Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24]>>[C:23]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[CH:27][CH:26]=1)#[N:24]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(C#N)cc3)c(F)cn2c1=O
Yield: 103 %

Procedure:
Ethyl 8-(4-cyano-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (151 mg, 0.47 mmol) and 4-cyano-phenyl-boronic acid (82 mg, 0.56 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH, 1:0 to 9:1) afforded the title compound as a yellow solid (189 mg, 100%). ESI-MS m/z: 391 (M+H)+.
Reaction SMILES: [C:1]([C:4]1C=C[CH:9]=[CH:8][C:5]=1CO)(=O)[NH2:2].Cl[O-].[Na+].[C:15]([O:18][CH:19]([CH3:21])C)(=[O:17])C>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].[Br-].[Na+]>[O:17]=[C:15]1[NH:2][C:1]2[CH:4]=[CH:5][CH:8]=[CH:9][C:21]=2[CH2:19][O:18]1
Reactant: CC(=O)OC(C)C
Reactant: NC(=O)c1ccccc1CO
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Br-]
Agent: [Cl-]
Product: O=C1Nc2ccccc2CO1
Temperature: 50 °C
Yield: 70 %

Procedure:
143 g (0.948 moles) of 2-carbamoyl-benzyl alcohol, 2.3 g (0.0226 moles) of sodium bromide, 6.7 g of Adogen 464 and 806 ml of isopropyl acetate were stirred together in a two liter flask and cooled in a water bath. 504 ml of a 14% w/v solution of sodium hypochlorite (1.0 mole) was added to the stirred mixture over 40 minutes and at 30° C. Vigorous agitation was maintained during the addition and for a further 2 hours. The two-phase reaction mixture was then warmed to 50° C. to dissolve all solids. The organic phase was separated and the medium distilled off. The formed solid was recrystallized from 3 volumes of toluene to form 99 g of the desired product as a pale brown solid; m.p. 112° C.; yield 70%.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[O:40][C:41]1[C:42]([CH3:48])=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:44][C:43]2[CH:45]=[CH:46][CH:47]=[C:41]([O:40][C:31]3[C:30]4[C:35](=[CH:36][C:37]([O:38][CH3:39])=[C:28]([O:27][CH3:26])[CH:29]=4)[N:34]=[CH:33][N:32]=3)[C:42]=2[CH3:48])=[O:19])[N:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3C)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c3C)c2cc1OC
Yield: 63.3 %

Procedure:
The title compound was prepared from phenyl 3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate (100 mg, 0.30 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)-2-methylaniline (94 mg, 0.30 mmol) using Example 115C to give 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-methylphenyl)urea (106 mg, 0.19 mmol, 64%). 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.55 (s, 1H), 8.41 (s, 1H), 7.72 (d, 1H), 7.59-7.51 (m, 5H), 7.39 (br s, 2H), 7.24 (t, 1H), 6.96 (d, 1H), 6.39 (s, 1H), 4.02 (s, 6H), 1.96 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 553 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][NH2:12]>>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:12][CH3:11])=[O:6]
Reactant: CN
Reactant: Nc1ncccc1C(=O)O
Product: CNC(=O)c1cccnc1N

Procedure:
The intended compound was obtained according to the method of Example 1-(1) but using 2-aminonicotinic acid and methylamine.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]([CH3:22])=[C:20](S)[N:19]=[N:18]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>[N+]([O-])(O)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]([CH3:22])=[CH:20][N:19]=[N:18]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(S)nnn1C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Product: Cc1cnnn1C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C

