Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Cl.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([O:4][CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=1)(=[S:3])[CH3:2]
Reactant: CC([O-])=S
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=S)OCc1ccccn1
Yield: 91.3 %

Procedure:
Potassium thioacetate (8.4 g, 73 mmol), 2-picolyl chloride hydrochloride 1 (6.0 g, 37 mmol) and potassium carbonate (5.0 g, 37 mmol) were stirred in DMF (35 mL) at room temperature (20-22°) for 18 h. The reaction mixture was poured into water (200 mL). The resultant mixture was extracted with Et2O (2×50 mL). The combined organic phases were washed with water and brine, dried (MgSO4), filtered and concentrated to give 2-picolyl thioacetate as a pale brown liquid (5.65 g). The product was used without purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][CH2:25][CH3:26])[C:16]=2[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[OH:35]>>[CH2:25]([O:24][CH2:23][CH2:22][O:21][C:17]1[C:16]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[C:15]([NH:14][S:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH2:3][OH:35])=[CH:10][CH:9]=2)(=[O:12])=[O:13])[N:19]([CH3:20])[N:18]=1)[CH3:26]
Reactant: CO
Reactant: CCOCCOc1nn(C)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc(C)cc1
Product: CCOCCOc1nn(C)c(NS(=O)(=O)c2ccc(C(C)(C)CO)cc2)c1-c1ccc(C)cc1
Reaction time: 48 h

Procedure:
Amycolata autotrophica ATCC35203 maintained on a quarter strength ATCC172 agar slope was inoculated as a loopful of spores into five 300 ml Erlenmeyer flasks each containing 50 ml of MY inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron™ Shaker with 1″ throw. Two mls of this inoculum was then transferred to each of sixty 300 ml Erlenmeyer flask containing 50 ml of MY production medium and incubated under the same conditions for a further 24 hours. At this point 20 mg of 4-(tert-butyl)-N-[3-(2-ethoxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide (Preparation 8) dissolved in 0.5 ml of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 6 hours. Each flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid, 2.0 g.
Reaction SMILES: [Cl:1][C:2]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8](=[O:23])[C:9]=1[N:10]2C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8](=[O:23])[C:9]=1[NH:10]2
Reactant: CC(C)(C)OC(=O)n1c2c(c3c(Cl)c(F)ccc31)CCCC2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCCc2c1[nH]c1ccc(F)c(Cl)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.5 %

Procedure:
To tert-butyl 5-chloro-6-fluoro-1-oxo-3,4-dihydro-1H-carbazole-9(2H)-carboxylate (0.4 g, 1.1 mmol) in DCM (10 mL), cooled to 0° C., was added TFA (1 mL). The reaction mixture was stirred at room temperature for 4 h, quenched with saturated NaHCO3 (pH-8) and then extracted with DCM (4×40 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude compound which was washed with hexane (2×5 mL) to provide the title compound (0.20 g, 71%). 1H NMR (200 MHz, DMSO-d6, δ in ppm) 12.04 (bs, 1H), 7.41-7.26 (m, 2H), 3.33 (t, J=6.0 Hz, 2H), 2.60 (t, J=5.8 Hz, 2H), 2.22-2.13 (m, 2H).
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.CN(C)C=O.[H-].[Na+].[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)(=O)C>[C:24]1([CH2:23][N:13]2[C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=4)[C:9]=3[CH:11]=[CH:12]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Nc1nc(N)c2c(ccc3c2ccn3Cc2ccccc2)n1
Reaction time: 1.5 h

