Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O.CC(C)=O>[CH2:13]([O:20][C:21]([N:10]1[CH2:9][CH2:8][N:7]2[CH2:12][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5][CH:6]2[CH2:11]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCC1CCC2CNCCN2C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCN2CC(CO)CCC2C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.6 %

Procedure:
To a solution of the title product of Example 6 (640 mg, 3.76 mmol)in acetone/water (6.3 ml and 2.2 ml, respectively), a solution of benzylchloroformate (0.61 ml, 729 mg, 4.27 mmol) in acetone (2,0 ml) was added dropwise over several minutes while maintaining the pH of the mixture at 9.5 by intermittent dropwise addition of saturated aqueous sodium carbonate. After completing the addition, the reaction was stirred for 5 minutes at ambient temperature. The acetone solvent was removed in vacuo, ethyl acetate (60 ml) and water (30 ml) were added, and the pH of the well-stirred mixture was adjusted to 9.5 (sodium carbonate). The separated organic phase was dried (anhydrous sodium sulfate)and concentrated in vacuo to an oil (940 mg). Rash chromatography of the entire sample [10 g, silica gel, 32-63 mesh, eluting initially with ethyl acetate (100 mg), followed by ethyl acetate/methanol (100 ml, 97:3 in volume) and finally ethyl acetate/methanol (200 ml, 90:10 in volume)]afforded the present title compound as a colorless oil, 350 mg (30.6% yield). TLC Rf (ethyl acetate/methanol/concentrated aqueous ammonia=9:2:0.2 in volume): 0.63.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([C:37]([O:39]C)=[O:38])[CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]#[N:36])[CH:28]=2)=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>CO>[C:1]([O:5][C:6]([NH:8][C:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([C:37]([OH:39])=[O:38])[CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]#[N:36])[CH:28]=2)=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)cc(-c2ccccc2C#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(Cc1ccccc1)c1nnc(-c2cc(C(=O)O)cc(-c3ccccc3C#N)c2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of methyl 5-(5-{(1R)-1-[(tert-butoxycarbonyl)amino]-1-methyl-2-phenylethyl}-1,3,4-oxadiazol-2-yl)-2′-cyanobiphenyl-3-carboxylate from Step A (780 mg, 1.45 mmole) in methanol (20 mL) at rt was added 0.43 mL of 5 N NaOH aq. The reaction was allowed to stir at rt overnight. The solution was poured into water (100 mL) and acidified by adding 1N HCl (10 mL). The resulting mixture was extracted with ethyl acetate (2×100 mL). The combined organics were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated at reduced pressure to give 5-(5-{1-[(tert-butoxycarbonyl)amino]-1-methyl-2-phenylethyl}-1,3,4-oxadiazol-2-yl)-2′-cyanobiphenyl-3-carboxylic acid (Intermediate XVII). 1H NMR (400 MHz, CDCl3) δ 8.77 (br s, 1H), 8.47 (m, 2H), 7.84 (d, J=7.7 Hz, 1H), 7.72 (t, J=7.7 Hz, 1H), 7.65-7.55 (m, 2H), 7.33-7.25 (m, 3H), 7.13-7.05 (2H, m) 5.25 (br s, 1H), 3.61 (d, J=13.5 Hz, 1H), 3.46 (d, J=13.5 Hz, 1H), 1.76 (s, 3H), 1.42 (s, 9H). LCMS [(M)+H]+=525
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:21]1([C:27]2[N:28]=[C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13]([N:35]3[CH2:36][CH2:37][N:32]([C:29]4[S:30][CH:31]=[C:27]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:28]=4)[CH2:33][CH2:34]3)=[O:20])=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ccc(-n2ccnc2)cc1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1ccc(-n2ccnc2)cc1)N1CCN(c2nc(-c3ccccc3)cs2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl [4-(1H-imidazol-1-yl)phenyl]carbamate (200 mg, 0.598 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (147 mg, 0.598 mmol), diisopropylethylamine (0.104 ml, 0.598 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (91.0 mg, 35.4%) as a solid.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][C:11]2(OCC[O:15]2)[C:10]1([CH3:26])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:25])[CH2:23][OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.S(=O)(=O)(O)O>O>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C:10]1([CH3:26])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:25])[CH2:23][OH:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CO)CCCC1(C)C(OCc2ccccc2)CCCC12OCCO2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CC(CO)CCCC1(C)C(=O)CCCC1OCc1ccccc1
Yield: 99.8 %

