Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([CH2:14][S:15][C:16]1(C)[S:20]CN=[N:17]1)=[C:7]2[C:11]([OH:13])=[O:12].Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[K+].[NH2:32][CH:33]1C(=O)N2[CH:34]1SCC(CSC1SC(C)=NN=1)=C2C(OC(C1C=CC=CC=1)C1C=CC=CC=1)=O>O.O1CCCC1>[CH3:34][C:33]1[N:17]=[C:16]([S:15][CH2:14][C:6]2[CH2:5][S:4][CH:3]3[N:8]([C:9](=[O:10])[CH:2]3[NH2:1])[C:7]=2[C:11]([OH:13])=[O:12])[S:20][N:32]=1
Reactant: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)s1
Reactant: CC1(SCC2=C(C(=O)O)N3C(=O)C(N)C3SC2)N=NCS1
Agent: O=C([O-])O
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: O
Product: Cc1nsc(SCC2=C(C(=O)O)N3C(=O)C(N)C3SC2)n1
Reaction time: 0.5 h

Procedure:
18 g. of 7-amino-3-[[(5-methyl-1,3,4-thiadiazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid are suspended in 350 ml. of tetrahydrofuran. 4.1 ml. of 70% perchloric acid are added dropwise. After 30 minutes, a slightly turbid solution forms. This solution is filtered and to the filtrate is added dropwise with stirring 12 g. of diphenyldiazomethane and 20 ml. of tetrahydrofuran. After three hours, the reaction mixture is poured into 2 liters of absolute ether. The solid, light brown precipitate, which is the perchloric acid salt of the desired product, is dried over Kieselgel in a desiccator. To obtain the base, the perchloric acid salt is dissolved in water and treated with the calculated equivalent of potassium bicarbonate. The aqueous solution obtained is extracted with chloroform. The chloroform phase is treated with activated carbon and sodium sulfate to obtain the 10 g. of the product, 7-amino-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2 -ene-2-carboxylic acid, diphenylmethyl ester, as a light brown powder, m.p. 157°-159°. The product is recrystallized from tetrahydrofuran/petroleum ether. The isomeric thiadiazolyl derivative is similarly obtained from the product of Example 20.
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][CH:12]=[N:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:35])[C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=2)=[O:20])[CH2:15]1>>[F:30][C:28]1[CH:29]=[C:24]([CH:25]=[C:26]([C:31]([F:34])([F:32])[F:33])[CH:27]=1)[C:23]([NH:22][CH2:21][C:19](=[O:20])[NH:18][CH:16]1[CH2:17][N:14]([CH:5]2[CH2:6][CH2:7][C:2]([OH:1])([C:9]3[S:13][CH:12]=[N:11][CH:10]=3)[CH2:3][CH2:4]2)[CH2:15]1)=[O:35]
Reactant: O=C(CNC(=O)c1cc(F)cc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(O)(c2cncs2)CC1
Product: O=C(CNC(=O)c1cc(F)cc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3cncs3)CC2)C1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-thiazol-5-yl-cyclohexanone, as prepared in Example 40 Step B, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-5-fluoro-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[N:6][C:5]=2[N:4]([CH3:25])[C:3]1=[O:26].Br[CH2:28][C:29]#[C:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:37][C:33]1[CH:32]=[C:31]([C:30]#[C:29][CH2:28][N:23]2[CH:24]=[C:20]([C:7]3[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:17])[CH3:18])[C:9]4[C:10](=[O:11])[N:2]([CH3:1])[C:3](=[O:26])[N:4]([CH3:25])[C:5]=4[N:6]=3)[CH:21]=[N:22]2)[CH:36]=[CH:35][CH:34]=1
Reactant: Fc1cccc(C#CCBr)c1
Reactant: Cn1c(=O)c2c(nc(-c3cn[nH]c3)n2COCC[Si](C)(C)C)n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1c(=O)c2c(nc(-c3cnn(CC#Cc4cccc(F)c4)c3)n2COCC[Si](C)(C)C)n(C)c1=O
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of 1,3-dimethyl-8-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (obtained following literature procedure U.S. Pat. No. 6,825,349) (0.100 g, 0.27 mmol), 1-(3-Bromo-prop-1-ynyl)-3-fluoro benzene (0.057 g, 0.27 mmol), K2CO3 (0.086 mg, 0.62 mmol) and acetone (5 ml) were refluxed at 80° C. for 5 hrs. The reaction mixture was cooled to room temperature and filtered off solid K2CO3 and evaporated excess of organic solvent under vacuum. The product was purified by column chromatography (2% methanol in dichloromethane) to get pure 8-{1-[3-(3-fluoro-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1,3-dimethyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.111 g, 82%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[OH:17][CH2:16][CH:13]1[CH2:14][CH2:15][N:10]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:11][CH2:12]1
Reactant: OB(O)c1ccncc1
Reactant: OCC1CCNCC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: OCC1CCN(c2ccncc2)CC1
Reaction time: 48 h
Yield: 70 %

