Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([NH2:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1)[C:2]([NH2:4])=[O:3].[CH:15](OCC)=[O:16]>>[NH:1]([C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([NH:14][CH:15]=[O:16])[CH3:13])[CH:8]=[CH:9][CH:10]=1)[C:2]([NH2:4])=[O:3]
Reactant: CC(N)Cc1cccc(NC(N)=O)c1
Reactant: CCOC=O
Product: CC(Cc1cccc(NC(N)=O)c1)NC=O

Procedure:
A mixture consisting of 4.8 gm of 1-(3'-ureido-phenyl)-2-amino-propane and 5 ml of ethyl formate was refluxed for 5 hours. Thereafter, the reaction solution was evaporated, and the residue was purified by chromatography on a silicagel column, using methanol/chloroform (2:8) as the flow agent. The eluate was evaporated, and the residue was recrystallized from ethanol and ether, yielding the compound of the formula ##STR25## which had a melting point of 133-136° C.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:23]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:34][CH:33]=1)[NH:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH2:5][CH2:6]C(OCC1C=CC=CC=1)C1C=CC(F)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl.[C:58]([O:61][CH2:62][CH3:63])(=O)[CH3:59]>O1CCCC1>[CH2:62]([O:61][CH:58]([C:59]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH2:6][CH2:5][CH:4]1[CH:23]([C:32]2[CH:33]=[CH:34][C:35]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:36][CH:37]=2)[N:24]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:3]1=[O:2])[C:63]1[CH:6]=[CH:5][CH:4]=[CH:23][CH:32]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)C(CCC(OCc1ccccc1)c1ccc(F)cc1)C(Nc1ccc(F)cc1)c1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(CCC(OCc2ccccc2)c2ccc(F)cc2)C(c2ccc(OCc3ccccc3)cc2)N1c1ccc(F)cc1
Temperature: -22.5 °C
Reaction time: 0.5 h

Procedure:
10 gms of 5-Benzyloxy-2-[(4-benzyloxy-phenyl)-(4-fluoro-phenylamino)-methyl]-5-(4-fluoro-phenyl)-pentanoic acid methyl ester was dissolved in 500 ml of tetrahydrofuran and cool the reaction mass to −20 to −25° C. To the reaction mass 16 ml of 1M Lithium bis(trimethylsilyl)amide was added under nitrogen atmosphere and stirred for about 30 minutes. To the reaction mass 100 ml of 2 N hydrochloride solution was added at 20-25° C. Stirred the reaction mass by adding 150 ml of ethyl acetate and separated the organic layer. Washed the organic layer with water and dried over sodium sulphate. Distilled the solvent completely under reduced pressure at 50-55° C. to get 8.0 gms of 3-[3-Benzyloxy-3-(4-fluoro-phenyl)-propyl]-4-(4-benzyloxy-phenyl)-1-(4-fluoro-phenyl)-azetidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]([C:21]2[CH:28]=[CH:27][C:24](C=O)=[CH:23][CH:22]=2)[CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:29]([CH2:34][CH:35]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:31][CH2:32][CH3:33])=[O:30].O.[CH2:56](Cl)Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]([C:21]2[CH:28]=[CH:27][C:24]([CH:56]=[C:34]([CH3:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=2)[CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClCCl
Reactant: O=Cc1ccc(C(CNS(=O)(=O)c2ccc(Cl)cc2)Cc2cccnc2)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C(C)=Cc1ccc(C(CNS(=O)(=O)c2ccc(Cl)cc2)Cc2cccnc2)cc1

