Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]1[CH:22]=[C:21]([CH:23]=[CH:24][C:25]#[N:26])[CH:20]=[C:19]([CH3:27])[C:10]1(C(O)=O)CNC1C=CC=CC=1.[NH3:31]>O>[CH3:8][C:9]1[CH:22]=[C:21]([CH:23]=[CH:24][C:25]#[N:26])[CH:20]=[C:19]([CH3:27])[C:10]=1[NH2:31]
Reactant: CC1=CC(C=CC#N)=CC(C)C1(CNc1ccccc1)C(=O)O
Reactant: N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(C=CC#N)cc(C)c1N
Temperature: 52.5 °C

Procedure:
Trifluoroacetic acid (600 ml) was slowly added to the residue of 2,6-dimethyl-4-(2-cyanoethenyl)-1-carboxybenzyl phenylamine obtained from example 2 (161 gms) at 25 to 30° C. and the reaction mass was stirred at 45-60° C. till completion of reaction as monitored by TLC. After completion of the reaction, water (1800 ml) was added to the reaction mass, neutralized with aqueous ammonia and extracted with toluene. The organic layer was separated and concentrated to give 2,6-dimethyl-4-(2-cyanoethenyl)phenylamine. The residue was admixed with 1:1 mixture of isopropanol and diisopropyl ether (1000 ml) and treated with HCl dissolved in isopropanol to yield 2,6-dimethyl-4-(2-cyanoethenyl)phenylamine hydrochloride salt (II) which was cooled to 25-30° C., filtered and dried.
Reaction SMILES: [NH2:1][C@H:2]([C@H:4]([OH:20])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:3].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22].C(N(CC)CC)C>ClCCl>[CH3:3][C@H:2]1[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[O:20][C:21](=[O:22])[NH:1]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCCCCCCCCCCCCC[C@@H](O)[C@H](C)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCC[C@H]1OC(=O)N[C@H]1C
Reaction time: 5 h

Procedure:
(2S, 3R)-2-amino-3-octadecanol (155, 750 μg, 2.6 μmol) was dissolved in dichloromethane (100 μL) to which 1,1′-carbonyldiimidazole (0.85 mg, 5.3 μmol) and triethylamine (0.4 μL, 2.9 μmol) was added. The solution was stirred for 5 h and then the solvent removed by a stream of nitrogen. The crude product 158 was analyzed without purification: IR (NaCl) 36, 2919, 2851, 1742, 1713, 1551, 1470, 1395, 1321, 49, 1239, 1094, 1061, 1001, 768, 743, 664 cm−1; FABMS m/z 785, 623, 474, 406, 362, 328, 312, 286, 268. Anal. Calcd. For C19H38NO2: 312.2903 (M+H). Found: 312.2903 (HRFABMS).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([NH2:22])[S:20][CH:21]=2)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:18]=[C:19]([NH:22][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=3)[S:20][CH:21]=2)=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1nc(-c2ccc(Cl)cc2)cs1
Product: O=C(Nc1nc(-c2ccc(Cl)cc2)cs1)c1cccnc1

Procedure:
In a manner similar to that described in Example 5 but using nicotinoyl chloride and 4-parachlorophenyl 2-amino thiazole, there is obtained a product of the formula: ##STR11##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[O:21]([C:28]1[CH:37]=[CH:36][C:31]([O:32][CH2:33][CH2:34]O)=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:34][CH2:33][O:32][C:31]2[CH:36]=[CH:37][C:28]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:29][CH:30]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCOc1ccc(Oc2ccccc2)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc(Oc3ccccc3)cc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 69.8 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-(4-phenoxyphenoxy)ethanol (1.5 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane; 4:1) and crystallized from diethyl ether-hexane to provide 1.1 g of alpha-oxo-4-[[2-(4-phenoxy-phenoxy)ethyl]oxy]benzeneacetic acid methyl ester, mp 97°-98° C.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[OH:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([N:2]([CH3:1])[S:27]([C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:31])[F:32])=[CH:26][CH:25]=2)(=[O:29])=[O:28])[CH2:4][CH2:5]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CN[C@H]1CC[C@H](O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To 3 g (23.2 mmol) trans-4-Methylamino-cyclohexanol in 120 ml CH2Cl2 were added 4.2 ml (24.4 mmol, 1.05 eq) N,N-diisopropylethylamine followed by 5.96 g (24.4 mmol, 1.05 eq) 4-(trifluoromethyl)-benzenesulfonyl chloride in 50 ml CH2Cl2. The mixture was stirred at RT over night and the organic phase extracted with 1M KHSO4, followed by 5% NaHCO3 and brine. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated. Column chromatography on silica gel with hexane:EtOAc 1:1 yielded 6.0 g (77%) trans-N-(4-Hydroxy-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as off-white solid, MS: 338 (MH+).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([NH2:12])[CH2:9]2)C=CC=CC=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[NH:8]1[CH2:11][CH:10]([NH:12][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:9]1
Reactant: CS(=O)(=O)Cl
Reactant: NC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC1CNC1
Reaction time: 0.5 h

