Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:23](=[O:25])[CH3:24]
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.6 g of 4-(2-dimethylamino-ethylamino)-nitrobenzene (according to Gabbay et al., J. Am. Chem. Soc. 91, 5136 (1969)) are dissolved in 50 ml of methylene chloride and 5.0 ml of triethylamine are added. 1.3 ml of acetyl chloride are slowly added dropwise to this mixture at room temperature and the mixture is stirred for 2 hours at room temperature. After this time another 5.0 ml of triethylamine and 1.3 ml of acetylchloride are added and the mixture is refluxed for another 2 hours. The solvent is removed, the residue is taken up in ethyl acetate and the organic phase is extracted twice with water. After drying over MgSO4 the solvent is removed and the residue dried in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[CH3:10][N:11]1[C:15]([CH3:16])=[C:14]([C:17](O)=[O:18])[C:13](=[O:20])[N:12]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:9][C:4]1[CH:3]=[C:2]([NH:1][C:17]([C:14]2[C:13](=[O:20])[N:12]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:11]([CH3:10])[C:15]=2[CH3:16])=[O:18])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: Nc1ccc(O)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(O)c(Cl)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 45 °C
Reaction time: 20 h
Yield: 70.9 %

Procedure:
To a suspension of 4-amino-2-chlorophenol (4.0 g, 28.00 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (7.4 g, 30.11 mmol) in DCM (70 mL) were added EDCI (6.65 g, 30.11 mmol) and HOAT (0.76 g, 5.68 mmol). The mixture was stirred at 45° C. for 20 hours, then cooled to rt and filtered. The filter cake was washed with DCM (20 mL×3), and dried at 50° C. in a vacuum oven overnight to give the title product as a gray solid (7.1 g, 72.1%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([CH:10]1[O:12][CH2:11]1)[Cl:9]>>[C:2]([C:3]([O:5][CH2:11][CH:10]([OH:12])[CH2:8][Cl:9])=[O:4])([F:7])([F:6])[F:1]
Reactant: O=C(O)C(F)(F)F
Reactant: ClCC1CO1
Product: O=C(OCC(O)CCl)C(F)(F)F
Temperature: 0 °C

Procedure:
To 22.8 g (0.2 mole) of trifluoroacetic acid stirred in an ice-cooled flask was added 102 grams (1.1 moles) of epichlorohydrin at such a rate as to maintain the reaction temperature at 60°-70° C. Excess epichlorohydrin was removed under reduced pressure (35 torr) to yield the initiator CF3CO2CH2CH(CH2Cl)OH product which contained some isomeric CF3CO2CH(CH2Cl)CH2OH. SnCl4 catalyst (3.1 g) was added. The temperature was held at 70°-75° C. while an additional 275 g epichlorohydrin was added over a 90-minute period. The reaction mixture was stirred an additional 16 hours at 70° C., stripped at 70° C. and 5 torr for two hours. The stripped, blocked polyepichlorohydrin intermediate was unblocked by reacting it with a mixture of 180 g methanol, 20 g water, and 20 g concentrated ammonium hydroxide, first at a temperature of 30° C. for 30 minutes and then at 65° C. for 90 minutes. The pH of the aqueous phase was neutral (about 7). The organic phase was washed twice with a solution of 180 g of methanol and 20 g of water, then stripped at 60° C. at 5 torr to yield the desired primary hydroxyl-terminated polyepichlorohydrin polyol, having a structure like that of formula III, supra, Scheme III, where R3 is --CH(CH2Cl)--. Proton nmr analysis at 100 MHz showed the presence of 19% primary and 81% secondary hydroxyl groups.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].Cl.Cl[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1>>[N:13]1[CH:14]=[CH:15][C:10]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[CH:11][CH:12]=1
Reactant: O=C1CNCCN1
Reactant: Clc1ccncc1
Agent: Cl
Product: O=C1CN(c2ccncc2)CCN1
Temperature: 200 °C
Yield: 23.5 %

