Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].[H-].[Na+].I[CH3:15].O>CN(C)C=O>[CH3:5][C:2]([C:6]1[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=1)([CH3:1])[CH2:3][O:4][CH3:15]
Reactant: CI
Reactant: CC(C)(CO)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(C)(C)c1ccncc1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-(1,1-dimethyl-2-hydroxyethyl)pyridine (15 g) in dry dimethylformamide (150 ml) was treated with sodium hydride (80% oil dispersion; 3.3 g) under nitrogen at 0° C. with stirring. After 15 minutes at 0° C., this mixture was cooled to -20° C., and a solution of iodomethane (7.4 ml) in dry dimethylformamide (50 ml) was added dropwise during 5 minutes. The mixture which changed from a white to an orange precipitate was allowed to slowly warm to ambient temperature, and stirred overnight under nitrogen. After pouring into excess water, the mixture was extracted with three portions of dichloromethane. The extract was washed with water twice, dried over anhydrous magnesium sulphate and evaporated in vacuo to give a dark oil after further evaporation of added toluene. This oil was chromatographed on silica gel (Merck; 0.04-0.063 mm) under medium pressure using a mixture of dichloromethane and ethyl acetate (2:1) as solvent to give 4-(1,1-dimethyl-2-methoxyethyl)pyridine (11.0 g) as a brown oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]([CH2:23][CH3:24])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].CO>C1COCC1>[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:13]([NH:12][C:10]3[N:9]([CH2:23][CH3:24])[C:8]4[CH:25]=[CH:26][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=4[N:11]=3)[S:14][C:15]=2[CH:21]=1
Reactant: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Yield: 90 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid (803.0 mg) was prepared by following General Procedure E starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid methyl ester (926.0 mg) and sodium hydroxide (2.0 N solution, 2.0 mL) MeOH (1.0 mL) and THF (2.0 mL).
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C>N1C=CC=CC=1>[C:22]([O:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1C(=Cc2ccc3c(c2)OCO3)Oc2cc(O)ccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Oc1ccc2c(c1)OC(=Cc1ccc3c(c1)OCO3)C2=O)c1ccccc1
Temperature: 25 °C

Procedure:
After 6-hydroxy-2-piperonylidene-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, benzoyl chloride 0.282 ml was added, and the mixture was refluxed for two hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml twice. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The crude extract was dissolved in ethyl acetate 10 ml and hexane 20 ml, and the precipitated crystals were dried over phosphorous pentoxide at a temperature of 60° C. for six hours under reduced pressure to obtain the desired compound 182.3 mg.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH2:19][C:20]#[N:21])=[CH:15][NH:16]2)=[CH:12][CH:11]=1)([O-:9])=[O:8].[CH3:22]I.O>CN(C)C=O>[CH3:22][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([N+:7]([O-:9])=[O:8])[CH:18]=2)[C:14]([CH2:19][C:20]#[N:21])=[CH:15]1
Reactant: CI
Reactant: N#CCc1c[nH]c2cc([N+](=O)[O-])ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(CC#N)c2ccc([N+](=O)[O-])cc21
Reaction time: 0.67 h
Yield: 98.8 %

Procedure:
65.5 g (0.474 mol) of powdered potassium carbonate was added to a solution of 28.9 g (0.143 mol) of (6-nitro-1H-indol-3,yl)-acetonitrile (13) from Step C above in 230 ml of dimethylformamide at room temperature. The suspension was stirred for 40 minutes then 25.48 g (0.179 mol) of methyl iodide was added dropwise over 65 minutes. After stirring at room temperature over night the reaction mixture was cooled and poured into a total of 600 ml of water. The precipitate was filtered, washed with a little water and dried on phosphor anhydride until reaching constant weight. The procedure yielded 30.4 g (95.4%) of (1-methyl-6-nitro-1H-indol-3-yl)acetonitrile (14), which was used without further purification.
Reaction SMILES: CC(C1C=CC(=C)CC1)C.[CH3:11][C:12]1[CH:17]=[CH:16][C@@H:15]([C@H:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH3:19])[CH2:14][CH:13]=1.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([CH2:35][CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])[CH3:34])=[CH:29][CH:28]=1>>[CH3:11][C:12]1[CH:13]=[CH:14][C@@H:15]([C@H:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:24])[CH3:25])[CH3:19])[CH2:16][CH:17]=1.[CH3:26][C:27]1[CH:28]=[CH:29][C@@H:30]([C@@H:33]([CH2:35][CH2:36][CH:37]=[C:38]([CH3:39])[CH3:40])[CH3:34])[CH2:31][CH:32]=1
Reactant: CC(C)=CCCC(C)c1ccc(C)cc1
Agent: C=C1C=CC(C(C)C)CC1
Agent: CC(C)=CCC[C@H](C)[C@@H]1C=CC(C)=CC1
Product: CC(C)=CCC[C@@H](C)[C@@H]1C=CC(C)=CC1

