Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:17][CH:18]([CH3:23])[CH:19]([OH:22])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:24](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1C=CC=CC=1.Cl>O>[CH2:1]([O:17][CH:18]([CH3:23])[CH:19]([OH:22])[CH2:20][O:21][C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCOC(C)C(O)CO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOC(C)C(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 48 h
Yield: 97.8 %

Procedure:
A mixture of 27.5 g of 3-(hexadecyloxy)-1,2-butanediol, 34.79 g of trityl chloride and 125 ml of pyridine was allowed to stand 48 hours and then poured into water. A mixture of ether-petroleum ether was added, followed by dilute hydrochloric acid. The organic layer was separated, washed with dilute hydrochloric acid, then brine, dried and the solvent removed. The residue was mixed with petroleum ether and allowed to stand several days. After filtration, the filtrate was evaporated, giving 46.6 g of the desired compound as an oil, which was used in Example 9 without further purification.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]2C(=C(CBr)[C:7]([Cl:17])=[CH:8][CH:9]=2)[N:4]=1.S(=O)(=O)(O)O.[N+]([O-])(O)=O.[C:31]([OH:35])(=[O:34])[CH2:32][CH3:33]>O>[F:1][C:2]([F:20])([F:21])[C:3]1[C:12]([C:13]([F:15])([F:16])[F:14])=[CH:11][C:10]2[C:33](=[C:32]([C:31]([OH:35])=[O:34])[C:7]([Cl:17])=[CH:8][CH:9]=2)[N:4]=1
Reactant: FC(F)(F)c1cc2ccc(Cl)c(CBr)c2nc1C(F)(F)F
Reactant: CCC(=O)O
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Solvent: O
Product: O=C(O)c1c(Cl)ccc2cc(C(F)(F)F)c(C(F)(F)F)nc12
Reaction time: 2 h
Yield: 80.9 %

Procedure:
2.4 g of 2,3-bis-(trifluoromethyl)-8-bromomethyl-7-chloroquinoline are suspended in 6.8 g of propionic acid and 6.8 g of 70% strength sulfuric acid, and 5.5 g of 65% strength nitric acid are added dropwise at 120° C. After 2 hours at 120° C., the mixture is diluted with water and the precipitate is filtered off under suction, washed and dried; 1.7 g (84%) of 2,3-bis-(trifluoromethyl)-7-chloroquinoline-8-carboxylic acid of melting point 108°-111° C. are isolated.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[Na+].[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([O-:29])(=[O:28])=[O:27])=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:18][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26]([OH:29])(=[O:28])=[O:27])=[C:6]1[CH3:15]
Reactant: O=Cc1ccccc1S(=O)(=O)[O-]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Agent: CC[SiH](CC)CC
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.6 %

Procedure:
A mixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (1.0 g), 2-formylbenzensulfonic acid sodium salt (0.94 g) and 1,2-dichloroethane (15 mL) at 0° C. was treated dropwise with a mixture of triethylsilane (4.3 mL), trifluoroacetic acid (1.0 mL) and 1,2-dichloroethane (10 mL), and the resulting mixture was stirred at room temperature for 6 hours. The mixture was extracted with ethyl acetate and the combined organic extract was dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of methanol and dichloromethane (0:1 to 1:9 by volume) to afford the title compound as a purple gum (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7](=[O:18])[C:8]3([CH2:17][CH2:16]3)[CH2:9][N:10]([CH:13]([CH3:15])[CH3:14])[C:11]=2[N:12]=1.[CH3:19]I.[H-].[Na+]>CC(N(C)C)=O.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:19])[C:7](=[O:18])[C:8]3([CH2:16][CH2:17]3)[CH2:9][N:10]([CH:13]([CH3:15])[CH3:14])[C:11]=2[N:12]=1
Reactant: CC(C)N1CC2(CC2)C(=O)Nc2cnc(Cl)nc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CC(C)N1CC2(CC2)C(=O)N(C)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a solution of 2′-chloro-9′-isopropyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 209; 5.055 g, 19 mmol) in DMA (300 mL) was added methyl iodide (1.305 mL, 20.9 mmol), followed by sodium hydride (60% mineral oil dispersion; 814 mg, 20.33 mmol). The mixture was stirred at room temperature for 30 minutes. The DMA was removed in vacuo, then water (50 mL) was added. The product precipitated as a sticky gum, which turned into a solid on sonication. The solid was collected by filtration to give a brown powder. This material was dissolved in DCM and dried over sodium sulfate, then purified by column chromatography, eluting with 25% ethyl acetate in hexane, to yield the title compound as a white solid (3.73 g, 70%)
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]2[O:48][CH2:47]2)[CH:41]=1)[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:49]([NH2:53])([CH3:52])([CH3:51])[CH3:50]>>[CH2:1]([O:17][CH2:18][CH:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]([OH:48])[CH2:47][NH:53][C:49]([CH3:52])([CH3:51])[CH3:50])[CH:41]=1)[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOCC(COCc1cccc(C2CO2)c1)OCCCCCCCCCCCCCCCC
Reactant: CC(C)(C)N
Product: CCCCCCCCCCCCCCCCOCC(COCc1cccc(C(O)CNC(C)(C)C)c1)OCCCCCCCCCCCCCCCC
Temperature: 100 °C
Yield: 27 %

