Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:20])[CH:12]=[C:13](N2CCCC2)[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:21][CH2:22][O:23][C:24](/[C:26](/Cl)=[N:27]\[OH:28])=[O:25].O>ClCCl>[CH3:14][C:13]1[O:28][N:27]=[C:26]([C:24]([O:23][CH2:22][CH3:21])=[O:25])[C:12]=1[C:11](=[O:20])[NH:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CC(=CC(=O)Nc1ccc([N+](=O)[O-])cc1)N1CCCC1
Reactant: CCOC(=O)/C(Cl)=N\O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1noc(C)c1C(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
A suspension of 12.38 g (45 mmol) of the crude N-(4-nitrophenyl)-3-pyrrolidyl-2-butenamide in 200 ml of dry dichloromethane was cooled to 0° C. and 7.50 g (49.5 mmol) of ethyl chlorooximidoacetate were added in one portion. The reaction mixture was stirred at -5° C. to 0° C. for 2 hours and was then poured into 200 ml of water. The aqueous layer was extracted with 100 ml of dichloromethane and the combined organic extract was washed with 100 ml of 10% HCl, 5% NaHCO3 solution and then dried over MgSO4. Evaporation of the solvent gave 10.91 g (76%) of ethyl 5-methyl-4-[N-(4-nitrophenyl)]carbamoyl-3-isoxazolecarboxylate as a white crystalline solid melting at 151°-53° C. (from ethyl acetate);
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:31][O:32][CH2:33][CH3:34])[N:21]([CH2:22][C:23]([CH3:30])([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][C:13]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43](=[O:66])[CH2:44][CH2:45][S:46]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:12][C:11]=2[N:10]=1.C([SiH](CC)CC)C>ClCCl>[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:31][O:32][CH2:33][CH3:34])[N:21]([CH2:22][C:23]([CH3:30])([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][C:13]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43](=[O:66])[CH2:44][CH2:45][SH:46])=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCCCCCCNC(=O)CCSC(c4ccccc4)(c4ccccc4)c4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCCCCCCNC(=O)CCS)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Reaction time: 1 h
Yield: 3.3 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a 0° C. solution of N-{6-[(4-amino-2-(ethoxymethyl)-1-{2-methyl-2-[(methylsulfonyl)amino]propyl}-1H-imidazo[4,5-c]quinolin-7-yl)oxy]hexyl}-3-(tritylthio)propanamide (0.22 g, 2.63 mmol) and triethylsilane (0.46 mL, 2.89 mmol) in dichloromethane (7 mL). The solution was stirred for 1 hour; then additional triethylsilane (0.05 mL) was added. After an additional hour at 0° C., the solution was concentrated under reduced pressure. The residue was concentrated under reduced pressure from ethyl acetate and toluene. The material was purified by HPFC on silica gel (gradient elution with 25-100% CMA in chloroform) and then subjected to the procedure described in Part D of the synthesis of IRM Compound 1 to provide 51 mg of N-{6-[(4-amino-2-(ethoxymethyl)-1-{2-methyl-2-[(methylsulfonyl)amino]propyl}-1H-imidazo[4,5-c]quinolin-7-yl)oxy]hexyl}-3-mercaptopropanamide, mp 152-157° C. MS (ESI) m/z 595 (M+H)+. Anal. Calcd for C27H42N6O5S2: C, 54.52; H, 7.12; N, 14.13; S, 10.78. Found: C, 54.41; H, 7.13; N, 13.85; S, 10.63.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH3:16])[CH:8]=[CH:7]1)(C)(C)C.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)[N:21]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:16][O:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[NH:6][CH:7]=[C:8]2[C:24]1[CH:25]=[CH:20][N:21]=[C:22]([NH:26][CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)[N:23]=1
Reactant: COc1cccc2ccn([Si](C)(C)C(C)(C)C)c12
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COc1cccc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)c[nH]c12