Procedure:
β-phellandrene, zingiberene and curcumene were not commercially available and had to be synthesised. Zingiberene and R-curcumene were isolated from ginger oil and 7-epi zingiberene and S-curcumene from S. habrochaites (PI27826) leaf material after Millar (1998, J. Nat. Prod 61, 1025).
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9]1[CH:10]=[C:11]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:12]2[N:13]([C:15]([CH3:18])=[N:16][N:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][CH2:29][CH2:30]Br.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH2:1]([N:8]([CH3:26])[C:9]1[CH:10]=[C:11]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:30][CH2:29][O:28][CH3:27])[CH2:22][CH2:21]2)[C:12]2[N:13]([C:15]([CH3:18])=[N:16][N:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nnc2c(NC3CCNCC3)cc(N(C)Cc3ccccc3)nn12
Reactant: COCCBr
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCC(Nc2cc(N(C)Cc3ccccc3)nn3c(C)nnc23)CC1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
N6-Benzyl-3,N6-dimethyl-N8-piperidin-4-yl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (0.05 g; 0.11 mmol) was slurred up in 0.3 ml DMA. 2-bromoethyl methyl ether (0.01 ml; 0.14 mmol) and DIPEA (0.04 ml; 0.23 mmol) were added and stirred at 50° C. for 16 hours. The crude material was purified by using reversed phase chromatography under basic conditions.
Reaction SMILES: [CH3:1][CH:2]([C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH:14]([NH:19][S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13]2)=[O:9])[CH2:3][C:4]([O:6]C)=[O:5].[OH-].[Na+]>>[CH3:1][CH:2]([C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH:14]([NH:19][S:20]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21])[CH2:13]2)=[O:9])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COC(=O)CC(C)C(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Agent: [Na+]
Agent: [OH-]
Product: CC(CC(=O)O)C(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2

Procedure:
Prepared analogously to Example 2 from methyl 3-methyl-4-(2-benzenesulphonamido-indan-5-yl)-4-oxobutyrate by hydrolysis with sodium hydroxide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([C:11]([OH:19])=[C:12]([C:17]#[N:18])[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1>C(O)CCC>[NH2:18][C:17]1[N:8]([CH2:9][CH3:10])[C:6]2[C:5]([C:11](=[O:19])[C:12]=1[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=2
Reactant: CCNc1nc(Cl)ccc1C(O)=C(C#N)C(=O)NC
Solvent: CCCCO
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Yield: 56.5 %

Procedure:
A solution of 19.0 g (49.8 mmol) of the crude product obtained from step 1.4 in 600 ml of n-butanol is heated for 48 hours at 110° C. The solvent is evaporated off under reduced pressure and the solid obtained is triturated in methanol. The solid is then filtered off and oven-dried. 7.9 g of the expected product are obtained in the form of a pale yellow solid. Yield=57%. Melting point: 283-286° C. MH+: 281.2 (tr=6.99 min., condition 1).
Reaction SMILES: [C:1]([CH:3]([O:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([F:19])[C:17]=1[F:18])[O:14][CH:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:11]2)[CH2:4][CH2:5][CH3:6])#[CH:2]>C(N(CC)C1C=CC=CC=1)C.CC(OC)(C)C>[F:19][C:16]1[C:17]([F:18])=[C:8]2[C:9]([CH:2]=[CH:1][CH:3]([CH2:4][CH2:5][CH3:6])[O:7]2)=[C:10]2[CH2:11][CH2:12][CH:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:14][C:15]=12
Reactant: C#CC(CCC)Oc1cc2c(c(F)c1F)OC(CCCCC)CC2
Solvent: COC(C)(C)C
Solvent: CCN(CC)c1ccccc1
Product: CCCCCC1CCc2c3c(c(F)c(F)c2O1)OC(CCC)C=C3