Procedure:
A mixture of (2S*, 3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-methyl-5'-hydroxypentyl)-cyclohexane (13.9 g, 0.0384 mol), acetone (150 ml), water (20 ml) and 0.002 N sulfuric acid (50 ml) is refluxed for 18 hours under a nitrogen atmosphere. The reaction mixture is cooled, the acetone evaporated under reduced pressure and the aqueous layer extracted with ether (3×500 ml). The combined organic layers are washed with saturated sodium bicarbonate (100 ml), saturated sodium chloride (2×200 ml) and dried (MgSO4). The solvents are removed to afford (2S*, 3R*)-3-benzyloxy-2-methyl-2-(4'-methyl-5'-hydroxypentyl)-cyclohexanone (crude product, 12.2 g, 100%): ir (neat) 3484 (OH), 1709 cm-1 (CO); nmr (CDCl3)δ 0.88 (d, J=6 Hz, 3H, --CH--CH3), 1.08 (s, 3H, CH3), 3.42 (m, 4H, HO--CH2 --CH--, OH and --CH--O--CH2Ph), 4.50 (d of d, J=10 Hz, 2H, Ph--CH2 --O--), 7.2 (s, 5H, aromatic).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C:12]1[NH:17][C:16](=[O:18])[C:15]2=[C:19]([CH3:25])[N:20]=[C:21]([CH2:22][CH2:23][CH3:24])[N:14]2[N:13]=1)[CH3:2].[Cl:26][S:27](O)(=[O:29])=[O:28]>>[CH2:1]([O:3][C:4]1[C:5]([C:12]2[NH:17][C:16](=[O:18])[C:15]3=[C:19]([CH3:25])[N:20]=[C:21]([CH2:22][CH2:23][CH3:24])[N:14]3[N:13]=2)=[CH:6][C:7]([S:27]([Cl:26])(=[O:29])=[O:28])=[C:8]([O:10][CH3:11])[CH:9]=1)[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3ccc(OC)cc3OCC)nn12
Product: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)c(OC)cc3OCC)nn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., 0.31 g (0.9 mmol) of 2-(2-ethoxy-4-methoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f]-[1,2,4]triazin-4-one are added slowly to 0.54 ml of chlorosulphonic acid. The reaction mixture is stirred at room temperature overnight and then poured into ice-water and extracted with dichloromethane. This gives 0.355 g (89%) of a colourless foam. Rf=0.50 (dichloromethane/methanol=20:1)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:10]#[N:11])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:10][NH2:11])[CH2:6][CH2:7][CH2:8][CH2:9]1)=[O:4]
Reactant: COC(=O)C1(C#N)CCCC1
Solvent: CC(=O)O
Product: COC(=O)C1(CN)CCCC1
Yield: 100.3 %

Procedure:
Methyl1-cyanocyclopentane-1-carboxylate (Intermediate 260; 6 g, 39.2 mmol) in acetic acid (70 mL) was hydrogenated using Pt O2 (600 mg) as a catalyst at room temperature under 4 Bar pressure for 4 hours. The reaction mixture was filtered and concentrated. The residue was taken up in methanol and absorbed on to an SCX column (3×50 g), which was then washed with methanol and eluted with ammonia in methanol. Concentration of product containing fractions yielded the title compound as a pale yellow liquid (6.18 g, 100%).
Reaction SMILES: [C:1]([C:3]([NH:6][C:7]([C:9]1[O:10][C:11]([CH3:14])=[N:12][N:13]=1)=[O:8])([CH3:5])[CH3:4])#[N:2].[NH2:15][OH:16].CCCCCCC>C(O)(C)C>[NH2:2]/[C:1](=[N:15]\[OH:16])/[C:3]([NH:6][C:7]([C:9]1[O:10][C:11]([CH3:14])=[N:12][N:13]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: NO
Reactant: Cc1nnc(C(=O)NC(C)(C)C#N)o1
Solvent: CC(C)O
Solvent: CCCCCCC
Product: Cc1nnc(C(=O)NC(C)(C)/C(N)=N/O)o1
Temperature: 52.5 °C
Reaction time: 0.5 h

Procedure:
N-(2-cyanopropan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamide (II) (185 gms) was suspended in isopropyl alcohol (462 ml), heated to 50 to 55° C. Aqueous hydroxylamine (IIIa; 76 ml) was added and the reaction mixture stirred for 30 minutes at 60° C. After completion, reaction mass was cooled between 0 and 5° C. and heptane (462 ml) was added to the reaction mass. The resultant slurry was filtered, washed with heptane (185 ml) and the wet cake was dried to give N-[(1Z)-1-amino-1-(hydroxyimino)-2-methylpropan-2-yl]-5-methyl-1,3,4-oxadiazole-2-carboxamide (IVa).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:9].[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17]
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: Clc1ccccc1Br
Agent: [Mg]
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1Cl
Yield: 64 %

