Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[F:18][CH:19]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:21]2[CH2:22][CH2:23][CH2:24][CH:19]([F:18])[CH2:20]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: FC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Cl)cc1N1CCCC(F)C1
Temperature: 40 °C
Yield: 97.8 %

Procedure:
A solution of 4-chloro-2-fluoro-1-nitro-benzene (0.30 g, 1.7 mmol) in toluene (5 mL) was treated with solid Na2CO3 (0.40 g, 3.7 mmol) and 3-fluoropiperidine (0.25 mg, 1.8 mmol) and heated to 40° C. for 6 h. The reaction was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (0.43 g, 98%) as a bright yellow oil. 1H-NMR (CDCl3; 400 MHz): δ 7.76 (d, 1H, J=8.8 Hz), 7.11 (d, 1H, J=2.4 Hz), 6.95 (dd, 1H, J=8.8, 2.4 Hz), 4.86-4.67 (m, 1H), 3.46-3.35 (m, 1H), 3.15-3.06 (m, 2H), 2.99-2.92 (m, 1H), 2.10-1.90 (m, 2H), 1.88-1.69 (m, 2H). LC-MS (ESI, m/z): Calcd. for C11H12ClFN2O2 259.1 (M+H), found 259.1.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[CH2:17]([C:19]1[NH:23][C:22]([C:24](O)=[O:25])=[N:21][CH:20]=1)[CH3:18].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[CH2:17]([C:19]1[NH:23][C:22]([C:24]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:25])=[N:21][CH:20]=1)[CH3:18]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCc1cnc(C(=O)O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCc1cnc(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)[nH]1
Yield: 55 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (0.20 g, 0.87 mmol), 5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (lb) (85 mg, 0.44 mmol), WSC hydrochloride (0.55 g, 2.87 mmol) and DMAP (115 mg, 0.94 mmol), to obtain 85 mg of the title compound as a pale yellow solid (55%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C)C=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]([C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C:5]#[N:6]
Reactant: N#CCc1ccccc1Cl
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(c1ncccn1)c1ccccc1Cl
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
A mixture of 2-chlorobenzyl cyanide (4.50 g, 0.297 mol), potassium carbonate (6.84 g, 0.0495 mol) and dimethylformamide is stirred 30 minutes at 100° C. and treated dropwise with a solution of 2-chloropyrimidine (2.30 g, 0.0201 mol) in dimethylformamide. The resultant mixture is stirred overnight at 100° C. and treated with additional 2-chlorobenzyl cyanide (1.54 g, 0.0102 mol). The mixture is stirred several more hours at 100° C., cooled and diluted with water. The mixture is extracted three times with ethyl acetate. The combined organic layers are washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant brown oil is chromatographed on silica gel with ethyl acetate-hexanes to afford the title compound as a brown oil (3.25 g, 70.8%) which is identified by NMR spectral analysis.
Reaction SMILES: Cl.FC(F)(F)O[C:5]1[CH:10]=[CH:9][C:8]([NH:11]N)=[CH:7][CH:6]=1.[C:15](O)(=O)[CH3:16]>>[NH:11]1[C:8]2[C:7](=[CH:6][CH:5]=[CH:10][CH:9]=2)[CH:16]=[CH:15]1
Reactant: CC(=O)O
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C

Procedure:
Ketone 2 (1.84 gr, 8.75 mmol) and 4-trifluoromethoxy phenylhydrazine hydrochloride (2.00 gr, 4.76 mmol) were stirred at 100° C. in acetic acid (40 ml, 0.22M) for 1 hour under nitrogen atmosphere to give a 1:2 mixture of 4- and 6-trifluoromethoxy indoles (desired 6-substituted indole is slightly less polar by TLC). The reaction was cooled to room temperature, the acetic acid was removed under reduced pressure and the residue was diluted with ethyl acetate and washed with water (1×) and brine (1×). The organic layer was dried with sodium sulfate, filtered and evaporated to afford 3 as a yellow oil after column chromatography (hexanes/ethyl acetate/1% acetic acid, 6:1); 1H-NMR (CDCl3, 500 MHz) δ 8.43 (br s, 1H), 8.16 (dd, 1H), 7.46 (d, 1H), 7.23 (t, 1H), 7.14 (t, 1H), 7.03 (d, 1H), 6.74 (d, 1H), 2.54 (s, 3H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23]>>[CH2:1]([S:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[C:21]2[S:17][C:18](=[O:23])[NH:19][C:20]2=[O:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(SCc2ccccc2)cc1
Product: O=C1NC(=O)C(=Cc2ccc(SCc3ccccc3)cc2)S1