Procedure:
9.0 g (26.8 mmol) of 6-(1-ethynylbutoxy)-7,8-difluoro-2-pentylchroman are heated at 205° C. for 3 h in 90 ml of N,N-diethylaniline. The batch is diluted with MTBE and washed a number of times with 3 N HCl. The organic phase is dried using sodium sulfate and evaporated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:MTBE=4:1), giving 5,6-difluoro-3-pentyl-8-propyl-1,2,3,8-tetrahydropyrano[3,2-f]-chromene as a pale-brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:15][C:16]3[C:21]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])=[CH:20][C:19]([N+:28]([O-])=O)=[CH:18][C:17]=3[CH3:31])=[O:14])=[CH:11][C:10]([C:32]([F:35])([F:34])[F:33])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl.[Zn]>[NH2:28][C:19]1[CH:20]=[C:21]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:16]([NH:15][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([C:32]([F:35])([F:34])[F:33])[CH:11]=2)=[O:14])=[C:17]([CH3:31])[CH:18]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: [Zn]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)cc(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Zinc dust (90 mg, 1.4 mmol) was added to a solution of the product from Step C (70 mg, 0.14 mmole) and trifluoroacetic acid (2 mL) at 70° C. Some foaming occurred. After 10 minutes at 70° C., the mixture was cooled to 25° C., diluted with dichloromethane, and filtered. The filtrate was concentrated to remove most of the trifluoroacetic acid and the resulting residue was dissolved in acetonitrile (3 mL) and 1,2-dichloroethane (3 mL). The resulting solution was treated with strongly-basic ion exchange resin (Dowex® 550A, OH− form, 2 g), shaken for 1 hour and then filtered. Concentration of the filtrate gave the title compound, a compound of the invention, as a yellow solid.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[CH2:1]([N:5]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])[S:36]([C:33]1[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=1)(=[O:38])=[O:37])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccc(F)cc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCN(c1ccc(F)cc1F)S(=O)(=O)c1ccc(C)cc1
Temperature: 90 °C
Reaction time: 48 h
Yield: 68.4 %

Procedure:
A solution of 14.8 g of N-butyl-2,4-difluoroaniline, 16.2 g of triethylamine and 0 5 g of dimethylaminopyridine in 150 ml of toluene is treated dropwise at 0-5° C. with a solution of 15.2 g of p-toluenesulphonyl chloride in 80 ml of toluene. The reaction mixture is then warmed to 90° C. and stirred at this temperature for 48 hours. After cooling, the mixture is washed with 5% strength HCl and with water, and the toluene solution is dried over Na2SO4 and evaporated. The residue is distilled at 0.01 mbar. 18.5 g of N-butyl-N-(2,4-difluorophenyl)-p-toluenesulphonamide are obtained at 150°-160° as a colourless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:20][C@H:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:22][OH:23])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[CH3:31][S:32](O)(=[O:34])=[O:33].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[F:9][C:7]1[CH:8]=[C:3]([CH2:2][NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[C:4]([NH:20][C@H:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:22][OH:23])=[N:5][C:6]=1[NH:10][C:11]1[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[NH:13][N:12]=1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cc3)c(CN)cc2F)n[nH]1
Reactant: CS(=O)(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cc3)c(CNS(C)(=O)=O)cc2F)n[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A round bottom flask was charged with (R)-2-(3-(aminomethyl)-5-fluoro-6-(5-isopropoxy-1H-pyrazol-3-ylamino)pyridin-2-ylamino)-2-(4-fluorophenyl)ethanol (Example 13; 0.10 g, 0.24 mmol), methanesulfonic acid loaded TFP resin (0.9 mmol/g loading, 0.24 mmol), DIEA (0.062 g, 0.48 mmol), DMAP (0.032 g, 0.26 mmol), and THF (5 ml). The resulting suspension was shaken vigorously at 60° C. for 8 hrs and filtered. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.075 g, 63%). 1H NMR (400 MHz, CD3OD) δ 7.48-7.45 (m, 2H), 7.20 (d, J=10.9 Hz, 1H), 7.05-7.01 (m, 2H), 5.30 (s, 1H), 5.04-5.01 (m, 1H), 4.56-4.53 (m, 1H), 4.20 (d, J=14.4 Hz, 1H), 4.12 (d, J=14.4 Hz, 1H), 3.86-3.73 (m, 2H), 3.01 (s, 3H), 1.32 (d, J=6.0 Hz, 3H). MS: Calcd.: 496. Found: [M+H]+ 497.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]=[N:7]2>C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][NH:7]2
Reactant: O=c1cnc2cc(Cl)ccc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CNc2cc(Cl)ccc2N1

