Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]1[CH:10]=[C:9]([S:11]CC2C=CC(OC)=CC=2)[CH:8]=[N:7]1)[CH3:2]>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]1[CH:10]=[C:9]([S:11][S:11][C:9]2[CH:8]=[N:7][N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21])[CH:10]=2)[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1cc(SCc2ccc(OC)cc2)cn1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cn1cc(SSc2cnn(CC(=O)OCC)c2)cn1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
[4-(4-Methoxy-benzylsulfanyl)-pyrazol-1-yl]-acetic acid ethyl ester (1.96 g, 6.4 mmol) was dissolved in trifluoroacetic acid (20 mL) and heated to 70° C. overnight. The temperature was increased to 120° C. and the reaction stirred overnight again. The reaction mixture was concentrated, azeotroping with toluene, then purified via silica gel chromatography (0-100% EtOAc in hexanes) to yield the title compound.
Reaction SMILES: [CH2:1]([C:3]1([OH:19])[C:15]2[CH:14]=[C:13]3[N:9]([CH2:10][CH2:11][C:12]3=O)[C:8](=[O:17])[C:7]=2[CH2:6][O:5][C:4]1=[O:18])[CH3:2].[C:20]([NH:23][CH:24]1[CH2:33][CH2:32][C:31]2[C:26](=[C:27]([NH2:34])[CH:28]=[CH:29][CH:30]=2)[C:25]1=O)(=[O:22])[CH3:21].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[C:20]([NH:23][CH:24]1[C:25]2=[C:11]3[CH2:10][N:9]4[C:13](=[CH:14][C:15]5[C@:3]([CH2:1][CH3:2])([OH:19])[C:4](=[O:18])[O:5][CH2:6][C:7]=5[C:8]4=[O:17])[C:12]3=[N:34][C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([C:26]=32)[CH2:32][CH2:33]1)(=[O:22])[CH3:21]
Reactant: CCC1(O)C(=O)OCc2c1cc1n(c2=O)CCC1=O
Reactant: CC(=O)NC1CCc2cccc(N)c2C1=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cccc3c1c2C(NC(C)=O)CC3
Reaction time: 24 h

Procedure:
361 mg of (S) 4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano-[3,4-f]indolizine-3,6,10(4H)-trione (hereinafter abbreviated as “trione”) was added to the solution of 300 mg of the compound prepared in (4) above in 200 ml of toluene. The mixture was heated under reflux using a Deanstark apparatus for 10 minutes. To the mixture was added 1 mg of pyridinium-p-toluenesulfonate (hereinafter abbreviated as “PPTS”) and the mixture was refluxed while stirring for a further 24 hours. After cooling, the residue obtained by removing toluene by concentration was suspended into 300 ml of chloroform-methanol (10:1) solvent. Insoluble substances were removed and the residue was powdered with methanol to obtain 336 mg of the title compound. mp: above 240° C. (decomposed)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4](S(C)=O)[N:3]=1.[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([C:9]#[N:10])=[C:6]([Cl:8])[N:7]=1
Reactant: CS(=O)c1nc(N)nc(Cl)c1C#N
Reactant: OCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(Cl)nc(N)nc1OCc1ccccc1

Procedure:
From 2-amino-4-chloro-6-methanesulfinyl-pyrimidine-5-carbonitrile, benzyl alcohol and DBU in DME. EI-MS m/e (%): 262 (M{37Cl}+, 22), 260 (M{35Cl}+,60), 91 (100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][CH:27]1[CH2:31][O:30][C:29](=[O:32])[N:28]1[CH3:33].[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36]>>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][CH:27]3[CH2:31][O:30][C:29](=[O:32])[N:28]3[CH3:33])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: CN1C(=O)OCC1CCCCl
Agent: O=C(O)C(=O)O
Product: CN1C(=O)OCC1CCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
Following the procedure of Example 1, α,α-bis(p-fluorophenyl)-4-piperidinemethanol and 4-[(3-chloro)propyl]-3-methyl-2-oxazolidinone are reacted and the product thereof is reacted with oxalic acid to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][C:14]([CH3:20])=[C:15]([OH:19])[C:16]=2[CH2:17][OH:18])=[O:8])=[CH:5][CH:4]=1)#[N:2].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][C:14]([CH3:20])=[C:15]([O:19][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)[C:16]=2[CH2:17][OH:18])=[O:8])=[CH:21][CH:22]=1)#[N:2]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1ncc(CNC(=O)c2ccc(C#N)cc2)c(CO)c1O
Product: Cc1ncc(CNC(=O)c2ccc(C#N)cc2)c(CO)c1OCc1ccc(C#N)cc1
Yield: 35 %

