Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:16])[CH2:9][C:10](OC)([O:12][CH3:13])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1(C)C=CC=CC=1>[CH:1]1([NH:7][C:8](=[O:16])/[CH:9]=[C:10](\[O:12][CH3:13])/[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(C)(CC(=O)NC1CCCCC1)OC
Solvent: Cc1ccccc1
Product: CO/C(C)=C\C(=O)NC1CCCCC1
Temperature: 145 °C
Reaction time: 3 h
Yield: 52.3 %

Procedure:
A mixture of 40 g of N-cyclohexyl-3,3-dimethoxy-butyramide in 200 ml of toluene was stirred and heated to 145° C. to distill an azeotrope of toluene and methanol. After 3 hours, the mixture was cooled and evaporated to dryness under reduced pressure. The oil residue was chromatographed over silica gel and was eluted with a 7-3 methylene chlorideethyl acetate mixture. The fractions with an Rf of 0.55 were recovered and were concentrated to dryness under reduced pressure. The residue was added to isopropyl ether which was iced and vacuum filtered. The recovered precipitate was dried to obtain 18 g of N-cyclohexyl-3-methoxy-crotonamide melting at 109° C.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[N:29]=[C:28]([C:30]([OH:32])=O)[O:27][N:26]=2)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[NH2:63][C@@H:64]([CH3:81])[CH2:65][N:66]1[CH:70]=[CH:69][C:68]([C:71]2[CH:78]=[C:77]([F:79])[C:74]([C:75]#[N:76])=[C:73]([Cl:80])[CH:72]=2)=[N:67]1>ClCCl>[Cl:80][C:73]1[CH:72]=[C:71]([C:68]2[CH:69]=[CH:70][N:66]([CH2:65][C@@H:64]([NH:63][C:30]([C:28]3[O:27][N:26]=[C:25]([C:23]4[N:22]=[CH:21][N:20]([C:1]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[CH:24]=4)[N:29]=3)=[O:32])[CH3:81])[N:67]=2)[CH:78]=[C:77]([F:79])[C:74]=1[C:75]#[N:76]
Reactant: O=C(O)c1nc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)no1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1nc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)no1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Into a flask containing 3-(1-trityl-1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxylic acid (0.148 g, 0.350 mmol) and anhydrous HOBt (0.047 g; 0.350 mmol), dichloromethane (2 ml), DIPEA (0.122 ml; 0.700 mmol) and EDCI (0.067 g; 0.350 mmol) were added and stirred for 10 min at RT. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.100 g, 0.269 mmol) dissolved in 2 ml of dichloromethane was added and the resulting mixture stirred overnight. Next day the temperature was raised to 50° C. and more EDCI (0.067 g; 0.350 mmol) was added. The reaction mixture was allowed to react with stirring for 4 h. DCM was added and the organic layer was extracted with 1M Na2CO3 and water. The organic layer was then evaporated and the residue purified with flash chromatography. LC-MS: [M+1]=684.133.
Reaction SMILES: [Br:1][C:2]1[C:13](=[O:14])[N:12]([CH2:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[CH:23]2[CH2:25][CH2:24]2)[C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>ClCCl>[Br:1][C:2]1[C:13](=[O:14])[N:12]([CH2:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[CH:23]2[CH2:25][CH2:24]2)[C:5]2[N:6]=[C:7]([S:10]([CH3:11])=[O:34])[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2cc(Br)c(=O)n(Cc3c(F)cccc3C3CC3)c2n1
Solvent: ClCCl
Product: CS(=O)c1ncc2cc(Br)c(=O)n(Cc3c(F)cccc3C3CC3)c2n1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a solution of 6-bromo-8-(2-cyclopropyl-6-fluorobenzyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (8, 500 mg, 1.2 mmol) in dichloromethane (20 mL) was added 3-chloroperbenzoic acid (77%, 253 mg, 1.1 mmol) in dichloromethane (15 mL) at 0-5° C. and the mixture was stirred at 0-5° C. for 1 h. The reaction mixture was washed with saturated sodium bicarbonate solution (2×30 mL) then with brine (30 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography eluting with chloroform to yield the title compound as a white solid (385 mg, 0.9 mmol, 74%). ESMS m/z 436 (M+H)+.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([C:33]2([F:37])[CH2:36][O:35][CH2:34]2)[CH:30]=[C:29]([F:38])[C:28]=1[C:39]1[N:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[CH:41][C:40]=1[F:48]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:45](=[O:46])[C:43]2[CH:42]=[CH:41][C:40]([F:48])=[C:39]([C:28]3[C:29]([F:38])=[CH:30][C:31]([C:33]4([F:37])[CH2:36][O:35][CH2:34]4)=[CH:32][C:27]=3[F:26])[N:44]=2)[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cc(C3(F)COC3)cc2F)n1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cc(C4(F)COC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(3-fluorooxetan-3-yl)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 194. 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.32 (dd, J=8.7, 4.0 Hz, 1H), 8.18 (t, J=8.9 Hz, 1H), 7.93 (s, 1H), 7.54 (d, J=8.8 Hz, 2H), 5.02 (s, 2H), 4.97 (s, 2H), 4.82 (dd, J=10.3, 3.7 Hz, 1H), 4.31-4.05 (m, 1H), 4.07-3.84 (m, 2H), 3.75 (s, 3H), 3.09-2.95 (m, 1H), 2.10-1.99 (m, 1H), 1.80-1.57 (m, 5H). LCMS (ES+) m/z 538 (M+1).
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[CH:16]1>N1C=CC=CC=1>[NH2:28][C:19]1[C:18]2[N:17]=[CH:16][N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)N1CCOCC1
Solvent: c1ccncc1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)N1CCOCC1
Temperature: 25 °C
Yield: 194.5 %