Procedure:
The compound of step (ii) (225 g) was dissolved by adding portions of 15-20 g to concentrated nitric acid (10M, 500 ml) on an ice bath with stirring. The mixture was stirred for 1 hr and poured onto an ice-cold solution of KOH (600 g) with continuous addition of ice. Then the reaction mixture was divided into 4 portions and each portion of 500 ml was extracted with 300 ml of chloroform. The combined organic layers were dried with anhydrous sodium sulfate and then evaporated in vacuo to give the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1(/[CH:13]=[CH:14]/[C:15]2[CH:16]=[C:17]([CH:20]([OH:23])[C:21]#N)[S:18][CH:19]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.N.CO.C(Cl)Cl.C1(COC2[N:43]=[C:42](C(OC)=O)C=CC=2)CCCCC1>>[NH2:43][CH2:42][CH2:21][CH:20]([C:17]1[S:18][CH:19]=[C:15](/[CH:14]=[CH:13]/[CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:16]=1)[OH:23]
Reactant: COC(=O)c1cccc(OCC2CCCCC2)n1
Reactant: N#CC(O)c1cc(/C=C/C2CCCCC2)cs1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Product: NCCC(O)c1cc(/C=C/C2CCCCC2)cs1

Procedure:
LiAlH4 reduction of (E)-2-(4-(2-cyclohexylvinyl)thiophen-2-yl)-2-hydroxyacetonitrile following the method used in Example 3 gave after flash chromatography purification (20%-30% 7N NH3/MeOH—CH2Cl2 gradient) Example 13 as a light yellow oil. Yield (0.44 g, 36%); 1H NMR (400 MHz, DMSO-d6) δ 7.19 (s, 1H), 7.13 (s, 1H), 6.25 (d, J=16.8 Hz, 1H), 5.98 (dd, J=16.0, 6.4 Hz, 1H), 4.84 (t, J=6.0 Hz, 1H), 2.72-2.58 (m, 2H), 2.24-2.08 (m, 1H), 1.78-1.58 (m, 7H), 1.38-1.02 (m, 5H); RP-HPLC tR=10.49 min; ESI-MS m/z 219.1.2 [M+H]+.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:51]([OH:53])=[O:52])[CH3:50])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[CH2:54]([C@H:61]([NH-:67])[CH:62]([OH:66])[CH2:63][C:64]#[N:65])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:51]([OH:53])=[O:52])[CH3:50])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:54]([C@H:61]([NH-:67])[CH:62]([OH:66])[CH2:63][C:64]#[N:65])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)O)C(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N#CCC(O)[C@@H]([NH-])Cc1ccccc1
Agent: On1nnc2ccccc21
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)O)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 142 mg of Z-Phe-His-OH, 140 mg of H-Leu-Val-Ala-1(S)-benzyl-3-cyano-2(R,S)-hydroxypropyl amide, 54 mg of HOBt and 91 mg of DCCI, the title compound is obtained after flash chromatography (65 g of silica gel 60, 40-63 μm, eluant system B7). Rf (B7)=0.32.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:12])[O:20][CH2:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: OCc1cccnc1
Solvent: c1ccccc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)OCc1cccnc1
Reaction time: 2 h
Yield: 99 %

Procedure:
p-Nitrophenylisocyanate (0.1 mole) was added to a solution of 3-pyridylcarbinol (0.1 mole) in 300 ml. of benzene. An exothermic reaction took place and a yellow solid formed. The suspension was heated to reflux and then stirred for 2 hours. The suspension was then cooled and filtered, affording 27 g. of a crude product melting at 230°-231° C. (decomposed). This is a 99% yield of 3-pyridylmethyl N-(4'-nitrophenyl)-carbamate. The product was purified by recrystallization from 2-methoxyethanol (methyl Cellosolve).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)[CH3:5])[CH3:2].[OH-].[Li+].Cl>CO.O>[CH2:1]([O:3][CH:4]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)[CH3:5])[CH3:2]
Reactant: CCOC(C)c1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.5 %

Procedure:
To the solution of methyl 4-(1-ethoxyethyl)benzoate (191 mg, 0.92 mmol) in methanol and water (50 mL/10 mL) was added lithium hydroxide (100 mg, 4.2 mmol), the solution was stirred at room temperature for 12 hours. Then the solution was acidified by hydrogen chloride (1 N/mol) pH to 6, extracted with dichloromethane (80 mL*3), evaporated the solvent to give 4-(1-ethoxyethyl)benzoic acid (167 mg, 93%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH2:10][CH:9]([CH2:11][CH2:12][CH:13]=O)[O:8][N:7]=1.Cl.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:13][CH2:12][CH2:11][CH:9]2[O:8][N:7]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH2:10]2)[CH2:26][CH2:25]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=CCCC1CC(c2cccs2)=NO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCC2CC(c3cccs3)=NO2)CC1
Yield: 92.4 %

