Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:3]=1[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7].[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:3]=1[CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7]
Reactant: N#CC(C#N)=Cc1c(F)cc(F)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#CC(C#N)Cc1c(F)cc(F)cc1F
Yield: 90 %

Procedure:
Using 1.42 g of (2,4,6-trifluorobenzyliden)malononitrile, 50 ml of ethanol and 0.08 g of sodium borohydride, and according to the process described in the REFERENCE PRODUCTION EXAMPLE 3, there was obtained 1.29 g of (2,4,6-trifluorobenzyl)malononitrile (the intermediate (21)).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.OO.[BrH:12]>>[Br:12][C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[C:5]([CH3:9])[C:6]=1[NH2:8]
Reactant: Br
Reactant: Cc1cc(N)c(C)cn1
Agent: OO
Product: Cc1cnc(C)c(Br)c1N
Temperature: 75 °C
Reaction time: 1 h

Procedure:
A mixture of 2,5-dimethylpyridin-4-amine (3.57 g, 29.3 mmol) in 48% hydrogen bromide aqueous solution (40 mL) was heated to 75° C. Then 15% hydrogen peroxide (7 mL) was added dropwise over 30 min. The reaction mixture was stirred at 75° C. for 1 h, and concentrated under reduced pressure. The pH of the solution was adjusted to 9 with 1 N sodium hydroxide solution. The aqueous mixture was extracted with DCM (250 mL×3), and the combined organic phase was washed with saturated sodium chloride solution (250 mL×1), dried with sodium sulfate, and concentrated to give 5.0 g of the product as a yellow solid. MS (ESI): m/z 203.1 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH2:13][CH2:12]1
Reactant: N#Cc1cccc(F)c1
Reactant: CN1CCNCC1
Product: CN1CCN(c2cccc(C#N)c2)CC1

Procedure:
According to a similar manner to that in Reference Example 17, the title compound was synthesized from 3-fluorobenzonitrile and 1-methylpiperazine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH2:14][CH2:15]OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:26].[Na+].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH2:14][CH2:15][I:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CCOC(=O)C1(CCOS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(CCI)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 39.9 %

Procedure:
To a solution of 4-ethoxycarbonyl-4-(2-methanesulfonyloxyethyl)-piperidine-1-carboxylic acid tert-butyl ester (2.38 g) in dimethylformamide (24 ml) was added sodium iodide (4.77 g), and the mixture was stirred at 70° C. for 7 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and dried under reduced pressure to give the title compound (1.03 g).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][CH2:2]1.[C:6]([NH:13][CH2:14][C:15](O)=[O:16])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>>[C:9]([O:8][C:6](=[O:7])[NH:13][CH2:14][C:15](=[O:16])[N:3]1[CH2:4][CH2:5][S:1][CH2:2]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: C1CSCN1
Product: CC(C)(C)OC(=O)NCC(=O)N1CCSC1

Procedure:
Thiazolidine (85 mmol) and Boc-glycine (57 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 60 hour reaction time) and the product used without purification. Yield 12.7g, 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].Cl[CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH:28]3[CH2:30][CH2:29]3)[CH:19]=2)[O:16][CH:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH2:9][CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH:28]3[CH2:30][CH2:29]3)[CH:19]=2)[O:16][CH:17]=1
Reactant: COc1ccc(-c2nc(CCl)co2)cc1OCC1CC1
Reactant: CC(=O)c1ccccc1Cl
Product: COc1ccc(-c2nc(CCC(=O)c3ccccc3Cl)co2)cc1OCC1CC1
Yield: 13.3 %

