Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH3:8])CCC.[S:9]([O:19][C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[C:24](OS(C2C=CC(C)=CC=2)(=O)=O)[N:23]=[C:22]([CH3:40])[N:21]=1)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH:41](N(CC)C(C)C)([CH3:43])[CH3:42]>ClCCl>[CH2:42]([N:1]([CH2:2][CH2:6][CH2:7][CH3:8])[C:24]1[N:23]=[C:22]([CH3:40])[N:21]=[C:20]([O:19][S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:25]=1[N+:26]([O-:28])=[O:27])[CH2:41][CH3:43]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCC(N)CCC
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(C)nc(OS(=O)(=O)c3ccc(C)cc3)c2[N+](=O)[O-])cc1
Solvent: ClCCl
Product: CCCCN(CCC)c1nc(C)nc(OS(=O)(=O)c2ccc(C)cc2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Aminoheptane (2.5 g) was added to a solution of 4,6-ditosyloxy-2-methyl-5-nitropyrimidine (10.5 g) and N,N-diisopropylethylamine (3.8 mL) in dichloromethane (219 mL). The reaction was stirred under nitrogen for 5 h at room temperature and then extracted with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated to yield N-(1-propyl)butyl-2-methyl-5-nitro-4-tosyloxypyrimidin-6-amine as a pale yellow solid (9.1 g)
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([C:7]1[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=1[CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:43]([O:47][C:48]([N:50]1[C@H:54]([CH:55]=O)[CH2:53][O:52][C:51]1([CH3:58])[CH3:57])=[O:49])([CH3:46])([CH3:45])[CH3:44]>C1(C)C=CC=CC=1>[C:43]([O:47][C:48]([N:50]1[C@H:54]([CH:55]=[CH:9][C:8]2[CH:29]=[CH:30][CH:31]=[CH:32][C:7]=2[C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:53][O:52][C:51]1([CH3:57])[CH3:58])=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)COC1(C)C
Reactant: CCOC(=O)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccccc1C=C[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a suspension of (2-ethoxycarbonylbenzyl)-triphenylphosphonium bromide (9.0 g, 17.77 mmol) in toluene (100 mL) is added potassium bis(trimethylsilyl)amide (0.5M in toluene, 40 mL) followed by the addition of (S)-4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (3.4 g, 14.83 mmol) and the mixture is refluxed for 1 h. After cooling to RT, ice/water is added and the solution extracted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated. The crude material is purified by column chromatography to afford the title compound as a yellow oil: (M+1)+=376.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[O:7][C:6](=[O:8])[CH:5]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[C:4](=[O:25])[O:3]1.C([Si](C)(C)N1C2=NC=CC([Cl:41])=C2C=C1)(C)(C)C>>[Cl:41][C:17]1[CH:16]=[CH:15][N:14]=[C:13]2[NH:12][CH:11]=[C:10]([CH:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:5]3[C:6](=[O:8])[O:7][C:2]([CH3:26])([CH3:1])[O:3][C:4]3=[O:25])[C:18]=12
Reactant: CC(C)(C)[Si](C)(C)n1ccc2c(Cl)ccnc21
Reactant: CC1(C)OC(=O)C(C(c2ccccc2)c2c[nH]c3ncccc23)C(=O)O1
Product: CC1(C)OC(=O)C(C(c2ccccc2)c2c[nH]c3nccc(Cl)c23)C(=O)O1

Procedure:
5-[(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione was prepared following the procedure described for preparation of 2,2-dimethyl-5-[phenyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-[1,3]dioxane-4,6-dione in example 1, using 1-(tert-butyl-dimethyl-silanyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[N+](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[CH2:7][CH:12]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 9.6 %

