Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([OH:25])[CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27].[I-].[Na+].[CH3:30][NH:31][CH3:32]>O1CCCC1>[CH3:30][N:31]([CH3:32])[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([OH:25])[CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27]
Reactant: COc1cc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc2cc1OCCCl
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc2cc1OCCN(C)C
Temperature: 125 °C

Procedure:
A mixture of 1 g (2.38 mmol) of 7-(2-chloro-ethoxy)-4-(3-hydroxy-4-methyl-phenylamino)-6-methoxy-quinoline-3-carbonitrile and 0.078 g of sodium iodide in 19.5 ml of 2M dimethylamine in tetrahydrofuran was placed in a sealed tube and heated to 125° C. for 14 hr. The solvent was removed and the residue was mixed with warm ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated and dried over magnesium sulfate. Solvent was removed and the residue was chromatographed on silica gel eluting with ethyl acetate-methanol-triethylamine 70:30:2.5 giving 0.89 g of the tide compound as a light yellow solid: mass spectrum (electrospray, m/e) M+H 393.0; (M+2H)+2 196.9.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]1([S:12]([N:15]2[CH:26]=[CH:25][C:24]3[C:16]2=[N:17][CH:18]=[C:19]2[C:23]=3[N:22]([C@H:27]3[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28]3)[N:21]=[N:20]2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:5][O:4][C:2](=[O:3])[NH:32][C@H:29]1[CH2:30][CH2:31][C@H:27]([N:22]2[C:23]3[C:19](=[CH:18][N:17]=[C:16]4[C:24]=3[CH:25]=[CH:26][N:15]4[S:12]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)(=[O:14])=[O:13])[N:20]=[N:21]2)[CH2:28]1
Reactant: COC(=O)Cl
Reactant: N[C@H]1CC[C@H](n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H]1CC[C@H](n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)C1
Reaction time: 4 h
Yield: 99.5 %

Procedure:
Methyl chloroformate (31.0 μL, 0.40 mmol) was added to a stirred mixture of racemic trans 3-(6-benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentylamine (150 mg, 390 μmol) and diisopropylethylamine (135 μL, 790 μmol) in DCM (3 mL) at ambient temperature. Stirring was continued for 4 hours. The mixture was concentrated under vacuum and the residue obtained purified by column chromatography on silica gel (gradient: 0 to 100% ethyl acetate in pentane) to afford 171 mg (98%) of racemic trans [3-(6-benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-carbamic acid methyl ester as a colourless foam. LCMS (Method B, ESI): RT=3.48 min, m+H=441.3.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)=[O:29])=[CH:26][N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C>[CH3:38][O:37][C:33]1[CH:32]=[C:31]([NH:30][C:28]([C:27]2[C:26]([NH:1][C@H:2]([C:4]3[N:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:8](=[O:16])[C:7]4=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]4[N:5]=3)[CH3:3])=[N:25][CH:24]=[N:23][CH:22]=2)=[O:29])[CH:36]=[CH:35][CH:34]=1
Reactant: COc1cccc(NC(=O)c2cncnc2Cl)c1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: COc1cccc(NC(=O)c2cncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Temperature: 120 °C
Yield: 24.2 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (15 mg, 0.06 mmol), 4-chloro-N-(3-methoxyphenyl)pyrimidine-5-carboxamide (14 mg, 0.05 mmol, prepared according to R. Tadiparthi et al PCT Int. Appl. 2007031829, 22 Mar. 2007), DIEA (50 μl, 0.29 mmol) and cesium fluoride (17 mg, 0.11 mmol) were suspended in tert-butanol (2 ml) and the mixture was heated at 120° C. in a sealed tube for 18 h. The solvent was evaporated under reduced pressure and the reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and brine. After evaporation of the solvent, the residue was purified by flash chromatography using SP1® Purification System (0% to 10%, dichloromethane-methanol) to obtain 6 mg (5% yield) of the title compound.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CCC(c2cccc(Cl)c2)CC1