Procedure:
The coupling of 4-cyano-N-[5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-benzamide (71) (580 mg, 3.0 mmol) and α-bromo-p-tolunitrile (580 mg, 3.0 mmol), as described in Example 3, gave 4-cyano-N-[5-(4-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-benzamide (72) (433 mg, 39% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:29][CH2:28][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=3)[CH2:32][CH2:31]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Reactant: Clc1cccc(N2CCNCC2)c1
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 82 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 82%). 1H NMR (200 MHz, CDCl3): δ 3.30 (s, 4H), 3.91 (s, 4H), 4.15 (s, 3H), 6.79-6.91 (m, 3H), 7.17-7.42 (m, 4H), 7.79 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15]C)=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:17])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:17])[CH3:2]
Reactant: CCOC(=O)Cn1c(C)cc2cc(OC)ccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)cc2cc(O)ccc21
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To a solution of (5-methoxy-2-methyl-indol-1-yl)-acetic acid ethyl ester (0.87 g, 3.51 mmol) in methylene chloride (25 mL) is added BBr3 (1.0 mL, 10.5 mmol) at −20° C. After stirred at −20° C. for 2 hrs, the reaction mixture is poured into ice, extracted with methylene chloride, dried over sodium sulfate. Concentration yields the crude title compound, which is used for next step without further purification.
Reaction SMILES: [CH2:1](OC(Cl)=O)C(C)C.[CH2:9]([O:13][C:14](=[O:21])[C:15]([CH2:17][C:18]([OH:20])=O)=C)[CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[BH4-].[Na+].Cl>C1COCC1.O>[CH2:9]([O:13][C:14](=[O:21])[CH2:15][C:17]([CH2:18][OH:20])=[CH2:1])[CH2:10][CH2:11][CH3:12]
Reactant: CC(C)COC(=O)Cl
Reactant: C=C(CC(=O)O)C(=O)OCCCC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(CO)CC(=O)OCCCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
iso-Butylchloroformate (6.83 g, 50.0 mmol) was added to a solution of itaconic acid mono-n-butyl ester (9.31 g, 50.0 mmol) and triethylamine (5.06 g, 50.0 mmol) in THF (40 mL) under a nitrogen atmosphere and cooled to 0° C. The reaction was stirred for 0.5 h, filtered to remove the solids, added to a solution of sodium borohydride (3.78 g, 100.0 mmol) in water (20 mL), and cooled to 10° C. The reaction was stirred for 2 h, made acidic with 3 N HCl and extracted with ethyl ether (3×). The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to give an oil. The product was purified by FCC on silica gel, eluting ethyl acetate:hexanes (1:2) to give 3-hydroxymethyl-but-3-enoic acid butyl ester (2.56 g, 30%) as an oil. MS found: (M+H)+=173.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([NH2:11])=O)=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH2:9][NH2:11])=[CH:4][CH:3]=1
Reactant: NC(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: B
Solvent: C1CCOC1
Product: NCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 37.8 %