Procedure:
Using 0.31 g of 1-(2-chlorophenyl)ethanone and 0.59 g of 4-chloromethyl-2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazole obtained in Reference Example 11, 0.11 g of colorless oily 1-(2-chlorophenyl)-3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one was obtained in the same manner as in Example 177.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:41])[CH:20]([NH:32][C:33]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:34])[CH2:21][S:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:24])=[O:23])[CH:13]([OH:42])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:41])[CH:20]([NH:32][C:33]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:34])[CH2:21][S:22]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:24])=[O:23])[C:13](=[O:42])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCCN(C(=O)OCc2ccccc2)CC1O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1CN(C(=O)OCc2ccccc2)CCCC1NC(=O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
3-Hydroxy-4-{2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionylamino}-azepane-1-carboxylic acid benzyl ester (100 mg, 0.167 mmol) was dissolved in DMSO (5 mL). Triethylamine (0.3 mL) and then SO3 pyridine complex (150 mg) were added and the mixture was stirred at ambient temperature for 3 hours. After dilution with ethyl acetate (100 mL), the solution was washed with water (50 mL) and brine, dried with MgSO4 and evaporated under vacuum. The residue was purified by flash chromatography on silica gel (Eluent: 5% methanol in ethyl acetate) to yield 4-{2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionylamino}-3-oxo-azepane-1-carboxylic acid benzyl ester (75 mg); 1H NMR: (DMSO) 8.23–8.08 (m, 1H), 7.40–7.29 (m, 10H), 7.06–6.98 (m, 1H), 5.20–5.09 (m, 2H), 4.79–4.65 (m, 1), 4.52–4.31 (m, 3H), 4.02–3.80 (m, 2H), 3.62–3.23 (m, 11H), 3.00–2.78 (m, 1H), 1.88–1.55 (m, 4H); MS: (M+H)+ 601.
Reaction SMILES: Br[C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([C:29]2([CH:33]=[O:34])[CH2:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1>C1COCC1>[OH:34][CH:33]([C:29]1([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:35])[F:36])[CH:24]=2)[CH2:30][CH2:31][CH2:32]1)[C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=CC1(c2cccc(C(F)(F)F)c2)CCC1
Reactant: CC(C)(C)OC(=O)Nc1cccnc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccnc1C(O)C1(c2cccc(C(F)(F)F)c2)CCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of Example 120A (400 mg, 1.465 mmol) in THF (5 mL) was added n-BuLi (3.08 mmol) at −78° C. The resulting solution was stirred at about −78° C. for about 1 hour and then a solution of Example 120C (365 mg, 1.611 mmol) in 10 mL of THF was added. The temperature was warmed to room temperature, stirred for another 1 hour, quenched with 10 mL of water, and extracted with ethyl acetate. The organic layer was washed with brine, and the combined organic phases were dried over sodium sulfate, filtered, and concentrated to give the desired crude product, which was used for next step without further purification. LC-MS: m/z (M+H) 439.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][C@H:6]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])[N:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[N:18]=1)=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])C.[OH-].[Li+]>C1COCC1.O>[C:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:22][C:20]1[N:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[N:18]=[C:17]([C:15]([NH:14][C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[CH2:5][C:4]([OH:39])=[O:3])=[O:16])[CH:21]=1)#[N:31]
Reactant: CCOC(=O)C[C@H](NC(=O)c1cc(OCc2ccccc2C#N)n(-c2ccccc2F)n1)c1ccccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1[C@H](CC(=O)O)NC(=O)c1cc(OCc2ccccc2C#N)n(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.6 %

Procedure:
210 mg (0.4 mmol) of (S)-3-{[5-(2-cyano-benzyloxy)-1-(2-fluoro-phenyl)-1H-pyrazole-3-carbonyl]-amino}-3-o-tolyl-propionic acid ethyl ester were dissolved in a mixture of THF, MOH and water (2 ml each), lithium hydroxide (28.7 mg, 1.2 mmol) was added, and the mixture was stirred for 3 h at room temperature. After evaporation of the solvent the residue was subjected to aqueous work-up using EA and a 10% aqueous solution of citric acid. After evaporation of the organic phase the residue was subjected to column chromatography (silica gel, DCM/MOH 10:1) to give 45 mg (23%) of the title compound.
Reaction SMILES: CC([C:5]1[C:18]2[N:19]=[C:20]([CH3:22])[S:21][C:17]=2[C:8]2[CH2:9][CH2:10][N:11](C([O-])=O)[CH2:12][CH2:13][C:7]=2[CH:6]=1)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:22][C:20]1[S:21][C:17]2[C:18]([N:19]=1)=[CH:5][C:6]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][C:7]=1[CH:8]=2
Reactant: Cc1nc2c(C(C)(C)C)cc3c(c2s1)CCN(C(=O)[O-])CC3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cc3c(cc2s1)CCNCC3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1-dimethylethyl-2-methyl-6,7,9,10-tetrahydro-8H-[1,3]thiazolo[5,4-g][3]benzazepine-8-carboxylate (167 mg), was dissolved in DCM (5 ml) and added to TFA (2 ml). The mixture was stirred at rt. for 1 h and then concentrated affording a 2:1 mixture of title compound and its regioisomer (139 mg) that was further used as such.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH2:9][CH3:10].[Li]CCCC.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH4+].[Cl-]>C1COCC1>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=2[CH2:9][CH3:10])([OH:29])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCc1c(Br)cccc1Br
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1c(Br)cccc1C1(O)CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 4 h
Yield: 71.5 %