Procedure:
An intimate mixture of piperazinone (4.2 g) and 4-chloropyridine hydrochloride (7.33 g) was stirred and heated at 200° C. for 10 minutes and allowed to cool. The product was purified by flash column chromatography and cluted with 1/9/0.1 v:v:v methanol/methylene chloride/0.88 S.G. aqueous ammonia. The solid thus obtained was recrystallised from ethanol to give 4-(4-pyridyl)piperazin-2-one (1.75 g); m.p. 268°-270° C.; NMR (d6DMSO) δ 8.2(3H,m); 6.8(12H,m); 3.85(2H,s); 3.52(2H,m); 3.31(2H,m); m/e 178(M+H)+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[N:16]=[CH:15][C:14]([C:17]2[N:26]([C:27]3[CH:32]=[CH:31][C:30]([CH:33]([CH2:35][CH3:36])[CH3:34])=[CH:29][CH:28]=3)[C:25](=[O:37])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:13][CH:12]=1>C([O-])([O-])=O.[Na+].[Na+].COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:33]([C:30]1[CH:29]=[CH:28][C:27]([N:26]2[C:25](=[O:37])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[C:17]2[C:14]2[CH:15]=[N:16][CH:11]=[C:12]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:13]=2)=[CH:32][CH:31]=1)([CH2:35][CH3:36])[CH3:34]
Reactant: CCC(C)c1ccc(-n2c(-c3ccc(Br)nc3)nc3ccccc3c2=O)cc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCC(C)c1ccc(-n2c(-c3cncc(-c4ccccc4)c3)nc3ccccc3c2=O)cc1
Yield: 46.3 %

Procedure:
Phenylboronic acid (0.058 g, 0.48 mmol) and Pd(PPh3)4 (0.004 g) were added to a mixture of 2-(6-bromopyridin-3-yl)-3-(4-sec-butylphenyl)quinazolin-4(3H)-one (0.175 g, 0.40 mmol) in 2 M Na2CO3 (0.4 mL) and DME (15 mL). After refluxing for 5 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in CHCl3 and washed with H2O, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 0% to 60% of EtOAc in CH2Cl2, afforded the title compound as a white solid (0.080 g, 46%). 1H-NMR (300 MHz, DMSO-d6): δ8.75 (s, 1H), 8.68 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 7.91-7.99 (m, 1H), 7.79-7.90 (m, 2H), 7.61-7.69 (m, 1H), 7.32-7.50 (m, 7H), 7.17-7.25 (m, 2H), 2.52-2.63 (m, 1H), 1.33-1.54 (m, 2H), 1.10 (d, J=6.9 Hz, 3H), 0.53 (t, J=7.3 Hz, 3H). MS (APCI) m/z: 432 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:11][CH:10]=1)C.[NH:36]1[CH2:41][CH2:40][CH2:39][N:38]=[C:37]1[NH2:42]>CN(C=O)C>[C:31]([O:30][C:28](=[O:29])[C@@H:16]([NH:17][S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)(=[O:19])=[O:20])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4](=[O:3])[NH:42][C:37]2[NH:38][CH2:39][CH2:40][CH2:41][N:36]=2)=[CH:10][CH:11]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: NC1=NCCCN1
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](NS(=O)(=O)c2ccc(C)cc2)C(=O)OC(C)(C)C)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccc(OCCCC(=O)NC3=NCCCN3)cc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
295 mg of 4-{4-[(2S)-2-tert-Butoxycarbonyl-2-(toluene-4-sulfonylamino)-ethyl]-phenoxy}-butyric acid ethyl ester were dissolved in 15 ml of anhydrous DMF and 287 mg of 1,4,5,6-tetrahydropyrimidin-2-ylamine were added to the solution. The reaction mixture was stirred overnight at room temperature, and the solvent was removed in vacuo. The residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic phase was dried with anhydrous magnesium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with a gradient of ethyl acetate/isopropanole/water (8/3/1 to 4/3/1). Yield 241 mg. MS: m/e=559.2 (M+H)+; 503.2.
Reaction SMILES: [F:1][C:2]1([CH2:8][C@H:9]2[CH2:13][O:12]C(C)(C)[N:10]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CO>[F:1][C:2]1([CH2:8][C@H:9]([NH:10][C:16](=[O:17])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:13][OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2(F)CCCCC2)COC1(C)C
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CO)CC1(F)CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.5 %