Procedure:
To a solution of 2,2-bis-(4-chloro-phenyl)-acetamide (0.50 g, 1.8 mmol) in THF (10 mL) at rt was added BH3-THF (1.0 M in THF, 4.5 mL, 4.5 mmol). The solution was heated at reflux for 2 h. The mixture was cooled in an ice bath, and the excess BH3 was quenched by careful addition of 10 mL of MeOH. HCl (2.0 M in MeOH, 5 mL) was added, and the resulting mixture was heated at reflux for 1 h. After cooling, the mixture was concentrated, and the residue was partitioned between 1 N HCl and Et2O. The acidic aqueous layer was basified with 10 N NaOH and extracted with Et2O (3×). The combined organic extracts were dried (MgSO4) and concentrated to provide the desired amine (181 mg, 38%). The amine was used without further purification. 1H NMR (400 MHz, CDCl3): 7.30-7.26 (m, 4H), 7.18-7.12 (m, 4H), 3.94 (t, J=7.5, 1H), 3.28 (d, J=7.6, 2H), 1.06 (br s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].Cl.[CH2:13](OCC)C>>[OH:11][CH:10]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[C:3]([O:2][CH2:1][CH3:13])=[O:4]
Reactant: CCOCC
Reactant: COC(=O)C1CCCCC1=O
Agent: Cl
Product: CCOC(=O)C1CCCCC1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
3.2 g of borane/tert-butylamine complex was added to 200 ml of diethyl ether solution containing 15.6 g (0.10 mol) of methyl cyclohexanone-2-carboxylate and stirred overnight at room temperature. An aqueous diluted hydrochloric acid was added thereto to make it weakly acidic, which was then subjected to liquid-liquid separation. The organic layer separated was dried, concentrated and then distilled under reduced pressure to obtain 13.4 g of ethyl 2-hydroxycyclohexanecarboxylate. Yield: 84.8%. b.p. 60° to 62° C. (0.3 mmHg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=3)[C:13]=2[CH2:17]Cl)[N:8]([CH2:30][C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])[CH:7]=1)=[O:5])[CH3:2].[CH3:39][NH:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=3)[C:13]=2[CH2:17][N:40]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH3:39])[N:8]([CH2:30][C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(Cc2c(F)cccc2F)c2ccc(Oc3ccc(NC(C)=O)cc3)c(CCl)c2c1=O
Reactant: CNCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2c(F)cccc2F)c2ccc(Oc3ccc(NC(C)=O)cc3)c(CN(C)Cc3ccccc3)c2c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
78 mg of 6-(4-acetamidophenoxy)-5-(chloromethyl)-1-(2′,6′-difluorobenzyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid-ethyl ester, dissolved in 3 ml of dimethylformamide, was mixed with 84 μl of N-methylbenzylamine and 84 μl of N,N-diisopropyl-ethylamine at 0° C. and stirred at room temperature for 20 hours. After 20 ml of aqueous sodium bicarbonate solution was added, the precipitate was suctioned off, washed with water and then with n-hexane, and dried at room temperature in a vacuum. 70 mg of the title compound is obtained.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[C:16]3[N:15]4[CH2:17][CH2:18][N:19]=[C:20]([CH3:21])[C:14]4=[CH:13][C:12]=3[CH2:11][CH2:10][C:9]=2[CH:22]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>CO.O.C(O)C>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[C:16]3[N:15]4[CH2:17][CH2:18][NH:19][CH:20]([CH3:21])[C:14]4=[CH:13][C:12]=3[CH2:11][CH2:10][C:9]=2[CH:22]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc2c(c1)CCc1cc3n(c1-2)CCN=C3C
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCO
Product: CCCCc1ccc2c(c1)CCc1cc3n(c1-2)CCNC3C
Yield: 19 %