Product: Clc1cccc(C2CCN(CCCc3onc4c3CCCCC4)CC2)c1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(3-chlorophenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(3-chlorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH2:26][NH2:27])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.[CH3:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38]>ClCCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH2:26][NH:27][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=3[CH3:34])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(CN)c3ccccc23)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(CNC(=O)c3ccccc3C)c3ccccc23)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-aminomethyl-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester (32) (60 mg, 0.153 mmol) in DCE (5 mL), was added pyridine (62 ul, 0.765 mmol), 2-methyl-benzoyl chloride (22 ul, 0.168 mmol) and dimethyl-pyridin-4-yl-amine (4 mg, 0.031 mmol). After stirring at 70° C. overnight, the resultant solution was concentrated in vacuo to give the crude product. Purification using reverse phase HPLC provided the title compound (G-1). LCMS showed m/z: 510 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]([C@@H:13]([NH:21][C:22](=[O:41])[C@H:23]([CH2:37][C:38](=[O:40])[NH2:39])[NH:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][N:4]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[NH2:5].[CH3:42][O:43][C:44]([NH:46][C@H:47]([C:51](O)=[O:52])[CH:48]([CH3:50])[CH3:49])=[O:45].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NN>CN1CCOCC1.CN(C=O)C.CN1CCOCC1.CN(C=O)C>[OH:1][C@H:2]([C@@H:13]([NH:21][C:22](=[O:41])[C@H:23]([CH2:37][C:38](=[O:40])[NH2:39])[NH:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][N:4]([CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[NH:5][C:51](=[O:52])[C@H:47]([CH:48]([CH3:49])[CH3:50])[NH:46][C:44]([O:43][CH3:42])=[O:45]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)CC1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)N[C@H](C(=O)NN(CC1CCCCC1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1)C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Under a nitrogen atmosphere, 100 mg (0.178 mmol) of 1-[2(S)-hydroxy-3(S)-(N-(quinoline-2-carbonyl)-(L)-asparaginyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]hydrazine (Example 71e) i)) and 34 mg (0.196 mmol) of N-methoxycarbonyl-(L)-valine (Example 73b) are dissolved in 1.75 ml of a 0.3M solution of NMM in DMF, 74 mg (0.196 mmol) of HBTU are added and the mixture is stirred at RT. Since, after 3 days, there is still unreacted hydrazine present, a further 0.3 equivalents in each case of N-methoxycarbonyl-(L)-valine and HBTU in 0.48 ml of 0.3M NMM/DMF is added. After 18 h the reaction mixture is concentrated by evaporation under HV, the residue is dissolved in methylene chloride and washed with saturated NaHCO3 solution, water and brine, the aqueous phases are extracted twice with methylene chloride, and the organic phases are dried with Na2SO4 and concentrated by evaporation. Column chromatography (SiO2, methylene chloride/methanol 15:1) and digestion from DIPE yields the title compound: TLC Rf (A')=0.17; tRet (V)=14.6 min; FAB-MS (M+H)+ =718.