Procedure:
A solution of 1-(diphenylmethyl)-3-azetidinamine (synthesized according to the methods of Arimoto et. al., J. of Antibiotics 39 (9), 1243-56, 1986)(197 mg, 0.83 mmol) in dichloromethane (10 mL) was treated with excess triethylamine at 0° C. followed by methanesulfonyl chloride (71 μL, 0.91 mmol). The reaction was stirred for 30 minutes and then concentrated and purified on silica gel (0-10% methanol/dichloromethane) to provide 185 mg of the desired product as a white solid. LC/MS: M+H 317.19 at 0.31 minutes, Method D.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[C:14]([CH3:19])[N:13]=1.Cl.[OH-].[K+]>O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16]2[CH:15]=[C:14]([CH3:19])[N:13]=[C:12]([NH2:11])[N:17]=2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ccc(Nc2cc(C)nc(N)n2)cc1
Yield: 94.2 %

Procedure:
Compound No. 17 (CNI-1794): A suspension of p-aminoacetophenone (1.35 g) and 2-amino-4-chloro-6-methylpyrimidine (1.435 g) in 20 mL water was treated with 0.85 mL conc HCl and heated at reflux for 1 hr. Addition of 20 mL 1N KOH gave a light buff solid, which was filtered out and dried to give 2.28 g 4-(4-acetylphenyl)amino-2-amino-6-methylpyrimidine, mp 194-196° C. Of this, 1.21 g was treated with methyl iodide (3 mL) in dimethylformamide (15 mL) at room temperature for 42 hr. Dilution with ethyl acetate and filtration gave 1.11 g 4-(4-acetylphenyl)amino-2-amino-1,6-dimethylpyrimidinium iodide as a white powder, mp 302-3° C.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][N:13]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[N:15]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:14]1=[O:37].CN1CCOCC1.Cl[S:46]([CH2:49][C:50]([O:52][CH2:53][CH:54]1[C:66]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:60]2[C:55]1=[CH:56][CH:57]=[CH:58][CH:59]=2)=[O:51])(=[O:48])=[O:47]>ClCCl>[CH:56]1[C:55]2[CH:54]([CH2:53][O:52][C:50](=[O:51])[CH2:49][S:46]([NH:12][N:13]3[CH2:17][CH:16]([C:18]4[CH:23]=[CH:22][C:21]([CH:24]5[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[N:15]([CH2:27][CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)[C:14]3=[O:37])(=[O:47])=[O:48])[C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[C:60]=2[CH:59]=[CH:58][CH:57]=1
Reactant: COc1ccc(CCN2C(=O)N(N)CC2c2ccc(C3CC3)cc2)cc1
Reactant: O=C(CS(=O)(=O)Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(CCN2C(=O)N(NS(=O)(=O)CC(=O)OCC3c4ccccc4-c4ccccc43)CC2c2ccc(C3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1-amino-3-[2-(4-methoxyphenyl)ethyl]-4-(4-cyclopropylphenyl)-2-imidazolidinone p-toluenesulfonic acid salt (2.61 g, 0.0050 mol), dichloromethane (12 mL), and N-methylmorpholine (1.53 mL, 0.014 mol) is added a solution of 9H-fluoren-9-ylmethyl chlorosulfonylacetate, 14, (1.76 g, 0.0052 mol) in dichloromethane (7 mL) slowly over 7 minutes at 15° C. to 20° C. The reaction is stirred at ambient temperature for 45 minutes, and then washed twice with 0.1 N HCl and water. The organic phase is dried (sodium sulfate) and concentrated to a foamy solid. The residue is purified over silica (0%-50% ethyl acetate/hexanes gradient) to afford 2.1 g of the desired compound. 1H NMR (CDCl3) δ 7.81 (d, J=7.5 Hz, 2H), 7.69 (d, J=7.5 Hz, H), 7.45 (m, 2H), 7.36 (m, 2H), 7.27 (s, 1H), 7.17 (m, 2H), 7.10 (m, 2H), 7.02 (m, 2H), 6.82 (m, 2H), 4.63 (m, 2H), 4.45 (t, J=8.4 Hz, 1H), 4.35 (m, 3H), 3.94 (t, J=8.4 Hz, 1H), 3.78 (s, 3H), 3.65 (m, 1H), 3.38 (t, J=8.1 Hz, 1H), 2.92 (m, 1H), 2.74 (m, 1H), 2.64 (m, 1H), 1.94 (m, 1H), 1.03 (m, 2H), 0.74 (m, 2H). MS 652 (MH+). Anal. calcd. for C37H37N3O6S ¾H2O: C, 66.80; H, 5.83; N, 6.32. Found: C, 66.78; H, 5.72; N, 6.30.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: Cc1noc(NS(=O)(=O)c2ccc(Cl)cc2)c1Br
Yield: 93 %