Procedure:
(S)-tert-butyl 4-((1-fluorocyclohexyl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (1.1 g, 3.50 mmol, 1.0 equiv) was dissolved in methanol (30 mL). To this mixture was added camphorsulfonic acid (202 mg, 0.875 mmol, 0.5 equiv) and the solution was stirred at rt for 3 h. After this time the starting material was consumed. Satd aq NaHCO3 was added and the methanol was removed in vacuo. The aqueous residue was extracted with EtOAc (3×10 mL) and the combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated. Flash chromatography on silica, eluting with 0-47% EtOAc in hexanes, afforded (S)-tert-butyl 1-(1-fluorocyclohexyl)-3-hydroxypropan-2-ylcarbamate (275 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].[O:23]=[C:24]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[N:51]=[CH:50][CH:49]=[CH:48][N:47]=3)=[CH:42][CH:41]=2)[CH2:36][CH2:35]1)[CH2:25][N:26]1[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.[Cl-].[Na+].O>[O:21]=[C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:22])[N:12]1[CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:31]([CH:28]3[CH2:29][CH2:30][N:26]([CH2:25][C:24](=[O:23])[N:34]4[CH2:35][CH2:36][N:37]([C:40]5[CH:45]=[CH:44][C:43]([C:46]6[N:47]=[CH:48][CH:49]=[CH:50][N:51]=6)=[CH:42][CH:41]=5)[CH2:38][CH2:39]4)[CH2:27]3)=[O:32])[CH:3]=2)[NH:7][N:6]=1
Reactant: Nc1ccc2[nH]nc(CN3C(=O)c4ccccc4C3=O)c2c1
Reactant: O=C(O)C1CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc2[nH]nc(CN3C(=O)c4ccccc4C3=O)c2c1)C1CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Reaction time: 4 h

Procedure:
2-(5-Amino-1H-indazol-3-ylmethyl)-isoindole-1,3-dione (compound 49 from Step 3, 614 gm, 2 mmol) and compound 12 (from Example 1 Step 9) were dissolved in 10 ml of DMF. O-(7-azabenzotriazol-1-yl-)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (660 mg, 1.7 mmol) and diisopropylethylamine (0.9 ml, 5 eq.). After stirring 4 hours, the reaction mixture was added to brine and extracted with ethylacetate, dried over magnesium sulfate and evaporated. The crude was chromatographed on silica gel to obtain 440 mg of title product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:34]=[CH:33][C:32]5[O:31][CH2:30][O:29][C:28]=5[CH:27]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-])=O.C(O)C>[Pt].[C].C1COCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([N:19]3[CH2:20][CH2:21][N:22]([CH2:25][C:26]4[CH:34]=[CH:33][C:32]5[O:31][CH2:30][O:29][C:28]=5[CH:27]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:15][CH:16]=2)=[N:8][CH:9]=1
Reactant: O=C(c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Agent: [Pt]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccc(C(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1
Temperature: 25 °C

