Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH:7]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:8]1[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1)=[O:5].Cl.CCN(C(C)C)C(C)C.[CH2:40]([S:43](Cl)(=[O:45])=[O:44])[CH2:41][CH3:42]>O1CCOCC1>[Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH:7]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:8]1[CH2:9][N:10]([S:43]([CH2:40][CH2:41][CH3:42])(=[O:45])=[O:44])[CH2:11]1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CC(C(NC(=O)c2ccc(Cl)cc2Cl)c2ccccc2)C1
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCCS(=O)(=O)N1CC(C(NC(=O)c2ccc(Cl)cc2Cl)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
To a solution of 2 (500 mg, 1.15 mmol) in 1,4-dioxane (10 mL) was added 4N HCl in dioxane (5.0 mL) and stirred at room temperature for 2 h. The reaction was concentrated under vacuum. The residue was dissolved in CH2Cl2 (10 mL) and DIPEA (300 mg, 2.30 mmol) and added 1-propanesulfonyl chloride (164 mg, 1.15 mmol). The reaction was stirred at room temperature for 20 h. The reaction was concentrated under vacuum and the residue was purified by column chromatography (silica gel) using 0 to 35% EtOAc in hexanes to afford 3a as white solid (285 mg, 56%); 1H-nmr (300 MHz, CDCl3) δ 7.69 (d, J=8.5 Hz, 1H), 7.60-7.30 (m, 10H), 7.08 (d, J=8.5 Hz, 1H), 5.68 (dd, J=9.5, 6.5 Hz, 1H), 5.29 (br s, 1H), 3.76-3.71 (m, 2H), 3.55-3.35 (m, 2H), 3.19-3.01 (m, 2H), 2.69 (br s, 1H), 1.98-1.82 (m, 2H), 1.08 (t, J=7 Hz, 9H); LC-MS (214) 98%, 3.30 min, m/z 475 (MMeOH+).
Reaction SMILES: [CH2:1](OC(=O)COC1C2C(=CC=CC=2)C(=O)N1CC1C=CC=CC=1)C.[CH2:25]([N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]1[O:42][CH2:43][C:44]([NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1)=[O:45])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][C:36]([CH3:1])=[CH:37][CH:38]=2)[CH:33]1[O:42][CH2:43][C:44]([NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1)=[O:45])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(COC1c2ccccc2C(=O)N1Cc1ccccc1)Nc1ccccn1
Reactant: CCOC(=O)COC1c2ccccc2C(=O)N1Cc1ccccc1
Product: Cc1ccc2c(c1)C(OCC(=O)Nc1ccccn1)N(Cc1ccccc1)C2=O

Procedure:
Compound 61 was prepared using the synthetic sequence in a manner analogous to the method described for the conversion of compound 21 to compound 23 and illustrated in Scheme 2. NMR (300 MHz, CDCl3): δ 8.8(br s, 1H), 8.45(m, 1H), 8.1(m, 1H), 7.75(m, 2H), 7.4-7.2(m, 7H), 7.05(m, 1H), 5.9(s, 1H), 5.0(d, J=15 Hz, 1H), 4.4(d, J=15 Hz, 1H), 3.65(d, J=19 Hz, 1H), 3.5(d, J=19 Hz, 1H), 2.4(s, 3H). MS: m/z (MNa+) 410.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:14]4[NH:15][C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=5[C:22](=[O:23])[C:13]=4[CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.Cl[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1.CO>CN(C=O)C>[N:26]1[CH:27]=[CH:28][CH:29]=[N:30][C:25]=1[N:11]1[CH2:12][C:13]2[C:22](=[O:23])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[NH:15][C:14]=2[CH:10]1[C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1
Reactant: Clc1ncccn1
Reactant: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)NC2
Solvent: CO
Solvent: CN(C)C=O
Product: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)N(c1ncccn1)C2