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:9][C@H:10]2[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12][CH2:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:17](Br)[CH2:18][CH3:19]>COCCOC>[CH:3]1([NH:9][C@H:10]2[CH2:15][CH2:14][C@@H:13]([O:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:11]2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CCCBr
Reactant: O[C@H]1CC[C@@H](NC2CCCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCO[C@H]1CC[C@@H](NC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of NaH (60% susp., 1.4 mmol) and ethylene glycol dimethylether (3 mL) was added cyclohexyl-cis-(4-hydroxycyclohexyl)-amine (0.36 mmol) and the mixture was stirred under N2 at rt for 5 min followed by addition of propylbromide (5.5 mmol). The mixture was refluxed for 18 h under N2. The reaction mixture was cooled to rt and quenched with anhydrous EtOH (0.5 mL). The mixture was filtered and the residue was extracted with ethylene glycol di-methylether (2 mL). The organic phase was evaporated to dryness under reduced pressure and co-evaporated with toluene (10 LI). The residue was added HCl in MeOH (1.25 M, 5 mL) and evaporated under reduced pressure affording a white solid. The solid was washed with TBME (2 mL) and dissolved in a mixture of DCM (5 mL) and 1 M aqueous NaOH (5 mL). The organic phase was washed with H2O (5 mL), dried (Na2SO4), and evaporated under reduced pressure to give the desired cyclohexyl-cis-(4-propoxycyclohexyl)amine as an oil which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]2[CH2:6][C@H:7](OC)[B:8]([OH:10])[O:9][C:4]=2[C:3]=1[C:15]([OH:17])=[O:16].[NH2:18][N:19]1[CH:23]=[N:22][N:21]=[C:20]1[SH:24]>>[NH2:18][N:19]1[CH:23]=[N:22][N:21]=[C:20]1[S:24][C@H:7]1[CH2:6][C:5]2[CH:13]=[CH:14][C:2]([F:1])=[C:3]([C:15]([OH:17])=[O:16])[C:4]=2[O:9][B:8]1[OH:10]
Reactant: Nn1cnnc1S
Reactant: CO[C@H]1Cc2ccc(F)c(C(=O)O)c2OB1O
Product: Nn1cnnc1S[C@H]1Cc2ccc(F)c(C(=O)O)c2OB1O

Procedure:
Compound (20) was prepared from 19G (example 19) following methods described in steps 5 and 6 of example 1 utilizing 4-amino-4H-1,2,4-triazole-3-thiol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:10][CH:9]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a stirred suspension of 4-(5-bromo-2-chlorobenzyl)phenol (5.0 g, 16.8 mmol) in N,N-dimethylformamide (20 mL) and cesium carbonate (11.0 g, 33.6 mmol) was added ethyl 2-bromoacetate (2.8 mL, 25.2 mmol). The mixture was stirred overnight at 80° C. The solution was diluted with water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine prior to drying over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give 5.0 g of white solid (78% yield).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl[C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=1.C(N(CC)CC)C>CN(C=O)C>[F:23][C:22]([F:25])([F:24])[C:20]1[CH:19]=[CH:18][N:17]=[C:16]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: FC(F)(F)c1ccnc(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cc(C(F)(F)F)ccn1
Temperature: 80 °C
Yield: 26.5 %

Procedure:
To a mixture of (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.6 g, 3.03 mmol) in DMF (5 mL) was added 2-chloro-4-trifluoromethylpyridine (0.2 g, 1.1 mmol) and triethylamine (0.22 g, 2.2 mmol). The reaction mixture was heated at reflux for 1 hour in a microwave reactor at 80° C. Then the solvent was evaporated in vacuo. The crude product was purified by column chromatography on silica gel with eluent (petroleum ether:ethyl acetate from 50:1 to 10:1) to afford the intermediate (1S,4S)-tert-butyl 5-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.1 g).