Procedure:
4-Chloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 4-chlorobenzenesulfonyl chloride according to the procedures described in Example 25b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a yellow powder, m.p. 145-150° C., yield 93%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][S:13]([O-:15])=[O:14].[Na+]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: CS(=O)[O-]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 130 °C
Yield: 74 %

Procedure:
A mixture of 3,4-difluoronitrobenzene (10 g, 62.9 mmol) and sodium methanesulfinate (8.3 g, 69.1 mmol) in DMSO (60 mL) was heated at 130° C. for 8 hours. After cooling down to room temperature, the mixture was poured into ice-water. The whole was extracted with ethyl acetate (200 mL×2), the combined organic layer washed with water (80 mL), brine (80 mL), dried over MgSO4, and concentrated in vacuo. The residue was crystallized from hexane and triturated withhexane to give the subtitle compound (10.2 g, 74% yield).
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH:2]=[CH2:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][OH:15])=[CH:10][CH:9]=1>C1C=CC=CC=1>[CH2:1]([NH:4][C:5]([N:14]([C:11]1[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=1)[OH:15])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCN=C=O
Reactant: ONc1ccc(Cl)cc1
Solvent: c1ccccc1
Product: C=CCNC(=O)N(O)c1ccc(Cl)cc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
Allyl isocyanate (5.8 g.) was added dropwise at 0° to 5° C. to a stirred solution of N-(4-chlorophenyl)-hydroxylamine (10 g.) dissolved in benzene (50 ml.). The reaction mixture was stirred for 1/2 hour at 15°-20° C., then cooled to 10° C. and the precipitated solid filtered. The solid was washed with hexane and dried to yield 1-allyl-3-(4'-chlorophenyl)-3-hydroxyurea as white crystals melting 117°-118° C.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]12[O:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14]2>O1CCCC1>[C:1]1([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCC2OC2C1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O[C@@H]1CCCC[C@H]1c1ccccc1
Temperature: 15 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
A 50-L reactor equipped with a stirrer, a gas bubbler, and an addition funnel was placed under argon, charged with 27.36 L (27.63 mole) of phenylmagnesium bromide (1.0 M), which is known, in tetrahydrofuran and cooled to 15° C. whereupon 235 g (2.37 mole) of CuC1 was added. The resulting mixture was further cooled to -25° C. To this well-stirred mixture was added dropwise over 1.0 hour 1.82 L (18.0 mole, 1766g) of cyclohexene oxide, which is known. After the addition was completed, the mixture was stirred between -10° C. and 0° C. for 4 hours. The reaction mixture was subsequently quenched with 6 L of saturated NH4SO4 solution followed by 4L of water. The organic layer was separated and the aqueous layer was then extracted with 3×6L=18 L of ethyl acetate. The combined organic layers were evaporated in vacuo. When the residue was dissolved into 8 L of methylene chloride, a small aqueous layer separated and was discarded. The organic layer was dried (Na2SO4) and evaporated in vacuo, finally at 0.5 mmHg. The residue on crYstallization from hexane, afforded in 3 crops, 2.96 kg (93%) of (±)-trans-2-phenylcyclohexanol as colorless needles, m.p. 55-57° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:5][N:4]=1.I[Si](C)(C)C>C(Cl)Cl.[Cl-].[Na+].O>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[N:4][CH:5]=1
Reactant: COc1ccc(-c2ccccc2-c2ccccc2C)cn1
Agent: C[Si](C)(C)I
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1-c1ccccc1-c1ccc(O)nc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 64.7 %