Procedure:
1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one (100 mg, 0.3265 mmol) (prepared as in Example 5) and 2-chloropyrimidine (38 mg, 0.3265 mmol) were stirred in DMF (2.5 mL) at 100° C. for 16 h. The solvent was removed under vacuum and the residue purified by column chromatography (silica gel, 5% CH3OH/CH3Cl) to yield a yellow oil. Trituration of the oil with MeOH afforded the product as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:26][C:27](=[O:29])[CH3:28])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:37])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:26][C:27](=[O:29])[CH3:28])=[C:8]2[C:16]([Cl:37])=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2cccc(OC)c2)c1OC(C)=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2cccc(OC)c2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 124(b) from 4-acetoxy-7-cyano-1-(3-methoxy-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and NCS in MeCN. The title compound, ESI MS (m/z): 428 (M+H)+.
Reaction SMILES: O[C:2]1[C:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:6](O)[N:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:30]>>[Cl:30][C:6]1[C:7]2[N:8]=[C:9]([C:10]3[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=3)[O:17][C:2]=2[N:3]=[CH:4][N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(Nc1c(O)ncnc1O)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-c2nc3c(Cl)ncnc3o2)cc1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 30 %

Procedure:
To a solution of N-(4,6-dihydroxypyrimidin-5-yl)-4-fluorobenzamide (0.30 g, 1.20 mmol) in POCl3 (6 ml) was added diisopropylethylamine (0.42 ml, 2.41 mmol). The reaction mixture was stirred under N2 at 90° C. for 3.5 hours. The reaction mixture was allowed to cool down to room temperature and the volatiles were evaporated to dryness. The residue was diluted with water and the aqueous phase was extracted with diethyl ether. The combined organic layers were washed with a saturated NaHCO3 solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (0.13 g, 30%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:22][CH3:23])=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[S:14][CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=1)[CH:9]=[C:8]2[OH:21])[CH3:2].C(C1N=C(C2C=C(O[CH:43]3[CH2:60][CH:59]4[CH:45]([C:46](=[O:66])[N:47]([CH3:65])[CH2:48][CH2:49][CH2:50][CH2:51][CH:52]=[CH:53][CH:54]5[C:56]([C:62]([OH:64])=[O:63])([NH:57][C:58]4=[O:61])[CH2:55]5)[CH2:44]3)C3C(=C(C)C(OC)=CC=3)N=2)SC=1)(C)C>>[CH2:1]([C:3]1[C:4]([O:22][CH3:23])=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[S:14][CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=1)[CH:9]=[C:8]2[O:21][CH:43]1[CH2:60][CH:59]2[CH:45]([C:46](=[O:66])[N:47]([CH3:65])[CH2:48][CH2:49][CH2:50][CH2:51][CH:52]=[CH:53][CH:54]3[C:56]([C:62]([OH:64])=[O:63])([NH:57][C:58]2=[O:61])[CH2:55]3)[CH2:44]1)[CH3:2]
Reactant: CCc1c(OC)ccc2c(O)cc(-c3nc(C(C)C)cs3)nc12
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Product: CCc1c(OC)ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc12

Procedure:
The title compound was prepared from 8-ethyl-4-hydroxy-2-(4-isopropylthiazole-2-yl)-7-methoxyquinoline (69) and intermediate 43 following the procedure (Steps D-F) reported for the preparation of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methyl-quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (46): m/z=661 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[O:13])=[CH:9][CH:10]=2)[N:5]([C:27]2[N:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][N:28]=2)[CH:4]=1.C[OH:40]>ClCCl>[CH3:1][S:2]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([N:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:18][CH2:19]3)=[O:13])=[CH:9][CH:10]=2)[N:5]([C:27]2[N:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:31][N:32]=2)[CH:4]=1)=[O:40]
Reactant: CO
Reactant: CSc1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)ccc12
Solvent: ClCCl
Product: CS(=O)c1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)ccc12
Yield: 54 %

Procedure:
Obtained from 12c) (300 mg, 0.56 mmol) according to the general procedure 2. The preparative TLC was performed with 3% methanol in dichloromethane as eluent. White solid. Yield: 170 mg (54% yield).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].Cl[CH2:6][C:7]([C:9](=[N:15][O:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[O:4]1[C:7]([C:9](=[N:15][O:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][S:1][CH2:2][CH2:3]1
Reactant: OCCS
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=NOC)C1=CSCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 798.4 %