Procedure:
The title compound was prepared as described in Example 215, starting from 1-(tert-butyl-dimethyl-silanyl)-7-methoxy-1H-indole (prepared by TBDMS protection of 7-methoxy-1H-indole) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by in situ cleavage of the TBDMS protecting group with catalytic amounts of TBAF. Yield: 660 mg (93%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([OH:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20]1([CH3:34])[CH2:25][CH2:24][C:23]2[CH:26]=[C:27]([S:30](Cl)(=[O:32])=[O:31])[CH:28]=[CH:29][C:22]=2[O:21]1>O.C(#N)C>[CH3:19][C:20]1([CH3:34])[CH2:25][CH2:24][C:23]2[CH:26]=[C:27]([S:30]([N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][C@H:2]3[C:10]([OH:12])=[O:11])(=[O:32])=[O:31])[CH:28]=[CH:29][C:22]=2[O:21]1
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1
Reactant: CC1(C)CCc2cc(S(=O)(=O)Cl)ccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC1(C)CCc2cc(S(=O)(=O)N3c4ccccc4C[C@H]3C(=O)O)ccc2O1
Yield: 73 %

Procedure:
1 g (6.13 mmol) of 2,3-dihydro-(2S)-1H-indole-2-carboxylic acid, and 0.97 g (7.05 mmol) of potassium carbonate are solubilised in 2 ml of water. 1.6 g (6.13 mmol) of 3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-sulfonyl chloride solubilised in 12 ml of acetonitrile and 2 ml of water are added. Agitation is allowed to take place for 5 hours at ambient temperature. Water is added to the reaction medium, washing is performed with ethyl acetate, the acidity of the aqueous phase is raised to pH 3 by a solution of hydrochloric acid 1 N, and then extraction is performed using ethyl acetate. The organic phases are collected, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by silica column chromatography eluting with the help of a dichloromethane/methanol (9/1; v/v) mixture. The expected product is obtained in the form of a beige foam with a yield of 73%.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[CH2:12][CH2:13][NH:14][CH2:15][CH:16]([OH:39])[C:17]1[CH:22]=[CH:21][C:20]([O:23]CC2C=CC=CC=2)=[CH:19][C:18]=1[O:31]CC1C=CC=CC=1.[H][H]>C(O)(C)C.O.[C].[Pd]>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[CH2:12][CH2:13][NH:14][CH2:15][CH:16]([OH:39])[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[OH:31]
Reactant: [H][H]
Reactant: COc1ccc(CCNCC(O)c2ccc(OCc3ccccc3)cc2OCc2ccccc2)cc1OC
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(CCNCC(O)c2ccc(O)cc2O)cc1OC
Yield: 92.7 %

Procedure:
0.6 g of α-(3,4-dimethoxyphenethylaminomethyl)-2,4-dibenzyloxybenzylalcohol oxalate is suspended in a mixture of 40 ml of isopropanol and 10 ml of water. 0.2 g of 10 % palladium-carbon are added to the suspension. Then, the mixture is subjected to catalytic hydrogenation in a hydrogen atmosphere at room temperature for 2 hours under atmospheric pressure. After the reaction is completed, the mixture is filtered to remove the catalyst. The filtrate is concentrated under reduced pressure, whereby 0.39 g of α-(3,4-dimethoxyphenethylaminomethyl)-2,4-dihydroxybenzylalcohol oxalate is obtained as amorphous powder. Yield: 93 %
Reaction SMILES: C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C@H:16]([CH3:21])[CH2:17][C:18](Cl)=[O:19])[CH:13]=[CH:14][CH:15]=1.C([C@H:25]1[CH2:30][CH2:29][C@H:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)CC>O>[CH:31]1([C:28]2[CH:27]=[CH:26][C:25]([C:18](=[O:19])[CH2:17][C@H:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH3:8])[CH:11]=3)[CH3:21])=[CH:30][CH:29]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: CCC[C@H]1CC[C@H](c2ccccc2)CC1
Reactant: COc1cccc([C@H](C)CC(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1cccc([C@H](C)CC(=O)c2ccc(C3CCCCC3)cc2)c1
Reaction time: 0.25 h