Procedure:
To a mixture of 4-chlorostyrene (1.20 ml, 10.0 mmol), Rh2(OAc)4 (0.221 g, 0.500 mmol), and toluene (20 ml) was added ethyl diazoacetate (1.09 ml, 10.50 mmol). Gas evolution was observed. The mixture was heated to 80° C. for 1 hour. The mixture was purified on silica gel (EtOAc in hexanes gradient) to provide 0.216 g of the title compound as an oil (9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([Cl:11])=[C:9]([C:12](Cl)=[O:13])[S:8][C:7]=2[CH:15]=1.[CH3:16][OH:17].Cl[Si](C)(C)C.CCCCCC>C(O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([Cl:11])=[C:9]([C:12]([O:17][CH3:16])=[O:13])[S:8][C:7]=2[CH:15]=1
Reactant: COc1ccc2c(Cl)c(C(=O)Cl)sc2c1
Reactant: CO
Agent: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: COC(=O)c1sc2cc(OC)ccc2c1Cl
Temperature: 25 °C

Procedure:
Crude 6-methoxy-3-chlorobenzo[b]thiophene-2-carbonyl chloride (2 g, 7.67 mmoles) was transferred to a 100 ml round bottomed flask. Anhydrous methanol (Aldrich, 50 ml) was added and the acid chloride dissolved by stirring. To this stirred solution was added chlorotrimethylsilane (2.5 equivalents, 19.16 mmole, 2.08 g, 2.43 ml). The reaction mixture was stirred overnight at room temperature. TLC analysis (Silica, 1:1 hexane:ethyl acetate, UV visualization) indicated complete conversion of the acid chloride to the methyl ester. The resulting slurry was concentrated in vacuo to give a yellow solid, which was shown by 1H NMR (DMSO-D6, 400 MHz) to be the desired material. The crude methyl ester was dissolved in hot ethanol (200 ml), the volume was reduced to 150 ml, and allowed to cool to room temperature. The resulting orange ethanolic solution was cooled to -10° C. for 15 minutes. The resulting precipitate was filtered off and dried in vacuo to give 1.25 g of the ester as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][CH:29]([OH:31])[CH3:30])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][CH:29]([OH:31])[CH3:30])(=[O:26])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: CC(O)CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CC(O)CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
2 g of 2-chloro-4-fluorobenzonitrile was reacted with 1-mercapto-2-propanol via Procedure Q to afford 2-chloro-4-(2-hydroxypropylthio)benzonitrile. 2.5 g of 2-chloro-4-(2-hydroxypropylthio)benzonitrile was reacted via Procedure T to give 2-chloro-4-(2-hydroxypropylthio)benzoic acid. 2.1 g of 2-chloro-4-(2-hydroxypropylthio)benzoic acid was reacted via Procedure R to give 2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid. 70 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 465.2 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9](Cl)[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])[CH3:2].[CH2:16]([O:23][C:24](=[O:36])[CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:29]([O:28][C:26](=[O:27])[CH:25]([C:9]1[CH:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:10]=1)[C:24]([O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Product: CCOC(=O)c1cc(C(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
The 5-chloro-2-nitrobenzoic acid ethyl ester (4.40 g) obtained in Example 9-4b) and malonic acid dibenzyl ester were subjected to reactions similar to those in Example 1-3a) to give the title compound (4.61 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:11]([Cl:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Nc2cccc(Cl)c2)nc1Nc1cccc(Cl)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-chloroaniline were reacted to yield N2,N4-bis(3-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.08 (d, 1H, J=5.4 Hz), 7.70 (t, 1H, J=1.8 Hz), 7.57 (t, 1H, J=1.2 Hz), 7.54 (m, 1H), 7.35 (m, 4H), 7.28 (t, 1H, J=1.8 Hz), 7.24 (m, 1H), 7.22 (t, 1H, J=1.8 Hz); 19F NMR (CD3OD): −43631; LCMS: ret. time: 28.99 min.; purity: 99%; MS (m/e): 349 (M+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].FC(F)(F)S(O[CH2:18][C:19]([F:31])([F:30])[C:20]([F:29])([F:28])[C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])(=O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[F:30][C:19]([F:31])([C:20]([F:28])([F:29])[C:21]([F:26])([F:27])[C:22]([F:25])([F:24])[F:23])[CH2:18][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7]
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 4 h
Yield: 17.9 %

