Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:15][C@@H:16]([CH3:25])[C:17](N1CCOCC1)=[O:18].[Mg].[Cl-].[NH4+]>O1CCCC1>[F:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:17](=[O:18])[C@@H:16]([O:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][O:9]1)[CH3:25]
Reactant: Fc1ccccc1Br
Reactant: C[C@H](OC1CCCCO1)C(=O)N1CCOCC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](OC1CCCCO1)C(=O)c1ccccc1F
Yield: 103.6 %

Procedure:
1-Bromo-2-fluorobenzene (15 g) and 4-[(2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (40 g) were dissolved in tetrahydrofuran (200 ml), to which magnesium (turnings: 4.4 g) was added. The mixture was stirred vigorously. The reaction flask was cooled when the temperature of the reaction solution reached to 35° C., and 1-bromo-2-fluorobenzene (16.7 g) was added thereto over the period of 10 minutes while the temperature of the reaction solution was kept at 35 to 37° C. After the reaction solution was stirred at 30 to 35° C. for 2 hours, it was cooled in an ice-bath. A saturated aqueous solution of ammonium chloride (100 ml) was added thereto and the mixture was extracted with ethyl acetate (200 ml×2, 100 ml). The extract was washed with water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was subjected to silica gel chromatography (eluent:hexane/ethyl acetate=10/1 to 5/1) to give (2S)-2'-fluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone (22.4 g) as a pale yellow oily substance.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[S:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2].Cl[C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][N:27]=1)[C:21]([O:23]C)=[O:22]>>[C:1]([C:3]1[CH:4]=[C:5]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][N:27]=2)[C:21]([OH:23])=[O:22])[CH:6]=[CH:7][C:8]=1[S:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: CC(C)CSc1ccc(B(O)O)cc1C#N
Product: CC(C)CSc1ccc(-c2cc(C(=O)O)ccn2)cc1C#N

Procedure:
Using [3-cyano-4-(isobutylthio)phenyl]boronic acid and methyl 2-chloroisonicotinate, 2-[3-cyano-4-(isobutylthio)phenyl]isonicotinic acid was obtained according to the method of Example 1. Then, 346 mg of the resulting 2-[3-cyano-4-(isobutylthio)phenyl]isonicotinic acid was suspended in 30 ml of ethanol, and 1.11 ml of a 1M aqueous sodium hydroxide solution was added to the suspension, followed by stirring at room temperature for 15 minutes. The reaction solution was concentrated under reduced pressure and the residue was washed with 2-propanol and subsequently with diethyl ether to obtain 208 mg of sodium 5-[3-cyano-4-(isobutylthio)phenyl]isonicotinate.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)[C:49]3=[O:52])=CC=2)=CC=1.COC1C=CC(N=C=S)=CC=1>>[CH3:49][O:52][C:6]1[CH:5]=[CH:4][C:3]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]4=[O:26])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:2][CH:7]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COc1ccc(N=C=S)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccc(OC)cc4)cc3)cc2C1=O

Procedure:
The compound of example 57 was prepared analogous to compound of example 51 by reaction of compound of example 6 with 4-methoxyphenyl isothiocyanate. The compound of example 57 was used directly without isolation for the preparation of compound of example 58.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:24][C:25]([C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[CH:26]=O>C1COCC1>[CH3:24][C:25]([C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[CH2:26][CH:2]=[O:3]
Reactant: Cc1ccc(CC(C)(C=O)c2cccnc2)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc(CC(C)(CC=O)c2cccnc2)cc1
Reaction time: 0.25 h

Procedure:
Under N2 Lithium bis(trimethylsilyl)amide solution (10.5 ml, 10.5 mmol, 1.0M in THF) was added to a mixture of methoxy methyltriphenyl phosphonium chloride (3.43 g, 10 mmol) in 25 ml THF dropwise at 0° C. After 15 min, it was added to a solution of the product of STEP 4 (1.65 g, 6.5 mmol) in 15 ml THF at 0° C. The reaction was stirred for 1 h and quenched with brine. The product was extracted with ethyl acetate. The organic layer was concentrated. The residue was dissolved in 50 ml THF and 50 ml 2N HCl solution. The reaction was stirred at room temperature for 18 h, and THF was evaporated. The residue was dilute with ethyl acetate and basified with 1N NaOH solution. The product was extracted thoroughly with ethyl acetate. The organic layer was washed with brine, and dried with MgSO4, and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/hexane=3/1) to yield a brown oil in 1.37 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)cc(Cl)cc1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: Clc1cc(Cl)c(CBr)c(Br)c1
Reaction time: 0.25 h
Yield: 45.8 %