Procedure:
To a methylene chloride suspension of aluminum chloride, a methylene chloride solution of (R)-3-(3-methoxyphenyl)butyric acid chloride was added dropwise under ice cooling. After stirring at the same temperature for 15 minutes, a methylene chloride solution of trans-4-propylcyclohexylbenzene was added dropwise. After the completion of the reaction, the reaction system was added to iced water and the organic layer was separated by adding methylene chloride. The organic layer was washed twice with water and then washed with saturated brine. The aqueous layer was washed with methylene chloride and, after combining the organic layer, the solvent was concentrated to obtain a crude product of (R)-1-(4-cyclohexylphenyl)-3-(3-methoxyphenyl)-butan-1-one. The resulting crude product was purified by column chromatography and recrystallized from ethanol to obtain (R)-1-(4-cyclohexylphenyl)-3-(3-methoxyphenyl)-butan-1-one (R-isomer of the compound represented by the formula (XI-c)).
Reaction SMILES: C1CO[C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2O1.ClC1N=C(NC2CCCCC2)C(F)=CN=1.[CH2:42]1[CH2:52]OC2C=CC(N)=CC=2[O:43]1>>[CH:5]1([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]4[O:43][CH2:42][CH2:52][O:26][C:22]=4[CH:21]=3)[N:13]=2)[CH2:6][CH2:7][CH2:8][CH2:3][CH2:4]1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Fc1cnc(Cl)nc1NC1CCCCC1
Product: Fc1cnc(Nc2ccc3c(c2)OCCO3)nc1NC1CCCCC1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-cyclohexyl-5-fluoro-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to yield N4-cyclohexyl-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.62 (d, 1H, J=4.2 Hz), 7.31 (d, 1H, J=2.1 Hz), 6.86 (dd, 1H, J=2.4 and 8.7 Hz), 6.68 (d, 1H, J=8.7 Hz), 4.234.16 (m, 4H), 3.99–3.89 (m, 1H), 2.03 (dd, 2H, J=2.1 and 12.3 Hz), 1.80 (dt, 2H, J=3.0 and 13.5 Hz), 1.72–1.65 (m, 1H), 1.49–1.20 (m, 5H); 19F NMR (CD3OD): −48332; LCMS: ret. time: 24.54 min.; purity: 95%; MS (m/e): 345 (MH+).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[O:18][C:17]2=[O:24])=[CH:12][CH:11]=1)=O)(C)(C)C.Cl>CCOCC.O1CCOCC1>[NH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[O:18][C:17]2=[O:24])=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N2CC(C(=O)O)OC2=O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCc1ccc(N2CC(C(=O)O)OC2=O)cc1

Procedure:
3.36 g of 3-(4-tert-butoxycarbonylaminomethylphenyl)-2-oxo-5-oxazolidinecarboxylic acid [obtainable according to Example 14; m.p. 166°] are stirred at room temperature for 1 h in a mixture of 30 ml of ether and 30 ml of dioxane, which has been saturated beforehand with HCl gas. The precipitate is then filtered off with suction and washed with ether. 3-(4-Aminomethylphenyl)-2-oxo-5-oxazolidinecarboxylic acid is obtained, m.p. 211°-212°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH2:12][CH2:13][Br:14])[NH:7][CH2:6][CH2:5]2.[F:15][C:16]([F:21])([F:20])[C:17]([NH2:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31].O>CN(C)C=O>[CH3:28][N:29]([CH3:33])[C:30]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH2:12][CH2:13][Br:14])[NH:7][CH2:6][CH2:5]2)=[O:31].[F:15][C:16]([F:21])([F:20])[C:17]([NH2:19])=[O:18]
Reactant: CN(C)C(=O)Cl
Reactant: Oc1ccc2c(c1)CCN[C@@H]2CCBr
Agent: NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Oc1ccc2c(c1)CCN[C@@H]2CCBr
Yield: 50.1 %