Procedure:
The solution of 220 mg of 4-[3-(4-chlorobenzenesulfonamido)-1-(3-pyridyl)-2-propyl]benzaldehyde and 420 mg of (carboethoxyethylidene)triphenylphosphorane in 20 ml of chloroform in solution was stirred under heating for five hours. To the reaction mixture was added water, followed by separation of the organic phase, which was then extracted with methylene chloride. After washing in saturated aqueous sodium chloride solution, the product was then dried over magnesium sulfate, followed by evaporation of the solvent. The residue obtained was subjected to preparative TLC on silica gel, which was developed with methylene chloride three times, to obtain 186 mg of ethyl 4-[3-(4-chlorobenzenesulfonamido)-1-(3-pyridyl)-2-propyl]-α-methylcinnamate. The spectrometric data thereof supports the structure of [46] as follows.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH:5]1[CH2:10][N:9]([C:11](=[O:24])[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:8][CH2:7][NH:6]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:35]2[S:36][CH:37]=[C:38]([C:40](O)=[O:41])[N:39]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:35]2[S:36][CH:37]=[C:38]([C:40]([N:6]3[CH2:7][CH2:8][N:9]([C:11](=[O:24])[C:12]4[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=4)[CH2:10][CH:5]3[CH2:4][O:3][CH3:2])=[O:41])[N:39]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]
Reactant: COc1ccc(-c2nc(C(=O)O)cs2)cc1OC
Reactant: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)c1csc(-c2ccc(OC)c(OC)c2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-methoxymethyl-4-(3,4,5trimethoxybenzoyl) piperazine hydrochloride obtained in Reference Example 6 (0.50 g), 2-(3,4-dimethoxyphenyl)thiazol-4-carboxylic acid (0.37 g), triethylamine (0.42 g) and N,N-dimethylformamide (5 ml) is added dropwise, while stirring under icecooling, diethyl cyanophosphonate (0.46 g). The reaction mixture is stirred at 0° C. for one hour and there poured into ice-water, followed by extraction with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is purified by means of a silica gel column chromatography (eluent: AcOEt) to give 1-[2(3,4-dimethoxyphenyl) thiazol-4-ylcarbonyl]-2-methoxymethyl-4-(3,4,5-trimethoxybenzoyl)piperazine. Recrystallization from EtOH gives colorless needles, m.p. 149-151° C.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[NH2:14][C@H:15]([C:23]([NH:25][C@H:26]([C:34]([OH:36])=[O:35])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:33])[NH2:32])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([BH3-])#N.[Na+]>>[C:3]([CH:2]([NH:14][C@H:15]([C:23]([NH:25][C@H:26]([C:34]([OH:36])=[O:35])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:32])[NH2:33])=[O:24])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:5])=[O:4]
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: N=C(N)NCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(CCc1ccccc1)C(=O)O)C(=O)O

Procedure:
In the manner described in example 24, one can condense 2-oxo-4-phenylbutyric acid and L-phenylalanyl-L-arginine in the presence of sodium cyanoborohydride to yield N-(1-carboxy-3-phenylpropyl)-L-phenylalanyl-L-arginine.
Reaction SMILES: [Si]([O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([CH:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH3:17])=[CH:11][C:10]=1[Cl:26])(C(C)(C)C)(C)C.CCOCC>CN(C=O)C.O>[Si:19]([O:18][CH:16]([C:12]1[CH:13]=[C:14]([Cl:15])[C:9]([OH:8])=[C:10]([Cl:26])[CH:11]=1)[CH3:17])([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:21])[CH3:20]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1cc(Cl)c(O[Si](C)(C)C(C)(C)C)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CC(O[Si](C)(C)C(C)(C)C)c1cc(Cl)c(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A sol. of (rac.)-2-(tert-butyldimethylsilanyloxy)-5-[1-(tert-butyldimethylsilanyloxy)ethyl]-1,3-dichlorobenzene (188 mg, 0.432 mmol) and CS2CO3 (76.2 mg, 0.126 mmol) in a mixture of DMF (0.50 mL) and water (50 μL) was stirred at rt overnight. Et2O (75 mL) was added. The sol. was washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification by FC(CH2Cl2) yielded the title compound (122 mg, 88%). LC-MS: tR=1.15 min.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:36]=[CH:35][N:16]3[C:17](=[O:34])[C:18]([CH:32]=O)=[C:19]([N:21]4[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[CH2:22]4)[N:20]=[C:15]3[CH:14]=2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Li+].FC(F)(F)COP([CH2:51][C:52]([O:54][CH3:55])=[O:53])(=O)OCC(F)(F)F.N12CCCN=C1CCCCC2>O1CCCC1>[C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:36]=[CH:35][N:16]3[C:17](=[O:34])[C:18](/[CH:32]=[CH:51]/[C:52]([O:54][CH3:55])=[O:53])=[C:19]([N:21]4[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([N:29]([CH3:30])[CH3:31])=[O:28])[CH2:22]4)[N:20]=[C:15]3[CH:14]=2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: CN(C)C(=O)C1CCCN(c2nc3cc(C(=O)Nc4nc(C(C)(C)C)cs4)ccn3c(=O)c2C=O)C1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)/C=C/c1c(N2CCCC(C(=O)N(C)C)C2)nc2cc(C(=O)Nc3nc(C(C)(C)C)cs3)ccn2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
The N8-[4-(tert-butyl)-1,3-thiazol-2-yl]-2-{3-[(dimethylamino)carbonyl]-piperidino}-3-formyl-4-oxo-4 H-pyrido[1,2-a]pyrimidine-8-carboxamide (84.2 mg, 0.18 mmol) obtained in (B) was dissolved in tetrahydrofuran (10 ml), added with lithium chloride (45.3 mg, 1.07 mmol), and added dropwise with bis(2,2,2-trifluoroethyl)-(methoxycarbonylmethyl)phosphonate (112.9 μl, 0.53 mmol) and 1,8-diazabicyclo-[5,4,0]undec-7-ene (73.4 μl, 0.53 mmol). After the reaction solution was stirred at room temperature for 2 hours, the solvent was evaporated, and the residue was purified by preparative TLC (chloroform:methanol=20:1, v/v) to obtain the title compound (63.7 mg, 68.2%) as a mixture of orange oil and solid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.Br.[NH:17]([C:19]1[S:20][CH2:21][CH2:22][N:23]=1)[NH2:18].C([O-])(=O)C.[Na+]>C(O)C>[S:20]1[CH2:21][CH2:22][NH:23][C:19]1=[N:17][N:18]=[C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[NH:9][C:10]2[C:15]1=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: Clc1c2ccccc2nc2ccccc12
Reactant: NNC1=NCCS1
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc2c(=NN=C3NCCS3)c3ccccc3[nH]c2c1