Procedure:
4-(Benzylthio)benzaldehyde (20.8 g) was fused with thiazolidine-2,4-dione according to the method of Example 5 to afford 15 g of present title product; m.p. 237°-238° C.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH:11]([CH3:13])[CH2:10][N:9](C(=O)C(F)(F)F)[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[NH:22][CH2:23][CH3:24].C([O-])([O-])=O.[K+].[K+].CO>O>[Cl:1][C:2]1[C:12]2[CH:11]([CH3:13])[CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[NH:22][CH2:23][CH3:24]
Reactant: CCNc1c(OC)nc2c(c1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCNc1c(OC)nc2c(c1Cl)C(C)CNCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of N-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (99.0 mg, 0.30 mmol) in MeCN (5 ml) was added NCS (44.0 mg, 0.33 mmol) at room temperature and the mixture was refluxed for 30 minutes. The reaction was quenched with excess of sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 40 mg (36%) of 4-chloro-N-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR (CDCl3) δ 4.39 (0.5H), 4.04 (0.5H), 3.94 (3H), 3.83 (1H), 3.78 (1H), 3.72 (1H), 3.45 (1H), 3.35 (2H), 3.25 (1H), 3.09 (1H), 1.19 (6H) ppm. A mixture of 4chloro-N-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (37.0 mg, 0.10 mmol), K2CO3 (40 mg), MeOH (1.5 ml) and H2O (0.3 ml) was stirred for 16 h at room temperature. After removal of solvent under reduced pressure, the mixture was taken into aq. NaHCO3 and extracted with DCM. The organic layer was dried and concentrated in vacuo to give 27 mg (93%) of 4-chloro-N-ethyl-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR (CDCl3) δ 3.85 (s, 3H), 3.47 (m, 1H), 3.23 (m, 2H), 3.16 (m, 2H), 3.08 (m, 1H), 2.89 (dd, 2H), 2.69 (dd, 1H), 1.22 (d, 3H), 1.09 (t, 3H) ppm.
Reaction SMILES: C[O:2][C:3](=[O:7])[CH:4](Br)[CH3:5].[CH3:8][O:9][C:10]1[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[C:51]([O:57][CH3:58])[C:11]=1/[CH:12]=[CH:13]/[CH:14]([S:24]([CH:27](/[CH:37]=[CH:38]/[C:39]1[C:44]([O:45][CH3:46])=[CH:43][C:42]([O:47][CH3:48])=[CH:41][C:40]=1[O:49][CH3:50])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([NH2:36])[CH:29]=1)(=[O:26])=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH2:23])[CH:16]=1>>[CH3:58][O:57][C:51]1[CH:52]=[C:53]([O:55][CH3:56])[CH:54]=[C:10]([O:9][CH3:8])[C:11]=1/[CH:12]=[CH:13]/[CH:14]([S:24]([CH:27](/[CH:37]=[CH:38]/[C:39]1[C:40]([O:49][CH3:50])=[CH:41][C:42]([O:47][CH3:48])=[CH:43][C:44]=1[O:45][CH3:46])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([NH:36][CH:4]([C:3]([OH:7])=[O:2])[CH3:5])[CH:29]=1)(=[O:26])=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH:23][CH:4]([C:3]([OH:2])=[O:7])[CH3:5])[CH:16]=1
Reactant: COC(=O)C(C)Br
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(N)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(C)C(=O)O)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(C)C(=O)O)c2)c(OC)c1

Procedure:
A solution of methyl-2-bromopropionate (40 mmol) and (E)-2,4,6-trimethoxy styryl-3-amino-4-methoxybenzylsulfone (10 mmol) was reacted according to General Method B. The product obtained was purified by recrystallization from acetone. (m.p. 176-180° C.)
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[C:5]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:6][C:7](C)=O.[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)([O-:16])=[O:15]>C(O)C.Cl>[N+:14]([C:17]1[CH:18]=[C:19]([CH:20]2[C:6]([C:5]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][NH:4][C:2](=[O:3])[NH:1]2)[CH:22]=[CH:23][CH:24]=1)([O-:16])=[O:15]
Reactant: NC(N)=O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=CNC(=O)NC1c1cccc([N+](=O)[O-])c1
Temperature: -20 °C