Procedure:
To a solution of 6-hydroxy-1-(R)-(2-bromoethyl)-3,4-dihydro-1H-isoquinoline-trifluoroacetamide (270 mg, 0.77 mmol) obtained in step (d) of Example 190 and potassium carbonate (268 mg, 1.94 mmol) in dimethylformamide (3 ml) was added dimethylcarbamyl chloride (0.2 ml, 1.55 mmol) gradually with stirring under cooling in an ice bath. Subsequently, the resulting mixture was stirred at 40° C., and after confirming the disappearance of the starting material by thin layer chromatography, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (80:20) as the eluent to afford the title compound (170 mg, yield: 52%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH2:20][CH2:19][C:18](OS(C)(=O)=O)([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:16]3)[O:11][C:10]2=[O:32])=[CH:5][CH:4]=1)#[N:2].CS(Cl)(=O)=O.[N:38]1C=CC=CC=1>N.C(O)C.C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH2:20][CH2:19][C:18]([NH2:38])([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:16]3)[O:11][C:10]2=[O:32])=[CH:5][CH:4]=1)#[N:2]
Reactant: c1ccncc1
Reactant: CCOC(=O)CC1(OS(C)(=O)=O)CCN(CC2CN(c3ccc(C#N)cc3)C(=O)O2)CC1
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC1(N)CCN(CC2CN(c3ccc(C#N)cc3)C(=O)O2)CC1
Reaction time: 2 h

Procedure:
1 g of ethyl 1-(3-(4-cyanophenyl)-2-oxo-5-oxazolidinylmethyl)-4-methanesulfonyloxypiperidine-4-acetate (obtainable from the 4-hydroxy compound (see Example 13) with methanesulfonyl chloride/pyridine) is dissolved in a 2% NH3 solution in 10 ml of a 1:1 mixture of ethanol and THF, and the solution is left to stand at 20° for 2 hours. The solution is concentrated by evaporation and subjected to conventional work-up to give ethyl 1-(3-(4-cyanophenyl)-2-oxo-5-oxazolidinylmethyl)-4-aminopiperidine-4-acetate, FAB 387.
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1)[CH3:2].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[S:15]([O:8][CH2:7][C:3]1([CH2:1][CH3:2])[CH2:6][O:5][CH2:4]1)([C:12]1[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC1(CO)COC1
Solvent: c1ccncc1
Product: CCC1(COS(=O)(=O)c2ccc(C)cc2)COC1
Temperature: 0 °C
Yield: 90.2 %

Procedure:
116 g of 3-ethyl-3-hydroxymethyloxetane (Toa Gosei's trade name, OXT-101) was added to 500 ml of pyridine, and cooled to 0° C. with stirring. 190 g of p-toluenesulfonyl chloride divided into a few portions was added to it intermittently. Kept at 0° C., this was stirred for 5 hours, and then 1 L of ice-water was poured into the reaction mixture. This was extracted with 500 ml of diethyl ether. The diethyl ether layer was washed with 3% hydrochloric acid until its pH became acidic, and then washed with saturated sodium carbonate solution and water in this order, and thereafter dried with anhydrous magnesium sulfate. The solvent was evaporated away, and 243 g of 3-[(tosyloxy)methyl]-3-ethyloxetane was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:20]4[CH:27]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=5)[NH:25][C:21]=4[N:22]=[CH:23][N:24]=3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41].C(=O)(O)[O-].[K+].O>CN(C)C=O>[CH2:38]([N:39]([CH2:42][CH3:43])[CH2:40][CH2:41][O:34][C:31]1[CH:30]=[CH:29][C:28]([C:26]2[NH:25][C:21]3[N:22]=[CH:23][N:24]=[C:19]([O:18][C:15]4[CH:14]=[CH:13][C:12]([NH:11][C:9]([NH:8][C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=5)=[O:10])=[CH:17][CH:16]=4)[C:20]=3[CH:27]=2)=[CH:33][CH:32]=1)[CH3:37]
Reactant: CCN(CC)CCCl
Reactant: O=C(Nc1ccc(Oc2ncnc3[nH]c(-c4ccc(O)cc4)cc23)cc1)Nc1cccc(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(-c2cc3c(Oc4ccc(NC(=O)Nc5cccc(F)c5)cc4)ncnc3[nH]2)cc1
Reaction time: 16 h