Procedure:
1.0 g of 9-chloroacridine, 0.926 g of 2-hydrazino-2-thiazoline hydrobromide and 0.767 g of anhydrous sodium acetate are dissolved in 100 ml of dry ethanol, heated to boiling under reflux for 2 hours and the red solution is then evaporated in vacuo. The residue is treated with water and the crystalline mass is filtered under suction. After recrystallization from ethanol, there is obtained 9-acridanone (2-thiazolidinylidene)hydrazone of melting point 212°-216° (decomposition).
Reaction SMILES: N([O-])=[O:2].[Na+].[CH:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20](N)[C:21]([OH:23])=[O:22])=[O:14])=[CH:7][CH:6]=1>O.OS(O)(=O)=O.C(#N)C>[CH2:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([OH:2])[C:21]([OH:23])=[O:22])=[O:14])[C:8]1[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: NC(CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(NCCCCC(O)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of NaNO2 in water (200 ml) was added dropwise during 3 hr to an ice-cooled and stirred solution of N-ε-CBZ-L-lysine in 1 N H2SO4 and acetonitrile. The mixture was stirred for an additional 2 hr after the addition of 0-5° C. and left to stand overnight. The resulting clear solution was concentrated under reduced pressure. The residual semi-solid was extracted with ether, and the ether extract was then crystallized in ether/petroleum ether. The products recovered was α-(N-CBZ-4-aminobutyl) glycolic acid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[I:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][CH:15]=1>C(O)(=O)C>[I:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][N:21]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:19])=[CH:16][CH:15]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccc(I)cc1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(I)cc1
Temperature: 100 °C
Yield: 83 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-iodobenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 430 mg of the title compound (83%) as a yellow solid in 98.7% purity by HPLC (Rt: 6.19, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C@H:9]1[CH2:37][C@@:36]2([CH3:38])[C@@H:20]([CH2:21][C@@H:22]([CH3:39])[C@@H:23]2[C:24](=[O:35])[CH:25]([O:27][C:28](=[O:34])[C@@H:29]([NH2:33])[CH:30]([CH3:32])[CH3:31])[OH:26])[C@H:19]2[C@H:10]1[C@:11]1([CH3:42])[C:16]([C@@H:17]([F:40])[CH2:18]2)=[CH:15][C:14](=[O:41])[CH:13]=[CH:12]1.[NH:43]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[C@H:44]([C:46]([NH:48][C@H:49]([C:51]([N:53]1[CH2:60][CH2:59][CH2:58][C@H:54]1[C:55](O)=[O:56])=[O:52])[CH3:50])=[O:47])[CH3:45].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[F:40][C@@H:17]1[C:16]2[C@:11]([CH3:42])([CH:12]=[CH:13][C:14](=[O:41])[CH:15]=2)[C@@H:10]2[C@H:19]([C@H:20]3[C@:36]([CH3:38])([CH2:37][C@@H:9]2[OH:8])[C@@H:23]([C:24](=[O:35])[CH:25]([O:27][C:28](=[O:34])[C@H:29]([CH:30]([CH3:32])[CH3:31])[NH:33][C:55](=[O:56])[C@@H:54]2[CH2:58][CH2:59][CH2:60][N:53]2[C:51](=[O:52])[C@H:49]([CH3:50])[NH:48][C:46](=[O:47])[C@H:44]([CH3:45])[NH:43][C:61]([O:63][C:64]([CH3:65])([CH3:66])[CH3:67])=[O:62])[OH:26])[C@H:22]([CH3:39])[CH2:21]3)[CH2:18]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)[C@H](N)C(=O)OC(O)C(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)OC(O)C(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
884 mg (1.50 mmol) of H-Val-O-FC x TFA (Example 31), 500 mg (1.40 mmol) of Boc-Ala-Ala-Pro-OH and 168 mg (1.40 mmol) of N-hydroxybenzotriazole are dissolved in this sequence in 50 ml of dichloromethane and 330 μl (3.00 mmol) of N-methylmorpholine is added. Then, a solution of 289 mg (1.40 mmol) of dicyclohexylcarbodiimide in 2 ml of dichloromethane is added and stirred for 2 hours at room temperature. Then, it is suctioned off from precipitated urea, the filtrate is concentrated by evaporation and filtered again. Chromatography of this amount of raw material (300 g of silica gel, hexane/acetone 1:1) yields 861 mg (76%) of N-(N-(N-(N-((1,1-dimethyl) ethoxycarbonyl) -L-alanyl) -L-alanyl)-L-prolyl)-L-valine [6α-fluoro-11β,21-dihydroxy-16α-methyl-3,20-dioxo-pregna-1,4-dien-21-yl] ester. 737 mg of pure product is obtained [one or more words missing] recrystallization from dichloromethane/diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:12][O:11]2)=[CH:4][CH:3]=1.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH2:12][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)([OH:11])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C1(CCc2ccc(Cl)cc2)CO1
Reactant: c1nc[nH]n1
Solvent: CCO
Product: CC(C)(C)C(O)(CCc1ccc(Cl)cc1)Cn1cncn1
Yield: 53.3 %