Reaction SMILES: [F:1][CH:2]([F:19])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([CH3:17])[CH:8]=1)=O.[NH2:20][C:21]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)=[CH:24][NH:23][N:22]=1>>[F:1][CH:2]([F:19])[C:3]1[N:22]2[N:23]=[CH:24][C:25]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=3)=[C:21]2[N:20]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([CH3:17])[CH:8]=2)[CH:4]=1
Reactant: Cc1cc(C(=O)CC(=O)C(F)F)ccc1C(F)(F)F
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Product: Cc1cc(-c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)c(C)c4)nc23)ccn1
Yield: 78.4 %

Procedure:
Reaction of 4,4-difluoro-1-(3-methyl-4-trifluoromethyl-phenyl)-butane-1,3-dione (140 mg, 0.5 mmol), prepared from 3-methyl-4-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2-methyl-pyridine, CAS No. 130138-46-4, as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (164 mg, 78%). MS (ISP) 419.3 [(M+H)+]; mp 221° C.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C:6](=S)[C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][C@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.[NH2:24][NH2:25]>CO>[C:12]([O:11][C:10](=[O:16])[NH:9][C@H:5]1[CH2:4][C@@H:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:2]([CH3:1])[NH:7][C:6]1=[N:24][NH2:25])([CH3:15])([CH3:14])[CH3:13]
Reactant: NN
Reactant: C[C@H]1NC(=S)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Solvent: O
Solvent: CO
Product: C[C@H]1NC(=NN)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Reaction time: 1.25 h

Procedure:
To a solution of tert-Butyl [(3S,5S,6R)-6-methyl-5-phenyl-2-thioxopiperidin-3-yl]carbamate (100 mg, 0.31 mmol) in methanol (3.1 mL) was added hydrazine hydrate (55%, 833 μL, 9.36 mmol). The mixture was stirred 75 min, and then concentrated. Saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate (×3). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude title compound. MS 319.4 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(P(CCCC)CCCC)CCC.[C:30]([O:34][CH3:35])(=[O:33])[C:31]#[CH:32]>C1COCC1>[CH3:35][O:34][C:30](=[O:33])[CH:31]=[CH:32][O:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:16])[CH3:8])[CH2:14][CH2:13]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](O)CC1
Reactant: C#CC(=O)OC
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COC(=O)C=CO[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
27 g (117.7 mmol) of trans-(4-hydroxy-cyclohexyl)-methyl-carbamic acid tert-butyl ester were dissolved in 500 mL of THF and were treated with 6.8 mL of tri-n-butylphosphine and 10.5 mL (117.7 mmol) of methyl propiolate at 0° C. for 2d. Additional 2.1 mL (23 mmol, 0.2 eq) of methyl propiolate and 3.4 mL (11.8 mmol, 0.1 eq) of tri-n-butylphosphine were added. After stirring for 1 h at RT, the solution was evaporated and the crude product was purified by flash chromatography with n-heptane:EtOAc 3:1. Trituration with n-heptane yielded 26.7 g (73%) of trans-3-[4-(tert-butoxycarbonyl-methyl-amino)-cyclohexyloxy]-acrylic acid methyl ester as white solid, MS: 314 (MH+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([CH2:11][O:12][C:13](N2C=CN=C2)=[O:14])[CH:7]=1.[N:20]1([C:26](=[O:28])[CH3:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([CH2:11][O:12][C:13]([N:23]2[CH2:24][CH2:25][N:20]([C:26](=[O:28])[CH3:27])[CH2:21][CH2:22]2)=[O:14])[CH:7]=1
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(OCc1cc(-c2ccco2)on1)n1ccnc1
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)OCc2cc(-c3ccco3)on2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
To a solution of 30 mg of imidazole-1-carboxylic acid 5-furan-2-yl-isoxazol-3-ylmethyl ester in 1 mL of methylene chloride was added 16 mg of 1-piperazin-1-yl-ethanone. After stirring at room temperature for 4 hrs, the reaction mixture was concentrated under reduced pressure. The concentrate was purified by column chromatography to afford 30 mg of the title compound. (Yield: 79%).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:24]([O:26][C:27]([C:29]1[S:33][C:32]([CH2:34]Br)=[N:31][CH:30]=1)=[O:28])[CH3:25]>>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[N:20]([CH2:34][C:32]4[S:33][C:29]([C:27]([O:26][CH2:24][CH3:25])=[O:28])=[CH:30][N:31]=4)[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cnc(CBr)s1
Reactant: O=c1[nH]cc(C2c3ccccc3C=Cc3ccccc32)c(=O)[nH]1
