Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OCC1[CH:19]=[CH:18][C:17]2[C:12](=[C:13]([C:24]#[N:25])[C:14]([O:20][CH2:21][O:22][CH3:23])=[CH:15][CH:16]=2)[N:11]=1>CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:5]([O:4][CH2:1][C:2]1[CH:19]=[CH:18][C:17]2[C:12](=[C:13]([C:24]#[N:25])[C:14]([O:20][CH2:21][O:22][CH3:23])=[CH:15][CH:16]=2)[N:11]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: COCOc1ccc2ccc(CO)nc2c1C#N
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COCOc1ccc2ccc(COC(C)=O)nc2c1C#N
Reaction time: 24 h
Yield: 95.1 %

Procedure:
Referring to FIG. 20, under a nitrogen atmosphere, DMAP (0.0102 g) and acetic anhydride (0.015 mL, 0.158 mmol) were added to a solution of 10b (0.0090 g, 0.0369 mmol) in chloroform (5 mL) and pyridine (1.5 mL). The reaction was stirred for 24 h. The solvents were evaporated, and the remaining residue was purified by column chromatography (3:7 EtOAc/hexane) to provide 11b (0.0100 g, 0.0351 mmol, 95% yield) as a white solid: 1H NMR (CDCl3) δ 8.16 (1H, d, J=8.0 Hz), 7.98 (1H, d, J=9.2 Hz), 7.55 (1H, d, J=9.2 Hz), 7.44 (1H, d, J=8.4 Hz), 5.46 (2H, s), 5.45 (2H, s), 3.58 (3H, s), 2.26 (3H, s); 13C NMR (CDCl3) δ 170.7, 162.2, 159.2, 148.2, 136.9, 133.5, 122.7, 118.5, 115.7, 114.5, 95.1, 66.7, 56.9, 21.0; FTIR (neat) 2924, 2342, 2224, 1738, 1612, 1508, 1246, 1157, 1070, 937, 846 cm−1; MS (ESI) m/z calculated for (C15H14N2O4+H)+ 287, found 287; HRMS (ESI) m/z calculated for (C15H14N2O4+H)+ 287.1033, found 287.1059.
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][C:15]=3[CH:23]=[CH:24]OC)[CH:10]=2)[CH:5]=1)([CH3:3])[CH3:2]>ClCCl>[CH:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:10]3[C:9](=[C:14]4[C:15](=[CH:23][CH:24]=3)[CH:16]=[C:17]([CH:20]([CH3:22])[CH3:21])[CH:18]=[CH:19]4)[CH:8]=[CH:7][C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: COC=Cc1cc(C(C)C)ccc1-c1ccc2cc(C(C)C)ccc2c1
Solvent: ClCCl
Product: CC(C)c1ccc2c(ccc3c4ccc(C(C)C)cc4ccc23)c1
Yield: 90 %

Procedure:
Under an atmospheric argon gas flow, 2-isopropyl-6-(4-isopropyl-2-(2-methoxy vinyl)phenyl)naphthalene in an amount of 4.3 g (12 mmol), several drops of methyl acid, and desiccated dichloromethane in an amount of 50 milliliter were placed into a three necked-flask equipped with a cooling pipe and having a capacity of 300 milliliter, and the resultant solution was stirred at the room temperature for 8 hours. After the reaction terminated, adding sodium bicarbonate solution in an amount of 100 milliliter into the reacted solution, crystals were separated by filtration. The resultant crude product was washed with the use of water and methanol, and then, it was vacuum dried at the temperature of 50° C. for 8 hours, and as a result, 3.5 g of an aimed compound (white crystal) was obtained (yield: 90%).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([NH2:18])=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:37]1([CH2:43][CH2:44][CH2:45]N)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>C1COCC1>[N:37]1([CH2:43][CH2:44][CH2:45][NH:18][C:16]([C:15]2[CH:14]=[C:13]3[C:9]([CH:10]=[N:11][N:12]3[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:8][C:7]=2[O:6][C:5]2[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=2)=[O:17])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: NCCCN1CCOCC1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(N)=O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)NCCCN3CCOCC3)cc21
Reaction time: 18 h
Yield: 70 %