Procedure:
A solution of 17.9 g (0.075 mole) of 2-(4-chlorophenylethyl)-2-tert.-butyloxirane and 6.9 g (0.1 mole) of 1,2,4-triazole in 30 ml of ethanol in a sealed tube is heated at 150° C. for 20 hours. The tube is allowed to cool and the reaction solution is evaporated. The residue is dissolved in ether, washed three times with water and once with sodium chloride solution, dried over sodium sulphate and evaporated. The residue is chromatographed over a column of silican gel (mobile phase: dichloroethane/ethyl acetate 1:1). 12.3 g (53.2% of theory) of 1-(4-chlorophenyl)-4,4-dimethyl-3-(1,2,4-triazol-1-yl-methyl)-3-pentanol are obtained as a viscous oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]([O:14][CH3:15])=[O:13])(=O)=O.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20].C(N(CC)CC)C>CN(C)C=O>[CH3:15][O:14][C:12]([C:8]1[S:9][CH:10]=[CH:11][C:7]=1[C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[O:13]
Reactant: COC(=O)c1sccc1OS(=O)(=O)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sccc1C#C[Si](C)(C)C
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A mixture of 2.07 g of 2-methoxycarbonyl-3-thienyl trifluoromethane sulfonate, 2.02 ml of trimethylsilylacetylene, 1.57 g of tetrakis (triphenylphosphine)palladium(0), 272 mg of cuprous iodide, 2.98 ml of triethylamine and 30 ml of N,N-dimethylformamide was stirred at 65° C. for 3 hours in a nitrogen atmosphere. Silica gel was added to the reaction solution, and the solvent was removed. The residue was subjected to silica gel column chromatography using 6% ethyl acetate/hexane, to give 1.78 g of the target compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[NH:5][CH:6]=[C:7]1[C:11](=[O:12])[N:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[N:9]=[C:8]1[CH3:22])[CH3:2].[NH3:27]>>[CH2:1]([C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[NH:5][CH:6]=[C:7]1[C:11](=[O:12])[N:10]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH2:27])=[O:18])=[CH:20][CH:21]=2)[N:9]=[C:8]1[CH3:22])[CH3:2]
Reactant: CCc1ccccc1NC=C1C(=O)N(c2ccc(C(=O)O)cc2)N=C1C
Reactant: N
Product: CCc1ccccc1NC=C1C(=O)N(c2ccc(C(N)=O)cc2)N=C1C