Procedure:
To a solution of 2-methoxy-5-(2′-methylbiphenyl-2-yl)pyridine (2.20 g) in DCM (50 mL) was added iodo(trimethyl) silane (5.0 g) at ambient temperature. The reaction mixture was stirred at ambient temperature for 4 days. To the reaction mixture was added brine (50 mL). The mixture was extracted with EtOAc and the organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (EtOAc:chloroform=3:7) to afford 5-(2′-methylbiphenyl-2-yl)pyridin-2-ol (1.35 g) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]([CH3:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CO.[OH-].[Na+]>O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([CH3:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(C)nn1-c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)O)n(-c2ncccc2Cl)n1
Yield: 89.4 %

Procedure:
A mixture of 0.30 g of ethyl 1-(3-chloro-2-pyridinyl)-3-methyl-1H-pyrazole-5-carboxylate, 5 ml of methanol and 5 ml of a 2N aqueous sodium hydroxide solution was heated to reflux for 3 hours. After the reaction mixture was allowed to cool, water was poured and the aqueous layer was washed with methyl t-butyl ether two times. The aqueous layer was adjusted to around pH 3 by an addition of 2N hydrochloric acid, and then extracted with methyl t-butyl ether three times. The combined organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.24 g of 1-(3-chloro-2-pyridinyl)-3-methyl-1H-pyrazole-5-carboxylic acid of the formula:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[C:25]1([C@@H:31]2[CH2:36][NH:35][CH2:34][CH2:33][NH:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:35]4[CH2:34][CH2:33][NH:32][C@H:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:36]4)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reactant: c1ccc([C@@H]2CNCCN2)cc1
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCN[C@H](c5ccccc5)C4)c(F)cc3cc2c1=O
Yield: 59.2 %

Procedure:
Working under the conditions of Example 39, but starting with 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.21 g) and (R)-2-phenylpiperazine (0.7 g), and after recrystallization in ethanol (22 cc) containing dimethylformamide (30%), (R)-3-ethoxycarbonyl-7,9-difluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine (1.02 g) is obtained in the form of a yellow solid, m.p. 216° C.
Reaction SMILES: [NH:1]([C:8]([NH:10][C:11]1[CH:31]=[CH:30][C:14]2[N:15]([C@@H:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][C:20]([O:22]C)=[O:21])[CH:16]=[N:17][C:13]=2[CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.Cl>O1CCCC1>[NH:1]([C:8]([NH:10][C:11]1[CH:31]=[CH:30][C:14]2[N:15]([C@@H:18]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[N:17][C:13]=2[CH:12]=1)=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@H](c1ccccc1)n1cnc2cc(NC(=O)Nc3ccccc3)ccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C(O)C[C@H](c1ccccc1)n1cnc2cc(NC(=O)Nc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 110 h

Procedure:
A solution of methyl (3R)-3-{5-[(anilinocarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (204 mg, 492 μmol) in a mixture of tetrahydrofuran (2 mL), acetonitrile (20 mL) and hydrochloric acid (50 mL of a 5N solution) was stirred at room temperature for 110 hours. The solution was evaporated in vacuo to afford the title compound, [LCMS (Method C, Mobile Phase I) RT=2.25 min, MH+ 401.34].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:20]=[C:19]3[N:10]([C:11](=[O:21])[NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=43)[N:9]=2)=[CH:4][CH:3]=1.[CH3:22][O-].[Na+].CI>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:20]=[C:19]3[N:10]([C:11](=[O:21])[N:12]([CH3:22])[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=43)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]c2ccccc2c2nc(-c3ccc(Cl)cc3)nn12
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CS(C)=O
Product: Cn1c(=O)n2nc(-c3ccc(Cl)cc3)nc2c2ccccc21
Temperature: 0 °C