Procedure:
A solution of 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (compound 10g, prepared as described in Example 46) in THF was treated with carbonyldiimidazole (1.2 equivalents) at room temperature under nitrogen atmosphere. After stirring for 18 hours, the reaction was treated with 3-morpholin-4-yl-propylamine (1 equivalent). After an additional 18 hours, the solvent was allowed to slowly evaporate and the residue was purified in a Sep Pak cartridge eluting with a gradient of 100% CH2Cl2 to 5% MeOH/CH2Cl2 to provide compound 11g-8 as an oil in 70% yield.
Reaction SMILES: C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25].[CH2:27]([O:34][C:35]1[CH:36]=[C:37]([CH:50]=[C:51]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:52]=1)[C:38]([NH:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][N:42]=1)=[O:39])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[CH2:54]([O:53][C:51]1[CH:50]=[C:37]([CH:36]=[C:35]([O:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:52]=1)[C:38]([NH:40][C:41]1[CH:49]=[CH:48][C:44]([C:45]([NH:25][CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])=[O:46])=[CH:43][N:42]=1)=[O:39])[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: CN(C)CCN
Reactant: O=C(O)c1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1
Yield: 25 %

Procedure:
Diisopropylethylamine (DIPEA, 0.23 ml, 1.3 mM) then 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (EDC, 126 mg, 0.66 mM) were added to a solution of 2-dimethylaminoethylamine (0.57 ml, 0.53 mM) and 6-{[3,5-Di-(benzyloxy)benzoyl]amino}nicotinic acid (0.20 g, 0.44 mM) in dichloromethane (10 ml) under argon at ambient temperature. After 16 hours the reaction mixture was evaporated in vacuo and then chromatographed on SiO2 using a gradient elution of 10 to 25% methanol in dichloromethane. The fractions containing product were evaporated to give a cream solid (0.052 g, 25%); 1H NMR δ (d6-DMSO): 2.67 (6H, s); 3.11 (2H, m); 3.62 (2H, m); 5.18 (4H, s); 6.88 (1H, s); 7.27-7.52 (12H, br m); 8.18-8.36 (2H, m); 8.90 (1H, s); 10.20 (1H, br s).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1Cl.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CN(C)P(=O)(N(C)C)N(C)C.O>C(O)(=O)C>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:3]2[C:4]3=[C:13]4[N:8]([CH:7]([CH3:19])[CH2:6][CH2:5]3)[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11](=[O:15])[C:12]4=[CH:14][C:2]=2[F:1])[CH2:24][CH2:23]1
Reactant: CC1CCc2c(Cl)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CN1CCNCC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(=O)O
Solvent: O
Product: CC1CCc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23

Procedure:
A mixture of 1.8 g of 9-fluoro-8-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 36 ml of N-methylpiperazine and 15 ml of hexamethylphosphoric triamide was heated at 150° to 160° C. for 4 hours. After completion of the reaction the solvent was removed by distillation under reduced pressure and the residue was washed with 10 ml of ethyl acetate. The crude crystals thus-obtained were mixed with 100 ml of water and adjusted to a pH of 4 with acetic acid. Insoluble materials were removed by filtration and the filtrate was treated with activated carbon followed by concentration under reduced pressure. The residue was mixed with 20 ml of water and the solution was adjusted to a pH of 9 with a 10% aqueous sodium hydroxide solution and extracted with 80 ml chloroform. After the extract was dried over anhydrous sodium sulfate and concentrated it was purified through a silica gel column chromatography (silica gel: Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.; eluent: chloroform-methanol (9:1 by volume)) to obtain 0.8 g of 8-(4-methyl-1-piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 262° to 263° C.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[NH:11][C:12]([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[N:22]=[C:23]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]([CH3:30])=[N:25]3)=[CH:13][C:14]=1[C:15]([O:17]CC)=[O:16])=O)(C)(C)C.[Li+].[OH-].O1CCOCC1.[ClH:44]>O>[ClH:44].[NH2:8][CH2:9][C:10]1[NH:11][C:12]([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[N:22]=[C:23]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]([CH3:30])=[N:25]3)=[CH:13][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC(C)(C)C)nc23)[nH]c1CNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3cc(C(=O)O)c(CN)[nH]3)c2nc1NC(C)(C)C
Temperature: 110 °C