Procedure:
Following the procedure outlined in Example 1, 1.3 g (52 mmol) of magnesium turnings, 10.0 g (52 mmol) of 1-bromo-2-chlorobenzene and 9.4 g (52 mmol) benzophenone gave 9.81 g (64%) of (2-Chlorophenyl) diphenyl methanol (Compound T3), mp: 91° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][N:3]=1.[F:13][C:14]1([F:60])[CH2:19][CH2:18][CH:17]([C:20]2[C:29]3[CH:28]([O:30]CC4C=CC(OC)=CC=4)[CH2:27][C:26]([CH3:41])([CH3:40])[CH2:25][C:24]=3[N:23]=[C:22]([CH:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)[C:21]=2[CH:48]([F:59])[C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[CH2:16][CH2:15]1>>[F:60][C:14]1([F:13])[CH2:19][CH2:18][CH:17]([C:20]2[C:29]3[CH:28]([OH:30])[CH2:27][C:26]([CH3:40])([CH3:41])[CH2:25][C:24]=3[N:23]=[C:22]([CH:42]3[CH2:47][CH2:46][N:45]([C:2]4[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][N:3]=4)[CH2:44][CH2:43]3)[C:21]=2[CH:48]([F:59])[C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:57])([F:58])[F:56])=[CH:51][CH:50]=2)[CH2:16][CH2:15]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: CCCCCc1cnc(Cl)nc1
Product: CCCCCc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1

Procedure:
Reactions similar to those of the first step of Example 2 and Example 38 were performed except for using 2-chloro-5-pentyl pyrimidine instead of 5-bromo-2-chloropyrimidine, and from 100 mg (0.148 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 95 mg of the title compound was obtained as a white solid (yield: 91%).
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)(=[O:3])[CH3:2].[H-].[Na+].Cl[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CS(C)=O.C(OCC)(=O)C.C(O)(=O)C>[C:1]([NH:4][C:5]1([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reactant: ClCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)NC1(CCc2ccccc2)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a suspension, maintained under nitrogen, of 1.8 g of (10 RS)-10-acetamido-5H,10H-imidazo[1,2-a]-indeno[1,2-e]pyrazin-4-one in 45 ml of dimethyl sulphoxide are added portionwise 960 mg of an 80% suspension of sodium hydride in oil. The mixture is stirred for 15 minutes at a temperature in the region of 20° C., followed by addition of a solution of 0.95 ml of (2-chloroethyl)benzene in 2 ml of dimethyl sulphoxide. After 15 hours at room temperature, a further 0.45 ml of (2-chloroethyl)benzene dissolved in 1 ml of dimethyl sulphoxide is added. The reaction medium is left for 6 hours at a temperature in the region of 20° C., and is then poured into a mixture of 150 g of ice, 260 ml of distilled water and 3.5 ml of acetic acid. 150 ml of ethyl acetate are added to the suspension obtained and the mixture is stirred, followed, after separation of the phases once settling has taken place, by removal of the ethyl acetate. The operation is repeated twice. The precipitate is filtered off on a sinter funnel. The solid is crystallized from 7 ml of dimethylformamide and is then recrystallized from 30 ml of methanol. 100 mg of (10 RS)-10-acetamido-10-phenethyl-5H,10H-imidazo[1,2-a]-indeno[1,2-e]pyrazin-4-one are thus obtained in the form of a grey solid melting above 260° C. (Analysis, % calculated C: 71.9, H: 5.2, N: 14.6, % found C: 71.9, H: 5.0, N: 14.6).
Reaction SMILES: C[Al](C)C.[CH:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7]([S:12]([NH:15][C:16]2[S:20][CH:19]=[CH:18][N:17]=2)(=[O:14])=[O:13])[CH:6]=1.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C@H:31]1[CH2:35][CH2:34][O:33][C:32]1=[O:36].Cl>CCCCCC.ClCCl.C(OC(=O)C)C>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C@@H:31]([CH2:35][CH2:34][OH:33])[C:32]([NH:11][C:10]1[CH:5]=[CH:6][C:7]([S:12](=[O:14])(=[O:13])[NH:15][C:16]2[S:20][CH:19]=[CH:18][N:17]=2)=[CH:8][CH:9]=1)=[O:36]
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: O=C1OCC[C@@H]1N1CCc2c(Cl)cccc21
Agent: C[Al](C)C
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(S(=O)(=O)Nc2nccs2)cc1)[C@H](CCO)N1CCc2c(Cl)cccc21
Temperature: 25 °C
Yield: 79.9 %