Procedure:
2.0 g of 2-(3,3,3-trifluoropropyl)malononitrile and 4.7 g of 2,2,3,3,4,4,5,5,5-nonafluoropentyl trifluoromethanesulfonate were dissolved in 10 ml of N,N-dimethylformamide, 2.0 g of potassium carbonate was added, and the mixture was stirred at 60° C. for 4 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.87 g of 2-(2,2,3,3,4,4,5,5,5-nonafluoropentyl)-2-(3,3,3-trifluoropropyl)malononitrile (hereinafter, referred to as the present compound (5.3)).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[O:12]1[CH2:16][CH2:15][CH2:14][S:13]1(=[O:18])=[O:17]>>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:16][CH2:15][CH2:14][S:13]([OH:18])(=[O:17])=[O:12])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=S1(=O)CCCO1
Product: COC(=O)c1ccc(NCCCS(=O)(=O)O)cc1
Yield: 70.9 %

Procedure:
Methyl 4-aminobenzoate (1.34 g, 8.87 mmol) and [1,2]oxathiolane 2,2-dioxide (1.02 g, 8.36 mmol) were heated at 100–110° C for 1 h. The cooled residue was washed with 1N HCl and water and air-dried to give 4-(3-sulfo-propylamino)-benzoic acid methyl ester (1.62 g, yield: 71%). 1H NMR (DMSO-d6) δ 7.70 (d, J=8.7 Hz, 2H), 6.65 (d, J=8.7 Hz, 2H), 5.88 (br, s, NH+SO3H), 3.19 (t, J=7.0 Hz, 2H), 2.63 (t, J=7.3 Hz, 2H), 1.87 (quint, J=7.0 Hz, 2H). LC/MS (ESI) 256.22 (M+H)+, tR=2.21 min (10–90% MeOH in H2O with 10 mM NH4OAc in a 4-min run).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:3]1.[Br:18][C:19]1[C:27]2[N:26]=[C:25](Cl)[NH:24][C:23]=2[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1>>[Br:18][C:19]1[C:27]2[NH:26][C:25]([N:7]3[CH2:6][CH2:5][N:4]([C:8]4[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:11]=[CH:10][N:9]=4)[CH2:3][C@H:2]3[CH3:1])=[N:24][C:23]=2[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1
Reactant: C[C@@H]1CN(c2ncccc2C(F)(F)F)CCN1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Product: C[C@@H]1CN(c2ncccc2C(F)(F)F)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1

Procedure:
The piperazine from step (a) above (0.37 g, 1.5 mmol) reacted with 4-bromo-2-chloro-6-trifluoromethyl-1H-benzoimidazole (0.36 g, 1.2 mmol, Example 6b) under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 508 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18]Br)=[C:14]([Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=1)[Si](C)(C)C)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:18][C:15]2[CH:16]=[CH:17][C:12]([NH:7][C:6](=[O:24])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:13][C:14]=2[Si:20]([CH3:23])([CH3:22])[CH3:21])[CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N(c1ccc(CBr)c([Si](C)(C)C)c1)[Si](C)(C)C
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc(NC(=O)OC(C)(C)C)cc2[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a solution of crude tert-butyl(4-bromomethyl-3-trimethylsilylphenyl)trimethylsilylcarbamate (2.57 g, 5.98 mmol) in THF (10 mL) was added Et3N (1.3 mL, 8.97 mmol) and 1-methylpiperazine (1.1 mL, 8.92 mmol). After stirring for 1 h at rt, aq. NaHCO3 was added, and the mixture was extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluted with 5% MeOH/DCM) to provide product as a pale yellow oil (1.60 g, 71%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8]CN)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C@H:23]1[CH2:26][C@H:25]([C:27]([OH:29])=O)[CH2:24]1)=[O:21].C1C2C(=CC=CC=2)C[N:31]1C(NC1C=CC(C(O)=O)=CC=1)=O>>[C:1]1([CH2:7][CH2:8][NH:31][C:27]([C@H:25]2[CH2:26][C@H:23]([NH:22][C:20]([N:12]3[CH2:11][C:19]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=4[CH2:13]3)=[O:21])[CH2:24]2)=[O:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: NCCCc1ccccc1
Reactant: O=C(N[C@H]1C[C@H](C(=O)O)C1)N1Cc2ccncc2C1
Product: O=C(N[C@H]1C[C@H](C(=O)NCCc2ccccc2)C1)N1Cc2ccncc2C1