Procedure:
4-Morpholinecarbonyl chloride (0.15 ml, 1.3 mmol) was added to a stirring solution of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.3 g, 1.2 mmol) and pyridine (70 ml). The reaction was maintained at room temperature overnight. The solvent was removed in vacuo and the residue was purified by flash column chromatography (silica gel, 9:1 dichloromethane\methanol). The fractions containing product were combined, washed with saturated aqueous sodium bicarbonate, dried (MgSO4), filtered, and concentrated to provide 0.86 g of N4-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-morpholinecarboxamide as a tan powder, m.p. 177.0–179.5° C. 1H NMR (300 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.04 (d, J=7.1 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.47 (t, J=7.1 Hz, 1H), 7.28 (t, J=7.1 Hz, 1H), 6.72 (broad s, 2H), 6.52 (t, J=5.4 Hz, 1H), 4.61 (t, J=6.9 Hz, 2H), 3.48 (t J=4.6 Hz, 4H), 3.18 (t, J=4.6 Hz, 4H), 3.05 (m, 2H), 1.84 (m, 2H), 1.44 (m, 2H); MS (EI) m/e 368.1966 (368.1961 calcd for C19H24N6O2).
Reaction SMILES: [F:1][CH:2]([F:22])[S:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH3:21])OCC[O:17]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.S(Cl)([Cl:26])(=O)=O>ClCCCl>[Cl:26][CH2:21][C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:4]([S:3][CH:2]([F:22])[F:1])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1)=[O:17]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC1(c2ccc(-c3ccc(SC(F)F)cc3)cc2)OCCO1
Solvent: ClCCCl
Product: O=C(CCl)c1ccc(-c2ccc(SC(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
A solution of 8.0 g (25 mmol) of 2-[4'-[(difluoromethyl)thio][1,1'-biphenyl]-4-yl]-2-methyl-1,3-dioxolane and 30 mL of anhydrous 1,2-dichloroethane was cooled to 5° C. and sulfuryl chloride (2.3 mL, 3.8 g, 28 mmol) was added via syringe. The solution was allowed to warm to ambient temperature and concentrated to dryness. Acetone (40 mL), 5 mL of water, and 2 mL of 37% HCl were added, and the mixture was heated at 55° C. for 18 h. The mixture was diluted with 20 mL of water with cooling and seeding to precipitate the product. After filtration, washing with cold 50% aqueous MeOH and drying, the crude solid (7.2 g, 92%) was slurried in 80 mL of hot isopropanol (i-PrOH) allowed to cool with good stirring for 30 min, and filtered to afford 5.6 g of 2-chloro-1-[4'-[(difluoro-methyl)thio][1,1'-biphenyl]-4-yl]ethanone, m.p. 102-104° C. A second crop of 0.9 g was obtained by partial concentration of the filtrate. An analytical standard was prepared by chromatography and/or recrystallization from CH2Cl2 /MeOH, m.p. 104 to 105° C. 1H-NMR(CDCl3): δ4.75 (s, 2H), 6.88 (t, 1H), 7.65 (ABq, 4H) 7.7 (d, A of ABq, 2H), 8.05 (d, B of ABq, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]3[CH3:18])=[N:7][C:6]([C:19]3[S:23][C:22]([NH2:24])=[N:21][CH:20]=3)=[N:5][C:4]=2[CH2:3]1.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>>[CH2:25]([NH:27][C:28]([NH:24][C:22]1[S:23][C:19]([C:6]2[N:7]=[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]3[CH3:18])[C:9]3[CH2:10][CH2:11][N:2]([CH3:1])[CH2:3][C:4]=3[N:5]=2)=[CH:20][N:21]=1)=[O:29])[CH3:26]
Reactant: C[C@H]1COCCN1c1nc(-c2cnc(N)s2)nc2c1CCN(C)C2
Reactant: CCN=C=O
Product: CCNC(=O)Nc1ncc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C)C3)s1
Yield: 11 %