Procedure:
A suspension of 13.95 g. 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 600 ml. dry dimethylformamide is stirred under nitrogen as 3.70 g. ca. 50% sodium hydride-mineral oil dispersion is added carefully. After stirring for 1.5 hours, a solution of 9.30 g. benzyl chloride (8.5 ml.) in 20 ml. dry dimethylformamide is added during ca. 10 min. Stirring is continued for 5 hours and then 120 ml. gl. acetic acid is added to the reaction mixture. After removal of solvent (in vacuo), the residue is stirred thoroughly with excess aqueous potassium carbonate solution and filtered. The solids are collected, washed with water, and dried. The crude product is dissolved in 1.4 l. boiling methanol, treated with charcoal, and filtered through Celite. The filtrate is concentrated to ca. 125 ml. and chilled. The crystalline solid is collected, washed with acetone, and again recrystallized from methanol to afford 11.76 g. title compound, m.p. 228°, NMR (dDMSO): δ 5.53 (singlet, N-CH2C6H5), 7.12 (doublet, J-3Hz, 9H), 7.23 (doublet, 8Hz, 5 or 6H), 7.63 (doublet, J=3Hz, 8H), 7.77 (doublet, J=9Hz, 5 or 6H) p.p.m.; λmax95%EtOH 235 (ε 26,900), 260 (ε 28,620), 317 (ε 9,640), 345 sh (ε 7,520) nm; λmin95%EtOH 243 (ε 26,020), 281 (ε 2,430) nm.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:16]=[N:17][NH:18][CH:19]=4)[C:11]=3[CH:20]=2)=[N:5][N:6]=1.Br[CH2:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>>[CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:19]=[N:18][N:17]([CH2:22][C:23]5[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=5[C:25]#[N:26])[CH:16]=4)[C:11]=3[CH:20]=2)=[N:5][N:6]=1
Reactant: N#Cc1ccccc1CBr
Reactant: Cc1nnc(-c2ccc3occ(-c4cn[nH]c4)c3c2)o1
Product: Cc1nnc(-c2ccc3occ(-c4cnn(Cc5ccccc5C#N)c4)c3c2)o1
Yield: 91 %

Procedure:
In the same manner as in Example 1 and using 2-methyl-5-[3-(1H-pyrazol-4-yl)-1-benzofuran-5-yl]-1,3,4-oxadiazole instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and using 2-(bromomethyl)benzonitrile instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 91%) was obtained as colorless crystals.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[C:22]([C:29]4[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=4)[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:28][CH:26]([F:27])[C:24]1[CH:23]=[C:22]([C:29]2[CH:30]=[N:31][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:34]=2)[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[CH:19]=2)[N:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)ccn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)ccn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 33.9 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic-acid tert-butylamide (0.36 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (MeOH, dichloromethane) yielded the title compound as a white solid (0.11 g, 21%). MS (ISP) 514.2 [(M+H)+]; mp 269.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH2:27][CH2:28][C:29](=[O:31])[CH2:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1.CO[CH:34](OC)[N:35]([CH3:37])[CH3:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH2:27][CH2:28][C:29](=[O:31])/[C:30](=[CH:34]\[N:35]([CH3:37])[CH3:36])/[C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CCC(=O)C5)cc2Cl)n1
Product: Cc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CCC(=O)/C5=C\N(C)C)cc2Cl)n1

Procedure:
The title compound was prepared following the method described for example 98 step 4, utilizing 4-({3-chloro-4-[(6-methylpyridin-2-yl)methoxy]phenyl}amino)-5,8-dihydro[1]benzothieno[2,3-d]pyrimidin-7(6H)-one (435 mg, 1.0 mmol) and dimethylformamide-dimethylacetal (230 mg, 1.9 mmol). The desired product was collected as a yellow solid (302 mg, 62%). 1H-NMR (DMSO-d6) (major rotomer) δ 8.26 (s, 1H), 8.18 (s, 1H), 7.75 (d, 1H), 7.72 (d, 1H), 7.51 (dd, 1H), 7.34 (d, 1H), 7.21 (d, 1H), 7.18 (d, 1H), 7.07 (s, 1H), 5.21 (s, 2H), 3.27 (t, 2H), 3.12 (s, 3H), 3.09 (s, 3H), 2.57 (t. 2H); LCMS RT=2.38 min; [M+H]+=506.1.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1([C:12]([C@@H:14]2[CH2:18][CH:17]([F:19])[CH2:16][N:15]2C(OC(C)(C)C)=O)=[O:13])[CH2:11][CH2:10][CH2:9]1>C(Cl)(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1([C:12]([C@@H:14]2[CH2:18][CH:17]([F:19])[CH2:16][NH:15]2)=[O:13])[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(F)C[C@H]1C(=O)N1CCC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C([C@@H]1CC(F)CN1)N1CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added under ice cooling to a 30 mL chloroform solution of 2.20 g of the compound obtained in step 7-2, after which the reaction mixture was stirred for 2 hours at room temperature. After this, the reaction mixture was concentrated under reduced pressure to obtain 3.82 g of residue (pale yellow oily substance). This compound was used in the following reaction without being purified.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:19])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=O)[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.Cl.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=1>C(OCC)(=O)C>[CH2:1]([NH:8][C:9](=[O:19])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:32]=2)=[O:18])[N:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)Nc1nc(C(=O)O)cs1
Reactant: CCOC(=O)COc1ccc(N)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(NC(=O)c2csc(NC(=O)NCc3ccccc3)n2)cc1
Reaction time: 20 h
Yield: 51 %