Procedure:
The mixture of 4-pyridineboronic acid (0.97 g, 7.8 mmol), 4-piperidinemethanol (1.82 g, 15.8 mmol), Cu(OAc)2 (2.88 g, 15.8 mmol), DMAP (catalytic amount), pyridine (2.5 mL, 32 mmol), 4A activated molecular sieve in 50 mL dry DCM was stirred for over 2 days. It was diluted with DCM, filtered through celite. It was washed with brine and water, dried, filtered through a silica plug, evaporated in vacuuo to give 4-(4-hydroxylmethylpiperidin-1-yl)pyridine in 70% yield. ES-MS: (M+H)+193.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:27](O)(=[O:29])=[O:28])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.CN.Cl.C[CH2:35][N:36](C(C)C)C(C)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:27]([NH:36][CH3:35])(=[O:29])=[O:28])[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(-c2nc3ccc(S(=O)(=O)O)cc3nc2-c2ccc(OC)cc2)cc1
Agent: CN
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc2nc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
A solution of 2,3-bis(4-methoxyphenyl)quinoxaline-6-sulfonic acid (200 mg, 0.47 mmol, 1.00 equiv) in thionyl chloride (20 mL) was heated under reflux for 3 h, then concentrated under vacuum. The residue was diluted with 10 ml of CH2Cl2 and added dropwise into a solution of MeNH2.HCl (318 mg, 4.75 mmol, 10.00 equiv) and DIEA (917 mg, 7.11 mmol, 15.00 equiv) in CH2Cl2 (20 mL) at 0° C. The resulting solution was stirred for overnight at room temperature, concentrated under vacuum, and purified by Prep-HPLC, yielding 100 mg (49%) of 2,3-bis(4-methoxyphenyl)-N-methylquinoxaline-6-sulfonamide as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[NH:8][C:7]2=[N:9][CH:10]=[CH:11][C:6]2=[C:5]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[N:4]=1.CCN(CC)CC.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.CN(C1C=CN=CC=1)C>[C:25]([N:9]1[C:7]2[N:8]=[C:3]([N:2]([CH3:17])[CH3:1])[N:4]=[C:5]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[C:6]=2[CH:11]=[CH:10]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)c1nc(-c2ccco2)c2ccnc-2[nH]1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)c1nc(-c2ccco2)c2ccn(C(=O)c3ccccc3)c2n1
Yield: 28.6 %