Procedure:
To a mixture of 2-(4-chlorophenyl)-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)one (6 g) in dry dimethylsulphoxide (150 ml) is added sodium methoxide (1.3 g). The mixture is heated under nitrogen for one hour at 85° and methyl iodide (1.3 ml) in dimethyl sulphoxide (10 ml) added. A white solid forms rapidly. The reaction mixture is heated three hours longer, cooled and poured into ice water (800 ml). The precipitated white solid is washed with water, air dried (7.2 g) and recrystallized from dimethylacetamide twice to afford pure 2-(4-chlorophenyl)6-methyl-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)one, mp 323°-325°.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:20])=[C:6]([O:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[C:7]([CH3:10])=[N:8][CH:9]=1)(O)=O.[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[C:15]([C:14]1[CH:13]=[C:12]([CH:19]=[CH:18][CH:17]=1)[O:11][C:6]1[C:7]([CH3:10])=[N:8][CH:9]=[C:4]([CH2:1][NH:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[C:5]=1[CH3:20])#[N:16]
Reactant: Cc1ncc(C(=O)O)c(C)c1Oc1cccc(C#N)c1
Reactant: N#Cc1ccc(N)cc1
Product: Cc1ncc(CNc2ccc(C#N)cc2)c(C)c1Oc1cccc(C#N)c1
Yield: 76.3 %

Procedure:
The reductive amination of 3-(5-carboxy-2,4-dimethyl-pyridin-3-yloxy)-benzonitrile (188 mg, 0.74 mmol) and 4-aminobenzonitrile (500 mg, 4.2 mmol), as described in Example 21, gave 4-{[3-(3-cyano-phenoxy)-2,4-dimethyl-pyridin-5-ylmethyl]-amino}-benzonitrile (95) (200 mg, 77% yield) as a brown oil.
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([NH2:26])[CH2:21]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:5]=2[N:4]=1.[Cl:34][CH2:35][S:36](Cl)(=[O:38])=[O:37].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:34][CH2:35][S:36]([NH:26][C@H:22]1[CH2:23][CH2:24][CH2:25][N:20]([C:10]2[N:9]=[C:8]([N:7]3[C:6]4[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:5]=4[N:4]=[C:3]3[CH:2]([F:1])[F:33])[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=2)[CH2:21]1)(=[O:38])=[O:37]
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC[C@H](N)C2)n1
Reactant: O=S(=O)(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC[C@H](NS(=O)(=O)CCl)C2)n1
Yield: 57 %

Procedure:
Reaction of (3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-piperidinamine (Example 46) with chloromethanesulfonyl chloride and K2CO3 in CH2Cl2 gave chloro-N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-piperidinyl}methanesulfonamide in 57% yield: mp (MeOH) 166-168° C.; 1H NMR (DMSO-d6) (rotamers) δ7.99 (br, 1H), 7.98 and 7.88 (2d, J=8.5, 8.4 Hz, 1H), 7.69 and 7.68 (2t, JHF=52.9 Hz, 1H), 7.41 and 7.37 (2t, J=8.1, 8.2 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 4.98-4.88 (m, 2H), 4.55-4.52 and 4.37-4.23 (2m, 2H), 3.97 (s, 3H), 3.80 (m, 4H), 3.69 (m, 4H), 3.45-3.11 (m, 3H), 1.99 (br, 1H), 1.83-1.80 (m, 1H), 1.64-1.48 (m, 2H); Anal. Calcd. for C22H27ClF2N8O4S.0.5H2O: C, 45.4; H, 4.85; N, 19.25. Found: C, 45.4; H, 4.8; N, 19.2%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32])#[N:25]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:24]#[N:25])=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: N#Cc1ccccc1O
Product: COc1ccc(-c2cc(Oc3ccccc3C#N)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (110 mg, 0.337 mmol) and 2-cyanophenol were reacted as starting materials at 150° C. for 24 hours and post-treatment was then conducted, whereby the title compound was obtained as a pale yellow amorphous solid (121.4 mg, 88.1%). Melting point: 197.7-201.1° C. (ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH2:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=1)[CH3:2].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@@H:16]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[NH:24][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCOc1ccc(C[C@H](NS(=O)(=O)c2ccc(C)cc2)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
411 mg of 4-[4-((2S)-2-amino-2-tert-butoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester were dissolved in 10 ml of anhydrous DMF and cooled to 0° C. 191 mg of 4-toluenesulfonyl chloride and 0.34 ml of diisopropylethylamine were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the solvents removed in vacuo. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/1). Yield 295 mg. MS (ES+): m/e=506.2 (M+H)+; 450.2.