Procedure:
[4-(5-nitropyridin-2-yloxy)phenyl](4-piperonylpiperazin-1-yl)methanone (0.36 g, 0.78 mmol) was dissolved in a mixed solvent consisting of ethanol (5 mL) and THF (5 mL). To the resulting solution was added 5% platinum-carbon (0.06 g), and stirred at room temperature under a hydrogen atmosphere. Two hours later, the 5% platinum-carbon was removed by filtration, and the solvent was evaporated under reduced pressure, to thereby yield 0.32 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:35][N:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O)[CH3:37]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:29]=[C:30]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=5[CH2:38][N:36]([CH3:37])[CH3:35])[CH:31]=[CH:32][CH:33]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)c4)cc3)cc2)CC1
Reactant: CN(C)Cc1ccccc1B(O)O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccccc5CN(C)C)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1-{4′-[4-(3-bromo-phenylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-(N,N-dimethylaminomethyl)-phenylboronic acid.
Reaction SMILES: [CH:1]12[CH2:7][C:6](=[CH:8][C:9]([O:11]CC)=[O:10])[CH:5]1[CH2:4][CH2:3][CH2:2]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+].Cl>CC(C)=O>[C@@H:1]12[CH2:7][C:6](=[CH:8][C:9]([OH:11])=[O:10])[C@@H:5]1[CH2:4][CH2:3][CH2:2]2
Reactant: CCOC(=O)C=C1CC2CCCC12
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)C=C1C[C@H]2CCC[C@@H]12
Yield: 33.4 %

Procedure:
The racemic ester of Example 4 (200 g; 1.11 mol) was added to a stirred solution of acetone (0.80 L) and potassium phosphate buffer (pH=7.2; 1.2 L). The hazy solution was stirred at 20–25° C. and Novozyme 435 (50 g), immobilized Candida Antarctica lipase B, was added to the reaction mixture. The suspension was then stirred at 20–25° C. for 120 hours. During this time a 1M aqueous solution of sodium hydroxide was added so as to maintain a pH of 8.1. Concentrated hydrochloric acid (45 ml) was added to pH 2–3 and the heterogeneous reaction mixture was filtered. The filter cake was washed with n-heptane (1.0 L). The two phase filtrate was separated and the aqueous phase re-extracted with tert-butylmethyl ether (0.50 L). The combined organic phases were extracted with a 1M aqueous solution of sodium hydroxide (0.4 L). The aqueous solution was then adjusted to pH 1–2 by the addtion of concentrated hydrochloric acid (40 ml) and extracted twice with tert-butylmethyl ether (0.40 L, then 0.20 L). The combined organic phases were washed with demineralised water (0.40 L) and concentrated in vacuo to give the title compound (56.5 g) in 33.5% yield as a pale yellow oil which crystallised on standing.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:13](CC3C=NC=CC=3)[CH2:12][C@@H:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]([S:28]([C:31]3SC=C[CH:35]=3)(=[O:30])=[O:29])[CH2:9][C:8]=2[CH:36]=1)#[N:3].BrC1C=CC2N(C(=O)CS(N)(=O)=O)C[C@@H](CC3C=CC=CC=3)N(S(CCN(C)C)(=O)=O)CC=2C=1>>[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][CH2:12][C@@H:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]([S:28]([CH:31]=[CH2:35])(=[O:29])=[O:30])[CH2:9][C:8]=2[CH:36]=1)#[N:3]
Reactant: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2Cc1cccnc1
Agent: CN(C)CCS(=O)(=O)N1Cc2cc(Br)ccc2N(C(=O)CS(N)(=O)=O)C[C@H]1Cc1ccccc1
Agent: Cl
Product: C=CS(=O)(=O)N1Cc2cc(C#N)ccc2NC[C@H]1Cc1ccccc1