Product: CCOC(=O)c1cnc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)s1

Procedure:
The subtitle compound was prepared from the product of example 1 step (iii) (1.0 g) and 2-(bromomethyl)-5-thiazolecarboxylic acid ethyl ester (0.9 g) according to the method of example 1 step (iv). The reaction mixture was evaporated to dryness under reduced pressure and the crude product was recrystallised from ethyl acetate/methanol. Yield 0.78 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH2:16][CH3:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4](=[O:18])[CH:3]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]#[N:30])=[C:24](B(O)O)[CH:25]=1>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>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:29]#[N:30])=[C:22]([C:2]2[CH:7]=[CH:6][N:5]([CH:8]([CH2:16][CH3:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4](=[O:18])[CH:3]=2)[CH:21]=1
Reactant: CCC(C(=O)OC(C)(C)C)n1ccc(Br)cc1=O
Reactant: N#Cc1ccc(Cl)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCC(C(=O)OC(C)(C)C)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
600 mg (purity 82%, 1.56 mmol) of tert-butyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)butanoate (racemate) and 325 mg (1.8 mmol) of 5-chloro-2-cyanophenylboronic acid in the presence of tetrakis(triphenylphosphine)palladium(0) were reacted according to General Method 2A. Yield: 543 mg (purity 59%, 55% of theory)
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH3:26])[CH2:22][CH:23]=O)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.CO.Cl.[O:32]([NH2:34])[CH3:33].C(=O)(O)[O-].[K+]>O>[CH3:33][O:32][N:34]=[CH:23][CH2:22][CH:21]([N:19]1[CH:20]=[C:16]([C:15]2[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:28])([CH3:1])[CH3:27])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:17]=[N:18]1)[CH2:25][CH3:26]
Reactant: CCC(CC=O)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: CON
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCC(CC=NOC)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal (prepared as in Example 498, step 1; 70 mg, 0.0002 mol) in methanol (2 mL, 0.05 mol) was added methoxylamine hydrochloride (19 mg, 0.00022 mol) and potassium bicarbonate (22 mg, 0.00022 mol). The reaction was stirred at room temperature for 2 h, water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, was filtered and was concentrated to give 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal O-methyloxime as a mixture of isomers (70 mg, 90%) crude product. LC/MS (M+H)+: m/z=429.
Reaction SMILES: C(O)(=O)C.OO.[CH:7]1([C:10]2[N:11]=[C:12](S)[N:13]([C:15]3[C:16]([CH3:24])=[CH:17][C:18]([F:23])=[C:19]([CH:22]=3)[C:20]#[N:21])[CH:14]=2)[CH2:9][CH2:8]1.S([O-])([O-])=O.[Na+].[Na+]>O>[CH:7]1([C:10]2[N:11]=[CH:12][N:13]([C:15]3[C:16]([CH3:24])=[CH:17][C:18]([F:23])=[C:19]([CH:22]=3)[C:20]#[N:21])[CH:14]=2)[CH2:8][CH2:9]1
Reactant: Cc1cc(F)c(C#N)cc1-n1cc(C2CC2)nc1S
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(F)c(C#N)cc1-n1cnc(C2CC2)c1
Temperature: 45 °C

Procedure:
In a 500 mL three neck round bottom flask was placed acetic acid (96 mL), water (19 mL) and hydrogen peroxide (30%, 7.47 mL, 65.88 mmol). The mixture was heated to 45° C. with stirring under nitrogen while monitoring the internal temperature. 5-(4-Cyclopropyl-2-mercapto-1H-imidazol-1-yl)-2-fluoro-4-methylbenzonitrile (6.00 g, 21.96 mmol) was then added as a solid in small portions over 30 minutes while maintaining an internal temperature below 55° C. When addition of the thioimidazole was complete the reaction was stirred for 30 minutes at a temperature of 45° C., and then cooled to room temperature, and a solution of 20% wt/wt sodium sulfite in water (6 mL) was slowly added. The mixture was stirred for 30 minutes and solvents were removed under reduced pressure. The residue was suspended in 250 mL of water and 4N aqueous ammonium hydroxide was added to bring the pH to ˜10. The mixture was extracted with dichloromethane (3×200 ml), the organics combined, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in 20 mL EA, and 80 mL of hexanes were added with stirring. The solvents were decanted off and an oily residue was left behind. This process was repeated and the product, 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzonitrile was obtained as a viscous oil (5.14 g, 21.33 mmol) Anal. LC/MS (m/z: 242, M+1)