Procedure:
After dissolving 114 mg of 1-(3-fluorophenyl)-3-{4-[6-(4-hydroxyphenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yloxy]phenyl}urea in 2 ml of dimethylformamide, there were added 44 mg (ca. 1 equivalent) of 2-chloroethyldiethylamine hydrochloride and 63 mg (2.5 equivalents) of potassium bicarbonate, and the mixture was stirred at 50–60° C. for 16 hours. There were then added 17 mg of 2-chloroethyldiethylamine hydrochloride, 20 mg of potassium bicarbonate and 1 ml of dimethylformamide, and the mixture was stirred overnight at the same temperature. It was then returned to room temperature, water was added, and liquid separation and extraction were performed with ethyl acetate-tetrahydrofuran. The organic layer was washed with water and saturated brine, concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 33 mg of a crude solid containing the title compound. This was washed with ethyl acetate to obtain 5 mg of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[CH:27]=[CH:26][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH:19]=[C:18]3[C:24]#[N:25])=[O:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[C:24]([C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([CH2:14][CH2:13][NH:12][C:10](=[O:11])[C:9]3[CH:8]=[CH:7][C:6]([C:3]([CH3:5])([CH3:4])[CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:27][CH:26]=3)[CH:16]=2)[NH:20][CH:19]=1)#[N:25]
Reactant: CC(C)(CN)c1ccc(C(=O)NCCc2ccc3[nH]cc(C#N)c3c2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(CNS(C)(=O)=O)c1ccc(C(=O)NCCc2ccc3[nH]cc(C#N)c3c2)cc1
Reaction time: 0.08 h
Yield: 80.2 %