Procedure:
Stir slowly, an intimate mixture of 220 g of 2-bromo-4,6-dichlorotoluene, 167 g of N-bromosuccinimide and 1 g of benzoyl peroxide in a flask (equipped with a condenser and stirrer) immersed in an 145° C. oil bath. After 10-20 min a vigorous eruption occurs and the mixture liquifies. Remove the oil bath and stir for an additional 5 min. Add 1.5 L of CCl4 slowly through the condenser. Cool the mixture and suction filter the resulting reaction mixture. Wash the filtrate with 5% aqueous sodium thiosulfate, dry over anhydrous K2CO3, filter and evaporate to a residue. Fractionally distill the residue to give 134 g of 2-bromo-4,6-dichlorobenzyl bromide, bp 94°-97° C. (0.2 tor).
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:9]([NH:11][C@H:12]([C:17]([CH2:19][C:20]([NH2:28])([CH3:27])[C:21]([NH:23][CH2:24][CH2:25][CH3:26])=[O:22])=[O:18])[CH2:13][C:14](=[O:16])[OH:15])=[O:10])[CH2:5][CH2:6][S:7][CH3:8].[C:29]([O:33][C:34]([NH:36][C@H:37]([C:48](N[C@H](C(N[C@H](C(N[C@@H](C(N)=O)C)=O)CC(=O)O)=O)CCSC)=[O:49])[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41][CH:40]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([NH:36][C@H:37]([C:48]([NH:3][C@H:4]([C:9]([NH:11][C@H:12]([C:17]([CH2:19][C:20]([NH2:28])([CH3:27])[C:21]([NH:23][CH2:24][CH2:25][CH3:26])=[O:22])=[O:18])[CH2:13][C:14](=[O:15])[OH:16])=[O:10])[CH2:5][CH2:6][S:7][CH3:8])=[O:49])[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41][CH:40]=1)=[O:35])([CH3:31])([CH3:32])[CH3:30]
Reactant: CCCNC(=O)C(C)(N)CC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)CCSC
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C)C(N)=O
Agent: Cl
Solvent: O
Product: CCCNC(=O)C(C)(N)CC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C

Procedure:
When an equivalent quantity of L-methionyl-L-aspartyl-N1 -propyl-2-amino-2-methylpropionamide hydrochloride hydrate is substituted for the L-methionyl-L-aspartyl-D-alanine amide hydrochloride of Example 6, and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonyl-L-tryptophanyl-L-methionyl-L-aspartyl-N1 -propyl-2-amino-2-methylpropionamide hydrated with 2/3 mole of water per mole. Actual elemental analysis shows C: 55.82%; H: 7.21%; N: 12.37% and S: 4.72%. Theoretical elemental analysis is C: 55.79%; H: 7.22%; N: 12.20% and S: 4.66%. This compound is represented by the following formula. ##STR17##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][CH2:13]C(OC(C)(C)C)=O)[N:7]=1)[CH3:2].Cl.O1CCOCC1>>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][CH3:13])[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(NCC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(NC)n1

Procedure:
A solution of ethyl-6-[(tert-butoxycarbonyl)methylamino]-2-pyridylacetate (0.6 g, 2 mmol) and 4 M HCl/dioxane (5 mL, 20 mmol) was stirred at RT overnight, then was concentrated. Reconcentration from toluene gave the title compound as white solid: MS (ES) m/e 195 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])(=[O:13])[C:10]([CH3:12])=O>>[CH2:15]([O:14][C:9](=[O:13])[C@H:10]([CH3:12])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: CC(=O)C(=O)OCC(C)C
Reactant: Nc1ccc(Cl)cc1
Product: CC(C)COC(=O)[C@H](C)Nc1ccc(Cl)cc1