Procedure:
A glass microwave reaction vessel was charged with ethyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (334b) (0.27 g, 0.56 mmol), LiOH hydrated (0.12 g, 2.82 mmol), dioxane (3 mL), and water (1 mL). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 110° C. for 3 h. The reaction mixture was acidified with HCl (1 N, 5 mL) and the orange solid obtained was filtered, washed with water, ether, and dried in a vacuum oven at 50° C. for 3 h. The orange solid was suspended in dioxane (2 mL), treated with HCl (2 mL of 4 N in dioxane), and stirred at RT for 4 h. The mixture was concentrated to half of its volume and the orange solid obtained was filtered, washed with ether and dried to give 2-(aminomethyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (334c), which was used as crude material and based on theoretical yield.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[H-].[Na+].I[CH3:17]>CN(C=O)C>[Br:1][C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:17]
Reactant: CI
Reactant: CC(C)c1ccc2[nH]ncc2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc2c(cnn2C)c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
A solution of 4-bromo-5-isopropylindazole (27) (488 mg, 2.04 mmol) in 5 nml of anhydrous DMF is added to a suspension of sodium hydride (122 mg, 60% in mineral oil, 3.06 mmol, 1.5 eq.) in 5 ml of DMF under nitrogen at 0° C. The resulting mixture is stirred at 0° C. for 30 minutes, then warmed to room temperature. After stirring at room temperature for an additional 2 hours, the reaction mixture is cooled to 0° C., and iodomethane (318 mg, 2.24 mmol, 1.1 eq.) is added dropwise, the mixture is stirred at 0° C. for 2 hours, then warmed to room temperature, and stirred overnight. The reaction mixture is poured into 30 ml of ice-water, extracted with ethyl acetate (30 ml×3), washed with water and brine, and dried over anhydrous sodium sulfate. The solvent is evaporated and the product is purified via flash chromatography to give 340 mg of 4-bromo-5-isopropyl-1-methylindazole 1H NMR (400 MHz, CDCl3) 7.95 (1H, s), 7.31 (2H, S), 4.05 (3H, S), 3.55 (1H, m), 1.27 (6H, d, J=6.8 Hz). MS (+VE) m/z 253(M+). 165 mg of 4-bromo-5-isopropyl-2-methylindazole (28). 1H NMR (400 MHz, CDCl3) δ 7.82 (1H, s), 7.59 (1H, d, J=9.2 Hz), 7.21 (1H, d, J=8.8 Hz), 4.16 (3H, s), 3.50 (1H, m), 1.21 (6H, d, J=6.8 Hz). MS (+VE) m/z 253(M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([O:18][CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:20])=[CH:16][CH:15]=[N:14]1.[N+:26]([O-])([OH:28])=[O:27].C(=O)([O-])O.[Na+]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([O:18][CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:20])=[C:16]([N+:26]([O-:28])=[O:27])[CH:15]=[N:14]1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(C)Oc1ccnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(C)Oc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 0.25 h
Yield: 49 %

Procedure:
17 g (0.05 mol) of 1-(2,6-dichloro-4-trifluoromethyl-phenyl)-5-(1-ethoxycarbonyl-ethoxy)-pyrazole are dissolved in 50 ml of acetic anhydride, and 10 ml of concentrated nitric acid are added dropwise with stirring at 0°-10° C. within 15 minutes. The reaction batch is stirred for a further 1 hour at room temperature and then poured onto ice water. After neutralization of the mixture using sodium hydrogen carbonate, the organic components are extracted with methylene chloride. The methylene chloride phase is dried over sodium sulphate and concentrated in vacuo. The crude yield of oily reaction product is 17 g. After trituration with petroleum ether, 10.8 g (49% of theory) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(1-ethoxycarbonyl-ethoxy)-4-nitro-pyrazole are obtained in the form of oily crystals.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19][CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:43][C:44]2[CH:49]=[C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:47]([OH:54])=[C:46]([C:55]([CH3:58])([CH3:57])[CH3:56])[CH:45]=2)C(OC(C)(C)C)=O)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[ClH:80]>>[ClH:80].[ClH:80].[ClH:80].[ClH:80].[C:55]([C:46]1[CH:45]=[C:44]([CH2:43][NH:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][CH2:16][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=2)[CH:49]=[C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:47]=1[OH:54])([CH3:56])([CH3:57])[CH3:58]
Reactant: CC(C)(C)OC(=O)N(CCCCCCCN(CCCCN(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CCCCN(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)OC(C)(C)C
Agent: Cl
Product: CC(C)(C)c1cc(CNCCCCNCCCCCCCNCCCCNCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O

Procedure:
Dissolve 1,19-bis[(3,5-di-t-butyl-4-hydroxyphenyl)methyl]-1,6,14,19-tetra(t-butyloxycarbonyl)-1,6,14,19-tetraazanonadecane (10.8 g, 10 mmol) in saturated methanolic hydrochloric acid (100 mL). Stir for several hours and evaporate the solvent in vacuo give the title compound.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]([Cl:15])([CH2:9]CCCCC)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N=NC(Cl)(C)CCC(OCCCC)=O)(C)(C)C.NN.C(OCC)(=O)CC(C)=O.C(NN)(C)(C)C>CC(C)=O>[C:1]([N:5]=[N:6][C:7]([Cl:15])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCC(C)(Cl)N=NC(C)(C)C
Agent: CC(C)(C)NN
Agent: CCCCOC(=O)CCC(C)(Cl)N=NC(C)(C)C
Agent: NN
Solvent: CCOC(=O)CC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)N=NC(C)(C)Cl