Procedure:
3-(3-(2-Thienyl)-4,5-dihydroisoxazol-5-yl)propanal (21.6 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.5 mg, 0.262 mmol) and diisopropylethylamine (26.9 L, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 31.0 mg (92.3%) of the target compound was obtained.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.Br[C:15]1[CH:16]=[N:17][C:18]2[C:19]3[N:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:27]([CH2:33][O:34][CH2:35][CH3:36])=[N:26][C:20]=3[C:21]([NH2:25])=[N:22][C:23]=2[CH:24]=1.N[C@@H]1CCCC[C@H]1N>[Cu]I.O1CCOCC1>[CH2:35]([O:34][CH2:33][C:27]1[N:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:19]2[C:18]3[N:17]=[CH:16][C:15]([N:9]4[CH:13]=[CH:12][N:11]=[CH:10]4)=[CH:24][C:23]=3[N:22]=[C:21]([NH2:25])[C:20]=2[N:26]=1)[CH3:36]
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)C
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCOCc1nc2c(N)nc3cc(-n4ccnc4)cnc3c2n1CC(C)C
Temperature: 110 °C
Reaction time: 240 h
Yield: 18.7 %

Procedure:
Copper (I) iodide (0.06 g, 0.53 mmol), potassium phosphate (1.18 g, 5.56 mmol), and imidazole (0.22 g, 3.17 mmol) were added to a glass tube. Sequential addition of 7-bromo-2-(ethoxymethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (1.0 g, 2.64 mmol), trans-1,2-diaminocyclohexane (0.06 g, 0.53 mmol) and dioxane (9 mL) followed. The tube was flushed with nitrogen, sealed, and heated to 110° C., and the reaction mixture was stirred for 10 days. The reaction mixture was then diluted with a 1:1 mixture of chloroform and methanol (50 mL) and filtered through CELITE filter aid. The filtrate was concentrated under reduced pressure to give a black liquid, which was purified by automated flash chromatography (using a silica gel cartridge, eluting with CMA:chloroform ranging in ratios from 0:100 to 20:80), and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give 0.18 g of 2-(ethoxymethyl)-7-(imidazol-1-yl)-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a tan solid, mp 175-176° C.
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[S:5][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:7][N:8]=1.[I-].[K+].Cl[CH:21]([F:23])[F:22]>O.O1CCOCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:22][CH:21]([F:23])[S:3][C:4]1[S:5][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:7][N:8]=1
Reactant: FC(F)Cl
Reactant: Sc1nnc(COc2ccc(Cl)cc2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [I-]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)Sc1nnc(COc2ccc(Cl)cc2)s1

Procedure:
2 g of potassium hydroxide are dissolved in 8 ml of water and the solution is diluted with 30 ml of dioxane. 5.2 g of 2-mercapto-5-(4-chlorophenoxymethyl)-1,3,4-thiadiazole are added, while stirring. After addition of 0.1 g of potassium iodide and 0.1 g of tetrabutylammonium bromide, chlorodifluoromethane is passed in at a bath temperature of 40° C., always with vigorous stirring, until the uptake has ended. The reaction mixture is evaporated in vacuo, the residue is taken up in methylene chloride and the mixture is washed with water and with 1 N sodium hydroxide solution in succession. After evaporation of the solvent, the title compound is obtained in crystalline form of melting point 56°-57° C. (from ether).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)=[C:16]([O:27][CH2:28][CH2:29][OH:30])[N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)(=O)C.Cl.O1CCOCC1.[C].[Pd]>[ClH:1].[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[C:12]([NH:11][S:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])=[N:13][CH:14]=[N:15][C:16]=2[O:27][CH2:28][CH2:29][OH:30])=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(-c2c(NS(=O)(=O)c3ccc(Cl)cc3)ncnc2OCCO)cc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Nc1ccc(-c2c(NS(=O)(=O)c3ccc(Cl)cc3)ncnc2OCCO)cc1
Reaction time: 16 h