Procedure:
A mixture of urea (52 mmol), ethyl acetoacetate (78 mmol) and m-nitrobenzaldehyde (49 mmol) in absolute ethanol (30 mL) and concentrated hydrochloric acid (10 drop) was heated to reflux for 4.5 hours. Upon cooling to -20° C., a crude product crystallized. The crude product was recrystallized from isopropanol to afford the desired product as a white solid (m.p. 230.5°-233° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1.[OH:11]O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:11])[C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: Clc1cnc2c(c1)CCC2
Reactant: OO
Solvent: CC(=O)O
Product: [O-][n+]1cc(Cl)cc2c1CCC2
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A solution of 3-chloro-6,7-dihydro-5H-[1]pyrindine (3.03 g, 19.7 mmol) in acetic acid (19.7 ml) was treated at room temperature with hydrogen peroxide (3.45 ml, 39.5 mmol). The mixture was heated to 70° C. and stirred at this temperature overnight. After completion, the reaction mixture was allowed to cool and was concentrated at reduced pressure. Water was added and the mixture was evaporated again. This procedure was repeated another 2 times. The residue was dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, then dried over sodium sulphate and evaporated at reduced pressure. The crude 3-chloro-6,7-dihydro-5H-[1]pyrindine 1-oxide was obtained as dark green crystals (2.07 g, 62%). (calculated) C8H8ClNO [169.61]; (found) [M+H]+=170.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.O[CH2:13][CH:14]([CH2:16]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.OS(O)(=O)=O.O>>[F:1][C:2]1[CH:8]=[C:7]2[C:5](=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1)[N:6]=[CH:16][CH:14]=[CH:13]2
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(F)cc2cccnc12
Yield: 84.4 %

Procedure:
In a similar fashion using route 10 general procedure 20, 4-fluoro-2-nitroaniline (1.0 g, 6.41 mmol), glycerol (1.83 g, 19.9 mmol), 3-nitrobenzenesulfonic acid sodium salt (1.8 g, 8.33 mmol) and H2SO4/H2O (6 ml, 7:5) gave the title compound (1.04 g, 84%) which was used in the next step without purification.
Reaction SMILES: [N+](=C)=[N-].N(CN[C:8](N)=[O:9])=O.[OH-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=O)=[O:21])=[CH:16][CH:15]=1>CCOCC.O1CCOCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([C:22]2([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH2:8][O:9]2)=[O:21])=[CH:18][CH:19]=1
Reactant: NC(=O)NCN=O
Reactant: O=C(C(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: C=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(c1ccc(Cl)cc1)C1(c2ccc(Cl)cc2)CO1
Reaction time: 16 h