Procedure:
The title compound was prepared from Compound A of Example 23 following the procedure of Compound A of Example 5.
Reaction SMILES: C(C1N(CC2C=CC(C3C=CC=CC=3C3NN=NN=3)=CC=2)C(C(O)=O)=C(Cl)N=1)CCC.[CH2:32]([C:36]1[N:37]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[C:58]3[N:62]([C:63]([C:76]4[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=4)([C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)[C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)[N:61]=[N:60][N:59]=3)=[CH:48][CH:47]=2)[C:38]([C:42]([OH:44])=[O:43])=[C:39]([Cl:41])[N:40]=1)[CH2:33][CH2:34][CH3:35].C1O[C@@H]2[C@H](O[N+]([O-])=O)CO[C@@H]2[C@H]1O.O[CH2:96][P:97](=[O:104])([O:101][CH2:102][CH3:103])[O:98][CH2:99][CH3:100]>>[CH2:32]([C:36]1[N:37]([CH2:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[C:58]3[N:62]([C:63]([C:70]4[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=4)([C:64]4[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=4)[C:76]4[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=4)[N:61]=[N:60][N:59]=3)=[CH:50][CH:51]=2)[C:38]([C:42]([O:44][CH2:96][P:97]([O:101][CH2:102][CH3:103])([O:98][CH2:99][CH3:100])=[O:104])=[O:43])=[C:39]([Cl:41])[N:40]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOP(=O)(CO)OCC
Agent: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: O=[N+]([O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Product: CCCCc1nc(Cl)c(C(=O)OCP(=O)(OCC)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
The title compound was prepared by following example 7, except that the reagent 2-butyl-4-chloro-1-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid was replaced by 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid, and isosorbide-5-mononitrate was replaced by diethyl (hydroxymethyl)phosphonate. 1H NMR (500 MHz, CDCl3) δ 7.94 (d, J=7.4 Hz, 1H), 7.52 (td, J=7.1, 1.3 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.39-7.34 (m, 4H), 7.28 (t, j=7.8 Hz, 6H), 7.13 (d, J=8.3 Hz, 2H), 6.95 (d, J=8.1 Hz, 6H), 6.80 (d, J=8.1 Hz, 2H), 5.47 (s, 2H), 4.49 (d, J=8.4 Hz, 2H), 4.24-4.16 (m, 4H), 2.53 (t, J=7.8 Hz, 2H), 1.67 (quintet, J=7.7 Hz, 2H), 1.33 (t, J=7.0 Hz, 6H), 1.30 (sextet, J=7.4 Hz, 2H), 0.88 (I, J=7.4 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]([C:21]3[C:22]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=4)=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:20])=[C:13]([F:36])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[Li+].[OH-].Cl.CO.ClCCl>O1CCCC1.O>[C:34]([C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[O:27][C:22]1[C:21]([C:19]([NH:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=3)=[CH:12][C:13]=2[F:36])=[O:20])=[CH:26][CH:25]=[CH:24][N:23]=1)#[N:35]
Reactant: COC(=O)c1cccc(-c2ccc(CNC(=O)c3cccnc3Oc3cccc(C#N)c3)c(F)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cccc(Oc2ncccc2C(=O)NCc2ccc(-c3cccc(C(=O)O)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.6 %

Procedure:
A mixture of 336 mg (0.7 mmol.) 4′-[[[2-[3-Cyano-phenoxy]-pyridine-3-carbonyl]-amino]-methyl]-3′-fluoro-biphenyl-3-carboxylic acid methyl ester and 0.8 mL (0.8 mmol.) 1.0 N LiOH in 20 mL tetrahydrofuran and 2 mL water was stirred at ambient temperature for 18 hours. The mixture was poured into water, acidified to pH 1 with 1N HCl, then extracted with ethyl acetate. The ethyl acetate extracts were combined, washed successively with water, brine then dried (MgSO4) and concentrated in vacuo to give a solid. Chromatography on Silica Gel eluting with methanol/dichloromethane (1:20) yielded a solid. Recrystallization from ethyl acetate/hexane afforded 280 mg 4′-[[[2-[3-cyano-phenoxy]-pyridine-3-carbonyl]-amino]-methyl]-3′-fluoro-biphenyl-3-carboxylic acid as a solid, mp 200-2° C.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]CC.[Na+].[C:23](#[N:26])[CH:24]=[CH2:25]>O1CCOCC1>[C:23]([CH2:24][CH2:25][C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:26]
Reactant: CCOC(=O)C(c1ccccc1)c1ccccc1
Reactant: C=CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(CCC#N)(c1ccccc1)c1ccccc1
Temperature: 45 °C