Procedure:
The title compound was prepared as described in Example 1C, substituting 2-phenylethylamine for 3-phenylpropan-1-amine and trans-3-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)cyclobutanecarboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.56 (s, 1H), 8.47 (d, J=5.0 Hz, 1H), 7.80 (t, J=5.6 Hz, 1H), 7.39 (d, J=5.1 Hz, 1H), 7.33-7.24 (m, 2H), 7.23-7.16 (m, 3H), 6.57 (d, J=7.6 Hz, 1H), 4.65-4.58 (m, 4H), 4.38-4.24 (m, 1H), 3.33-3.23 (m, 2H), 2.84-2.74 (m, 1H), 2.72 (t, J=7.3 Hz, 2H), 2.32-2.22 (m, 2H), 2.24-2.09 (m, 2H); MS (ESI(+)) m/e 365 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8](F)[N:7]=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[N:5]=1.[CH2:16]([OH:18])[CH3:17]>>[NH2:3][C:4]1[N:9]=[C:8]([O:18][CH2:16][CH3:17])[N:7]=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[N:5]=1
Reactant: Nc1nc(F)nc(OC(F)(F)F)n1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Product: CCOc1nc(N)nc(OC(F)(F)F)n1
Reaction time: 0.25 h

Procedure:
2.3 g (0.093 mol) of 97% strength sodium hydride were added a little at a time to 300 ml of ethanol at from 20° to 35° C., and stirring was carried out until a solution was obtained, which took 15 minutes. 18.5 g (0.093 mol) of 2-amino-4-fluoro-6-trifluoromethoxy-1,3,5-triazine were then added at 0° C. in the course of 10 minutes while stirring, and stirring was continued for one hour at 0° C. and overnight at 22° C. The mixture was evaporated down under reduced pressure, after which the residue was taken up in methylene chloride and the solution was extracted with water and dried. Evaporating down gave 17.9 g (85.9% of theory) of the title compound of melting point 69°-91° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]2[S:17][CH2:16][NH:15][C:14]2=[O:18])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])[CH3:3].[Mg].C(OCC)(=O)C>CO>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]2[S:17][CH2:16][NH:15][C:14]2=[O:18])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(C=C2SCNC2=O)ccc1O
Agent: [Mg]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(CC2SCNC2=O)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
A portion of the title compound from Example 78 (395.1 mg; 1.5 mmol) was dissolved in 9 ml of methanol. Magnesium (72.9 mg; 3.0 mmol) was then added to the solution and the resulting reaction mixture was stirred at room temperature for 3 hours. After 3 hours, most of the magnesium which had been added originally appeared to be gone so an additional 182.3 mg (7.5 mmol) of magnesium were added. Stirring of the reaction solution at room temperature continued overnight. By the next morning a yellow precipitate had formed. This precipitate was dissolved by adding the methanolic reaction solution to an ethyl acetate/1N hydrochloric acid mixture. The organic layer from the resulting two-phase mixture was isolated and then dried over sodium sulfate. The volatile components of the organic layer were removed and the resulting residue was chased with methylene chloride. The residue was then dissolved in 25 ml of methylene chloride and the resulting solution was chromatographed on a silica gel chromatography column using a 5-20% isopropyl alcohol in hexanes gradient. Those fractions identified as containing essentially pure product were evaporated to provide 0.29 g of title compound. m.p. 65-70° C.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:24])[N:15]([CH3:23])[CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH:8]=2)=[C:4]([F:27])[CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([C:38]2([C:41](O)=[O:42])[CH2:40][CH2:39]2)=[O:37])=[CH:31][CH:30]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[F:27][C:4]1[CH:3]=[C:2]([NH:1][C:41]([C:38]2([C:36]([NH:35][C:32]3[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=3)=[O:37])[CH2:40][CH2:39]2)=[O:42])[CH:26]=[CH:25][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:15]([CH3:23])[CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)=[O:24])[CH:8]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)CC1
Reaction time: 3.5 h
Yield: 41.6 %