Procedure:
Prepared using general procedure 58. Under an N2 atmosphere at RT, 2M-trimethyl aluminium in hexane (9.13 mL) was added dropwise to a stirring solution of sulfathiazole (4.6 g, 18.27 mmol) in dichloromethane (100 mL) in 30 minutes. Upon completion of addition, the mixture was stirred at RT for an hour. Added (S)-3-(4-chloroindolin-1-yl)dihydrofuran-2(3H)-one (3.56 g, 14.97 mmol) in dichloromethane (20 mL) to above solution over 30 minutes. The mixture was stirred for 16 hrs at RT. The reaction mixture was diluted with 500 mL of ethylacetate were added. The aqueous phase was acidified to pH 2 with an (IN) aqueous HCl solution. The ethyl acetate layer was washed with (IN) aqueous HCl (3×200 mL) till LCMS showed disappearance of sulfathiazole. The organic layer was dried over MgSO4, filtered, concentrated. Purification via silica gel chromatography using 2-10% methanol in dichloromethane gave the amide as a white solid (5.9 g, 80% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=493.2; tR=1.46 min. 1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 7.74 (s, 4H), 7.24 (d, J=4.6 Hz, 1H), 6.98 (t, J=8.0 Hz, 1H), 6.81 (d, J=4.5 Hz, 1H), 6.56-6.54 (m, 2H), 4.71 (t, J=4.8 Hz, 1H), 4.43-4.39 (m, 1H), 3.79 (q, J=9.3 Hz, 1H), 3.64-3.58 (m, 2H), 3.51-3.48 (m, 1H), 3.17 (d, J=5.2 Hz, 1H), 3.00-2.89 (m, 1H), 1.93 (dd, J=6.0, 13.5 Hz, 1H), 1.88 (s, 1H).
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[N:5]([C:9]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH:6]=[CH:7][N:8]=1>O.CC(O)CC>[CH:25]1([C:9]2[N:5]3[CH:6]=[CH:7][N:8]=[C:3]([NH2:1])[C:4]3=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[N:10]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: N
Reactant: Clc1nccn2c(C3CCCCC3)nc(-c3ccc(Oc4ccccc4)cc3)c12
Solvent: CCC(C)O
Solvent: O
Product: Nc1nccn2c(C3CCCCC3)nc(-c3ccc(Oc4ccccc4)cc3)c12
Reaction time: 8 h

Procedure:
20 M NH3 in H2O (4 mL) was added to a suspension of 8-chloro-3-cyclohexyl-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazine (82 mg, 0.20 mmol) in 2-butanol (0.9 mL). The mixture was heated in an oil bath set at 105° C. overnight. The reaction was stopped at this time and concentrated in vacuo. Purification by prep TLC using 3% NH3 in MeOH in DCM afforded 41.4 mg of the title compound as an off white solid. 1H NMR (400 MHz, CDCl3): δ=1.27-1.52 (m, 3H), 1.73-1.96 (m, 5H), 1.99-2.10 (m, 2H), 2.84-3.02 (m, 1H), 5.28 (br. s., 2H), 7.01-7.08 (m, 3H), 7.09-7.14 (m, 3H), 7.23 (d, J=5.31 Hz, 1H), 7.32-7.40 (m, 2H), 7.58-7.65 (m, 2H). MS (ES+): m/z 385.03 (100)[MH+]. HPLC: tR=2.83 min (Open Lynx polar—5 min).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([C@@H:13]3[C@@H:18]([CH3:19])[CH2:17][CH2:16][CH2:15][C:14]3([CH3:21])[CH3:20])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH3:22][Li]>O1CCCC1>[CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([C@@:11]([C@@H:13]3[C@@H:18]([CH3:19])[CH2:17][CH2:16][CH2:15][C:14]3([CH3:20])[CH3:21])([OH:12])[CH3:22])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: [Li]C
Reactant: C[C@H]1CCCC(C)(C)[C@@H]1C(=O)c1ccc2c(c1)CCNC2
Solvent: C1CCOC1
Product: C[C@H]1CCCC(C)(C)[C@@H]1[C@@](C)(O)c1ccc2c(c1)CCNC2
Temperature: -78 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
To a stirred solution of the product of Example 13b (95 mg, 0.33 mmol) in anhydrous tetrahydrofuran (6 mL) under argon at −78° C. was added methyl lithium (1.6 M in diethyl ether) (1.04 mL, 1.66 mmol). The reaction was stirred at −78° C. for 1 hour, after which the reaction was allowed to warm gradually to room temperature and stirring was continued overnight. The reaction was quenched with saturated aqueous ammonium chloride (25 mL) and the organics were extracted with ethyl acetate (25 mL×3). The combined organic phase was washed with brine (40 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (eluent: dichloromethane/methanol=50/1->5/1) afforded 30 mg of the impure title compound as a yellow oil which was used directly in the next step. Mass spectrum (ESI +ve) m/z 302 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N-:11]=[N+:12]=[N-:13].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]2[NH:13][N:12]=[N:11][N:5]=2)=[C:2]([CH:9]=1)[NH2:1]
Reactant: Cc1ccc(C#N)c(N)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2nnn[nH]2)c(N)c1
Temperature: 100 °C
Yield: 42.2 %