Procedure:
419 mg of 2-(3-benzyl-ureido)-thiazole-4-carboxylic acid, 265 mg of CDMT, 4.5 ml of THF and 0.18 ml of N-MM are 4.5 hrs. at RT. After the addition of 350 mg of ethyl 4-amino-phenyloxyacetate hydrochloride and 0.18 ml of N-MM the mixture is stirred for a further 20 hrs. at RT. For the working up, the mixture is diluted with ethyl acetate and washed in succession with dilute hydrochloric acid, water, dilute sodium carbonate solution, water and saturated sodium chloride solution, dried over sodium sulphate and evaporated in a vacuum. Chromatography on silica gel with methylene chloride-alcohol 99:1 and crystallization from ether gives 350 mg of ethyl (4-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-phenoxy)-acetate, m.p. 173° C., MS: 455 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.Cl[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=2)[N:17]=1>C(O)C>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=2)[N:17]=1
Reactant: CNCCc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc2nc(CCl)ccc2c1
Solvent: CCO
Product: CN(CCc1ccc([N+](=O)[O-])cc1)Cc1ccc2cc([N+](=O)[O-])ccc2n1

Procedure:
N-Methyl-4-nitrophenethylamine (0.39 g, 2.15 mmole) and 2-chloromethyl-6-nitroquinoline (0.40 g, 2.1 mmole) were heated at reflux temperature in ethanol (30 ml) for 6 hours. The solvent was then evaporated and the residue diluted with 2M hydrochloric acid and extracted with methylene chloride. The aqueous layer was basified with aqueous sodium carbonate (to pH ~12) and extracted three times with methylene chloride. These latter organic extracts were combined, dried (MgSO4) and evaporated giving an oil which was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 1%). The product-containing fractions were combined and evaporated to give a solid which was recrystallised from ethanol to give the title compound, yield 0.21 g, m.p. 104°-105°.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([NH2:7])[CH2:3]1.[CH2:8]([O:15][C:16](N1C(=O)CCC1=O)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(#N)C>[OH:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:16](=[O:17])[O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1
Reactant: O=C1CCC(=O)N1C(=O)OCc1ccccc1
Reactant: N[C@H]1CC[C@H](O)C1
Solvent: CC#N
Product: O=C(N[C@H]1CC[C@H](O)C1)OCc1ccccc1
Yield: 981.6 %

Procedure:
A solution of crude trans-3-hydroxycyclopentanamine (0.42 g, 4.2 mmol) and N-(benzyloxycarbonyl)succinimide (1.05 g, 0.42 mmol) in acetonitrile (40 ml) was stirred at ambient temperature under nitrogen for 18 hours. The mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate (150 ml), washed with water (3×75 ml), and brine (50 ml), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give benzyl (trans-3-hydroxycyclopentyl)carbamate (0.97 g, 98%), as a white solid.
Reaction SMILES: C=O.[Cl:3][C:4]1[C:5]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH:31]([CH3:35])[C:32]([NH2:34])=[O:33])=[N:6][C:7]([NH:10][C:11]2[CH:12]=[N:13][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:15][CH:16]=2)=[N:8][CH:9]=1.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Cl:3][C:4]1[C:5]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH:31]([CH3:35])[C:32]([NH2:34])=[O:33])=[N:6][C:7]([NH:10][C:11]2[CH:12]=[N:13][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:36])[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)=[N:8][CH:9]=1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)nc2)ncc1Cl
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCN(C)CC3)nc2)ncc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.5 %