Procedure:
With cooling and stirring, an ethereal diazomethane solution prepared by reaction of 5.34 g of N-nitrosomethylurea with aqueous sodium hydroxide solution in ether is added dropwise to a solution of 5 g of 4,4'-dichlorobenzil in 50 ml of dioxane. When the dropwise addition is complete, stirring is continued for 16 hours at room temperature, and the reaction solution is then concentrated by evaporation. The residual oil is crude 2-(4-chlorobenzoyl)-2-(4-chlorophenyl)oxirane which is purified by high vacuum distillation.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:18]=[C:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:20]([CH:23]2[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]2)=[CH:21][CH:22]=1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:64][CH2:65][CH2:66][CH2:67][CH2:68][O:69][C:70]1[CH:79]=[CH:78][CH:77]=[C:76]([OH:80])[C:71]=1[C:72]([O:74][CH3:75])=[O:73].C(N(CC)C(C)C)(C)C>CN(C)C=O.C(#N)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:18]=[C:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:20]([CH:23]2[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]2)=[CH:21][CH:22]=1)[C:13]([NH:64][CH2:65][CH2:66][CH2:67][CH2:68][O:69][C:70]1[CH:79]=[CH:78][CH:77]=[C:76]([OH:80])[C:71]=1[C:72]([O:74][CH3:75])=[O:73])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)cc2-c2ccccc2)S(=O)(=O)N1
Reactant: COC(=O)c1c(O)cccc1OCCCCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(-c2ccccc2)c1)NC(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To a solution of (2S)-2-[(benzyloxy)carbonyl]amino-3-[6-(1,1-dioxido-3-oxoisothiazolidin-5-yl)biphenyl-3-yl]propanoic acid (18.0 mg, 0.0354 mmol) in N,N-dimethylformamide (1.00 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (16.4 mg, 0.0372 mmol) at 0° C. The reaction was stirred for 15 min and then methyl 2-(4-aminobutoxy)-6-hydroxybenzoate (9.32 mg, 0.0389 mmol) and N,N-diisopropylethylamine (18.5 μL, 0.106 mmol) was added. The resulting solution was stirred for 3 h and then diluted with acetonitrile and purified by preparative LCMS to afford a white solid (12.4 mg, 48%). 1H NMR (400 MHz, CD3OD): δ 8.07 (m, 1H), 7.56 (m, 1H), 7.29 (m, 13H), 6.46 (m, 2H), 5.05 (m, 3H), 4.35 (m, 1H), 3.94 (m, 2H), 3.84 (s, 3H), 3.19 (m, 5H), 2.96 (m, 1H), 1.60 (m, 4H). LCMS found for C38H40N3O10S (M+H)+: m/z=730.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([OH:16])=O)=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:17])[CH:3]=1.[CH:18]1([CH2:21][CH2:22][NH2:23])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][CH2:22][NH:23][C:14]([C:10]2[S:9][C:8]([N:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][C:4]3=[O:17])=[N:12][C:11]=2[CH3:13])=[O:16])[CH2:20][CH2:19]1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)O
Reactant: NCCC1CC1
Product: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCCC1CC1
Yield: 64 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with 2-cyclopropylethanamine, the title compound was obtained as a colorless solid in 64% yield: mp 234-236° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.58 (d, J=8.0 Hz, 1H), 8.16 (t, J=5.6 Hz, 1H), 6.25 (dd, J=8.0, 2.6 Hz, 1H), 5.81 (d, J=2.5 Hz, 1H), 3.26-3.20 (m, 2H), 2.50 (s, 3H), 1.40-1.34 (m, 2H), 0.76-0.59 (m, 1H), 0.39-0.33 (m, 2H), 0.03-0.01 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 167.8, 161.8, 161.6, 153.9, 149.4, 132.6, 124.2, 104.3, 98.0, 39.9, 34.4, 17.4, 9.0, 4.6; MS (ES+) m/z 320.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=2)[CH:5]=[CH:6][N:7]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:20]=[O:21]>>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:20]=[O:21])=[C:9]([CH2:11][CH3:12])[N:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CN(C)C=O
Reactant: CCc1cn2ccnc(Cl)c2n1
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc2c(Cl)nccn2c1C=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
8-Chloro-2-ethylimidazo[1,2-a]pyrazine (600 mg, 3.3 mmol) was dissolved in N,N-dimethylformamide (3.3 mL), phosphorus oxychloride (1.2 mL, 13.2 mmol) was added dropwise at room temperature, and the mixture was heated under stirring at 90° C. for 2 hours. After being allowed to cool, the reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated to give the title compound (472 mg) as white crystals.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:20]([N:22](CC)CC)[CH3:21].N1C=CC=CC=1.CNC.ClCC[S:39](Cl)(=[O:41])=[O:40]>O1CCCC1.C([O-])(O)=O.[Na+]>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH:21]=[CH:20][NH:22][SH:39](=[O:41])=[O:40])=[CH:3][CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Reactant: CCN(CC)CC
Agent: CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=[SH](=O)NC=Cc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Reaction time: 1 h
Yield: 12 %