Procedure:
Sodium borohydride (5.10 g) is added to a mixture of 6-chloro-1,2-dihydroquinoxalin-2-one (5.60 g), and ethanol (200 ml). The resultant solution is stirred for 2.5 hr at 20°-25°. The material is partitioned between water and ethyl acetate, the phases are separated, the organic phase is dried over magnesium sulfate and concentrated under reduced pressure to give a solid which is recrystallized from ethyl acetate/hexane to give the title compound, mp 171-174° ; IR (mineral oil) 2953, 2925, 1687, 1517, 1408, 1307 and 1299 cm-1 ; NMR (CDCl3 -MeOD) 6.6-6.8 and 3.95 δ; MS (m/z) 182, 153.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:33])=[C:4]([N:8]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+].C1C=CC2N(O)N=[N:42]C=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([CH3:33])=[C:4]([N:8]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:24])=[O:25])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH2:42])=[O:20])=[CH:21][CH:22]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2ccc(C(=O)O)cc2)c2cccc(Cl)c2C)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2ccc(C(N)=O)cc2)c2cccc(Cl)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
185 mg of 4-[({N-(3-chloro-2-methylphenyl)-N-[(4-methylphenyl)sulfonyl]glycyl}amino)methyl]benzoic acid, 25 mg of ammonium chloride, and 62 mg of HOBt were dissolved in 2.00 mL of DMF, and 78 mg of WSC was added thereto, followed by stirring at room temperature overnight. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was washed with water, an aqueous sodium hydrogen carbonate solution, and water, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:80 to 0:100) to obtain a product, which was recrystallized from ethanol/water (95:5) to obtain 89 mg of 4-[({N-(3-chloro-2-methylphenyl)-N-[(4-methylphenyl)sulfonyl]glycyl}amino)methyl]benzoic acid amide.
Reaction SMILES: [F:1][CH:2]([F:14])[CH2:3][N:4]1[CH2:8][CH:7]([C:9]([OH:11])=O)[N:6]([CH3:12])[C:5]1=[O:13].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N1CCOCC1)C.[Cl:46][C:47]1[CH:52]=[C:51]([Cl:53])[CH:50]=[CH:49][C:48]=1[CH2:54][NH2:55]>ClCCl>[Cl:46][C:47]1[CH:52]=[C:51]([Cl:53])[CH:50]=[CH:49][C:48]=1[CH2:54][NH:55][C:9]([CH:7]1[CH2:8][N:4]([CH2:3][CH:2]([F:1])[F:14])[C:5](=[O:13])[N:6]1[CH3:12])=[O:11]
Reactant: CN1C(=O)N(CC(F)F)CC1C(=O)O
Reactant: NCc1ccc(Cl)cc1Cl
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)N(CC(F)F)CC1C(=O)NCc1ccc(Cl)cc1Cl
Reaction time: 0.17 h
Yield: 11.4 %

Procedure:
A mixture of 1-(2,2-difluoroethyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid (125 mg, 0.6 mmol), 1-hydroxybenzotriazole hydrate (110 mg, 0.720 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (138 mg, 0.720 mmol) and N-ethylmorpholine (0.305 ml, 2.400 mmol) in dichloromethane (5 ml) was stirred for 10 minutes. [(2,4-Dichlorophenyl)methyl]amine (106 mg, 0.600 mmol) was added and the solution was stirred at room temperature for 3 days. The reaction mixture was diluted with dichloromethane (10 ml), washed with saturated sodium hydrogen carbonate solution (10 ml), water (10 ml) and brine (10 ml). The organic phase was dried (magnesium sulphate) and evaporated. The residue was purified by the mass-directed automated HPLC. The fraction containing the desired product was evaporated and the residue was triturated with diethyl ether and dried to give N-[(2,4-dichlorophenyl)methyl]-1-(2,2-difluoroethyl)-3-methyl-2-oxo-4-imidazolidinecarboxamide (25 mg). LC/MS [M+H]+=366, retention time=2.09 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.[CH3:23][O:24][CH2:25][CH2:26]O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>C1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH2:26][CH2:25][O:24][CH3:23])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: COCCO
Reactant: O=C(O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: COCCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Yield: 100.5 %

