl2 (100 ml). The mixture was sirred for 1 h, diluted with EtOAc (300 ml), then washed with a 1:1 mixture of sat. Na2S2O3 and sat. NaHCO3 (100 ml) followed by brine (100 ml). The mixture was dried (MgSO4) then concentrated. The residue was purified by flash chromatography to afford 2.2 g (70%) of 216e as a colourless solid: mp 102-107° C.; [α]D32 −82.5 (c 0.1, CH2Cl2); IR (KBr) 3374, 2937, 1739, 1661, 1525, 1433, 1275, 1260, 1152; 1H NMR (CDCl3) δ7.85-7.78 (2H, m), 7.57-7.32 (6H, m), 7.09 (1H, d, J=7.9), 7.01 (1H, d, J 7.3), 5.25-5.16 (1H, m), 5.16-5.05 (1H, m), 5.15 (1H, d), 5.03 (1H, d), 4.99-4.90 (1H, m), 4.68-4.54 (1H, m), 3.31-3.17 (1H, m), 3.17-2.72 (4H, m), 2.45-2.35 (1H, m), 2.30-1.66 (5H, m), 1.44 (9H, s); Anal. Calcd for C33H36Cl2N4O9.0.5H2O: C, 55.62; H, 5.23; N, 7.86; Cl, 9.95. Found: C, 55.79; H, 5.15; N, 7.80; Cl 9.81. MS (ES+) 729/7/5 (M+Na), 707/5/3 (M+1), 163 (100%).
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][CH:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:30]=3)[C:25]([OH:27])=O)=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[CH3:39][C:40]1[N:41]=[C:42]([NH2:45])[S:43][CH:44]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:30]=3)[C:25]([NH:45][C:42]3[S:43][CH:44]=[C:40]([CH3:39])[N:41]=3)=[O:27])=[N:19][CH:20]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: CN1CCC(Oc2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(C(=O)O)c2)C1=O
Reactant: Cc1csc(N)n1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1csc(NC(=O)c2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(O[C@@H]3CCN(C)C3=O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
1-Chloro-N,N,2-trimethyl-prop-1-en-1-amine (0.16 mL, 1.2 mmol) was added to a solution of 3-[5-(azetidine-1-carbonyl)pyrazin-2-yl]oxy-5-(1-methyl-2-oxo-pyrrolidin-3-yl)oxy-benzoic acid (Intermediate 10) (288 mg, 0.68 mmol) in DCM (5 mL) and stirred at ambient temperature for 30 minutes. 4-Methyl-1,3-thiazol-2-amine (156 mg, 1.36 mmol) and pyridine (0.11 mL, 1.4 mmol) were added and the reaction stirred for 16 hours. The solvent was evaporated under reduced pressure. The residue dissolved in ethyl acetate (30 mL), washed with water (2×10 mL) and brine (10 mL), dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica, eluting with a gradient of 0-5% methanol in DCM, to afford the product (117 mg, 34%). 1H NMR δ (300 MHz, CDCl3) 2.10-2.26 (m, 4H), 2.38 (quintet, 2H), 2.50-2.63 (m, 1H), 2.93 (s, 3H), 3.33-3.56 (m, 2H), 4.26 (t, 2H), 4.69 (t, 2H), 4.84 (t, 1H), 6.54 (s, 1H), 7.15 (s, 1H), 7.36 (s, 1H), 7.53 (s, 1H), 8.32 (s, 1H), 8.82 (s, 1H), 10.43 (s, 1H); m/z 509 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[C:4]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:3]=1.[O:34]=[C:35]([CH3:39])[C:36](Cl)=[O:37]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:19])(=[O:18])[NH:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])=[CH:13][CH:12]=2)=[C:4]([N:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:36](=[O:37])[C:35](=[O:34])[CH3:39])[CH:3]=1
Reactant: CC(=O)C(=O)Cl
Reactant: CC(C)(O)CNS(=O)(=O)c1ccc(CCC(=O)c2ccc(Cl)cc2Nc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C(=O)N(c1ccccc1)c1cc(Cl)ccc1C(=O)CCc1ccc(S(=O)(=O)NCC(C)(C)O)cc1
Temperature: 120 °C

Procedure:
To 4-[3-(4-chloro-2-phenylaminophenyl)-3-oxo-propyl]-N-(2-hydroxy-2-methylpropyl)-benzenesulfonamide (0.138 g) in toluene (10 mL) was added 2-oxopropionyl chloride (0.3 mL), and the mixture heated at 120° C. for 3 h to form N-(5-chloro-2-{3-[4-(2-hydroxy-2-methylpropylsulfamoyl)-phenyl]-propionyl}-phenyl)-2-oxo-N-phenyl-propionamide, which was used without further purification.