Procedure:
t-Butylamine (30 ml) and 1,2-di-O-(n-hexadecyl)-3-O-[3-(1,2-epoxyethyl)-benzyl]-glycerol (2.0 g, 2.97 mmol) were placed in a steel bomb and heated to 100° C. for 9 hours. After cooling the reaction mixture, t-butylamine was removed under reduced pressure and the resulting oil purified by silica gel chromatography, eluted with benzene/ethanol. The desired fractions were saturated with gaseous hydrochloric acid, concentrated under reduced pressure, and recrystallized from ethyl acetate to give pure 1,2-di-O-(n-hexadecyl)-3-O-[3-(1-hydroxy-2-t-butylaminoethyl)-benzyl]-glycerol (630 mg, 27%): mp 49°-51° C.; NMR (CDCl3) δ 1.47 [s, 9, --C(CH3)3 ].
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](ON2C(=O)CCC2=O)=[O:31])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:41][C@H:42]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:43][CH2:44][C:45](=[O:47])[OH:46].CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:40])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:31])[NH:41][C@H:42]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:43][CH2:44][C:45]([OH:46])=[O:47])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH:8]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)ON2C(=O)CCC2=O)cc(C(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C)cc(C(=O)OC(C)(C)C)c1
Reaction time: 4 h

Procedure:
To a solution of 5-[9-(2,5-Dioxo-pyrrolidin-1-yloxycarbonyl)-nonyloxy]-isophthalic acid di-tert-butyl ester (62 mg, 0.11 mmol) in dry DMF (1 ml), H-Glu-OtBu (0.027 g, 0.13 mmol) and DIPEA (0.05 ml) was added. The mixture was stirred over night under nitrogen for 4 h. The mixture was concentrated. The residue was redissolved in EtOAc and washed with 0.1 N HCl (2×), brine (1×), dried (Na2SO4) and concentrated to give a syrup.
Reaction SMILES: C[O:2][C:3]([C:5]12[CH:12]3[CH:7]4[C:8]5([C:13](=O)[NH:14][C:15]6[C:16](=[O:29])[N:17]([CH2:26][CH2:27][CH3:28])[C:18](=[O:25])[N:19]([CH2:22][CH2:23][CH3:24])[C:20]=6[NH2:21])[CH:11]3[CH:10]1[CH:9]5[CH:6]24)=[O:4].[OH-].[Na+]>CO>[O:25]=[C:18]1[N:19]([CH2:22][CH2:23][CH3:24])[C:20]2[N:21]=[C:13]([C:8]34[CH:11]5[CH:10]6[CH:9]3[CH:6]3[CH:7]4[CH:12]5[C:5]36[C:3]([OH:2])=[O:4])[NH:14][C:15]=2[C:16](=[O:29])[N:17]1[CH2:26][CH2:27][CH3:28]
Reactant: CCCn1c(N)c(NC(=O)C23C4C5C2C2C3C4C52C(=O)OC)c(=O)n(CCC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C34C5C6C3C3C4C5C63C(=O)O)nc2n(CCC)c1=O
Yield: 75.8 %