Procedure:
3.3 g of 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetic acid and 1.5 g of 2-methoxyethanol were dissolved in 50 ml of benzene, followed by addition of 0.5 g of p-toluene sulfonic acid. Then, the mixture was heated under reflux for 3 hours. After completion of the reaction, to the reaction mixture was added 50 ml of ether. The resulting mixture was washed with water by the customary method and dried over anhydrous sodium sulfate, followed by evaporation-removal of the solvent under reduced pressure, thereby to obtain 3.9 g of 2-methoxyethyl 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetate.
Reaction SMILES: C([N:4]([S:26]([CH3:29])(=[O:28])=[O:27])[N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:21]([F:24])([F:23])[F:22])=[C:11]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:12]=2)[NH:7][C:6]1=[O:25])(=O)C>Cl>[CH3:29][S:26]([NH:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:21]([F:22])([F:24])[F:23])=[C:11]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:12]=2)[NH:7][C:6]1=[O:25])(=[O:28])=[O:27]
Reactant: CC(=O)NCc1cc2c(=O)n(N(C(C)=O)S(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Agent: Cl
Product: CC(=O)NCc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Yield: 8 %

Procedure:
A solution of N-[3-(acetyl-methanesulfonyl-amino)-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-ylmethyl]-acetamide (305 mg, 0.70 mmol) in 2M aq HCl (5 mL) was stirred at 80° C. for 1 d. Subsequently, the solvent was evaporated and the crude product was purified by preparative thin-layer chromatography (DCM/MeOH 8/2) to yield N-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-ylmethyl)-acetamide (22 mg, 0.056 mmol, 8%) as a light beige solid. 1H-NMR (DMSO-d6, 400 MHz) 3.13 ppm (s, 3H, SO2—CH3); LC-MS rt=2.35 min; MS: m/z 394.9 [M+H]+ Column: SunFireC18, 4.6*50 mn, 3.5 um; Positive MS Water/Acetonitrile 95:5 to 5:95 in 5 min, Flow: 1.5 mL/min
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][NH2:27]>>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:27][CH2:26][CH2:25][C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: NCCc1cccs1
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Product: Clc1nc(SCc2ccccc2)nc2nc(NCCc3cccs3)sc12

Procedure:
Prepared by the method of Example 231, using the product of Example 219 and 2-(2-thienyl)ethylamine.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][C:26]([C:31]([N:33]2[CH2:38][CH2:37][C:36]([F:40])([F:39])[CH2:35][CH2:34]2)=[O:32])=[CH:25]3)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[F:40][C:36]1([F:39])[CH2:37][CH2:38][N:33]([C:31]([C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([O:21][CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[CH:30][CH:29]=3)=[O:32])[CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc2cc(OC3CCNCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (4.13 mL, 10.0 eq.) was added to a cold (0° C.) solution of 4-[2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (example 43, step 5, 2.5 g, 1.0 eq.) in dichloromethane (20 mL). The mixture was stirred for 1 h at room temperature, evaporated to dryness and purified on silica gel, eluting with dichloromethane/methanol/ammonium hydroxide 95:5:0.25, to yield 1.7 g (86%) from the desired product as white solid. MS (m/e): 364.4 (MH+, 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[O:6][CH:5]([C:7]([NH:9][C:10]2[C:11]([I:37])=[C:12]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[C:13]([I:31])=[C:14]([C:29]=2[I:30])[C:15]([NH:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][O:21][C:22](=[O:24])[CH3:23])=[O:16])=[O:8])[CH2:4][O:3]1.C(=O)([O-])[O-].[C:43]([O:46][CH2:47][CH2:48]Br)(=[O:45])[CH3:44].O>CS(C)=O>[C:43]([O:46][CH2:47][CH2:48][N:9]([C:10]1[C:11]([I:37])=[C:12]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[C:13]([I:31])=[C:14]([C:29]=1[I:30])[C:15]([NH:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][O:21][C:22](=[O:24])[CH3:23])=[O:16])[C:7]([CH:5]1[CH2:4][O:3][C:2]([CH3:38])([CH3:1])[O:6]1)=[O:8])(=[O:45])[CH3:44]
Reactant: CC(=O)OCCBr
Reactant: CC(=O)OCc1c(I)c(NC(=O)C2COC(C)(C)O2)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)OCCN(C(=O)C1COC(C)(C)O1)c1c(I)c(COC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Temperature: 45 °C
Reaction time: 17 h

Procedure:
5-(2,2-Dimethyl-1,3-dioxolane-4-carboxamido)-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide (0.44 g, 0.50 mmol) was dissolved in dimethylsulfoxide (3 ml) and cesmium carbonate (0.33 g, 1.0 mmol) was added. 2-Bromoethyl acetate (0.25 g, 2.5 mmol) was added dropwise. The mixture was stirred at 45° C. for 17 h then added slowly into water (50 ml). A precipitate was formed, filtered off and the filtercake was dissolved in chloroform (60 ml). The organic phase was washed with water (2×30 ml), then dried (Na2SO4) and evaporated to a solid product. Yield: 0.46 g (93%).