Procedure:
200 mg of p-chloro-N-[6-(2-hydroxyethoxy)-5-(p-nitrophenyl)-4-pyrimidinyl]benzenesulfonamide in 15 ml of glacial acetic acid and 2 ml of 4N HCl in dioxane were hydrogenated over 50 mg of palladium-carbon (10%) at room temperature and normal pressure. After filtering the catalyst under suction, the solution was evaporated under reduced pressure. The residue was dissolved in 30 ml of methanol and the solution was treated with 1 ml of dioxane-HCl. After 16 hours, the solution was evaporated under reduced pressure and the residue was recrystallized from methanol and acetonitrile. There was obtained N-[5-(p-aminophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-p-chlorobenzenesulfonamide hydrochloride, melting point 206° C. (with decompositon).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][C:4]=1[O:10][CH2:11][CH3:12].O.[CH3:15][N:16](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([C:15]#[N:16])=[CH:5][C:4]=1[O:10][CH2:11][CH3:12]
Reactant: CN(C)C=O
Reactant: CCOc1cc(I)ccc1N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCOc1cc(C#N)ccc1N(C)C
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
N,N-dimethyl-2-ethoxy-4-iodo-aniline (0.75 g, 2.58 mmol) was dissolved in DMF (4 mL). Zinc cyanide (0.18 g, 1.54 mmol) was added. Argon was passed through the mixture for 10 min. Tetrakis(triphenylphosphine)palladium (148 mg, 0.13 mmol) was added and the mixture was heated at 110° C. for 24 h. The reaction mixture was cooled and poured into water. The mixture was extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. Evaporation of the solvents and chromatography of the residue over silica gel using 20% ethyl acetate in hexanes gave N,N-dimethyl-2-ethoxy-4-cyano-aniline (187 mg, 38%).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]#[N:12].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=[O:19]>C(Cl)(Cl)Cl.ClCCl>[C:11]([CH2:10][NH:9][C:18]([C:14]1[O:13][CH:17]=[CH:16][CH:15]=1)=[O:19])#[N:12]
Reactant: O=C(Cl)c1ccco1
Reactant: N#CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: N#CCNC(=O)c1ccco1
Yield: 49.3 %

Procedure:
A 20.2-g (0.2 mol) sample of triethylamine was added dropwise over 20 minutes to a stirred and cooled (ice bath) mixture of 9.3 g (0.1 mol) aminoacetonitrile hydrochloride in 150 ml chloroform. A solution of 13.2 g (0.1 mol) 2-furoyl chloride in 25 ml dichloromethane was then added dropwise over 20 minutes. The ice bath was removed and the reaction mixture stirred for 25 minutes. The reaction mixture was then washed with water, dried over magnesium sulfate and evaporated to give 7.4 g of crude N-cyanomethyl-2-furamide, as a beige solid, m.p. 85°-93° C. Recrystallization from benzene gave the furamide as a white solid, m.p. 101°-102° C. Elemental analysis for C7H6N2O showed: %C, calc. 56.0, found 56.0; %H, calc. 4.06, found 4.11; %N, calc. 18.7, found 19.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[CH:14]=[C:13]([NH:15][C:16]([NH2:18])=[S:17])[O:12][N:11]=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CI.[C:27](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[CH:14]=[C:13]([NH:15][C:16](=[NH:18])[S:17][CH3:27])[O:12][N:11]=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C([O-])[O-]
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1cc(NC(N)=S)on1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CSC(=N)Nc1cc(C(C)c2ccc(-c3ccccc3)c(F)c2)no1

Procedure:
3-[1-(2-Fluoro-biphenyl-4-yl)-ethyl]-isoxazol-5-yl-thiourea (Japanese Patent Unexamined Publication No. 63-152368) (3.03 g) was dissolved in N,N-dimethylformamide (90 ml), followed by adding thereto methyl iodide (1.51 g) and potassium carbonate (0.86 g), and the resulting mixture was stirred at 40° C. for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, and the extract solution was washed with water and dried. The solvent was distilled off under reduced pressure and the residue was purified by a silica gel column chromatography to obtain the desired compound (2.67 g).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][O:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([CH3:27])=[C:18]3[CH:25]([NH2:26])[CH2:24][CH2:23][CH2:22][N:19]32)=[CH:15][CH:14]=1.O>O1CCCC1>[CH3:11][O:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([CH3:27])=[C:18]3[CH:25]([NH:26][CH:1]=[O:3])[CH2:24][CH2:23][CH2:22][N:19]32)=[CH:15][CH:14]=1
Reactant: COc1ccc2c(C)c3n(c2c1)CCCC3N
Reactant: O=CO
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(C)c3n(c2c1)CCCC3NC=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 76.4 %