Procedure:
3-[4-(4-Amino-2-fluorophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (40.8 mg) was dissolved in N,N-dimethylformamide (1.0 ml). 1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (73 mg), triethylamine (0.0456 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (145 mg) were added under a nitrogen atmosphere at room temperature and stirred for 3.5 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was removed and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=97:3) to provide the titled compound as white powder (26.3 mg, 42%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].O.[Cl:10][C:11]([Cl:15])([Cl:14])[CH:12]=[O:13].C(N(CC)CC)C>C(Cl)Cl>[OH:1][C:2]1[CH:7]=[C:6]([CH:12]([OH:13])[C:11]([Cl:15])([Cl:14])[Cl:10])[CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: Oc1ccccc1O
Reactant: O=CC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Oc1ccc(C(O)C(Cl)(Cl)Cl)cc1O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
To the solution of 440 g of 1,2-dihydroxybenzene dissolved in 1 L of methylene dichloride was added 1036 g of trichloroacetaldehyde monohydrate and then the reaction solution was cooled down to 0° C. 102 g of triethylamine was slowly added dropwise thereto. The reaction solution was warmed to room temperature, stirred for about 20 minutes, heated to 50° C. and then stirred for further 3 hours while maintaining the same temperature. After the reaction is completed, the reaction mixture was distilled under reduced pressure to remove methylene dichloride. The residue was dissolved in 4 L of ethylacetate, washed successively with 2400 ml of 0.5N-aqueous hydrochloric acid solution and 2 L of saturated saline, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent and to obtain 540 g of the title compound.
Reaction SMILES: C([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][CH2:8][C@@H:7]3C[C@H](N(CC4CC4)CC4CC4)C[C:5]=1[C:6]=23)(=O)C.C([N:27]([CH2:30]C)CC)C.ClC(Cl)(Cl)C[O:35]C(Cl)=O>C(Cl)Cl>[C:30]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:12][CH:11]=2)[CH2:7][CH2:8]1)(=[O:35])[NH2:27]
Reactant: CC(=O)c1ccc2c3c1C[C@@H](N(CC1CC1)CC1CC1)C[C@H]3CN2
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 248.2 %

Procedure:
To a solution of (-)(2aR,4S)-6-acetyl-4-[di-(cyclopropylmethyl)amino]-1,2,2a,3,4, 5-hexahydrobenz[cd]indole (2.5 g, 7.7 mmol) and triethylamine (1.1 ml, 8 mmol) in 90 ml CH2Cl2 was added dropwise a solution of 2,2,2-trichloroethylchloroformate (1.7 g, 8 mmol) in 10 ml CH2Cl2. The reaction mixture was stirred at room temperature for one hour and then extracted with water and 1N HCl. The organic solution was washed with a saturated NaHCO3 solution and a saturated brine solution, dried over MgSO4 and then concentrated to dryness in vacuo to give 3.1 g of the 1-carbamylindoline.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:39][C:40]([F:43])([F:42])[F:41].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(C)C>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:39][C:40]([F:43])([F:41])[F:42])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CN1CCC(NC(=O)c2ccc(N)c(OC(F)(F)F)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(OC(F)(F)F)c2)CC1
Yield: 11.5 %

Procedure:
A mixture of 0.10 g (0.32 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20), 0.11 g (0.35 mmole) of 4-amino-N-(1-methyl-piperidin-4-yl)-3-trifluoromethoxy-benzamide, 0.090 g (0.48 mmole) of p-toluenesulfonic acid monohydrate and 4 mL of isopropanol was heated in a pressure tube at 140 degrees overnight, then cooled and diluted with dichloromethane and saturated sodium carbonate. The mixture was extracted twice with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-60:40) gave 0.022 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-3-trifluoromethoxy-benzamide (I-181) as a white solid.