Procedure:
Following General Procedure AA above and using 4-chloroaniline (Aldrich) and iso-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.6 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant);
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]1([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C@H:23]3[CH2:40][C@@:38]4([CH3:39])[C@@H:34]([CH2:35][CH2:36][C:37]4=[O:41])[C@H:33]4[C:24]3=[C:25]3[C:30]([CH2:31][CH2:32]4)=[CH:29][C:28](=[O:42])[CH2:27][CH2:26]3)=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na+].[Cl-].C1CCCCC1>CN(C)C=O>[Cl:1][C:29]1[C:28](=[O:42])[CH2:27][CH2:26][C:25]2[C:30]=1[CH2:31][CH2:32][C@@H:33]1[C:24]=2[C@@H:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:22][CH:21]=2)[CH2:40][C@@:38]2([CH3:39])[C@H:34]1[CH2:35][CH2:36][C:37]2=[O:41]
Reactant: C[C@]12C[C@H](c3ccc(OCc4ccccc4)cc3)C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CCC2=O
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Product: C[C@]12C[C@H](c3ccc(OCc4ccccc4)cc3)C3=C4CCC(=O)C(Cl)=C4CC[C@H]3[C@@H]1CCC2=O
Reaction time: 0.17 h

Procedure:
5.295 g of N-chlorosuccinimide is added at 60° C. under an inert atmosphere to a solution of 13.6 g of 11β-[4-(phenylmethoxy)phenyl]-estra-4,9-diene-3,17-dione in 120 ml of dimethylformamide, agitation is carried out for 10 minutes then the reaction medium is poured into a saturated aqueous solution of NaCl, followed by extraction, washing, drying and evaporating under reduced pressure until the crude product is obtained (m=19.128 g). A second trial is carried out, the crude products are collected and purified by chromatography eluting with an ethyl acetate-cyclohexane mixture 30/70. 23.28 g of expected pure product is obtained. (Rf ACOET/cyclohexane 30/70=0.19).
Reaction SMILES: [Br:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C@@H:6]2[OH:13].N1C=CN=C1.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O.O>[Br:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C@@H:6]2[O:13][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1ccc2c(c1Br)CC[C@@H]2O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCc2c1ccc(C#N)c2Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-4-Bromo-1-hydroxy-indan-5-carbonitrile (0.90 g, 3.78 mmol), imidazole (0.64 g, 9.45 mmol) and tert-butyldimethylchlorosilane (0.80 g, 5.29 mmol) are suspended in dry N,N-dimethylformamide and stirred at room temperature for 3 hours. The mixture is diluted with water and extracted with ethyl acetate. The organic extracts are dried and the solvent removed to give the crude product which is used directly in the next step (Yield 1.20 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.Cl[Si](C)(C)C.[C:17]1([CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>C(Cl)Cl.C(N(CC)CC)C>[C:7]([C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([OH:9])=[O:8]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)CCCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCc1ccccc1)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(Aminomethyl)benzoic acid (3.6 g) is suspended in methylene chloride (100 mL), to which 15 mL triethylamine is added. Chlorotrimethylsilane (10 mL) is then added and the mixture allowed to stir at room temperature for 1 hr. The mixture is then cooled in an ice bath and 4-phenylbutyryl chloride (5.3 g) in methylene chloride (10 mL) is added dropwise and the resulting mixture stirred for 30 min at 0° C., followed by an additional 3 hrs at ambient temperature. The mixture is treated with 75 mL 1N HCl, after which the organic layer is separated and extracted with 1N HCl. The precipitate which had formed is recovered by filtration and recrystallized two times from methanol/l N HCl to give pure N-(4-carboxybenzyl)-4-phenylbutyramide. M.p. 178°-179° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH:13]2[CH2:17][NH:16][C:15](=[O:18])[CH2:14]2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Cl)C1C=CC=CC=1>>[CH2:19]([N:16]1[CH2:17][CH:13]([C:9]2([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][CH2:11][CH2:10]2)[CH2:14][C:15]1=[O:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(C2CNC(=O)C2)CCC1
Solvent: ClCc1ccccc1
Product: CC(C)(C)OC(=O)NC1(C2CC(=O)N(Cc3ccccc3)C2)CCC1

Procedure:
Next, 4-(1-tert-butoxycarbonylaminocyclobutyl)-2-pyrrolidone is allowed to react with benzyl bromide or benzyl chloride using a base to yield 1-benzyl-4-(1-tert-butoxycarbonylaminocyclobutyl)-2-pyrrolidone.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[CH3:30][CH:31]1[CH2:35][CH2:34][CH2:33][NH:32]1>>[CH3:30][CH:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Reactant: CC1CCCN1
Product: CC1CCCN1c1cc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)ccn1