Procedure:
3-n-Butyl-5,6,10,11-tetrahydro-8-methyl-benzo[g]pyrazino[1,2-a]indole (0.47 g) was dissolved in a mixture of 20 ml of methanol and 2 ml of water under argon. The solution was treated portionwise with 0.18 g of sodium borohydride while stirring and stirred at room temperature for 4 hours. Thereafter, the methanol was removed in a vacuum and the residue was stirred with 50 ml of ether and 20 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted once with 50 ml of ether. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 0.47 g of yellowish oil, was dissolved in a 20-fold amount of ethanol and boiled briefly with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.11 g (19%) of 3-n-butyl-5,6,8,9,10,11-hexahydro-8-methyl-benzo[g]pyrazino[1,2-a]indole fumarate (2:1); m.pt.: 174°-176° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH:4]([N:17](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH2:5][N:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[NH:14][N:15]=[CH:16][C:8]=2[CH2:7]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:32])[CH:4]([NH2:17])[CH2:5][N:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[NH:14][N:15]=[CH:16][C:8]=2[CH2:7]1
Reactant: COC(=O)C(CN1Cc2cn[nH]c2C(C)(C)C1)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(N)CN1Cc2cn[nH]c2C(C)(C)C1
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a solution of 2-(di-tert-butoxycarbonylamino)-3-(7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-propionic acid methyl ester (0.49 g, 1 equiv) in methylene chloride (5 mL, 0° C.) was added trifluoroacetic acid (1.5 mL). The ice bath was removed and stirring continued for 2 h. The solution was concentrated, redissolved in methanol, and loaded onto a column of strong cation exchange resin. After flushing with methanol, the product was removed from the column by eluting with 2M ammonia in methanol to afford the product as its free base (250 mg, 94%). 1H-NMR (CDCl3, 500 MHz) δ 1.27 (s, 3H), 1.28 (s, 3H), 2.41 (d, J=11.3, 1H), 2.50 (d, J=11.3, 1H), 2.69 (dd, J=12.5, 7.9, 1H), 2.82 (dd, J=12.5, 5.2, 1H), 3.45 (d, J=12.8, 1H), 3.52 (d, J=12.8, 1H), 3.67 (m, 1H), 3.69 (s, 3H), 7.19 (s, 1H). Mass spec.: 253.16 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C@@H:17]([OH:22])[CH2:18][N:19]=[N+]=[N-])[CH:13]=2)[NH:8][C:7]=1[CH3:23])=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C@@H:17]([OH:22])[CH2:18][NH2:19])[CH:13]=2)[NH:8][C:7]=1[CH3:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)[nH]c2ccc(OC[C@@H](O)CN=[N+]=[N-])cc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)[nH]c2ccc(OC[C@@H](O)CN)cc12
Reaction time: 4 h
Yield: 101.1 %

Procedure:
A solution of 0.56 g (1.76 mmol) of 5-((2S)-3-azido-2-hydroxy-propoxy)-2-methyl-1H-indole-3-carboxylic acid ethyl ester (which was obtained in Example 140) and 1.2 g of triphenylphosphine polymer resin (3 mmol/g) was stirred in 15 mL toluene for 1.5 hours under nitrogen. The resin was collected by filtration and washed twice with 25 mL of toluene. The resin was then stirred in 60 mL of 9:1 THF/methanol for four hours. The resin was removed by vacuum filtration and washed with 9:1 THF/methanol. The filtrate was concentrated in vacuo. Then the solid was dried under vacuum to give 0.52 g of the title compound as a beige solid; mp 66-68° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.32-1.37 (m, 3H), 1.80 (brs, 1H), 2.61 (s, 3H), 2.69-2.75 (m, 2H), 3.69-3.76 (m, 1H), 3.82-3.95 (m, 2H), 4.23 (q, J=6.93 Hz, 2H), 4.90 (brs, 1H), 6.76 (dd, J=2.52 Hz, 8.73 Hz, 1H), 7.23 (d, J=8.7 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 8.85 (brs, 1H), 11.65 (s, 1H); MS (ES) m/z: 293.0 (MH+); HRMS Calcd. for C15H21N2O4 (MH+): 293.1501. Found: 293.1498.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3]1.[BH4-].[Na+].Cl>CO>[OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:3]1
Reactant: CCOC(=O)C1CCC(=O)C=C1c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1CCC(O)C=C1c1ccccc1
Reaction time: 0.75 h
Yield: 99.8 %