Procedure:
The product of Example 1A (5.58 g) was dissolved in anhydrous dioxane (15 mL). Sodium ethoxide (1.58 g) was added, and the mixture was heated to 40-50° C. for 30 minutes. Acrylonitrile (1.44 mL) was added dropwise with stirring. The mixture was heated at 60-70° C. for one hour. The dioxane was removed in vacuo, and the residue was taken up in diethyl ether, washed with water and brine, dried with magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (3-10% ethyl acetate/hexane) to obtain the title compound. MS (DCI+) m/z 311 (M+NH4)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[N:10]=[C:11]=[O:12].[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.ClCCl>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1)=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C=Nc1c(F)cc(Cl)cc1Br
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2c(F)cc(Cl)cc2Br)CC1

Procedure:
1-Bromo-5-chloro-3-fluoro-2-isocyanatobenzene (D6) (4.4 mmol, 1.1 g) and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (1 eq., 4.4 mmol, 0.88 g) were mixed together. Dichloromethane (5 ml) was added to the mixture at room temperature for 1 hour. THF (5 ul) was added at room temperature for one hour. Solvent was subsequently evaporated and the crude obtained was purified by chromatography to afford the title compound, 0.6 g, 30%.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])=[N:13][C:12]=1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]([F:34])[F:33])=[CH:27][CH:26]=1>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][CH:18]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH:32]([F:33])[F:34])=[CH:29][CH:30]=3)[C:17]2=[O:21])=[N:13][C:12]=1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)Oc1ccc(CBr)cc1
Reactant: Cc1nc(N2CCCC2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(N2CCC(Cc3ccc(OC(F)F)cc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 27 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use N-benzyl-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with 1-(bromomethyl)-4-(difluoromethoxy)benzene in place of 1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound was obtained as a white solid in 27% yield: mp 132-133° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.41-7.24 (m, 5H), 7.18 (d, J=8.2 Hz, 2H), 7.03 (d, J=8.2 Hz, 2H), 6.46 (dt, J=73.9, 1.0 Hz, 1H), 5.94 (t, J=5.5 Hz, 1H), 4.57 (d, J=5.5 Hz, 2H), 4.11-3.98 (m, 1H), 3.93-3.81 (m, 1H), 3.28-3.16 (m, 1H), 3.08-2.93 (m, 1H), 2.80 (dd, J=13.7, 8.8 Hz, 1H), 2.62 (s, 3H), 2.33-2.19 (m, 1H), 1.99-1.84 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 174.6, 162.3, 155.3, 152.7, 137.8, 135.4, 130.3, 128.8, 127.9, 127.7, 119.9, 119.5, 118.7, 115.9, 45.9, 44.4, 44.1, 35.6, 24.2, 17.3; MS (ES+) m/z 472.3 (M+1).
Reaction SMILES: ClCC(=O)C(=O)C.C(N)=S.Br[CH:12]([C:14](=O)[C:15](=[O:18])[CH2:16][CH3:17])[CH3:13].[C:20]([NH2:23])(=[S:22])[CH3:21]>>[CH3:21][C:20]1[S:22][C:12]([CH3:13])=[C:14]([C:15](=[O:18])[CH2:16][CH3:17])[N:23]=1
Reactant: CC(N)=S
Reactant: CCC(=O)C(=O)C(C)Br
Agent: CC(=O)C(=O)CCl
Agent: NC=S
Product: CCC(=O)c1nc(C)sc1C

Procedure:
It will be appreciated that reaction of 1-chloro-2,3-butanedione with thioformamide will lead to 4-acetylthiazoles, similarly, reaction of 2-bromo-3,4hexanedione with thioacetamide will yield 2,5-dimethyl-4-propionylthiazole.