Procedure:
The product from step 1 was treated as described for example 85 with ethyl isocyanate. The mixture was concentrated in vacuo and the material purified by prep HPLC at high and low pH, yielding the title compound (15.5 mg, 0.037 mmol, 11% over 2 steps).
Reaction SMILES: [NH2:1][C:2]([CH2:16][OH:17])([CH2:14][OH:15])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1.[CH2:18](C(CC)(CC)C([O-])([O-])[O-])[CH3:19].C(O)(=O)C>ClC(Cl)C>[OH:17][CH2:16][C:2]1([CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=2)[CH2:14][O:15][C:18]([CH3:19])=[N:1]1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: CC(=O)c1ccc(CCC(N)(CO)CO)cc1
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)c1ccc(CCC2(CO)COC(C)=N2)cc1
Temperature: 80 °C

Procedure:
To a suspension of 1-[4-(3-amino-4-hydroxy-3-hydroxymethyl-butyl)-phenyl]-ethanone (1 mmol) in anhydrous dichloroethane (2 mL) is added triethylorthoacetate (1.1 mmol) and acetic acid (0.05 mmol). The resulting mixture is heated at 80° C. for 12 hours. After concentration, the residue is purified by flash column chromatography (EtOAc) to give 1-{4-[2-(4-hydroxymethyl-2-methyl-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-ethanone as an oil; MS: (ES+): 262.1 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:1][C:2]1[C:11]([NH:12][C:13]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[S:23][CH3:22])[CH2:35][CH2:34]2)=[O:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Reactant: CSc1ccccc1N1CCNCC1
Product: CSc1ccccc1N1CCN(C(=O)Nc2cc3ccccc3nc2C)CC1
Yield: 76 %

Procedure:
Phenyl N-(2-methylquinolin-3-yl)carbamate and 1-(2-methylthiophenyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound.
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][CH2:5][Cl:6].[O:7]=[C:8]1[CH:15]2[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:17][CH:9]1[CH:10]3[OH:18])[CH2:14]2.C(N(CC)CC)C>C1COCC1>[O:7]=[C:8]1[CH:15]2[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:17][CH:9]1[CH:10]3[O:18][CH2:2][O:3][CH2:4][CH2:5][Cl:6])[CH2:14]2
Reactant: ClCCOCCl
Reactant: O=C1C2CC3CC(C2)C(O)C1C3
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1C2CC3CC(C2)C(OCOCCCl)C1C3
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A two neck Kjeldahl flask of 50 ml into which a stirrer was put was charged with 1.55 g (12 mmol) of 2-chloroethyl chloromethyl ether obtained in Example 1 (1), 1.66 g (10 mmol) of 4-oxo-2-adamantanol, 1.52 g (15 mmol) of triethylamine and dried THF, and it was equipped with a coiled condenser to reflux and stir the solution for 8 hours. Triethylamine hydrochloride was filtered, and gas chromatographic analysis was carried out to find that 4-oxo-2-adamantanol was converted by 98.3 and that 2.56 g (9.8 mmol, isolation yield: 97.6%) of a colorless liquid which was the intended product was obtained at a selectivity of 99.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[N:3]=1
Reactant: C1CCNCC1
Reactant: Cc1cccc(Cl)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(CN2CCCCC2)n1
Yield: 41 %