Procedure:
To a stirred solution of 2-mercaptoethanol (7.8 g.) and ethyl 2-(2-chloroacetyl)-2-methoxyiminoacetate (2.08 g.) in dry chloroform (200 ml.) was added a solution of triethylamine (11 g.) in dry chloroform (30 ml.) at 20° C., and stirred at the same temperature for 3 hours. The resultant solution was washed with 10% hydrochloric acid twice, a saturated aqueous solution of sodium hydroxide twice and water twice in turn, and dried over magnesium sulfate. The solution was concentrated in vacuo at 40° C., and the residue was dissolved in dry toluene (200 ml.). After adding p-toluenesulfonic acid (3 g.) to the solution, the solution was heated under reflux for 30 minutes while removing the produced water. The resultant solution was allowed to cool at room temperature and treated with activated charcoal, and then ethyl acetate (150 ml.) was added thereto. The solution was washed with a saturated aqueous solution of sodium bicarbonate and water twice in turn dried over magnesium sulfate, and then concentrated in vacuo at 40° C. to give ethyl 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetate (mixture of syn isomer and anti isomer, 18.5 g.), yellow oil.
Reaction SMILES: O[C:2]1[CH:10]=C[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11](Cl)(=[O:13])[CH3:12]>CO>[OH:13][C:11]1[CH:10]=[CH:2][C:3]([C:4]([OH:6])=[O:5])=[C:7]([CH3:8])[CH:12]=1
Reactant: O=C(O)c1ccccc1O
Reactant: CC(=O)Cl
Solvent: CO
Product: Cc1cc(O)ccc1C(=O)O
Temperature: 5 °C
Yield: 67.6 %

Procedure:
50 g (0.36 mole) of hydroxy-benzoic acid are dissolved in methanol in a 1 liter capacity Erlenmeyer. The mixture is cooled to a temperature of about 5° C. Thereafter, 70 ml (1 mole) of acetyl chlorine are added drop by drop and the mixture is left to return to ambient temperature. A magnetic stirring is carried out over a period of about ten hours. The methanol is then flushed out under vacuum, in the same way as the hydrochloric acid that is formed and the remaining acetyl chloride. 55 g of a solid brown product are recovered. At this step, the yield of the reaction is 99%. A recrystallization in ethanol produces 37 g of pure product, the melting point of which is 123° C. The overall yield of the reaction is 67%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].[CH3:16][CH2:17]O>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])c(F)cc1F
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1F
Temperature: 0 °C
Yield: 89 %

Procedure:
A solution of (2,4-difluoro-5-nitro-phenyl)acetic acid (16 g, 74 mmol) in EtOH (200 mL) and 98% H2SO4 (14 mL) was refluxed at 80′C for 2.5 h under a N2 atmosphere. The reaction mixture was poured into ice water, and the resultant solution was extracted with Et2O. The combined organic extracts were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography to give ethyl 2-(2,4-difluoro-5-nitrophenyl)acetate (16 g, 89% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.22 (t, J=8.1 Hz, 1H), 7.55 (t, J=11.1 Hz, 1H), 4.06 (m, 2H), 3.77 (s, 2H), 1.13 (t, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][C:12](=O)[CH2:13][CH2:14][C:15]2([CH3:22])[C:19](=[O:20])[CH2:18][CH2:17][C:16]2=O)[CH:6]=[CH:7][CH:8]=1.O>C1C=CC=CC=1>[CH3:22][C@:15]12[CH2:14][CH2:13][C:12]3[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH2:9][CH2:10][C:11]=3[C:16]1=[CH:17][CH2:18][C:19]2=[O:20]
Reactant: COc1cccc(CCCC(=O)CCC2(C)C(=O)CCC2=O)c1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)C(=O)CC=C12
Yield: 75.2 %

Procedure:
To 2-(6-m-methoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione (3 g) in benzene (100 cc) add polyphosphoric acid (from orthophosphoric acid, 15 g. and phosphorus pentoxide, 6 g.) and heat the mixture at 90° for 4 minutes under such reduced pressure as the need to control frothing will allow. Cool, add water, and extract the mixture with ether and ethyl acetate; isolate the product from the resulting solution to obtain the colorless crystalline 13β-methyl-3-methoxygona-1,3,5(10), 8,14-pentaen-17-one (2 g), b.p. 115°-116°; ultraviolet absorption peak at 313 mμ (ε35,100).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[NH:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[C:30]([O:34][C:35](=[O:45])[NH:36][C:37]1([CH2:43]O)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35](=[O:45])[NH:36][C:37]1([CH2:43][N:19]2[C:18](=[O:23])[C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)[S:21][C:20]2=[O:22])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: O=C1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)NC1(CO)CCOCC1
Product: CC(C)(C)OC(=O)NC1(CN2C(=O)SC(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CCOCC1