Procedure:
Formaldehyde (31.2 μL, 0.419 mmol, 37 wt % in H2O) was added to a suspension of 2-(2-(2-(5-chloro-2-((6-(piperidin-4-yl)pyridin-3-yl)amino)pyrimidin-4-yl)ethyl)phenyl)propanamide 37 (39.0 mg, 0.084 mmol) in MeOH (2.0 mL) under an atmosphere of nitrogen. Sodium triacetoxyborohydride (178 mg, 0.839 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 2.5 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (10 mL) and sat. aq. NaHCO3 (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with water (20 mL) and brine (15 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the resulting solid was suspended in DCM (20 mL) and cyclohexane (30 mL). The solid was filtered to give the title compound 38 (34 mg, 84%). LCMS-C: rt 4.19 min; m/z 479.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:25]([CH3:27])[CH3:26])[C:13]([NH:15][C:16]1[C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]([C:13](=[O:14])[NH:15][C:16]1[CH:17]=[CH:18][N:19]=[CH:20][C:21]=1[C:22](=[O:24])[NH:39][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:25]([CH3:26])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC(C)C(NC(=O)OCc1ccccc1)C(=O)Nc1ccncc1C(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)C(NC(=O)OCc1ccccc1)C(=O)Nc1ccncc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
Formulae 508 and 509 where R1, R3 and R4 are H; R5 is Benzyl; R6 is Isopropyl; R6′ is H; W, Y and Z are —C═; and X is —N═: A solution of dichloromethane (200 mL), 4-(2-benzyloxycarbonylamino-3-methyl-butyrylamino)-nicotinic acid (10.0 g, 26.9 mmol) and EDC (7.74 g, 40.4 mmol) was stirred at room temperature for 2 hours until the complete consumption of the starting material was observed by reverse phase HPLC. Benzylamine (5.88 mL, 53.8 mmol) was then added and the mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum and purified by silica gel chromatography using hexane-EtOAc (stepwise gradient from 3:1 to 1:2) as eluents to obtain the uncyclized product of Formula 508, [1-(3-benzylcarbamoyl-pyridin-4-ylcarbamoyl)-2-methyl-propyl]carbamic acid benzyl ester (4.45 g, 35.9%) and the cyclized product of Formula 509, [1-(3-benzyl-4-oxo-3,4-dihydro-pyrido[4,3-d]pyrimidin-2-yl)-2-methyl-propyl]-carbamic acid benzyl ester (1.85 g, 15.5%). 508: MS (Cl) M/E: 461.2; 509: MS (Cl) M/E: 443.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.[C:23]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH:23]1([N:19]2[CH2:18][CH2:17][N:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH:4]3[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]3)[CH2:21][CH2:20]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2ccccc2N2CCN(C3CCCC3)CC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (25 mg, 0.0832 mmol) produced in Example (8b), cyclopentanone (9.1 mg, 0.108 mmol), sodium triacetoxyborohydride (33.5 mg, 0.158 mmol) and acetic acid (0.009 mL, 0.158 mmol) was stirred for 1 hour and 40 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed three times with ethyl acetate. The organic layer was concentrated to produce a residue, which was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 1-cyclopentyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][N:20]=[N+]=[N-])[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2].[H][H]>C(O)C.C(=O)([O-])[O-].[Ba+2].[Pd+2].C(=O)([O-])[O-]>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][NH2:20])[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cc(CN=[N+]=[N-])cc(-c2cccc(C#N)c2)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Product: COC(=O)c1cc(CN)cc(-c2cccc(C#N)c2)c1
Reaction time: 6 h