Procedure:
To a stirred solution of ethyl 4-oxo-2-phenylcyclohex-2-enecarboxylate(500 mg, 2.05 mmol) in MeOH(10 ml) at 0° C., NaBH4 (77.5 mg, 2.05 mmol) was added by portions. After stirring for 45 minutes, dil.HCl aq. was added to the reaction mixture and the solvent was evaporated under reduced pressure. The residue was added water and extracted with AcOEt. The organic layer was washed with water and brine, dried over MgSO4. Concentration of the organic layer afford 504 mg of ethyl 4-hydroxy-2-phenylcyclohex-2-enecarboxylate(y=100%) as a pale yellow crystal. 1H-NMR(ppm, 300 MHz, CDCl3) δ 7.23-7.34(5H, m), 6.10-6.22(1H, m), 4.30-4.50(1H, m), 3.90-4.08(1H, m), 3.72 and 3.64(1H, t and t, J=5.8 and 5.3 Hz), 1.60-2.30(4H, m), 1.00 and 1.10(3H, m)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[C:20]([CH:22]=[O:23])[CH:19]=[CH:18][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([O:3][C:4]1[CH:21]=[C:20]([CH2:22][OH:23])[CH:19]=[CH:18][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1Oc1ccccc1CC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOc1cc(CO)ccc1Oc1ccccc1CC(=O)OC
Yield: 65.6 %

Procedure:
A stirred solution of 1.74 g (5.54 mmol) of the product of Step A dissolved in 22 mL of methanol was treated with 0.105 g (2.8 mmol) of sodium borohydride at room temperature. After 5 minutes the reaction mixture was partitioned between ethyl acetate and 1N hydrochloric acid, and the organic layer was separated. The product was washed with water, brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 30% ethyl acetate/hexane to afford 1.15 g (66%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]([CH3:16])[N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:34]=[C:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([F:45])[CH:38]=1)[CH3:36]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:34]=[C:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([F:45])[CH:38]=1)[CH3:36])[C:6]1[CH:11]([CH3:16])[N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1
Reactant: COc1ccc(C(C)=CBr)cc1F
Reactant: CC1c2[nH]c3ccc(Cl)cc3c2CCN1C
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)=Cn2c3c(c4cc(Cl)ccc42)CCN(C)C3C)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.5 %

Procedure:
6-chloro-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (80 mg, 0.34 mmol) was dissolved in DMF (6 mL). To this solution was added CuI (6 mg, 0.034 mmol), L-proline (8 mg, 0.068 mmol), K3PO4 (145 mg, 0.68 mmol). The reaction mixture was stirred for 10 min at room temperature followed by addition of 4-(1-bromoprop-1-en-2-yl)-2-fluoro-1-methoxybenzene (100 mg, 0.40 mmol). The reaction mixture was heated at 80° C. for 18 h. Solvent was evaporated under reduced pressure, the residue was diluted with brine and extracted with ethyl acetate. Organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain 17 mg of 6-chloro-9-(2-(3-fluoro-4-methoxyphenyl)prop-1-enyl)-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. 1H NMR (DMSO) OXALATE SALT 7.65 (d, 2H), 7.47 (dd, 1H), 7.25 (d, 2H), 7.20 (s, 1H), 7.12 (s, 1H), 3.90 (s, 3H), 3.40 (m, 3H), 2.96 (m, 2H), 2.80 (s, 3H), 1.80 (s, 3H), 1.50 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13](Cl)=[O:14].[CH2:22]([NH2:24])[CH3:23]>O1CCCC1.O>[CH2:22]([NH:24][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:10]([S:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:11]=1)[CH3:23]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Reactant: CCN
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-(2,4-difluorophenylthio)-4nitrobenzoyl chloride (1 g) in tetrahydrofuran (3 ml) was added to a stirred solution of 70% ethylamine (0.5 ml) in water (5 ml) at 5° to 10° C. The mixture was stirred at the same temperature for 1 hour and at room temperature for 1 hour. Water (30 ml) was added to the reaction mixture. The precipitates were filtered, washed with water, and dried under reduced pressure to give a yellow powder of N-ethyl-3-(2,4-difluorophenylthio)-4-nitrobenzamide (0.94 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[F:32]C1C=CC(CCC(O)=O)=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[F:32][C:7]1[CH:6]=[CH:5][C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:3][CH:2]=1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: O=C(O)CCc1ccc(F)cc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCc2ccc(F)cc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(4-fluoro-phenyl)-propanoic-acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.