Procedure:
Compound is formed by reacting 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide and 2-methylpyrrolidine under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.24 (m, 2H), 7.86 (m, 1H), 7.57 (m, 2H), 7.49 (d, 1H), 7.09 (d, 1H), 7.05 (s, 1H), 7.01 (s, 1H), 4.31 (t, 2H), 3.60 (m, 6H), 2.88 (t, 2H), 2.57 (m, 4H), 2.07 (m, 4H), 1.70 (m, 1H), 1.21 (d, 3H). MS: 461.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[OH:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC.[OH-].[Na+]>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCCCC2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(=O)C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of (2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanol (5.46 g, 9.17 mmol) in methylene chloride (150 mL) at room temperature was added Dess-Martin periodinane (4.36 g, 10.3 mmol). The mixture was stirred at room temperature for 2 hours, diluted with ether (50 mL) and 1N sodium hydroxide (40 mL) was added. The mixture was extracted with ethyl acetate (2×100 mL). Combined organic layers were washed with 1N sodium hydroxide (2×40 mL), brine (50 mL), dried with sodium sulfate and concentrated in vacuo. The crude was purified by chromatography over 40+M Biotage silica column (eluted with 0-30% ethyl acetate in heptane) to afford the title compound as a pale yellow oil (5.2 g, 96%). 1H NMR (400 MHz, CDCl3) δ ppm 1.16-1.42 (m, 5H) 1.70 (d, J=12.03 Hz, 1H) 1.80 (d, J=9.54 Hz, 4H) 2.96-3.05 (m, 1H) 4.18 (s, 3H) 4.79 (s, 2H) 4.82 (s, 2H) 7.53 (s, 1H) 7.57 (d, J=8.30 Hz, 1H) 7.64 (d, J=7.88 Hz, 1H) 7.66 (s, 2H) 7.72 (s, 1H). MS (ES+) Calc: 593.2, Found: 594.5 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[C:18]4[S:22][C:21](SC)=[N:20][C:19]4=[O:25])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:28]([F:31])([F:30])[F:29])[CH:4]=1.[NH:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37]([OH:39])=[O:38]>>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[C:18]4[S:22][C:21]([N:32]5[CH2:36][CH2:35][CH2:34][C@@H:33]5[C:37]([OH:39])=[O:38])=[N:20][C:19]4=[O:25])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:28]([F:30])([F:29])[F:31])[CH:4]=1
Reactant: COc1ccc(Cn2ncc3cc(C=C4SC(SC)=NC4=O)ccc32)c(C(F)(F)F)c1
Reactant: O=C(O)[C@H]1CCCN1
Product: COc1ccc(Cn2ncc3cc(C=C4SC(N5CCC[C@@H]5C(=O)O)=NC4=O)ccc32)c(C(F)(F)F)c1

Procedure:
1-{5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-2-(R)-carboxylic acid was prepared from 5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and pyrrolidine-2-(R)-carboxylic acid following General Procedure C.
Reaction SMILES: [CH2:1](O)[CH3:2].S(Cl)(Cl)=O.[Cl:8][CH2:9][CH:10]=[N:11][O:12][CH2:13][C:14]([OH:16])=[O:15]>>[Cl:8][CH2:9][CH:10]=[N:11][O:12][CH2:13][C:14]([O:16][CH2:1][CH3:2])=[O:15]
Reactant: CCO
Reactant: O=C(O)CON=CCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CON=CCCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A dry 25 ml two-necked round bottom flask was equipped with a stirring bar, addition funnel, reflux condenser and nitrogen bubbler. The flask was charged with absolute ethanol (9.2 gm, 200 mmoles) and the addition funnel charged with thionyl chloride (4.3 gm, 36 mmoles). The flask and its contents were cooled to about 0° C. The thionyl chloride was added dropwise while maintaining the flask temperature at 5° C. or below. After the addition was completed, the resulting mixture was stirred for 1 hour at 0° C. Beta-chloroethylideneaminooxyacetic acid (2.7 gm, 18 mmoles) was added in one portion. The resulting mixture was allowed to warm to room temperature during 1 hour. The flask was warmed to 40°-45° C. and maintained for 4 hours. The resulting mixture was cooled, then solvents were removed in vacuo. The residue was taken up in ethyl acetate which was extracted with an aqueous solution of sodium bicarbonate. The ethyl acetate layer was dried over magnesium sulfate, filtered, then taken to "dryness" in vacuo. A brown oil (2.1 gm) was obtained. Distillation at 0.5 mm Hg gave the desired product as a clear oil (2.0 gm), b.p. 60°-70° C.
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:11]1C=CC=CC=1>CC#N.CCOC(C)=O>[C:8](=[O:9])([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH2:11]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Intermediates 10 to 18 were prepared by treatment of the appropriate aminoheterocycle intermediate with 1 equivalent of phenylchloroformate in dry CH3CN and 1 equivalent of pyridine. The reagents were stirred at rt for 4 h, diluted with EtOAc, washed with NaHCO3, and dried over MgSO4. The material was purified by FCC to provide pure phenyl carbamate intermediates.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[C@@H:5]([C:18]([OH:20])=O)[CH2:4][CH2:3]1.[NH2:21][CH:22]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:23]([OH:27])[C:24]([NH2:26])=[O:25].O[NH-].O=[N-]>>[NH2:26][C:24](=[O:25])[C:23](=[O:27])[CH:22]([NH:21][C:18]([C@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:15])([F:16])[F:17])=[O:20])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1ccccc1C(F)(F)F
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1C(F)(F)F