Procedure:
From the reaction of 4-(4-(2-ethylanilinomethylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzoic acid and diluted ammonia solution, 4-(4-(2-ethylanilinomethylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzamide is obtained, Mp 225.2° C.
Reaction SMILES: [OH-].[K+].SCC(O)=O.[CH2:8]([N:15]([CH2:28][CH2:29][C:30]1[N:31]([C@@H:36]2[CH2:45][C:44]3[C:39](=[C:40]([F:47])[CH:41]=[C:42]([F:46])[CH:43]=3)[O:38][CH2:37]2)[C:32](=[S:35])[NH:33][CH:34]=1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO>O.CS(C)=O>[CH2:8]([NH:15][CH2:28][CH2:29][C:30]1[N:31]([C@@H:36]2[CH2:45][C:44]3[C:39](=[C:40]([F:47])[CH:41]=[C:42]([F:46])[CH:43]=3)[O:38][CH2:37]2)[C:32](=[S:35])[NH:33][CH:34]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCc1c[nH]c(=S)n1[C@H]1COc2c(F)cc(F)cc2C1)Cc1ccccc1
Agent: O=C(O)CS
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: CO
Product: Fc1cc(F)c2c(c1)C[C@@H](n1c(CCNCc3ccccc3)c[nH]c1=S)CO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
To a solution of potassium hydroxide (5M aqueous solution, 52.5 ml, 263 mmol) in water at 10° C. was added dropwise 2-mercaptoacetic acid (8.30 ml, 119 mmol). The resulting solution was stirred at room temperature for 10 minutes and a solution of (R)—N-benzyl-N-(2-(3-(6,8-difluorochroman-3-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-yl)ethyl)-2-nitrobenzenesulfonamide (28 g, 47.7 mmol) in DMSO (150 ml) was added dropwise over 20 minutes. During the addition of KOH, an exothermic event was observed. The resulting slurry was stirred at 40° C. under HPLC control for 3 h. The reaction was then cooled to 20° C. and methanol (105 ml) was added followed by water (45 ml). The resulting slurry was aged for 30 minutes at 20° C. and then filtered. The beige solid was successively washed with water/MeOH (9:1) (100 ml), water (200 ml) and finally methyl tert-butyl ether (MTBE) (50 ml), dried to give (R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione (compound RY′, 18.3 g, 12.35 mmol, 96% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:28](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([C@H:14]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[CH3:28])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC2CCC(NC(=O)OC(C)(C)C)CC2)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Br)cc(N(C)[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c1C
Temperature: 80 °C

Procedure:
To a stirred solution of mixture of cis isomer of methyl 5-bromo-3-((4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-2-methylbenzoate (4 g, 9.09 mmol) in acetonitrile (50 mL) was added cesium carbonate (5.9 g, 18.18 mmol) and methyl iodide (6.45 g, 45.45 mmol). The resulting reaction mixture was heated at 80° C. for 7 h. On completion, the reaction mixture was cooled to room temperature and filtered, the residue was washed with ethyl acetate and filtrate was concentrated to afford desired crude compound which then purified by column chromatography giving desired compound (1.4 g, 34%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[OH:23]OS([O-])=O.[K+].OS([O-])(=O)=O.[K+].[OH2:35]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]2[CH:16]=[CH:17][C:18]([S:21]([CH3:22])(=[O:23])=[O:35])=[CH:19][CH:20]=2)=[CH:4][CH:3]=1
Reactant: O=S([O-])OO
Reactant: O
Reactant: CSc1ccc(C2=C(c3ccc(F)cc3)CC(C)(C)C2)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CO
Product: CC1(C)CC(c2ccc(F)cc2)=C(c2ccc(S(C)(=O)=O)cc2)C1
Reaction time: 4 h
Yield: 38 %

Procedure:
A solution of 120 mg (0.39 mmol) of 1-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylthio)benzene (Step 9) in 3 mL of methanol/water (1:1) was slowly treated with 470 mg (0.76 mmol) of Oxone® [2 KHSO5.KHSO4. K2SO4 ]in 2 mL of water. After stirring for 4 hours, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine, dried (MgSO4), and reconcentrated. Purification by silica gel chromatography (MPLC) with hexane/ethyl acetate (5:1) and subsequent lyophilization from acetonitrile/water (1:1) gave 50 mg (38%) of 1-[2-(4-fluorophenyl)-4,4-dimethyl cyclopenten-1-yl]-4-(methylsulfonyl)benzene (41 in Synthetic Scheme X when R1 and R2 =CH3, RS=F, R10 =SO2CH3, and R3, R4, R6, R7, R8, R9, R11 and R12=H) as a colorless solid: NMR (CDCl3) δ1.24 (s, 6H), 2.71 (s, 4H), 3.4 (s, 3H), 6.92 (t, J=8 Hz, 2H), 7.05-7.12 (m, 2H), 7.30 (d, J=9 Hz, 2H), 7.75 (d, J=9 Hz, 3H); MS (EI) m/e (rel intensity) 344 (100), 329 (33), 250 (18), 235 (20), 109 (35), 69 (44); HRMS. Calc'd for C20H21FO2S: 344.1246. Found: 344.1272.