Procedure:
To a solution of 1,3-dibromo-2-ethyl-benzene (30 g, 113.65 mmol) in THF (150 mL) was added 45.5 mL of BuLi (2.5M in hexane, 113.65 mmol) under nitrogen. The mixture was stirred for 4 hr at −78° C. Then N-benzyl-4-piperidone (21.51 g, 113.65 mmol) was added to the above mixture and stirred overnight, The mixture was poured into sat. aqueous NH4Cl solution and extracted with DCM. The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure give the crude 1-benzyl-4-(3-bromo-2-ethyl-phenyl)-piperidin-4-ol (D116) (30.4 g). MS (ES): C20H24BrNO requires 373. found 374 (M+H+).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[CH2:15][CH2:14][CH2:13]3)[N:4]=[CH:3]1.[CH3:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[CH:27]=O>[OH-].[K+].CCO>[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[C:15](=[CH:27][C:23]2[S:24][CH:25]=[CH:26][C:22]=2[CH3:21])[CH2:14][CH2:13]3)[N:4]=[CH:3]1
Reactant: O=C1CCCc2cc(OCCc3c[nH]cn3)ccc21
Reactant: Cc1ccsc1C=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccsc1C=C1CCc2cc(OCCc3c[nH]cn3)ccc2C1=O
Yield: 63.1 %

Procedure:
According to the method of Example 4, 6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one, monohydrochloride (0.146 g, 0.50 mmol) was reacted with 3-methyl-thiophene-2-carboxaldehyde (0.095 g, 0.50 mmol) in 5 mL of 4% KOH in EtOH to afford 0.115 g (63%) of the title compound as a coarse cream powder, mp 191-193° C.: CI-MS m/e 365 (M+).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][CH2:5][C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:9][CH:10]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[S:7][C:6]([CH2:5][CH2:4][C:3]([OH:18])=[O:2])=[CH:10][CH:9]=1
Reactant: COC(=O)CCc1ccc(-c2ccccc2F)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCc1ccc(-c2ccccc2F)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
500 mg (1.9 mmol) of 3-[5-(2-fluoro-phenyl)-thiophen-2-yl]-propionic acid methyl ester was dissolved in 5 ml of dioxane and 5 ml of a 2 N sodium hydroxide solution. The reaction mixture was stirred at room temperature for 16 h, diluted with water and acidified to pH=2 by the addition of concentrated hydrochloric acid. The precipitated product was isolated by filtration. Yield: 398 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[O-:16][C:17]#[N:18].[K+]>C(O)(=O)C.O>[CH2:12]([CH:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:1][C:17]([NH2:18])=[O:16])=[CH:3][CH:4]=2)[C:8](=[O:9])[O:7]1)[CH2:13][CH2:14][CH3:15]
Reactant: N#C[O-]
Reactant: CCCCC1OC(=O)c2cc(N)ccc21
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCC1OC(=O)c2cc(NC(N)=O)ccc21
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a solution of 8.27 g (0.04 mol) of the compound obtained in Example 4 in 39.4 ml of glacial acetic acid there are added, with sting, 25 ml of water, and to this solution there is slowly added a solution of 6.54 g of potassium cyanate in 10 ml of water. Once a white precipitate appears, the remaining potassium cyanate solution is added in one portion immediately. The mixture is warmed at 55° C., and stirred for 1 hour, then put aside at room temperature for 3 hours. 50 ml of water are added and the mixture is cooled to 5° C.; the separated solid is collected and dissolved in 10% sodium carbonate solution. Any insoluble material is filtered off and the filtrate is acidified with dilute sulphuric acid. The solid is collected and washed with water and dried, giving the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.CN(C=O)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:31]=[C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[CH3:33]>>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34](/[C:32](/[CH3:33])=[CH:31]/[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]3[CH2:14][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][C:5]2=3)=[CH:35][CH:36]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: COc1ccc(C(C)=CBr)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(/C(C)=C/n2c3c(c4cc(C)ccc42)CCN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (78 mg, 0.36 mmol) was dissolved in DMF (5 mL) Copper (I) iodide (7 mg, 0.036 mmol) L-proline (8 mg, 0.073 mmol) and K3PO4 (156 mg, 0.734 mmol) were added and the reaction mixture was stirred for 10 min at RT. 1-(1-Bromoprop-1-en-2-yl)-4-methoxybenzene (100 mg, 0.44 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). 1HNMR (DMSO-d6, Oxalate salt) δ (ppm): 7.62 (d, 2H), 7.30 (s, 1H), 7.0 (m, 4H), 6.95 (d, 1H), 3.80 (s, 3H), 3.40 (m, 4H), 3.10 (m, 4H), 2.80 (s, 3H), 2.40 (s, 3H), 1.82 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11]O)=[CH:8][C:6]=2[N:7]=1.P(Br)(Br)[Br:20]>C1C=CC=CC=1>[Br:20][CH2:11][C:9]1[S:10][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[CH:8]=1
Reactant: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: BrP(Br)Br
Solvent: c1ccccc1
Product: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Temperature: 25 °C