Procedure:
Following this procedure, the following α-chloroazos were likewise prepared ("t-BH" is t-butylhydrazone and "t-CH" is t-cumylhydrazone): 2-t-butylazo-2-chlorooctane (in 45.8% crude yield from 2-octanone t-BH), n-butyl 4-t-butylazo-4-chlorovalerate (in 61% crude yield from n-butyl levulinate t-BH), 2-t-cumylazo-2-chloropropane (in 49% crude yield from acetone t-CH prepared by refluxing acetone and an aqueous solution of t-cumylhydrazine, the hydrazine being prepared according to the method of C. G. Overberger et al., J. Am. Chem. Soc. 80, 6562 (1958)), 2-t-cumylazo-2-chloro-4-methylpentane (in 50% crude yield from methyl isobutyl ketone t-CH prepared from methyl isobutyl ketone and t-cumylhydrazine), and ethyl 3-t-butylazo-3-chlorobutirate (in 33.6% crude yield from ethyl acetoacetate t-BH prepared from t-butylhydrazine and ethyl acetoacetate).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20](=[S:22])[NH2:21])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH:24]([C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:25][C:26]([OH:28])=[O:27]>C(OCC)(=O)C>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[S:22][C:24]([CH2:25][C:26]([OH:28])=[O:27])=[C:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:21]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(-c2cc3cc(CC(N)=S)ccc3o2)n1
Reactant: O=C(O)CC(Br)C(=O)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1csc(-c2cc3cc(Cc4nc(-c5ccccc5)c(CC(=O)O)s4)ccc3o2)n1
Yield: 6.6 %

Procedure:
A solution of 4-tert-butyl-2-[5-(thiocarbamoylmethyl)-benzofuran-2-yl]thiazole (740 mg) and 3-bromo-4-oxo-4-phenylbutanoic acid (600 mg) in ethyl acetate (8.0 ml) was heated under reflux for 13.5 hours. After being cooled, the resulting precipitates were collected by filtration and washed with ethyl acetate. The precipitates were dissolved in ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate and concentrated under reduced pressure to give a mixture. The mixture was subjected to column chromatography on silica gel and eluted with a mixture of chloroform, methanol and ethyl acetate (20:1:1 to 20:1:2). The fractions containing object compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-{5-[(5-carboxymethyl-4-phenylthiazol-2-yl)methyl]benzofuran-2-yl}thiazole (72 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[N:8]([CH2:15][C:16]([OH:20])([CH3:19])[CH2:17][OH:18])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[N:11]=1.Cl>N1C=CC=CC=1>[Cl:6][C:7]1[N:8]([CH2:15][C:16]([OH:20])([CH3:19])[CH2:17][O:18][S:2]([CH3:1])(=[O:4])=[O:3])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[N:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(O)(COS(C)(=O)=O)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Methanesulfonyl chloride (2.01 ml, 25.72 mmol) was added to a solution of 2-chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 3 (5.05 g, 21.43 mmol) in pyridine (10 ml) with cooling on ice-bath and the resulting mixture was stirred at room temperature for 1.5 hours. 6N hydrochloric acid was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, and then concentrated under reduced pressure to afford 2-chloro-1-(2-hydroxy-3-methanesulfonyloxy-2-methylpropyl)-4-nitroimidazole (6.72 g, quantitative) as a yellow oil.
Reaction SMILES: [SH:1][C:2]1[N:6]=[C:5]([SH:7])[S:4][N:3]=1.Br[CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13]>C(C(C)=O)C>[F:15][C:11](=[C:12]([F:14])[F:13])[CH2:10][CH2:9][S:1][C:2]1[N:6]=[C:5]([S:7][CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13])[S:4][N:3]=1
Reactant: FC(F)=C(F)CCBr
Reactant: Sc1nsc(S)n1
Solvent: CCC(C)=O
Product: FC(F)=C(F)CCSc1nsc(SCCC(F)=C(F)F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1.0 gram (0.004 mole) of the dipotassium salt of 3,5-dimercapto-1,2,4-thiadiazole in 35 ml of methyl ethyl ketone was stirred and 1.7 grams (0.009 mole) of 4-bromo-1,1,2-trifluoro-1-butene was added. The reaction mixture was heated under reflux for two hours then allowed to cool to ambient temperature where it stirred for 18 hours. The reaction mixture was concentrated under reduced pressure lo a residue. The residue was stirred in 25 ml of water and the mixture was extracted with two 25 ml portions of toluene. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 1.1 grams of 3,5-di-(3,4,4-trifluoro-3-butenylthio)-1,2,4-thiadiazole as a liquid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10]1[N:15]=[C:14]([N:16](C(OC(C)(C)C)=O)[NH:17]C(OC(C)(C)C)=O)[CH:13]=[C:12]([N+:32]([O-:34])=[O:33])[CH:11]=1.O1CCOCC1.Cl>O>[NH:16]([C:14]1[CH:13]=[C:12]([N+:32]([O-:34])=[O:33])[CH:11]=[C:10]([C:4]2[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:15]=1)[NH2:17]
Reactant: COc1ccc(C)cc1-c1cc([N+](=O)[O-])cc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C)cc1-c1cc([N+](=O)[O-])cc(NN)n1
Reaction time: 14 h