Procedure:
To a solution of 4-[2-amino-1,1-dimethyl-ethyl]-N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-benzamide (97 mg, 0.27 mmol) (reference example 105) in CH2Cl2 (1 ml) was added pyridine (24 μL, 0.30 mmol) and methanesulfonyl chloride (23 μL, 0.30 mmol). The reaction was stirred for 5 min then concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 8% 7M NH3 in CH3OH/CH2Cl2 to give 95 mg of product. MS (ion spray) m/z 439 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]1[NH:15][C:14]([C:16]2([CH3:20])[CH2:19][O:18][CH2:17]2)=[N:13][C:12]=1[CH3:21].CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.Cl.[NH:40]1[CH2:45][CH2:44][CH:43]([C:46]2[CH:53]=[CH:52][C:49]([C:50]#[N:51])=[CH:48][CH:47]=2)[CH2:42][CH2:41]1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:40]2[CH2:45][CH2:44][CH:43]([C:46]3[CH:53]=[CH:52][C:49]([C:50]#[N:51])=[CH:48][CH:47]=3)[CH2:42][CH2:41]2)=[O:8])=[CH:4][C:3]=1[C:11]1[NH:15][C:14]([C:16]2([CH3:20])[CH2:19][O:18][CH2:17]2)=[N:13][C:12]=1[CH3:21]
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2(C)COC2)nc1C
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1-c1[nH]c(C2(C)COC2)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5, except 4-methyl-3-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoic acid (compound 177.2) was used in place of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 455 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 11.78 (br, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 7.40-7.23 (m, 3H), 4.92 (t, J=6.0 Hz, 5.2 Hz, 2H), 4.78-4.52 (m, 1H), 4.43 (t, J=5.2 Hz, 4.8 Hz, 2H), 3.91-3.71 (m, 1H), 3.24-3.08 (m, 1H), 2.98-2.88 (m, 2H), 2.34 and 2.25 (2 singlets, CH3, 3H), 2.16 and 2.03 (2 singlets, amide rotamers, CH3, 3H), 1.91-1.59 (m, 4H), 1.69 and 1.68 (2 singlets, CH3, 3H).
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]#[C:8][C:9]([C:15]1[CH:20]=[CH:19][C:18]([N:21]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:29]1([S:26]([N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:18]2[CH:17]=[CH:16][C:15]([C:9]([OH:14])([C:10]([F:11])([F:12])[F:13])[C:8]#[C:7][C:6]([OH:35])=[O:5])=[CH:20][CH:19]=2)(=[O:28])=[O:27])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)CN(c1ccc(C(O)(C#CC(=O)OC(C)(C)C)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN(c1ccc(C(O)(C#CC(=O)O)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 0.56 g (1.1 mmol) of 4-[4-(benzenesulfonyl-isobutyl-amino)-phenyl]-5,5,5-trifluoro-4-hydroxy-pent-2-ynoic acid tert-butyl ester (Example 71) in 15 mL of CH2Cl2 was added 0.3 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 24 h. After this time the solvent was evaporated, and the residue was purified by chromatography (silica, hexanes:EtOAc, 1:1) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2([C:14]([S:16]C)=S)[S:13][CH2:12][CH2:11][CH2:10][S:9]2)[CH:5]=[CH:4][CH:3]=1.[CH3:18][NH2:19].C(OCC)(=O)C.C>C(O)C>[CH3:18][NH:19][C:14]([C:8]1([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[S:13][CH2:12][CH2:11][CH2:10][S:9]1)=[S:16]
Reactant: CSC(=S)C1(c2cccc(C)n2)SCCCS1
Reactant: CN
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNC(=S)C1(c2cccc(C)n2)SCCCS1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a suspension of methyl 2-(6-methyl-2-pyridyl)-1,3-dithiane-2-carbodithioate (130.5 g) in 1.2 liters of ethanol maintained at a temperature in the region of 20° C., a 33% (weight/volume) solution (840 cc) of methylamine in ethanol is added dropwise in the course of 10 minutes. The mixture is then stirred for 4 hours at the same temperature. The crystals which appear are separated by filtration, washed twice with ethyl acetate (100 cc in total), 4 times with isopropyl ether (400 cc in total) and dried under reduced pressure (0.2 mm Hg; 0.03 kPa) at a temperature in the region of 20° C. The product thereby obtained (100.2 g), to which is added some product (18.4 g) prepared under the same conditions in a previous operation, is dissolved in boiling ethyl acetate (3.3 liters); to this solution is added decolorising charcoal (33 g), and the solution is filtered hot. The filter is washed 4 times with boiling ethyl acetate (400 cc in total). The filtrate and the washing liquors are combined and cooled for 4 hours to a temperature in the region of 0° C. The crystals which appear are separated by filtration, washed 4 times with ethyl acetate (200 cc in total, 6 times with isopropyl ether (600 cc in total), and then dried under reduced pressure (0.2 mm Hg; 0.03 kPa) at 55° C. N-Methyl-2-(6-methyl-2-pyridyl)-1,3-dithiane-2-carbothiamide (99.1 g), m.p. 168° C., is thereby obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O.C(Cl)(=O)C(Cl)=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][CH2:10][C:11]2=[O:13]
Reactant: O=C(O)CCCc1ccccc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: O=C1CCCc2c(Br)cccc21
Temperature: 0 °C
Yield: 92 %

Procedure:
To a benzene solution (60 ml) of 4-(o-bromophenyl) butyric acid (5 g) was added oxalyl chloride (3.6 ml) and the reaction refluxed for 11/2 hrs. The solution was evaporated to dryness, the residue was dissolved in CH2Cl2 (50 ml) then cooled to 0° C., followed by the addition of AlCl3 (3.1 g). The mixture was stirred at 0° C. warming to room temperature overnight. The reaction was poured onto ice, then extracted with CH2Cl2. The organic layer was separated, washed with 1N NaOH, then brine, separated, dried (MgSO4), filtered and evaporated affording the desired product (4.26 g).