Reaction SMILES: [CH2:1]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[K+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>CS(C)=O>[ClH:21].[ClH:21].[CH2:1]([N:9]1[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][Cl:21])[CH2:13][CH2:14]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: ClCCCBr
Reactant: c1ccc(CCN2CCNCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cl
Product: ClCCCN1CCN(CCc2ccccc2)CC1
Yield: 188.8 %

Procedure:
The procedure described in Example 1(a) was followed, using 29.4 g of 1-phenethyl piperazine, 25.0 g of potassium hydroxide, 100 ml of dimethyl sulfoxide and 24.0 g of 1-bromo-3-chloropropane. Work-up, as described above, gave 32.6 g (64% of theory) of 1-phenethyl-4-(3-chloropropyl)piperazine dihydrochloride as an off-white crystalline solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[CH:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([CH:23]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:24](O)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.ON1C2C=CC=CC=2N=N1.CC[N+](CCCN(C)C)=C=N>ClCCl>[CH2:1]([N:8]1[CH2:12][C@H:11]2[C@@H:13]([NH:16][C:24](=[O:25])[CH:23]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Reactant: O=C(O)C(C1CCCCC1)C1CCCCC1
Agent: CC[N+](=C=N)CCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)C(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(3aS*,6aR*)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-amine (500 mg, 2.311 mmol), 2,2-dicyclohexylacetic acid (570 mg, 2.54 mmol), and 1-hydroxybenzotriazole (389 mg, 2.54 mmol) were combined in dichloromethane (20 mL). The reaction was stirred at room temperature for 10 minutes, then N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (0.449 mL, 2.54 mmol) was added dropwise. The reaction was stirred at room temperature for 20 hours, and then the reaction was quenched with 10 mL of water. The reaction mixture was extracted with 2×20 mL of dichloromethane, the solvent was removed in vacuo, and the crude material was chromatographed over a silica gel cartridge (Analogix®, Burlington, Wis., RS-40) eluting with 30-50% ethyl acetate/hexanes to give the title compound as the first eluting diastereomer: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.60 (d, J=5.1, 1H), 7.45-7.38 (m, 4H), 7.35 (m, 1H), 4.49-4.41 (m, 1H), 3.57 (d, J=12.6, 1H), 3.37 (d, J=12.5, 1H), 2.76 (d, J=9.6, 1H), 2.69 (dd, J=7.9, 15.7, 1H), 2.50 (d, J=9.1, 1H), 2.48-2.41 (m, 1H), 2.28 (t, J=8.2, 1H), 2.15-2.08 (m, 1H), 1.99-1.06 (m, 26H), 1.04-0.92 (m, 1H); MS (ESI+) m/z 423 (M+H)+.