Procedure:
To a solution of 4-(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl)-cubane-1-carboxylic acid methyl ester (400 mg, 0.966 mmol) in MeOH (20 ml) was added 4 ml of a 20% aq. NaOH solution and the resulting turbid mixture was heated at reflux overnight (12 h). The cool reaction mixture was concentrated in vacuo, diluted with several small ice chips and acidified by the dropwise addition of concentrated HCl. The resulting white precipitate was collected, dried, and washed with ether to give a white solid (280 mg, 76%). 1H NMR (400 MHz, DMSO-d6) δ 1.05 (coincident t, 6H), 1.70 (m, 2H), 1.83 (m, 2H), 3.99 (m, 2H), 4.08 (m, 2H), 4;27 (m, 3H), 4.38 (m, 3H). MS. 383 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][CH2:30]Br)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C(N(CC)CC)C>CN(C=O)C.[I-].[Na+]>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][CH2:30][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Nc1ncnn2c(CCCCBr)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnn2c(CCCCN3CCCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 55 °C
Yield: 83.1 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(4-bromobutyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (440 mg, 0.93 mmol) in DMF (5.0 mL) was added pyrrolidine (155 μL, 1.86 mmol), triethylamine (387 μl, 2.78 mmol), and sodium iodide (1.4 mg, 0.009 mmol). The reaction was heated (55° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and water (25 mL). The layers were separated and the organic was washed with water (2×20 mL), brine, dried (Na2SO4) and evaporated to afford 360 mg (84%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.87 (s, 1 H), 7.78 (d, 1 H), 7.56 (s, 1 H), 7.36-7.26 (m, 5 H), 7.13 (dd, 1 H), 6.57 (s, 1 H), 5.64 (s, 2 H), 2.88 (t, 2 H), 2.42-2.33 (m, 6 H), 1.78-1.66 (m, 2 H), 1.67-1.60 (m, 4 H), 1.57-1.46 (m, 2H); ES-MS m/z 466.3 [M+H]+, HPLC RT (min) 2.20.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[S:5](Cl)([C:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:13]([N:14]([CH3:16])[CH3:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].[OH-].[Na+]>C(Cl)(Cl)Cl>[S:5]([NH:3][CH2:2][CH2:1][NH2:4])([C:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:13]([N:14]([CH3:16])[CH3:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: NCCN
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CN(C)c1cccc2c(S(=O)(=O)NCCN)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
To a solution of ethylenediamine (635 mg, 10.6 mmol) in chloroform (10 ml), a solution of dansyl chloride (285 mg, 1.06 mmol) in chloroform (12 ml) was dropwise added, and the reaction mixture was stirred at room temperature overnight, followed by addition of a bit of 1 N sodium hydroxide thereto for hydrolysis of unreacted dansyl chloride. The reaction mixture was concentrated, and the residue was combined with acetone. Insoluble materials were removed by filtration, and the filtrate was concentrated. Water (50 ml) was added to the residue, and extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in a small amount of ethyl acetate, a bit of n-hexane was added thereto, and the resultant mixture was allowed to stand at room temperature overnight. The precipitate was collected and recrystallized from ethyl acetate to give Compound (1) (124 mg). Yield, 63 %.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[N:17][N:16]([CH3:19])[C:15]=3[CH:20]=2)=[C:6]([CH:9]=1)[CH2:7]O.N1C=CC=CC=1.S(Cl)([Cl:29])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[N:17][N:16]([CH3:19])[C:15]=3[CH:20]=2)=[C:6]([CH2:7][Cl:29])[CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1nnc2ccc(Cc3ccc(Cl)cc3CO)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1nnc2ccc(Cc3ccc(Cl)cc3CCl)cc21
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To the solution of 5-chloro-2-[(1-methyl-1H-benzotriazole-6-yl)methyl]benzyl alcohol (0.16 g) from Example 77 and pyridine (0.05 ml) in methylene chloride (2 ml) was added thionyl chloride (0.04 ml) at 0° C., the mixture was stirred for 30 minutes. After removal of the solvent, the resulting residue was purified by chromatography on a silica gel column (methylene chloride:methanol=199:1), to give the title compound (0.12 g; 70%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[CH:7]=1)=[O:5])[CH3:2].[I:13]I.O.S(=O)(O)[O-].[Na+]>CC([O-])=O.ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:7]=1[I:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)nn1C
Reactant: II
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)c1c(I)c(C)nn1C