Procedure:
(4-{5-[1-(4-Chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-ylmethyl}tetrahydro-2H-pyran-4-yl)carbamic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]thiazolidine-2,4-dione and (4-hydroxymethyltetrahydro-2H-pyran-4-yl)carbamic acid tert-butyl ester following General Procedure J.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[CH:19][N:20]2[C:25]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)([CH2:30][CH3:31])[C:26]([O:28][CH3:29])=[O:27])=O)(C)(C)C>C(Cl)Cl>[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[CH:19][N:20]2[C:25]([C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1)([CH2:30][CH3:31])[C:26]([O:28][CH3:29])=[O:27]
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (37.5 mL, 487 mmol) was added rapidly dropwise to a stirred solution of 3a (8.62 g, 19.5 mmol) in DCM (100 mL) at 0° C. After 1 h, the reaction was quenched by careful addition of saturated aqueous sodium bicarbonate, followed by NaHCO3(s) and extracted with ether. The organics were washed with saturated aqueous sodium bicarbonate, dried (MgSO4), filtered and concentrated in vacuo to afford the title compound 3b. m/z (ES) 343 (MH)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][CH2:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[N-:29]=[N+:30]=[N-:31].[Na+].Cl.N1C=CC=CC=1>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]3[NH:31][N:30]=[N:29][N:24]=3)=[CH:25][CH:26]=2)=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(CCc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: c1ccc2nc(COc3ccc(CCc4ccc(-c5nnn[nH]5)cc4)cc3)ccc2c1
Temperature: 110 °C

Procedure:
A mixture of 0.35 g (0.96 mmol) of 4-(4-(2-quinolinylmethyloxy)phenethyl)benzonitrile, 0.31 g (4.8 mmol, 5 equiv.) of sodium azide, and 0.55 g (4.8 mmol, 5 equiv.) of pyridine hydrochloride in 15 ml of DMF are heated at 110° C. for 48 hours. The mixture is poured into ice water and the precipitate that forms filtered off and recrystallized from methanol-water to obtain 5-(4-(4-(2-quinolinylmethyloxy) phenethyl)phenyl)tetrazole. (M.P. 203° C.-206° C.)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH2:21][C:22]([NH2:24])=[NH:23]>>[NH2:23][C:22]([NH2:24])=[N:21][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[C:10]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)=[CH:11][C:2]=1[CH3:1]
Reactant: N=C(N)N
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(-n2cccc2)cc1C
Product: Cc1cc(-n2cccc2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N

Procedure:
in stage g) by reaction of methyl 2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzoate with guanidine to give the end-product N-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide, the guanidino group is introduced.
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:10][C:11](=[O:14])[CH2:12][NH2:13]>>[CH:1]1([NH:13][CH2:12][C:11]([OH:14])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CN
Reactant: O=C1CCCCCC1
Product: O=C(O)CNC1CCCCCC1

Procedure:
N-Cycloheptylglycine was synthesized by reductive amination of cycloheptanone with glycine methyl ester following the procedure described in Gera et al., Immunopharmacology. 33:174-177 (1996). The crude product was converted to the N-Boc derivative (mp, 89-90° C.).
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]([CH2:30]Br)[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:32]#[N:33].[Na+].C(OCC)(=O)C>CS(C)=O>[C:1]([O:9][CH2:10][CH:11]([CH2:30][C:32]#[N:33])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCCCOCC(CBr)COC(=O)c1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCCOCC(CC#N)COC(=O)c1ccccc1
Temperature: 90 °C
Yield: 100.6 %