Procedure:
A solution of 7-amino-4-[(3-bromophenyl)-amino]quinazoline (J Med Chem, 1995;38:3482) (500 mg, 1.59 mmol), triethylamine (Et3N) (0.60 mL) and dimethylamine pyridine (DMAP) (catalytic) in tetrahydrofuran (THF) (30 mL) was reacted with chloroethanesulfonyl chloride (1.6 mol eq., 2.54 mmol, 265 μL) at 25° C. for 1 hour, stirred under N2. The reaction mixture was diluted with saturated NaHCO3 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and chromatographed on silica gel eluting with MeOH/CH2Cl2/EtOAc (3:47:50). Crystallization from CH2Cl2/hexane, gave N-[4-[(3-bromophenyl)amino]-quinazolin-7-yl]vinylsulfonamide (80 mg, 12%) as a cream powder, mp 218° C. decomposes (dec).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[S:7][C:8]=1[CH3:9])([O-:3])=[O:2].[CH2:14]([O:21][C:22]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[CH:26][C:23]=1[CH:24]=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1CCCC1>C(O)C>[CH2:14]([O:21][C:22]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[CH:26][C:23]=1/[CH:24]=[CH:9]/[C:8]1[S:7][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Solvent: C1CCNC1
Solvent: CCO
Product: COC(=O)c1cc([N+](=O)[O-])c(/C=C/c2ccc(OCc3ccccc3)cc2OCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a solution of methyl 4-nitro-5-methylthiophene-2-carboxylate (1.50 g, 7.46 mmol) in ethanol (7.5 ml) were added 2,4-bisbenzyloxybenzaldehyde (2.49 g, 7.83 mmol) and pyrrolidine (0.65 ml, 7.83 mmol). After stirring for 1 hr with heating under reflux, the reaction mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration. The solid was washed with ethanol (3 ml×3), and dried under reduced pressure to give methyl (E)-5-[2-(2,4-bisbenzyloxyphenyl)vinyl]-4-nitrothiophene-2-carboxylate (3.08 g, yield 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH2:25]O)[S:23][CH:24]=1)=[CH:16][CH:15]=3.C(N(S(F)(F)[F:38])CC)C.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH2:25][F:38])[S:23][CH:24]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CO)n4)ccc3n(C)c21
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CF)n4)ccc3n(C)c21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
150 mg (0.319 mmol) of compound from Example 9, 3-(2,4-dichlorophenyl)-6-(2-hydroxymethylthiazol-4-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one, are dissolved in 3 ml of CH2Cl2. 51 μl of (diethylamino)sulphur trifluoride (DAST) are added at 0° C. The mixture is stirred at 0° C. for 2 hours. A further 100 μl of DAST are added (presence of starting product) and the mixture is left to stir at ambient temperature for a further 16 hours. H2O is added, the mixture is extracted with CH2Cl2, and the organic phase is dried over MgSO4, filtered and concentrated to dryness, adsorbing onto silica. Purification is carried out on a silica column, elution being carried out with EtOAc/40% cyclohexane and then with EtOAc/30% cyclohexane. The residue is taken up in MeOH and the precipitate is filtered off, and washed with MeOH and then with a minimum amount of Et2O.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC([C:49]3N(CCNC(C)C)[CH:51]=[C:52]([C:54]4C=CC(F)=C(C(F)(F)F)C=4)[N:53]=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:49][NH:53][CH:52]([CH3:54])[CH3:51])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: CC(C)NCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Product: CC(C)NCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-isopropylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=535, obsd.=535).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]1[C:14]2[N:15]([CH3:19])[C:16](=O)[NH:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:16]1[N:15]([CH3:19])[C:14]2[C:9]([N:4]3[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]3[CH2:1][CH3:2])=[CH:10][CH:11]=[CH:12][C:13]=2[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC1CCCCN1c1cccc2[nH]c(=O)n(C)c12
Product: CCC1CCCCN1c1cccc2nc(Cl)n(C)c12
Yield: 89.8 %

Procedure:
A mixture of 7-(2-ethyl-1-piperidinyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (200 mg, 0.77 mmol) and phosphorus oxychloride (3.55 g, 23.1 mol) was refluxed for 12 h with stirring and concentrated to dryness under vacuum. The residue was purified by column chromatography eluting with a 10% acetone/hexanes mixture to afford 192 mg (90%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[NH2:15][C:16]([NH2:18])=[NH:17]>>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:15]=[C:16]([NH2:18])[N:17]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: N=C(N)N
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Product: Cc1nc(C)c(-c2ccnc(N)n2)s1

Procedure:
This compound was prepared by heating equimolar amounts of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone and guanidine in refluxing 2-methoxethanol. 1H-NMR (300 MHz, CDCl3) δ2.67 (s, 3H, CH3), 2.68 (s, 3H, CH3), 5.14 (br, 2H, NH2), 6.83 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 8.30 (d, 1H, J=5.3 Hz, pyrimidinyl-H).