Procedure:
A mixture of formic acid (8.5 g,) and acetic anhydride (15.2 g) was heated to 60° C. for 4 hours, then cooled to 0° C. A solution of 6,7,8,9-tetrahydro-3-methoxy-10-methylpyrido[1,2-a]indol-9-amine (6.1 g, 26.6 mmol) in tetrahydrofuran (50 mL) was added at 0° C. The reaction mixture was stirred at 0° C. for 3 hours under exclusion of moisture. It was then poured into water (75 mL) and extracted with ether (3×100 mL). The combined organic layers were washed with 5% hydrochloric acid (50 mL), and then with saturated sodium bicarbonate (3×50 mL). The separated organic layer was dried over MgSO4, filtered, and evaporated to afford 5.25 g (77%) of the title compound as an off white solid, m.p. 181°-182.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH2:10].I[C:12]([F:24])([C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[C:13]([F:16])([F:15])[F:14].S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>O.COC(C)(C)C.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:24][C:12]([C:7]1[CH:6]=[C:5]([CH3:9])[C:4]([NH2:10])=[C:3]([O:2][CH3:1])[CH:8]=1)([C:13]([F:14])([F:15])[F:16])[C:17]([F:22])([F:23])[C:18]([F:21])([F:20])[F:19]
Reactant: FC(F)(F)C(F)(F)C(F)(I)C(F)(F)F
Reactant: COc1cccc(C)c1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: COC(C)(C)C
Product: COc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-methoxy-6-methylphenylamine (8.23 g, 60 mmol) in a mixture of water (60 ml) and tert-butyl methyl ether (60 ml) was added, successively 2-iodononafluorobutane (24.9 g, 11.86 ml, 72 mmol), sodium hydrosulfite (15.29 g, 72 mmol), sodium hydrogen carbonate (6.05 g, 72.0 mmol) and tetrabutyl ammonium hydrogen sulfate (“TBAHS”) (2.24 g, 6.60 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The mixture was filtered and the filtrate was extracted twice with tert-butyl methyl ether. The combined organic phases were washed with aqueous hydrochloric acid (1N), dried over sodium sulfate and concentrated to give 4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-2-methoxy-6-methylphenylamine which was used without further purification. LC-MS (Method 2): RT=2.05, [M+H]+=356.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:25][O:26][C:27]([CH3:32])([CH3:31])[C:28](O)=[O:29])[C:11]([CH3:24])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.FC1C(O)=C(F)C(F)=C(F)C=1F.[NH2:57][CH2:58][C:59]1[CH:67]=[CH:66][C:62]([C:63]([OH:65])=[O:64])=[CH:61][CH:60]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH2:25][O:26][C:27]([CH3:32])([CH3:31])[C:28]([NH:57][CH2:58][C:59]3[CH:60]=[CH:61][C:62]([C:63]([OH:65])=[O:64])=[CH:66][CH:67]=3)=[O:29])[C:11]([CH3:24])=[N:12][C:13]=2[C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=2)=[CH:6][CH:7]=1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)c(-c2ccc(Cl)cc2)cc1COC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)c(-c2ccc(Cl)cc2)cc1COC(C)(C)C(=O)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 280 mg of 2-[5-(4-Chloro-phenyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-2-methyl-propionic acid in 3 ml of DMF, 138 mg of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), 133 mg of pentafluorophenol and 392 mg of NEM were added and the reaction mixture was stirred for 2 h at room temperature. Then, 180 mg of 4-Aminomethyl-benzoic acid and 300 mg of NEM in 5 ml of DMF were added. After 16 h, the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 36 mg.