Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([SH:21])=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[S:28](Br)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29].C(Cl)(Cl)(Cl)Cl>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([S:21][S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(S)c(C(C)(C)C)cc21
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)Sc2cc3c(cc2C(C)(C)C)N(C(=O)OC(C)(C)C)CC3)cc1

Procedure:
The title compound was prepared according to General Method 15 using 6-tert-Butyl-5-mercapto-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (prepared in Example FF), pyridine, tosyl bromide, carbon tetrachloride, and EtOAc.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[S:11][C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=2)[CH:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:20]=1[NH2:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[S:11][C:12]([C:15]([NH:21][C:20]3[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:19]=3[Cl:18])=[O:17])=[CH:13][N:14]=2)[CH:3]=1
Reactant: Cc1cccc(Cl)c1N
Reactant: Cc1nc(Br)cc(Nc2ncc(C(=O)O)s2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(Br)cc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
2-(6-bromo-2-methylpyrimidin-4-ylamino)thiazole-5-formic acid (Compound 12) (31.5 g, 0.1 mol), DMF (630 mL) and 2-chloro-6-methylaniline (Compound 8) (17.0 g, 0.12 mol) were mixed in a reaction flask, and then HATU (45.6 g, 0.2 mol) and triethylamine (25.3 g, 0.25 mol) was added when controlling the temperature at 20° C. Then the mixture reacted by stirring at room temperature overnight. After that water (3150 mL) was added and stirred for 30 min and then filtrated. The cake was dried to give target Compound 14 (31.2 g, yield: 71.1%).
Reaction SMILES: S(=O)(O)[O-].[Na+].[C:6]([C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)([OH:8])=[O:7].[NH2:17][C:18]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:19]=1[NH2:20].[CH2:28](O)C>O.CN(C=O)C>[N+:25]([C:22]1[CH:23]=[CH:24][C:18]2[NH:17][C:13]([C:12]3[CH:15]=[CH:16][C:9]([C:6]([O:8][CH3:28])=[O:7])=[CH:10][CH:11]=3)=[N:20][C:19]=2[CH:21]=1)([O-:27])=[O:26]
Reactant: CCO
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc3cc([N+](=O)[O-])ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium bisulfite (7.0 g, 0.036 mol) in water (70 ml) is added to 4-carboxybenzaldehyde (11.0 g, 0.071 mol) in ethanol (70 ml). The mixture is stirred at room temperature for 15 minutes, the solid is filtered off, the filtrate is coevaporated with toluene and a solution of 2-amino-5-nitroaniline (11.1 g, 0.071 mol) in DMF (250 ml) is added. This mixture is refluxed for 3 hours and concentrated, and the product is recrystallized from dilute HCl, filtered off and washed with water. The solid is suspended in methanol (300 ml) and HCl gas is bubbled through at 5-15° C. for 3 hours. The mixture is allowed to warm to room temperature and is then refluxed for 3 hours. The solution is concentrated to 1/3 of its volume and cooled to +5° C., and the precipitate is filtered off and recrystallized from NaHCO3 and finally from 3/1 isopropyl ether/hexane. Yield: 15 g (71%); IR (KBr): 3570, 3472, 3112, 1707, 1301 cm−1; 1H-NMR (d6-DMSO) 7.7-8.5 (m, 7H); 5.9 (m, 1H); 3.88 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][CH:15]=2)O)=[CH:4][CH:3]=1.[ClH:30].[O:31]1CCCC1>>[ClH:30].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][CH:15]2[OH:31])=[CH:4][CH:3]=1
Reactant: OC(C1=CCN(Cc2ccccc2)CC1)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: C1CCOC1
Agent: Cl
Product: OC1CN(Cc2ccccc2)CCC1=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 10 °C
Reaction time: 7 h
Yield: 58.7 %