Procedure:
A solution of N,N-dimethyl-4-(2-furyl)-1H-pyrrolo[2,3-d]pyrimidine-2-amine (181 mg, 0.8 mmol) in THF (3 mL) was treated with Et3N, (111 μL, 0.8 mmol), benzoyl chloride (93 μL, 0.8 mmol) and a catalytic amount of DMAP, stirred at room temperature for 16 h, quenched with water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography (EtOAc:Heptane, 1:9 then Heptane:DCM, 2:1) to give the title compound (76 mg) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH2:24]([O:31][CH:32]1[CH2:35][CH:34]([NH2:36])[CH2:33]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][CH:32]1[CH2:35][CH:34]([NH:36][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:33]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CC(OCc2ccccc2)C1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CC(OCc3ccccc3)C2)cn1
Yield: 43 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (300 mg, 0.97 mmol) was converted, using rac 3-benzyloxy-cyclobutylamine instead of 2-aminoethyl isopropylether, to the title compound (350 mg, 43%) which was obtained as a white solid. MS: m/e=470.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14](O)=[O:15])[C:11]3[C:17]([CH:24]=[O:25])=[C:18]([C:20]([O:22][CH3:23])=[O:21])[S:19][C:10]=3[C:9]=2[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:65]([N:68]1[CH2:72][CH2:71][CH:70]([NH:73][CH3:74])[CH2:69]1)([CH3:67])[CH3:66]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][C:14]([N:73]([CH:70]3[CH2:71][CH2:72][N:68]([CH:65]([CH3:67])[CH3:66])[CH2:69]3)[CH3:74])=[O:15])[C:11]3[C:17]([CH:24]=[O:25])=[C:18]([C:20]([O:22][CH3:23])=[O:21])[S:19][C:10]=3[C:9]=2[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc2c(C3CCCCC3)c(-c3ccc(Cl)cc3)n(CC(=O)O)c2c1C=O
Reactant: CNC1CCN(C(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1sc2c(C3CCCCC3)c(-c3ccc(Cl)cc3)n(CC(=O)N(C)C3CCN(C(C)C)C3)c2c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
A solution (0.13 M) of [5-(4-chlorophenyl)-6-cyclohexyl-3-formyl-2-(methoxycarbonyl)-4H-thieno[3,2-b]pyrrol-4-yl]acetic acid in DMF was treated with DIEA (3 eq.), HATU (1.5 eq.) and a solution (0.5 M) of 1-isopropyl-N-methylpyrrolidin-3-amine (1.5 eq.) in DMF. The reaction mixture was stirred at RT for 3 h. The reaction was quenched with aqueous NaHCO3 (saturated solution) and extracted with AcOEt. The combined organic phase was washed with brine and dried. Evaporation under reduced pressure gave a residue that was purified by flash chromatography on silica gel (1:49 Et3N/AcOEt) to afford the title compound (62%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([CH:10]([F:12])[F:11])[N:6]=1)=[O:4].[Cl:13]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:9]([Cl:13])=[CH:8][N:7]([CH:10]([F:12])[F:11])[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccn(C(F)F)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC(=O)c1nn(C(F)F)cc1Cl
Temperature: 50 °C
Yield: 85.5 %

Procedure:
A mixture of 1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester (535 mg, 3 mmol) and N-chloro-succinimide (1.22 g, 9.1 mmol) in N,N-dimethylformamide (5 ml) was heated at 50° C. overnight. The reaction mixture was cooled, partitioned between ethyl acetate and water, the organic layer was washed with water, dried, evaporated and the residue was purified by chromatography on silica gel using cyclohexane/ethyl acetate (3:1) as the eluent to give the title compound (540 mg) as a white solid. MS (ISP): m/z=209.9 [M]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1(B(O)O)[CH2:15][CH2:14][CH2:13][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].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.C(O)C>[C:11]1([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: OB(O)C1=CCCC1
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: [Cs+]
Solvent: CCO
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(C2=CCCC2)cc1
Temperature: 105 °C
Yield: 83.2 %

Procedure:
To 1-bromo-4-nitro-benzene (700 mg, 3.46 mmol), 1-cyclopentenylboronic acid (392 mg, 3.50 mmol), Pd(PPh3)4 (200 mg, 0.17 mmol), and Cs2CO3 (2258 g, 6.93 mmol) was added DME (8.4 mL) and ethanol (1.4 mL) and the reaction mixture was heated at 105° C. for 3 h. The reaction was concentrated in vacuo and purified by silica gel chromatography (0-100% ethyl acetate/hexanes) to provide 1-(1-cyclopentenyl)-4-nitro-benzene (545 mg, 83% yield). 1H NMR (400.0 MHz, CDCl3) δ 8.19-8.15 (m, 2H), 7.58-7.52 (m, 2H), 6.44-6.42 (m, 1H), 2.77-2.71 (m, 2H), 2.62-2.56 (m, 2H), 2.11-2.03 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([OH:20])=O)[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C([N+:27]([O-])=O)=CC=C(O)C=1.C1(N=C=NC2CCCCC2)CCCCC1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([NH2:27])=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NCCCC[C@H](NC(=O)OCc1ccccc1)C(N)=O