Reaction SMILES: [CH:1]1[CH2:8][CH2:7]C=C[CH2:4][CH2:3][CH:2]=1.[C:9]1([PH2:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OOC(C)(C)C)(C)(C)C.[CH3:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[C:9]1([P:15]2[CH:29]([CH:28]3[CH2:4][CH2:3][CH2:2][CH2:1][CH2:8][CH2:7][CH2:26][CH2:27]3)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1=CCCC=CCC1
Reactant: Pc1ccccc1
Reactant: CCCCCCCCCCC
Agent: CC(C)(C)OOC(C)(C)C
Product: c1ccc(P2CCCCCCCC2C2CCCCCCCC2)cc1
Temperature: 135 °C
Reaction time: 2 h

Procedure:
This procedure is a modification of Mason and Van Winkle's. See U.S. Pat. No. 3,400,163. All glassware is dried at 120° C. and assembled hot under a purge of argon. A 250 mL, 3-neck flask is fitted with magnetic spin bar, thermometer, reflux condenser, a rubber syringe septum, argon inlet, and flowmeter. The reactor system is purged overnight with argon flowing at 3 mL/min., and then charged with redistilled 1,5cyclooctadiene [43.3 g (49.1 mL), 0.4 mole, density =0.882 g/mL, from Aldrich Chemical Co.] and phenylphosphine [44.0 g (44.0 mL), 0.4 mole, density =1.00 g/mL, from Strem Chemicals]while under a stream of argon. The reaction solution is heated to 135° C. Di-t-butylperoxide [1.46 g (1.8 mL), 0.01 mole, density=0.796 g/mL, from Aldrich Chemical] is mixed with 5 mL of undecane and added with a syringe pump over 1 hour while maintaining the temperature of the exothermic reaction at 135°-145° C. A second portion of di-t-butylperoxide (1.8 mL in 5 mL of undecane) is added rapidly, and the temperature is increased to 150° C. and held for an additional hour. Periodic aliquots, taken with a syringe through the septa, are examined by infrared spectroscopy, and the disappearance of the olefin band at 1645 cm- 1 and the P-H band at 2300 cm- 1 is monitored. After two hours total reaction time, both of these bands had disappeared. The reaction mixture is distilled through a 6-inch Vigreux column and a mixture, 58.3 g (67%) of 9-phenyl-9phosphabicyclo[4.2.1]nonane and 9-phenyl-9phosphabicyclo[3.3.1]nonane, is collected [b.p. 123-125 at 0.1 mmHg], and stored in a refrigerated and septum-sealed flask under a nitrogen gas atmosphere. Reported b.p.: 134°-135° C. at 0.3 mm (Hg). Gas chromatography shows the mixture is 67% 9- phenyl-9-phosphabicyclo[4.2.1]nonane (the earlier eluting isomer) and 33% 9-pheny-9-phosphabicyclo[3.3.1]nonane.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].Br[CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH3:2]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCOC(CN)OCC
Product: CCOC(CNCc1ccc2ccccc2c1)OCC
Yield: 77.6 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-1, 2,2-diethoxyethanamine (5.82 ml, 40 mmol) was reacted with 2-(bromomethyl)naphthalene (4.42 g, 20 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: n-hexane:ethyl acetate=90:10 to 80:20) to obtain the title compound (4.24 g, 78%).
Reaction SMILES: Cl[C:2]1[C:10](Cl)=[C:9]2C(CC(C3CCCC3)(C)[C:8]2=[O:12])=CC=1O.[CH2:20]([C:24]1([CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:32][C:31]2[C:26](=[C:27]([Cl:35])[C:28]([Cl:34])=[C:29]([OH:33])[CH:30]=2)[C:25]1=[O:36])[CH2:21][CH2:22][CH3:23].C([OH:44])C>>[CH2:20]([C:24]1([CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:32][C:31]2[C:26](=[C:27]([Cl:35])[C:28]([Cl:34])=[C:29]([O:33][CH2:2][CH2:10][CH2:9][C:8]([OH:12])=[O:44])[CH:30]=2)[C:25]1=[O:36])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: CCO
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Product: CCCCC1(C2CCCC2)Cc2cc(OCCCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
By following substantially the procedure in Example 8, Step B, but substituting for (+) 6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one an equimolar quantity of (+) 2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-1H-inden-1-one described therein, there is obtained (+) 4-[(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]butanoic acid which melts at 139°-139.5° C., [α]D25 +18.4° (C=5, ethanol).