Procedure:
To a stirred solution of 50.9 parts of α,α-bis(4-fluorophenyl)-1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinemethanol in 270 parts of tetrahydrofuran were added 750 parts of a hydrochloric acid solution 1N. The whole was stirred first for 7 hours at reflux temperature and then for 8 hours at room temperature. The precipitated product was filtered off and set aside. The filtrate was evaporated till all traces of tetrahydrofuran were removed. After cooling, the solid precipitated product was filtered off and suspended, together with the precipitated product which was set aside (see above), in 80 parts of acetonitrile. The product was filtered off and stirred in 40 parts of acetonitrile while heating. After cooling to 10° C., the product was filtered off and dried, yielding 32.6 parts (58.7%) of 4-[bis(4-fluorophenyl)methylene]-1-(phenylmethyl)-3-piperidinol hydrochloride; mp. 266° C. (intermediate 23).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@@H:6]1OS(C(F)(F)F)(=O)=O)(=[O:3])[CH3:2].C[Si]([N:36]=[N+:37]=[N-:38])(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(Cl)(Cl)(Cl)Cl>C1COCC1>[C:1]([O:4][C@@H:5]1[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:6]1[N:36]=[N+:37]=[N-:38])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@@H](OS(=O)(=O)C(F)(F)F)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
1,3,4,6-Tetra-O-acetyl-2-O-trifluormethanesulfonyl-β-D-mannopyranose (6) (53 mg, 0.11 mmol) was dissolved at 25° C. in 3 mL of THF. Trimethylsilyl azide (19 μL, 0.15 mmol) was added via syringe followed by TBAF (150 μL, 0.15 mmol). The solution was stirred at 25° C. for 22 h. The reaction mixture was filtered through a plug of silica gel and concentrated in vacuo to give a yellow oil which was chromatographed (2:1, hexane/EtOAc) to afford 30 mg (73%) of β-anomer as a colorless oil. IR (CCl4) 2113, 1762; 1H NMR (CDCl3) 5.56 (d, J=8.8), 5.10 (t, J=9.5), 5.05 (t, J=9.5), 4.31 (dd, J=4.8, 12.5), 4.09 (dd, J=12.5), 3.79 (ddd, J=9.5, 4.8, 2.0), 3.65 (dd, J=9.5, 8.8), 2.18 (s, 3H), 2.08 (s, 3H), 2.06 (s, 3H), 2.01 (s, 3H). The spectra for the anomeric mixture has been previously reported (Vasella, A. et al., Helv. Chim. Acta 74:2073-2077 (1991)).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[NH:7][CH:8]=1)([CH3:3])[CH3:2].[I:20]I.[OH-].[Na+]>C(Cl)Cl.CO.O>[I:20][C:8]1[NH:7][C:6]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[N:5][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: COc1ccc(COCc2nc(C(C)C)c[nH]2)cc1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(COCc2nc(C(C)C)c(I)[nH]2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
In methylene chloride (60 ml)-methanol (660 ml) was dissolved 165 g (0.67 mol) of 4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (3d), followed by addition of 170 g of solid iodine. Then, an aqueous solution prepared by dissolving 27.3 g (0.67 mol) of sodium hydroxide in 85 ml of water was added dropwise under ice-cooling. After completion of dropwise addition, the reaction mixture was stirred at room temperature for 1.5 hours. This reaction mixture was extracted with methylene chloride and the organic layer was washed with an aqueous solution of sodium sulfite and dried over anhydrous magnisium sulfate. The solvent was then distilled off under reduced pressure arid the residue was rinsed with isopropyl ether and collected by filtration to provide 209.5 g (yield 81%) of 5-iodo-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (4d). mp 78-79° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=S.O.[NH2:14][NH2:15].[CH:16]([O-])([O-])OC>O1CCCC1>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][N:14]3[N:15]=[CH:16][N:6]=[C:5]3[C:4]=2[CH:3]=1
Reactant: COC([O-])[O-]
Reactant: Fc1ccc2nc[nH]c(=S)c2c1
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc2ncn3ncnc3c2c1
Temperature: 15 °C

Procedure:
3. 2.9 g of crude 6-fluoro-3H-quinazoline-4-thione are suspended in 75 ml of tetrahydrofuran. 7.9 ml of hydrazine hydrate are then added at room temperature while stirring. A solution results for a short time after about 15 min., then a precipitate separates. The mixture is stirred at room temperature for 3 h., 75 ml of methyl orthoformate are then added thereto and the tetrahydrofuran is distilled off. The residual suspension is stirred at room temperature for 3 h. The reaction solution is evaporated in a vacuum. The residue is taken up in 300 ml of water, stirred at room temperature for 1 h. and then cooled to 15° C. The crystals are filtered off and dried in a vacuum, 2.9 g of crude product are obtained. 2.4 g of 9-fluoro-1,2,4-triazolo[1,5-c]quinazoline of m.p. 193°-195° C. are obtained after recrystallization from ethanol.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Cl[C:14]1[C:15]2[C:28]([CH3:29])=[CH:27][S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:19]=[C:14]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][CH:2]=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=3)[C:15]3[C:28]([CH3:29])=[CH:27][S:26][C:16]=3[N:17]=2)[CH:21]=1
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Reactant: NCc1ccc(F)c([N+](=O)[O-])c1
Product: Cc1csc2nc(-c3cccnc3)nc(NCc3cccc([N+](=O)[O-])c3)c12