Procedure:
Na -t-butyloxycarbonyl-Ne -benzyloxycarbonyl-L-lysine was dissolved in ethyl acetate and esterified with p-nitrophenol using dicyclohexylcarbodiimide as a coupling agent. Sodium bicarbonate (10%) was added and the product extracted into the organic layer and crystallized from solution, then added to aqueous ammonium hydroxide to form Na -t-butyloxycarbonyl-Ne -benzyloxycarbonyl-L-lysine amide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[CH:12][CH:11]=2)O)=[N:4][CH:5]=[CH:6][N:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[CH:12][CH:11]=2)[N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC(c1ccc2cccnc2c1)c1nccnc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C(c1ccc2cccnc2c1)c1nccnc1Cl
Temperature: 0 °C
Reaction time: 21.5 h

Procedure:
To a suspension of (3-chloropyrazin-2-yl)-quinolin-7-ylmethanol (600 mg, 2.21 mmol), phthalimide (356 mg, 2.42 mmol), and PS—PPh3 (loading 2.12 mmol/g; 1.56 g, 3.31 mmol) in dry THF (20 mL), cooled by ice/water, was added DIAD (480 μL, 493 mg, 2.44 mmol), then the cooling bath was removed and the flask was vortexed at ambient temperature for 21.5 h. More PS—PPh3 (520 mg, 1.10 mmol) and DIAD (160 μL, 164 mg, 0.81 mmol) were added, and vortexing was continued for 6.5 h. The resin was filtered and washed with THF and CH2Cl2. The crude material was chromatographed on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with hexanes:EtOAc 3:1 (1-14)→2:1 (15-29)→1:1 (30-65)→1:2 (66-80)], yielding the title compound as pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 7.12 (s, 1H), 7.41 (dd, J=4.4, 8.0 Hz, 1H), 7.54 (dd, J=2.0, 8.4 Hz, 1H), 7.72-7.78 (m, 2H), 7.81-7.89 (m, 3H), 8.01 (d, J=0.8 Hz, 1H), 8.16 (dd, J=0.8, 8.4 Hz, 1H), 8.39 (d, J=2.4 Hz, 1H), 8.50 (d, J=2.4 Hz, 1H), 8.90 (dd, J=1.6, 4.2 Hz, 1H); MS (ES+): m/z 401.0/402.9 (100/38) [MH+].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[SH:12][C:13]1[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([S:12][C:13]2[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: Cn1ccnc1S
Product: Cn1ccnc1Sc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 37.1 %

Procedure:
Starting with 1.92g (10 moles) 2,5-dichloronitrobenzene and 1.14 g (10 mmoles) of 2-mercapto-1-methylimidazole and following the procedure described in Example 1 there was obtained 1.0 g (37%) of the product as yellow prisms, mp 143°-145° C.
Reaction SMILES: [NH2:1][C:2]1[C:12]([Br:13])=[C:11]([F:14])[CH:10]=[CH:9][C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl.O>C1(C)C=CC=CC=1>[Br:13][C:12]1[C:11]([F:14])=[CH:10][CH:9]=[C:3]2[C:2]=1[NH:1][C:16](=[O:18])[N:6]([CH2:7][CH3:8])[C:4]2=[O:5]
Reactant: CCNC(=O)c1ccc(F)c(Br)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCn1c(=O)[nH]c2c(Br)c(F)ccc2c1=O
Temperature: 25 °C
Yield: 291 %

Procedure:
A solution of 2-amino-3-bromo-N-ethyl-4-fluorobenzamide (512a, 2.00 g, 7.66 mmol) and triphosgene (Aldrich; 0.796 g, 2.68 mmol) in toluene (80 mL) was heated at 110° C. for 18 h (water-cooled reflux condenser attached to flask). The reaction mixture was then cooled to RT and concentrated in vacuo to give 8-bromo-3-ethyl-7-fluoroquinazoline-2,4(1H,3H)-dione (2.238 g, 7.80 mmol) as a light-yellow solid: m/z (ESI, +ve) 286.9/288.8 (M+H)+. This material was used directly in the subsequent transformation.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[N:19]=[C:20]([C:23]6[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=6)[CH:21]=[N:22][C:17]5=[N:16][N:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:33][C@@H:34]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:43][C:42]([CH3:45])([CH3:44])[C@H:34]([NH:33][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([C:20]2[CH:21]=[N:22][C:17]3[N:18]([C:14]([C:11]4([C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[CH2:13][CH2:12]4)=[N:15][N:16]=3)[N:19]=2)=[CH:31][CH:30]=1)[C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36]
Reactant: O=C(O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoic acid (40 mg, 0.10 mmol), tert-butyl (2S)-2-amino-3,3-dimethylbutanoate hydrochloride (26 mg, 0.12 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (45.5 mg, 0.103 mmol), and N,N-diisopropylethylamine (60 μL, 0.34 mmol) in methylene chloride (1.5 mL) was stirred at RT overnight. The mixture was diluted with DCM, and washed with saturated NaHCO3 solution, water and brine, dried over Na2SO4, filtered, and concentrated to yield desired product which was directly used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([C:13]([F:12])([F:21])[F:22])=[CH:15][CH:16]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1cc(Cl)ccc1O
Yield: 75 %