Procedure:
The Methyl 3-(3-cyanophenyl)-5-(azidomethyl)benzoate obtained as above was put in a flask, dissolved in 66 mL of ethanol, and after 1.1 g of palladium-barium carbonate was added, the air in flask was displaced with hydrogen. Stirring was continued at room temperature for 6 hours, the catalyst was subjected to celite-filteration, and the filtrate was concentrated and purified with silica gel chromatography to produce 794 mg of the title compound (Yield of the two steps: 90%).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:29][C:28]4[C:23](=[N:24][CH:25]=[CH:26][C:27]=4[O:30][C:31]4[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH:40][C:41](=[O:49])[CH2:42][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)=[S:39])=[CH:33][C:32]=4[F:50])[CH:22]=3)=[CH:17][CH:16]=2)[CH2:10]1)(C(C)(C)C)(C)C>CC#N.CO.Cl>[F:50][C:32]1[CH:33]=[C:34]([NH:37][C:38]([NH:40][C:41](=[O:49])[CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[S:39])[CH:35]=[CH:36][C:31]=1[O:30][C:27]1[CH:26]=[CH:25][N:24]=[C:23]2[CH:22]=[C:21]([C:18]3[CH:17]=[CH:16][C:15]([CH2:14][N:11]4[CH2:12][CH2:13][C@H:9]([OH:8])[CH2:10]4)=[CH:20][CH:19]=3)[S:29][C:28]=12
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=S)NC(=O)Cc6ccccc6)cc5F)c4s3)cc2)C1
Agent: Cl
Solvent: CC#N
Solvent: CO
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CC[C@H](O)C5)cc4)sc23)c(F)c1
Reaction time: 2 h
Yield: 8.7 %

Procedure:
To a solution of 103 (34 mg, 0.047 mmol) in CH3CN/MeOH (0.5 mL/2.0 mL), concentrated HCl (8 drops) was added and the reaction was allowed to stir 2 h. The solvents were removed under reduced pressure and the resultant solid was triturated with diethyl ether followed by purification by Gilson HPLC preparative system, column Aquasil C18 (25% MeOH in water to 100% MeOH), to afford title compound 104 (2.5 mg, 9% yield), as a white solid. 1H NMR (DMSO) δ (ppm): 11.82 (1H, s), 8.51 (1H, d, J=5.28 Hz), 8.23 (1H, s), 8.02-7.98 (2H, m), 7.82 (2H, d, J=7.83 Hz), 7.52 (2H, br), 7.41 (2H, d, J=7.83 Hz), 7.33-7.25 (5H, m), 6.64 (1H, d, J=5.09 Hz), 4.20 (1H, br), 3.83 (2H, s), 3.38 (2H, s), 2.34-2.32 (2H, m), 2.03-1.96 (2H, m), 1.56 (2H, br). MS (m/z) 613.3 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[C:19]([CH2:34][CH3:35])=[C:20]([CH2:24][CH2:25][N:26]4[CH2:29][CH:28]([C:30]([O:32]C)=[O:31])[CH2:27]4)[CH:21]=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+]>C(O)(C)C.O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[C:19]([CH2:34][CH3:35])=[C:20]([CH2:24][CH2:25][N:26]4[CH2:27][CH:28]([C:30]([OH:32])=[O:31])[CH2:29]4)[CH:21]=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:11])[CH3:12])#[N:2]
Reactant: CCc1c(CCN2CC(C(=O)OC)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCc1c(CCN2CC(C(=O)O)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.7 %

Procedure:
To a solution of methyl 1-{2-[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylate (D83) (188 mg) in isopropanol (40 mL) and water (10 mL) stirred under nitrogen at room temperature was added a solution of NaOH (30.7 mg) in water in one charge. The reaction mixture was stirred at room temperature overnight. Isopropanol was removed in vacuo. The residue was dissolved in water and acidified with 1N HCl to pH=5. The solvent was removed in vacuo, the residue was dissolved in THF, and filtered. The filtrate was purified by Mass Directed AutoPrep to give 1-{2-[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylic acid (E34) (14 mg) as a TFA salt (white solid). δH (DMSO-d6, 400 MHz): 1.07 (3H, t), 1.36 (6H, d), 2.69 (2H, m), 2.87 (2H, m), 3.59 (3H, m), 4.28 (4H, m), 4.90 (1H, m), 7.30 (2H, m), 7.37 (1H, m), 7.44 (1H, d), 7.85 (1H, s), 8.22 (1H, dd), 8.27 (1H, d), 9.98 (1H, br s), 13.19 (1H, br s). δF (DMSO-d6, 376 MHz): −73.5. MS (ES): C27H29N3O3S requires 475. found 476.2 (M+H+).