Procedure:
A mixture of the title compound from Example 19 Step B (2.0 g, 2.2 mmol), 23 mL 1,4-dioxane and concentrated HCl (2 mL) was stirred for 14 h. Concentrated HCl (8 mL) was added dropwise. After 1 h, concentrated HCl (4 mL) was added dropwise. After 4 h, the reaction mixture was diluted with water and concentrated to a solid form. The solid was further washed by ether twice to give the crude title compound which was used without further purification: LCMS m/z 275.5 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](O)[CH:8]=[C:7]([CH2:12][CH2:13][O:14][CH3:15])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:18].O>C1(C)C=CC=CC=1.CN(C=O)C>[C:1]([C:5]1[N:10]=[C:9]([Cl:18])[CH:8]=[C:7]([CH2:12][CH2:13][O:14][CH3:15])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCc1cc(O)nc(C(C)(C)C)n1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COCCc1cc(Cl)nc(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of 2-tert-butyl-6-(2-methoxy-ethyl)-pyrimidin-4-ol (20 g, 95 mmol) in toluene (200 mL) and DMF (2 mL) was added dropwise POCl3 (36.5 g, 238 mmol) in an ice bath. The mixture was stirred for 3 hrs at room temperature. The reaction mixture was poured into water, extracted with DCM (400 mL×3). The organic layer was dried over Na2SO4 and concentrated to give the title compound (20 g, 92% yield) as a yellow oil.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:16][CH3:17])[CH2:3][O:4][C:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1)=[O:6].S(Cl)([Cl:20])=O>>[CH3:1][C@@H:2]([CH2:16][CH3:17])[CH2:3][O:4][C:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:20])=[O:12])=[CH:9][CH:8]=1)=[O:6]
Reactant: CC[C@H](C)COC(=O)c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CC[C@H](C)COC(=O)c1ccc(C(=O)Cl)cc1

Procedure:
The resulting carboxylic acid was treated with thionyl chloride to obtain 4-[(S)-2-methylbutoxycarbonyl]benzoyl chloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=2)=[N:3][CH:4]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 4-isopropylaniline gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-(4-isopropylphenyl)-2,4-pyrimidinediamine. LCMS: ret. time: 23.08 min.; purity: 99%; MS (m/e): 439 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[CH:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=3)[CH2:12][C:11]=2[CH:10]=[C:9]1[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1
Reactant: COc1ccc(-c2cc3c(n2-c2ccccc2Cl)CCNC3)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(-c2cc3c(n2-c2ccccc2Cl)CCN(Cc2ccc(F)cc2)C3)cc1
Yield: 97.6 %

Procedure:
A solution of 1-(2-chlorophenyl)-2-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 2, 677.7 mg, 0.50 mmol), 4-fluorobenzaldehyde (0.13 mL, 0.60 mmol), acetic acid (0.03 mL, 0.60 mmol), and NaBH(OAc)3 (148.4 mg, 0.70 mmol) in methylene chloride (15 mL) was stirred at rt for 24 h. Sodium hydroxide (1N) was added, and the solution was extracted with diethyl ether (3×30 mL). The combined ether layers were dried (sodium sulfate), filtered, and evaporated. The residue was purified by silica gel column, eluting with 3:1 hexanes:ethyl acetate. The product was isolated as a white solid (218.1 mg, 97%). LC-MS m/z (MH+) 447, retention time 2.65 min (method 1).