Procedure:
Using 5-chlorosalicylic acid and 4-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[OH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CC(N(C)C)=O>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:18]3[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][OH:12])[CH2:16][CH2:17]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: Fc1ccc2nnc(Cl)n2c1
Reactant: OCCN1CCNCC1
Solvent: CC(=O)N(C)C
Product: OCCN1CCN(c2nnc3ccc(F)cn23)CC1
Yield: 23.4 %

Procedure:
A solution of Intermediate 24b (485 mg, 2.82 mmol) and 1-(2-hydroxylethyl)-piperazine (1.39 mL, 11.3 mmol) in DMA (10 mL) was heated in the microwave at 170° C. for 8 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-20% (2M NH3 in MeOH) in DCM, to give impure product. Further purified by FCC, using 0-7% (2M NH3 in MeOH) in DCM gave the title compound as a pale brown gum (175 mg, 23%). LCMS (Method 3): Rt 0.43 min, m/z 266 [MH+].
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][N:35]=[C:36]=[O:37])[CH:29]=1.CN1CCOCC1>C(Cl)Cl>[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH2:5][CH2:6][N:7]([C:36](=[O:37])[NH:35][CH2:34][C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)[CH2:8][CH2:9]1)#[N:3]
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCNCC1
Reactant: O=C=NCc1cccnc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCN(C(=O)NCc2cccnc2)CC1

Procedure:
The title compound is prepared from morpholine-4-carboxylic acid[1-(4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide hydrochloride and 3-pyridyl-methyl isocyanate in the presence of a tertiary amine base such as N-methylmorpholine in a solvent such as methylene chloride.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][C:13](=[CH:16][O:17][CH3:18])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:19](/[CH:24](CO)[CH2:25][OH:26])=[CH:20]\[CH2:21][CH2:22][CH3:23].C1(C)C=CC=CC=1>S(=O)(=O)(O)O.O>[F:1][C:2]1[CH:9]=[C:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C@H:16]3[O:26][CH2:25][C@H:24](/[CH:19]=[CH:20]/[CH2:21][CH2:22][CH3:23])[CH2:18][O:17]3)[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COC=C1CCC(c2ccc(C#N)c(F)c2)CC1
Reactant: CCC/C=C/C(CO)CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCC/C=C/[C@H]1CO[C@H]([C@H]2CC[C@H](c3ccc(C#N)c(F)c3)CC2)OC1
Reaction time: 1 h

Procedure:
A mixture of 0.98 g of 2-fluoro-4-[4-(methoxymethylidene)cyclohexyl]benzonitrile (U.S. Pat. No. 4,784,471), 0.70 g of 2-(1E-pentenyl)-1,3-propanediol, 45 ml of toluene, 2 ml of water and 10 drops of 10 percent sulphuric acid was stirred at about 85° C. for 75 minutes, then heated to boiling for 1 hour, whereby moist solvent distilled off and was replaced by fresh toluene. The reaction mixture was treated with 12 drops of triethylamine and, after cooling, washed three times with 15 ml of water, dried over sodium sulphate, filtered and concentrated. Chromatography of the residue (1.86 g) on 50 g of silica gel with hexane/ethyl acetate (vol. 9:1) and two-fold recrystallization from 8 ml of hexane each time gave 0.65 g of pure 2-fluoro-4-[trans-4-[trans-5-(1E-pentenyl)-1,3-dioxan-2-yl]cyclohexyl]benzonitrile, m.p. (C-N) 91.2° C., cl.p. (N-I) 192.5° C.