Procedure:
To a solution of (2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanol (100 mg, 0.4 mmol) in benzene (3.0 mL) at 0° C. was added PBr3 (30 μL, 0.4 mmol). The reaction was heated at reflux for 1 hour. After cooling to room temperature the reaction was quenched by the addition of water. The aqueous layer was extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude material did not require further purification (115 mg, 94%). MS (Q1) 350 (M)+
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](Cl)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3].[CH:23]([SH:26])([CH3:25])[CH3:24].[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([S:26][CH:23]([CH3:25])[CH3:24])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3]
Reactant: CC(C)S
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)SC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(C)O)C2C1
Temperature: 0 °C

Procedure:
A solution of benzyl 6-(1-hydroxyethyl)-3-chloro-1-azabicyclo[3.2.0]hept-2-ene-7-one-2-carboxylate (32 mg) in anhydrous dimethylformamide (DMF, 2 ml) is cooled to -40° C. and stirred under a nitrogen atmosphere. A solution of isopropylmercaptan (8 mg) in anhydrous DMF (1 ml) containing 57% sodium hydride (4.4 mg) is added dropwise over 10 mins. The resulting solution is stirred for 2 hrs, with gradual warming to 0° C. The solution is diluted with ethyl acetate (20 ml), washed with water (5×10 ml) and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue is purified by plc on silica gel GF to yield benzyl 6-(1-hydroxyethyl)-3-isopropylthio-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][N:13]([CH2:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])[N:20]=1)[CH3:14]>CO>[CH3:14][N:13]([CH2:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21][S:22][CH2:23][CH2:24][NH:25][C:7]2[C:3]([O:2][CH3:1])=[N:4][S:5](=[O:11])(=[O:10])[N:6]=2)[N:20]=1)[CH3:12]
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: CN(C)Cc1nc(CSCCN)cs1
Solvent: CO
Product: COC1=NS(=O)(=O)N=C1NCCSCc1csc(CN(C)C)n1

Procedure:
To a cooled (6°) suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (0.74 g; 4.17 mmoles) in 80 ml of methanol was added dropwise over a period of 45 minutes a solution of 2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamine (0.96 g; 4.17 mmoles) [prepared in Step E] to give 3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide, Rf=0.64 [Silica/CH2Cl2 :CH3OH (9:1)]. The temperature was maintained at 6° and anhydrous methylamine was bubbled into the solution for 8 minutes. The reaction mixture was evaporated under reduced pressure and the residue placed on 80 g of silica gel and chromatographed using a gradient elution of methylene chloride-methanol. The appropriate fractions were combined and the residue was rechromatographed on 25 g of aluminum oxide using a gradient elution of methylene chloride-methanol to give 0.52 g of product. Recrystallization from isopropyl alcohol/ether yielded the title compound, mp 144°-148° (foaming).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[O:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH2:37][NH2:38].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:29])([F:31])[F:30])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:38][CH2:37][C:33]1[O:32][CH:36]=[CH:35][N:34]=1)=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCc1ncco1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCc1ncco1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 15.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), oxazol-2-ylmethanamine (6.82 mg, 0.070 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 35-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-N-(oxazol-2-ylmethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (3.7 mg, 7.23 μmol, 15.60% yield): LCMS=512.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.16 (2 H, d, J=8.28 Hz), 7.50-7.83 (9 H, m), 7.09 (1 H, s), 5.20 (1 H, s), 4.45-4.67 (2 H, m); HPLC peak RT=2.6 min (Method E).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([CH3:20])[CH:14]=1)#[CH:12].N>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:12]=2)=[CH:14][C:15]=1[CH3:20]
Reactant: C#Cc1ccc(F)c(C)c1
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: Cc1cc(-c2cc(-c3cccnc3)no2)ccc1F

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 4-ethynyl-1-fluoro-2-methylbenzene (Aldrich, 67 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 1.96 (s, 3H), 7.38 (t, J=9.6 Hz, 1H), 7.62-7.75 (m, 2H), 7.80 (ddd, J=7.9, 5.4, 2.2 Hz, 1H), 7.89 (dd, J=6.9, 1.8 Hz, 1H), 8.42 (dt, J=8.1, 1.8, 1.6 Hz, 1H), 8.79 (dd, J=5.2, 1.6 Hz, 1H), 9.16 (d, J=2.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 255 (M+H)+.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[O:20]1[CH2:25][CH2:24][CH:23]([CH2:26][C:27](O)=[O:28])[CH2:22][CH2:21]1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:27](=[O:28])[CH2:26][CH:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: O=C(O)CC1CCOCC1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)CC3CCOCC3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and tetrahydropyran-4-yl acetic acid, the tide compound was prepared as white powder. MS: m/e=407(M+H+).