Procedure:
To 2-chloro-6-methylpyridine (50.0 g, 0.392 mole) in 393 mL of carbon tetrachloride was added N-bromosuccinicide (87.2 g, 0.49 mole) and 1.0 g of benzoyl peroxide. The mixture was stirred at reflux for 22 hours, cooled to 10° and filtered. The chilled filtrate then was treated slowly with piperidine (83.5 g, 0.98 mole) and allowed to stir at ambient temperature for 18 hours. After removal of the piperidine hydrobromide by filtration, the filtrate was concentrated to about half volume and extracted with 6N HCl (65 mL) and 3N HCl (40 mL). The acid extracts were made basic with 40% sodium hydroxide and the product was extracted into methylene chloride. The solvent was evaporated and the residue distilled to yield 41% of the title compound as a colorless oil, b.p. 101°-103°/0.45 mm Hg.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]3[CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[C:16]([OH:25])[C:15]=2[C:14]2[C:13]([C:26]([NH2:28])=[O:27])=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]3[CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[C:16]([O:25][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[C:26](=[O:27])[NH2:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)c3c(cc1n2Cc1ccccc1)CCCC3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1c2c(cc3c1c1c(C(N)=O)cccc1n3Cc1ccccc1)CCCC2
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 31.2 %

Procedure:
40% Methanolic Triton B (0.148 mL, 0.325 mM) was added to a solution of 5-benzyl-11-hydroxy-7,8,9,10-tetrahydro-5H-benzo[b]carbazole-1-carboxylic acid amide, (0.094 g, 0.25 mM) in 5 mL DMF at room temperature. After 2 minutes, methyl bromoacetate (0.049 mL, 0.076 g, 0.5 mM) was added and the resultant mixture stirred at room temperature for 2 h. Cesium carbonate (0.041 g, 0.125 mM) was then added as a solid, and the mixture allowed to stir at room temperature for an additional 2 h. The mixture was diluted with ethyl acetate, washed with H2O, 1N HCl, saturated aqueous NaHCO3 solution, and saturated brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting tan foam was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 0.035 g (31%) of the title compound (5-benzyl-1-carbamoyl-7,8,9,10-tetrahydro-5H-benzo[b]carbazol-11-yloxy)-acetic acid, methyl ester as a white solid (MP 174–177° C., MW 442.52).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][CH2:20][OH:21].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][CH2:20][O:21][S:30]([CH3:29])(=[O:32])=[O:31]
Reactant: Cc1cc2c(cc1C)C(CCO)N(c1cccnc1)C2=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc2c(cc1C)C(CCOS(C)(=O)=O)N(c1cccnc1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a solution of the product of above-mentioned (13-a) (5.5 g, 20 mmol) in methylene chloride (1.4.0 ml) was added triethylamine (5.4 ml, 29 mmol) and methanesulfonyl chloride (2.4 ml, 21 mmol), and stirred at 25° C. for 2 hrs. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give 5.5 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29].[CH2:30]([N:32]([CH2:43][CH3:44])[CH2:33][CH2:34][O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH3:31]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:40][C:39]3[CH:38]=[CH:37][C:36]([O:35][CH2:34][CH2:33][N:32]([CH2:43][CH3:44])[CH2:30][CH3:31])=[CH:42][CH:41]=3)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1ccccc1)C(=O)N(c1ccc(Cl)cc1Cl)C2
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(c2ccccc2)C(=O)N(c2ccc(Cl)cc2Cl)C3)cc1
Temperature: 180 °C
Yield: 8 %

Procedure:
A mixture of 300 mg (0.65 mmol) of 3-(2,4-dichlorophenyl)-3,4-dihydro-7-methanesulfonyl-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one and 400 mg (1.9 mmol) of 4-[2-(diethylamino)ethoxy]aniline was heated at 180° C. for 30 minutes. The mixture was cooled and the product purified by column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, evaporated and the residue evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to afford 30 mg (8%) of 3-(2,4-dichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 106-108° C.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>S(Cl)(Cl)=O>[N:1]1[CH:6]=[C:5]([C:7]([O:9][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc(C(=O)O)nc1
Solvent: O=S(Cl)Cl
Product: O=C(OCc1ccccc1)c1ccc(C(=O)OCc2ccccc2)nc1