Procedure:
1,3-Dimethyl-5-pyrazolcarboxylic acid ethyl ester (185 g, 1.1 mol), iodine (140 g, 0.55 mol) and HIO3 (38.7 g, 0.22 mol) are heated, under reflux, in acetic acid glacial (450 ml), water (150 ml) and 1,2-dichloroethane (150 ml) for 1.5 hours. The mixture is discoloured with saturated sodium bisulfite, evaporated under reduced pressure and the product extracted with ether. The organic phase is washed with sodium bisulfite and aqueous sodium bicarbonate solution.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[C:12](Cl)(=[O:15])[CH:13]=[CH2:14]>O.C(Cl)Cl>[C:12]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:15])[CH:13]=[CH2:14]
Reactant: C=CC(=O)Cl
Reactant: NCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)NCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 10 h
Yield: 82.4 %

Procedure:
Sodium hydroxide (7.6 g, 190 mmol) and 6-aminohexanoic acid (10 g, 76 mmol) were dissolved in distilled water (50 mL) at room temperature. Acryloyl chloride (8.24 g, 91 mmol) in dry CH2Cl2 (50 mL) was slowly added to the mixture at room temperature. The resulting mixture was stirred at room temperature for 10 h. The reaction was quenched by adding 10% HCl (20 mL, pH 3) at room temperature and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over MgSO4 and concentrated to give a product as a white solid (11.6 g, 82%). This compound was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].C[O-].[Na+].[C:16](O)(=[O:18])C>CO>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[C:3]([C:1](=[NH:2])[O:18][CH3:16])[CH:4]=1
Reactant: N#Cc1cnc2ccccc2c1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1cnc2ccccc2c1
Reaction time: 22 h

Procedure:
3-cyanoquinoline (1.58 g, 10.2 mmol) was dissolved in methanol (20 ml), and sodium methoxide (0.06 g, 1.1 mmol) was added. The reaction was conducted at room temperature for 22 hours. After the reaction was completed, acetic acid (0.07 g, 1.1 mmol) was added to neutralize the reaction solution, and the solution was concentrated under reduced pressure. Diethyl ether (60 ml) was added to the concentrated residue, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure to give the crude product of methyl 3-quinolinecarboximidate.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([CH:19]=O)[C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].O.[N+:27]([CH3:30])([O-:29])=[O:28]>>[N+:27](/[CH:30]=[CH:19]/[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[CH:11][N:10]2[S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])([O-:29])=[O:28]
Reactant: O=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: O=[N+]([O-])/C=C/c1cccc2c1ccn2S(=O)(=O)c1ccccc1

Procedure:
1-(Phenylsulfonyl)-1H-indole-4-carbaldehyde, Intermediate 5 (45.4 g, 0.159 mol) was dissolved in nitromethane (300 ml) and ammonium acetate (4.9 g, 0.064 mol, 0.4 eq.) was added. Mixture was heated at reflux for 4 hours and left overnight at ROOM TEMPERATURE Water (150 ml) was added, organic phase was separated. The aqueous phase was extracted with DCM (3×50 ml). Combined organic phase was washed with brine and dried on Na2SO4. The crude material (HPLC purity 85%) was passed through a silica column using DCM/EtOAc (8:1) as eluent. The product containing fractions were evaporated to a small volume when crystallization started. The yellow crystals were filtered, washed with petro/ether/EtOAc (2:1), and dried in vacuo. Yield: 33.1 g. MS m/z 329 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[N:3]=1.[CH2:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:14]>C(O)C>[Cl:11][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([N:15]([CH2:13][CH3:14])[CH2:16][CH2:17][CH2:18][CH3:19])[N:3]=[C:4]([CH3:12])[N:5]=1
Reactant: CCCCNCC
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CCO
Product: CCCCN(CC)c1nc(C)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92 %