Procedure:
With the procedure of Example 1, the reaction of 4-fluoro-3-nitrobenzylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3-nitrobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[CH:10]([C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[CH2:10][C:12]1[NH:16][CH:15]=[CH:14][N:13]=1
Reactant: CCc1cccc(Cl)c1C(O)c1ncc[nH]1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cccc(Cl)c1Cc1ncc[nH]1
Temperature: 100 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
This compound was prepared using methodology described in J. Chem. Soc., Perkin Trans. 1, 2002, 1061-1066. To a stirred solution of 2.10 g (8.87 mmol) rac-(2-chloro-6-ethyl-phenyl)-(1H-imidazol-2-yl)-methanol in 10 ml 1,2-dichloroethane in a pressure tube were added dropwise 14.1 ml (88.7 mmol) triethylsilane and 8.04 ml (106 mmol) trifluoroacetic acid. The tube was sealed and the reaction mixture was stirred at 100° C. for 16 hours, before being cooled to room temperature and diluted with dichloromethane. The mixture was washed sequentially with 2 N aqueous sodium hydroxide solution and water and then the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/heptane gradient) followed by trituration in ether to afford 0.66 g (34%) of the title compound as a white crystalline solid. MS (ISP): 223.1 ([M+H]+), 221.2 ([M+H]+).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[ClH:10].Cl.[CH2:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[C:22]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH2:39][CH2:40][CH2:41]O)(=[O:38])=[O:37])=[CH:32][CH:31]=3)[N:21]=2)[CH2:16][CH2:15]1)[CH3:13].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[ClH:10].[ClH:10].[CH2:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[C:22]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH2:39][CH2:40][CH2:41][F:7])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[N:21]=2)[CH2:16][CH2:15]1)[CH3:13]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCN1CCN(c2nc(-c3ccc(S(=O)(=O)CCCO)cc3)cc3ccccc23)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCN1CCN(c2nc(-c3ccc(S(=O)(=O)CCCF)cc3)cc3ccccc23)CC1
Temperature: -78 °C

Procedure:
Diethylaminosulfur trifluoride (DAST, 0.14 ml) was added to anhydrous methylene chloride (3 ml), and the resulting mixture was stirred at −78° C. in nitrogen atmosphere, to which was then added a solution of 1-(4-ethylpiperazin-1-yl)-3-[4-(3-hydroxypropyl)sulfonylphenyl]isoquinoline (0.31 g) obtained in Example 352 in methylene chloride (5 ml), and the mixture was further stirred for 6 hr. DAST (0.09 ml) was further added thereto, and the resulting mixture was further stirred overnight. The bulk temperature was raised to room temperature. The reaction solution was diluted with chloroform, followed by the addition of a 10% aqueous solution of sodium carbonate. The organic layer was separated, and then it was washed with brine and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.23 g of the free compound of the title compound as a pale brown viscous oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3][CH2:2]1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>>[CH:34]1([C:37]([N:1]2[CH2:2][CH2:3][CH:4]([CH2:7][NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[C:28]6[O:27][CH2:26][O:25][C:24]=6[CH:23]=[CH:22][C:21]=5[O:29][CH2:30][CH:31]5[CH2:32][CH2:33]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:5][CH2:6]2)=[O:38])[CH2:36][CH2:35]1
Reactant: O=C(NCC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: O=C(Cl)C1CC1
Product: O=C(NCC1CCN(C(=O)C2CC2)CC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-4-ylmethyl)-amide (example A144) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:7][NH:8][CH2:9][C:10]#[CH:11].[C:12]([OH:17])(=[O:16])[C:13]([OH:15])=[O:14]>C(O)C.CCOCC>[C:12]([OH:17])(=[O:16])[C:13]([OH:15])=[O:14].[CH2:2]([N:8]([CH2:9][C:10]#[CH:11])[CH3:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C#CCNC
Reactant: CCCCCBr
Agent: O=C(O)C(=O)O
Solvent: CCOCC
Solvent: CCO
Product: C#CCN(C)CCCCC
Yield: 60 %