Procedure:
Coupling of (R)-5-Oxo-1-(2-trifluoromethyl-benzyl)-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [C:1]([CH:6]1[CH:11]([OH:12])[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]([CH2:17][CH:18]([S:20][CH2:21][CH:22]=[CH2:23])[CH3:19])[CH2:8][CH:7]1[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl-].[CH2:26](O[NH3+])[CH:27]=[CH2:28]>C(O)C.C([O-])(=O)C.[Na+]>[CH2:28]([O:5][C:1](=[C:6]1[C:11](=[O:12])[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]([CH2:17][CH:18]([S:20][CH2:21][CH:22]=[CH2:23])[CH3:19])[CH2:8][C:7]1=[O:24])[CH2:2][CH2:3][CH3:4])[CH:27]=[CH2:26]
Reactant: C=CCSC(C)CC1CC(O)C(C(=O)CCC)C(O)C1C(=O)OC
Reactant: C=CCO[NH3+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: C=CCOC(CCC)=C1C(=O)CC(CC(C)SCC=C)C(C(=O)OC)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
10.6 parts by weight of 2-butyryl-4-methoxycarbonyl-5-(2-allylthiopropyl)-cyclohexane-1,3-diol are dissolved in 150 parts by volume of ethanol, 3.3 parts by weight of allyloxiammonium chloride and 2.9 parts by weight of sodium acetate are added and the mixture is stirred for 20 hours at room temperature. Thereafter, the mixture is poured into ice water, the resulting mixture is extracted with methylene chloride and the latter is stripped off to give 11.3 g of 2-(1-allyloxibutylidene)-4-methoxycarbonyl-5-(2-allylthiopropyl)-cyclohexane-1,3-dione as a yellow oil.
Reaction SMILES: CO.[CH3:3][NH2:4].[Cl:5][C:6]1[S:7][C:8]([CH2:11][NH:12][C:13](=[N:16][N+:17]([O-:19])=[O:18])SC)=[CH:9][N:10]=1>C(#N)C>[Cl:5][C:6]1[S:7][C:8]([CH2:11][NH:12][C:13]([NH:4][CH3:3])=[N:16][N+:17]([O-:19])=[O:18])=[CH:9][N:10]=1
Reactant: CSC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reactant: CN
Solvent: CO
Solvent: CC#N
Product: CNC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reaction time: 1.5 h

Procedure:
349 mg of a 40% methylamine methanol solution was dropwise added to a mixture consisting of 1 g N-(2-chloro-5-thiazolylmethyl)-S-methyl-N'-nitroisothiourea and 30 ml acetonitrile, at room temperature, over 5 minutes. After stirring for 1.5 hours, the resultant white precipitate was collected by filtration and then dried to afford 410 mg of N-(2-chloro-5-thiazolylmethyl)-N'-methyl-N"-nitroguanidine (compound No.14) as a white powder. The mother liquor after the filtration was concentrated, then 20 ml of ethanol was added, followed by stirring thoroughly, and the crystals formed were collected by filtration to obtain additional 330 mg of compound No.14 (mp 172-173° C.). Upon recrystallization from acetonitrile, this product exhibited mp 173-174° C.