Procedure:
A mixture of 13.845 g (27.9 mM) of 2-bromomethyl-3-n-hexadecyloxypropyl benzoate n3 and 1.439 g (27.9 mM) of sodium cyanide (95% purity) in 150 ml of dimethylsulfoxide is heated at 90° C. for 1 hour. Theproduct is isolated by ethyl acetate extraction. The ethyl acetate layer is washed with water (four times) and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated to obtain 12.42 g of the crude product of the titled compound n3'.
Reaction SMILES: [CH3:1][S:2]([NH:5][N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:27]([F:30])([F:29])[F:28])=[C:12]([N:17]3[CH:21]=[CH:20][C:19]([CH2:22][O:23]C(=O)C)=[CH:18]3)[CH:13]=2)[NH:8][C:7]1=[O:31])(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].P([O-])([O-])([O-])=O>CO>[OH:23][CH2:22][C:19]1[CH:20]=[CH:21][N:17]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][C:11]=2[C:27]([F:29])([F:28])[F:30])[NH:8][C:7](=[O:31])[N:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:15]3=[O:16])[CH:18]=1
Reactant: CC(=O)OCc1ccn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(CO)c3)cc2c1=O
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of 100 mg (0.22 mmol) of acetic acid 1-(3-methanesulfonylamino-2,4-dioxo-7 -trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-pyrrol-3-ylmethyl ester in 0.5 ml of methanol are added 36.4 mg (0.26 mmol) of potassium carbonate and the reaction mixture is stirred at 55° C. for 8 hours. The mixture is cooled to room temperature and stirred for another 12 hours. Subsequently a pH 7 phosphate buffer solution for neutralization is added to the reaction mixture and the solvents are evaporated carefully (risk of degradation). The crude residue is purified by preparative thin layer chromatography (dichloromethane/methanol, 8/2) to yield N-[6-(3-hydroxymethyl-pyrrol-1-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide: 1H-NMR; DMSO-d6 (400 MHz, ppm): 7.82 (s, 1H , aromatic); 7.64 (s, 1H , aromatic); 6.86 (m, 1H, N-CH═CH in pyrrol); 6.84 (s, 1H, N-CH═C(CH2) in pyrrol); 6.21 (m, 1H, CH═CH-C(CH2)-N in pyrrol); 4.37 (d, 2H, CH2-OH); 3.16 (s, 3H, S02-CH3); LC-MS: 417 [M-H]-; Agilent LC/MSD 1100 Series, LC-MS method: Column: SunFireC18, 4.6*50 mm, 3.5 μm; negative MS; water/acetonitril 95:5 to 5:95 in 5 min, flow: 1.5 ml/min.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCc1ccc(Cl)cc1
Product: Clc1ccc(CNc2nccc(-n3cnc4ccccc43)n2)cc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 4-chlorobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 336.0 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.59 (s, 1H); 8.43 (d, J=4.6 Hz, 1H); 8.02 (br s, 1H); 7.86 (m, 1H); 6.86 (d, J=5.5 Hz, 1H); 5.79 (br s, 1H ); 4.73 (d, J=5.9 Hz, 2H).
Reaction SMILES: CC1(C)O[C:6](=[O:8])[CH:5]=[C:4]([CH3:9])[O:3]1.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([CH2:21][NH:22][C:6](=[O:8])[CH2:5][C:4](=[O:3])[CH3:9])=[CH:19][CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)NCc1ccc(C(C)(C)C)cc1
Temperature: 130 °C
Yield: 55.9 %

Procedure:
2,2,6-Trimethyl-4H-1,3-dioxin-4-one (1.6 ml, 12.09 mmol) and (4-tert-butylphenyl)methanamine (2.0 ml, 11.36 mmol) were dissolved in toluene (2 ml) and heated at 130° C. for 28 hours. Reaction was cooled to room temperature and diluted with EtOAc (40 ml). The organic phase was washed with HCl (2*30 ml, 1M) and NaHCO3 (2*30 ml, sat aq), dried over MgSO4 and evaporated. The crude product was purified by precipitation from toluene/pet.ether to give 1.57 g (56%) of N-(4-tert-butylbenzyl)-3-oxobutanamide as a pale powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1.[N:31]1([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27][N:34]3[CH2:35][CH2:36][N:31]([C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=4)[CH2:32][CH2:33]3)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)cc1
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: COc1ccc(CNC(=O)C2(CCCCN3CCN(c4ccc5ccccc5n4)CC3)c3ccccc3-c3ccccc32)cc1

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-methoxy-benzylamide and 2-piperazin-1-yl-quinoline.