Procedure:
1-Bromopentane (12.1 g, 80 mmoles) and N-methylpropargylamine (11.1 g, 160mmoles) were refluxed in absolute ethanol (75 mL) for 72 h. to give (after addition to 80 mmoles of oxalic acid in ether) the title compound in 60% yield after recrystallization from methanol-ether, m.p.=101°-103° C.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[F:20][C:21]1[C:34]([NH:35][C:36]([CH:38]2[NH:43][CH2:42][CH:41]3[CH:39]2[CH2:40]3)=[O:37])=[CH:33][C:24]2[N:25]([CH2:30][C:31]#[CH:32])[C:26](=[O:29])[CH2:27][O:28][C:23]=2[CH:22]=1.O>C(Cl)Cl>[F:20][C:21]1[C:34]([N:35]2[C:36](=[O:37])[CH:38]3[CH:39]4[CH2:40][CH:41]4[CH2:42][N:43]3[C:2]2=[O:4])=[CH:33][C:24]2[N:25]([CH2:30][C:31]#[CH:32])[C:26](=[O:29])[CH2:27][O:28][C:23]=2[CH:22]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C#CCN1C(=O)COc2cc(F)c(NC(=O)C3NCC4CC43)cc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCN1C(=O)COc2cc(F)c(N3C(=O)C4C5CC5CN4C3=O)cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of triphosgene (57 mg) in CH2Cl2 (1 mL) was added dropwise to a stirred solution of triethylamine (0.2 mL) and the compound of Step G, Example 3, (190 mg) in CH2Cl2 (50 mL) under N2 at room temperature. The solution was stirred at room temperature for 20 minutes. 30 mL of water was added. The organic layer was separated, dried (MgSO4) and evaporated to dryness. Flash chromatography yielded the title compound of Step H, a compound of the invention, as a white solid (127 mg), 62%; m.p. 217°-219° C.; IR (nujol, cm-1): 3253.6 and 2129.3 (C≡C), 1625 and 1715 (C=O).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([O:10][CH3:11])=[CH:8][C:6]([NH2:7])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[CH3:15][C:16](=O)[CH:17]=[CH:18][CH3:19]>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:11][O:10][C:9]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]2[C:8]=1[C:16]([CH3:15])=[CH:17][C:18]([CH3:19])=[N:7]2
Reactant: COc1cc(N)c([N+](=O)[O-])cc1OC
Reactant: CC=CC(C)=O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])c2nc(C)cc(C)c2c1OC
Yield: 14 %

Procedure:
4,5-Dimethoxy-2-nitroaniline and 3-penten-2-one were subjected to a Skraup reaction. A black, tarry substance was obtained, from which an orange solid could be isolated by chromatography over silica gel using benzene-ethyl acetate (19:1) to elute the product. That material was thrice crystallized from 2-propanol, re-chromatographed, and again crystallized to afford 14% yield of golden 5,6-dimethoxy-2,4-dimethyl-8-nitroquinoline. Although it melted 85°-108°, it showed a single spot on two tlc systems.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:34]C(=O)C)[C:10]2[N:11]=[CH:12][N:13](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:14]=2)=[CH:5][C:4]=1[F:38])#[N:2].[OH-].[Na+].[CH2:41]1COCC1>O>[F:38][C:4]1[CH:5]=[C:6]([CH:9]([OH:34])[C:10]2[N:11]([CH3:41])[CH:12]=[N:13][CH:14]=2)[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: C1CCOC1
Reactant: CC(=O)OC(c1ccc(C#N)c(F)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1cncc1C(O)c1ccc(C#N)c(F)c1
Reaction time: 1 h

Procedure:
Acetic acid (4-cyano-3-fluoro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methyl ester (as described in Step C above) (1.26 g, 4.59 mmol) and NaOH (5.5 mL, 5.5 mmol) were dissolved in THF (15 mL) and H2O (25 mL). After 1 h, the reaction was diluted with satd. NaHCO3 solution, extracted with CH2Cl2 (3×), dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[N:38][C:37]=1OS(C(F)(F)F)(=O)=O.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].O>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:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([C:37]4[N:38]=[CH:39][C:40]5[C:45]([C:36]=4[CH3:35])=[CH:44][CH:43]=[CH:42][CH:41]=5)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)ncc2ccccc12
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: O
Solvent: C1COCCO1
Product: Cc1c(-c2cc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)cnc2N)ncc2ccccc12
Temperature: 100 °C