Procedure:
Part A. A solution of 4,6-dichloro-2-methyl-5-nitropyrimidine (prepared rising the methods of Albert, et al., J. Chem. Soc. 1954, p. 3832) (2.77 g, 13.3 mmol) in absolute ethanol (25 mL) was cooled to 0° C., and treated with triethylatine (2.00 mL, 14.3 mmol). Then, a solution of ethylbutylamine (1.80 mL, 13.2 mmol) in ethanol (3 mL) was added dropwise with stirring. The mixture was allowed to stir and warm to ambient temperature overnight, then was partitioned between water and ethyl acetate (100 mL each). The organic phase was separated, washed with satd. aq. brine (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was separated by column chromatography (silica gel, dichloromethane) to afford 4-chloro-6-(ethylbutylamino)-2-methyl-5-nitropyrimidine as an oil (3.34 g, 12.2 mmol, 92%). Spectral data: TLC RF 0.59 (dichloromethane). 1H NMR (300 MHz, CDCl3): δ3.45 (2H, q, J=7.0 Hz), 3.38 (2H, t, J=7.7 Hz), 2.50 (3H, s), 1.62-1.52 (2H, m), 1.38-1.26 (2H, m), 1.20 (3H, t, J=7.0 Hz), 0.94 (3H, t, J=7.3 Hz). MS (NH3 --CI): m/e 276 (4), 275 (40), 274 (16), 273 (100).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C(#N)C>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=2)[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cncc(Cl)n1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1

Procedure:
A mixture of 10 mmol 2,6-dichloropyrazine and 21 mmol of N-BOC-piperazine in 15 ml acetonitrile was heated under reflux for 1.5 hours. The reaction mixture was concentrated and purified by chromatography (SiO2; dichloromethane/methanol 95:5) to yield the title compound as a colorless solid. MS (m/e): 299.2 (MH+, 100%)
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.I[CH:30]([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:31][CH:30]([N:3]1[C:2](=[O:1])[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]12)[CH3:32]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C(C)C)c2ncnn12
Temperature: 100 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.8 g), 2-iodopropane (0.43 mL), potassium carbonate (0.6 g) and N,N-dimethylacetamide (10 mL) was stirred at 100° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.48 g, 53%).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:13][NH:14]C(=O)OC(C)(C)C)#[N:2].[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:14][CH2:13][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[C:3]=1[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(F)(F)F)c1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1c(CN)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl {[2-cyano-3-(trifluoromethyl)phenyl]methyl}carbamate (0.190 g, 0.63 mmol) was dissolved in dichloromethane (4 ml) and treated with trifluoroacetic acid (4 ml). The mixture was stirred at room temperature for 1 hr and then evaporated. The residue was twice taken up in dichloromethane and evaporated again to give crude 2-(aminomethyl)-6-(trifluoromethyl)benzonitrile trifluoroacetate which was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:17](=[O:23])[N:18]([CH2:21]C)CC)=[C:9]([CH:16]=1)CNC(=O)OC)([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Li+].Cl>CO>[C:1]([C:5]1[CH:16]=[C:9]2[C:8](=[CH:7][CH:6]=1)[C:17](=[O:23])[NH:18][CH2:21]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC)C(=O)c1ccc(C(C)(C)C)cc1CNC(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(c1)CNC2=O
Temperature: 110 °C
Yield: 56.2 %

Procedure:
A 25-mL microwave vial equipped with a magnetic stirrer was charged with 102b (858 mg, 2.68 mmol), tetrahydrofuran (5 mL), methanol (5 mL) and 2 M aqueous lithium hydroxide (5 mL). The vial was loaded in a Biotage microwave and heated at 110° C. for 2.5 h. After this time, the solution was neutralized with 2 M hydrochloric acid to pH 7 and concentrated in vacuo. The resulting residue was partitioned between ethyl acetate (150 mL) and water (30 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 50% ethyl acetate to 100% ethyl acetate/hexanes) to afford a 56% yield (285 mg) of 102c as an off-white solid: mp=132-134° C.; 1H NMR (300 MHz, CDCl3) δ 7.80 (d, 1H, J=7.8 Hz), 7.52 (m, 2H), 6.71 (br s, 1H), 4.44 (s, 2H), 1.37 (s, 9H), MS (ESI+) m/z 190.1 (M+H).