Procedure:
To a mixture of 2-amino-4-methylbenzonitrile (500 mg, 3.3 mmol), sodium azide (4.3 mmol, 1.3 eq.), and triethylamine hydrochloride (4.3 mmol, 1.3 eq.) in a sealed tube, 8 mL of toluene was added. The tube was tightly capped and the reaction was stirred and heated to 100° C. overnight. The mixture was cooled to room temperature, diluted with another 10 mL of toluene, transferred to a separatory funnel and washed 3×20 mL with water. The aqueous layer was collected and acidified to a pH of 4 with concentrated HCl. The solid was collected by filtration, washed with acetonitrile, and dried under vacuum to afford 244 mg of 5-methyl-2-(1H-tetrazol-5-yl)aniline. MS (EI) for C8H9N5: 176 (M+H). Step 2: N-[5-Methyl-2-(1H-tetrazol-5-yl)phenyl]thiophene-2-carboxamide: To a solution of 5-methyl-2-(1H-tetrazol-5-yl)aniline (240 mg, 1.4 mmol) in 6 mL of DCM was added DIPEA (7.5 mmol, 5.5 eq.) followed by thiophene-2-carbonyl chloride (6.8 mmol, 5 eq.). The reaction was stirred at room temperature overnight. The organic solution of the crude reaction mixture was extracted twice with aqueous HCl (0.1 M), twice with aqueous sodium hydroxide (0.1 M), and once with a saturated aqueous solution of sodium chloride. The basic aqueous extractions and final brine extraction were combined and acidified to a pH of 4 with concentrated HCl. The resulting solid was collected by filtration. This crude material was further purified by redissolving the material into minimum volume of aqueous NaOH (0.1 M), and then reacidified with concentrated HCl. The solid was collected by filtration, washed with EtOAc, and dried under vacuum to afford 26.8 mg of the desired product. 1H-NMR (400 MHz, d6-DMSO): δ 11.60 (s, 1H), 8.35 (s, 1H), 7.98-7.94 (m, 2H), 7.90 (d, 1H), 7.33 (t, 1H), 7.20 (d, 1H), 2.42 (s, 3H). MS (EI) for C13H11N5OS: 286 (M+H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CS(O[CH2:15][C:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:18])[CH3:17])(=O)=O>CN(C=O)C>[CH3:18][C:16]([NH:19][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:15])[CH2:17][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CC(C)(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(COc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 9 %

Procedure:
To a solution of phenol (2.1 g, 22.4 mmol, 3 equiv) in DMF (10 ml) at room temperature were added NaH (60% dispersion in mineral oil, 360 mg, 9.0 mmol, 1.2 equiv) and after 10 min 2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylpropyl methanesulfonate (D273) (2 g, 7.5 mmol, 1 equiv) and the resulting solution was stirred at 50° C. for 2 h then cooled to room temperature and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 9/1 to 6/1) gave 1,1-dimethylethyl [1,1-dimethyl-2-(phenyloxy)ethyl]carbamate (D274) (180 mg, 9%) as a yellow oil.
Reaction SMILES: C[C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18][CH2:19][CH2:20]C2C=CC=CC=2)=[O:15])=[N:10][CH:9]=1)(C)[C:3]([OH:5])=[O:4].C(O)CC#C.C(OC(=O)C(SC1SC(N)=NC=1)C)C>>[CH2:17]([N:16]([C@H:27]1[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]1)[C:14](=[O:15])[NH:13][C:11]1[S:12][C:8]([S:7][CH2:2][C:3]([OH:5])=[O:4])=[CH:9][N:10]=1)[CH2:18][C:19]#[CH:20]
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCCCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: C#CCCO
Agent: CCOC(=O)C(C)Sc1cnc(N)s1
Product: C#CCCN(C(=O)Nc1ncc(SCC(=O)O)s1)[C@H]1CC[C@H](C)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-(4-phenyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 3-butyn-1-ol and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.