Procedure:
To a solution of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB3) (86.3 mg, 0.184 mmol), trifluoromethanesulfonic acid 4-methylisoquinolin-3-yl ester (54.8 mg, 0.188 mmol), and Pd(PPh3)4 (14 mg, 0.012 mmol) in 1,4-dioxane (2.8 mL, 36 mmol) in a sealable microwave tube was added a solution of Cs2CO3 (118 mg, 0.361 mmol) in H2O (0.80 mL, 44 mmol). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 100° C. for 30 min. The reaction mixture was diluted with DCM, washed with water and brine, and dried over MgSO4. The crude material was chromatographed on silica gel [20 g/70 mL prepacked cartridge, eluting with DCM→1% MeOH in DCM→2% MeOH in DCM→2.5% MeOH in DCM→3% MeOH in DCM→3.5% MeOH in DCM→4% MeOH in DCM]. Fractions containing the title compound were combined and dried in vacuo, giving the title compound as a glassy solid. 1H NMR (400 MHz, CDCl3): δ=9.22 (s, 1H), 8.30 (d, J=2.4 Hz, 1H), 8.08 (dd, J=0.8, 8.6 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.81 (ddd, J=1.2, 6.8, 8.3 Hz, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.68 (ddd, J=0.8, 7.0, 8.0 Hz, 1H), 7.62 (s, 1H), 7.57 (d, J=2.4 Hz, 1H), 4.85 (brs, 2H), 4.42-4.13 (m, 3H), 2.90 (brt, J=11.2 Hz, 2H), 2.62 (s, 3H), 2.15 (brdd, J=2.0, 12.4 Hz, 2H), 1.95 (dq, J=4.0, 12.0 Hz, 2H), 1.48 (s, 9H). MS(ES+): m/z=485.14 (100) [MH+], 429.12 (66) [MH+-isobutene]. HPLC: tR=2.62 min (polar—5 min, ZQ3).
Reaction SMILES: Cl[CH:2]([C:7]1[CH:8]=[N:9][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:11][CH:12]=1)[C:3]([CH3:6])([CH3:5])[CH3:4].[C-:17]#[N:18].[Na+].C(=O)(O)[O-].[Na+].ClCCl>CS(C)=O.C(OCC)(=O)C>[CH3:4][C:3]([CH3:6])([CH3:5])[CH:2]([C:7]1[CH:8]=[N:9][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:11][CH:12]=1)[C:17]#[N:18]
Reactant: CC(C)(C)c1ncc(C(Cl)C(C)(C)C)cn1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)c1ncc(C(C#N)C(C)(C)C)cn1
Temperature: 25 °C
Yield: 155.7 %

Procedure:
A solution of 1-chloro-2,2-dimethyl-1-[2-(1,1-dimethylethyl)pyrimidin-5-yl]propane (5.08 g) and sodium cyanide (2.07 g) in dry dimethylsulphoxide (50 cm3) was heated to 60° C., under an atmosphere of dry nitrogen for a period of 17 hours. After cooling to the ambient temperature, the solution was poured into aqueous sodium bicarbonate solution and extracted with diethyl ether, washed with brine, dried over anhydrous magnesium sulphate, and concentrated by evaporation of the solvent under reduced pressure. The resulting brown oil was combined with the crude product from a similar reaction and subjected to column chromatography on silica gel using dichloromethane followed by dichloromethane containing 5% by volume ethyl acetate to give 3,3-dimethyl-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]butyronitrile (7.6 g), identical in all respects to the material obtained in Example 15 (ii) above.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].CCN=C=NCCCN(C)C.Cl>>[O:26]=[C:25]([NH:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7](=[O:8])[NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C@@H:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:28]
Reactant: Nn1ccnc1C(=O)Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1ccnc1C(=O)Nc1ccccc1
Yield: 73 %

Procedure:
The title compound was prepared following the experimental procedure described in preparation 20a, from 1.12 g (5.54 mmol) of 1-amino-N-phenyl-1H-imidazole-2-carboxamide, 1.26 g (6.65 mmol) of (S)-2-(tert-butoxycarbonylamino)propanoic acid and 1.03 g (6.65 mmol) of EDC.HCl. The solid obtained was triturated in diisopropylether to give 1.51 g (67% yield) of the title compound.