Procedure:
Analogously to Example 1, 20 g of pyridine-2,5-dicarboxylic acid are converted into the acid chloride with 160 ml of thionyl chloride and this is reacted with 25.9 g of benzyl alcohol. The product is recrystallized from ethyl acetate, with the addition of active charcoal.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH3:14]>C(O)C>[C:2]([C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:14]
Reactant: N
Reactant: ClC(Cl)(Cl)c1nc2ccccc2[nH]1
Solvent: CCO
Product: N#Cc1nc2ccccc2[nH]1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
1.0 Gram of a 2-(trichloromethyl)benzimidazole compound [compound (107)] of the formula (XI) in which X is H and Z is CF2CF2O was dissolved in 20 ml of ethanol. The resulting solution was added by drops to 5 ml of a 25% aqueous ammonia at 5° C. After stirring for 30 minutes at 5° C., the reaction solution was poured into an ice/conc. hydrochloric acid mixture and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removing the solvent from the dried layer by distillation gave 0.6 g of a 2-cyanobenzimidazole compound [compound (vii)] of the formula (II) in which X is H and Z is CF2CF2O.
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH2:15][CH3:16])[C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([OH:10])=O)[CH2:2][CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:29][C@@H:30]([CH2:46][C:47]1[CH:52]=[C:51]([F:53])[CH:50]=[C:49]([F:54])[CH:48]=1)[C@H:31]([OH:45])[CH2:32][NH:33][C:34]1([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]#[CH:44])[CH:38]=2)[CH2:36][CH2:35]1>ClCCl>[F:53][C:51]1[CH:52]=[C:47]([CH:48]=[C:49]([F:54])[CH:50]=1)[CH2:46][C@H:30]([NH:29][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][N:13]=[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:14][CH2:15][CH3:16])[CH:6]=1)[C@H:31]([OH:45])[CH2:32][NH:33][C:34]1([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]#[CH:44])[CH:38]=2)[CH2:36][CH2:35]1
Reactant: CCCN(CCC)c1cc(C(=O)O)ccn1
Reactant: C#Cc1cccc(C2(NC[C@@H](O)[C@@H](N)Cc3cc(F)cc(F)c3)CC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C#Cc1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)c3ccnc(N(CCC)CCC)c3)CC2)c1
Reaction time: 8 h
Yield: 60 %

Procedure:
2-(Dipropylamino)isonicotinic acid (0.206 g) was dissolved in dichloromethane (10 mL). 1,1′-Carbonyldiimidazole was added (0.142 g) and the mixture was stirred for 2 h at room temperature, at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethynylphenyl)cyclopropyl]amino}butan-2-ol (0.284 g) in dichloromethane was added. The mixture was allowed to stir overnight and then was partitioned between dichloromethane, water, and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was chromatographed on silica gel using methanol/dichloromethane (4/96) to give N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethynylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-2-(dipropylamino)isonicotinamide (0.268 g). MS (ESI+) for C33H38F2N4O2+H1 m/z 561.30 (M+H)+.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:16])[CH:5]=[CH:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13].C(O)CO.[F-:21].[K+]>CCOCC>[F:21][CH2:2][CH:3]=[C:4]([CH3:16])[CH:5]=[CH:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13]
Reactant: [F-]
Reactant: CC(C)=CCCC(C)CC=CC(C)=CCBr
Agent: [K+]
Solvent: CCOCC
Solvent: OCCO
Product: CC(C)=CCCC(C)CC=CC(C)=CCF

Procedure:
A mixture of 33 g. of 1-bromo-3,7,11-trimethyldodeca-2,4,10-triene and 100 ml. of dry ethylene glycol is slowly added with stirring, to a suspension of 11.5 g. of potassium fluoride in 30 ml. of dry ethylene glycol and heated to about 120°, under an inert atmosphere. When addition is completed, the reaction mixture is stirred for about an additional 16 hours while maintaining the temperature at 120°. Then the mixture is cooled and 200 ml. of ether added. The mixture is washed thoroughly with water and the ether phase dried over sodium sulfate and solvent evaporated under reduced pressure to yield 1-fluoro-3,7,11-trimethyldodeca-2,4,10-triene.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[CH3:16][S-:17].[Na+]>CS(C)=O.O>[CH3:16][S:17][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]1=[O:15]
Reactant: C[S-]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of N-(3-bromopropyl)phthalimide (500 mg) in DMSO (8 mL) was added sodium thiomethoxide (144 mg) and the reaction stirred at room temperature for 16 h. Then with water (2 mL) was added and the mixture stirred at room temperature for 10 min. The reaction was diluted with water (20 mL) and extracted into ethyl acetate (2×20 mL). The combined organics were washed with aqueous brine solution (2×20 mL), dried (MgSO4) and reduced in vacuo to give 2-(3-methylsulfanyl-propyl)-isoindole-1,3-dione as a white solid.