Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.O[C:6]1([C:34]([F:37])([F:36])[F:35])[CH:14]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[C:12]2[CH2:23][NH:24][CH:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][N:10]3[C:11]2=[C:7]1[CH:8]=[CH:9]3>N1C=CC=CC=1>[CH2:15]([C:14]1[C:6]([C:34]([F:37])([F:36])[F:35])=[C:7]2[C:11]3=[C:12]([CH2:23][NH:24][CH:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][N:10]3[CH:9]=[CH:8]2)[CH:13]=1)[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)C1Cn2ccc3c2C(=CC(CCc2ccccc2)C3(O)C(F)(F)F)CN1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Reaction time: 2 h
Yield: 54.3 %

Procedure:
Thionyl chloride (0.7 g; 5.8 mmol) was added to a solution of tert-butyl 7-hydroxy-6-phenethyl-7-(trifluoromethyl)-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indole-2(1H)-carboxylate (2.7 g; 5.8 mmol) in pyridine (7 mL) at O° C. After 2 h at 0° C., the resulting mixture was concentrated and the residue purified by silica gel chromatography (heptane-ethyl acetate) to yield tert-butyl 6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indole-2(1H)-carboxylate (1.4 g, 53%).
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17]Cl)[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:20][CH:21]([CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][OH:23].[H-].[Na+]>O1CCOCC1>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17][O:23][CH2:22][CH:21]([CH3:20])[CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Reactant: CC(CO)CCC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(COCC(C)CCC(C)(C)C)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (7.0 g, 25.6 mmol) is partly solved in dioxane (190 mL) at 80° C. 2,5,5-Trimethyl-hexan-1-ol (124.1 g, 731 mmol) and sodium hydride (1.7 g, 42 mmol, 60% in mineral oil) are added subsequently. The orange reaction mixture is stirred at 80° C. for one hour and evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with water. The organic layer is dried over sodium sulphate, filtered and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:12) to yield 4.8 g of 2-(2H-Benzotriazol-2-yl)-6-(2,5,5-trimethylhexyloxymethyl)-4-methyl-phenol.
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1)([CH3:6])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[CH3:6][C:2]([N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1)([CH3:1])[C:3]([O:5][CH2:17][CH3:18])=[O:4]
Reactant: CCO
Reactant: CC(C)(C(=O)O)n1cccn1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)(C)n1cccn1

Procedure:
2-Methyl-2-(1H-pyrazol-1-yl)propanoic acid 16 was treated with sulfuric acid in ethanol to give 17.
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.Br[C:29]1[C:30]([O:49][CH3:50])=[C:31]([C:36]([CH2:39][S:40]([N:43]2[CH2:47][CH2:46][CH:45]([OH:48])[CH2:44]2)(=[O:42])=[O:41])=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33]>>[O:25]1[CH:26]=[CH:27][C:23]([C:29]2[C:30]([O:49][CH3:50])=[C:31]([C:36]([CH2:39][S:40]([N:43]3[CH2:47][CH2:46][CH:45]([OH:48])[CH2:44]3)(=[O:42])=[O:41])=[CH:37][CH:38]=2)[C:32]([O:34][CH3:35])=[O:33])=[CH:24]1
Reactant: COC(=O)c1c(CS(=O)(=O)N2CCC(O)C2)ccc(Br)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Product: COC(=O)c1c(CS(=O)(=O)N2CCC(O)C2)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-6-(3-hydroxypyrrolidin-1-ylsulphonylmethyl)-2-methoxybenzoate (Intermediate 166).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][NH:6][C:7](=[O:28])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:20][C:21]2[CH:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:9]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35]([C:24]2[N:23]=[CH:22][C:21]([O:20][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:29])=[O:28])=[CH:9][CH:10]=3)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:26][CH:25]=2)=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCCCCC(Oc1ccc(Cl)nc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Product: CCCCCC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compounds are prepared in a manner substantially similar to Example 62 starting from 3-{4-[1-(6-chloro-pyridin-3-yloxy)-hexyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. Isomer 1 MS: 513.3 [M−H]−; Isomer 2 MS: 513.3 [M−H]−.
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:5][N:6]([CH2:8]Cl)[CH:7]=1.[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:2][C:3]1[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:5][N:6]([CH2:8][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])[CH:7]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: CC(C)(C)c1nn(CCl)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1nn(CC(C#N)(C#N)CCC(F)(F)F)cc1Br
Yield: 78.8 %

Procedure:
1.85 g of 4-bromo-3-t-butyl-1-(chloromethyl)-1H-pyrazole hydrochloride and 1.18 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 21 ml of N,N-dimethylformamide. 2.02 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.91 g of [(4-bromo-3-t-butyl-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (12), hereinafter) shown by below formula.
Reaction SMILES: [OH-].[Na+].CS([C:6]1[N:11]=[CH:10][C:9]2=[CH:12][CH:13]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[N:8]2[N:7]=1)=O.C(O)(=[O:25])C>O>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]1[N:8]2[C:9]([CH:10]=[N:11][C:6]([OH:25])=[N:7]2)=[CH:12][CH:13]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1-c1ccc2cnc(O)nn12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Into a 8-dram vial, 19.10 M of Sodium hydroxide in Water (10.0 mL, 191 mmol) and Water (10.0 mL) water were added. The mixture was heated at 100° C. 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (2.00 g, 6.96 mmol) was added portion wise over 10 minutes. The reaction mixture was heated at 120° C. for 60 minutes. HPLC suggested no SM. The reaction was cooled to room temperature. Glacial acetic acid was added to adjust pH to 4. The mixture was stirred at room temperature for 30 minutes. The solid was filtered, washed with water and subsequently with Et2O. The resulting solid was dried under vacuum overnight to give 7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol as a yellow solid (1.50 g, 85%). LCMS 242.15 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH:12]2[CH2:14][O:13]2)=[C:6]([CH:9]=1)C=O.C1C=C(Cl)C=C([C:22]([O:24]O)=[O:23])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:22]([O:24][C:6]1[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:10][CH2:11][CH:12]1[CH2:14][O:13]1)=[O:23]
Reactant: O=Cc1cc(Br)ccc1OCC1CO1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=COc1cc(Br)ccc1OCC1CO1

Procedure:
To a solution of 5-bromo-2-(oxiran-2-ylmethoxy)benzaldehyde (12.3 g, 47.7 mmol) in DCM (50 ml) was added m-CPBA (12.8 g, 57.2 mmol). The solution was heated at reflux for 3 h and 30 min and then brought to ambient temperature. Aqueous sodium bicarbonate (saturated) and DCM was added and the phases were separated. The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to dryness to give the crude title compound. Crude yield: 12.3 g. MS m/z (rel. intensity, 70 eV) 272 (M+, 7), 244 (50), 189 (95), 188 (bp), 57 (93).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])S(C1C=CC=CC=1)(=O)=O>C1COCC1>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:14]=[N:24]/[C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30]
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1Cl)S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/N=C/c1ccccc1Cl
Temperature: 25 °C

Procedure:
A quantity of 12.53 g (90.7 mmol) of potassium carbonate was heated through in an HV and then cooled under an argon atmosphere. Quantities of 140 ml of anhydrous THF and 5.77 g (15.1 mmol) of the compound from Example 110A were added and the mixture was stirred under an argon atmosphere at reflux temperature for 16 h. After cooling to RT, the reaction mixture was filtered over celite. The solid was washed with a little THF. The entire filtrate was freed from the solvent on a rotary evaporator. The oily residue was dried in an HV. This gave 3.55 g (98% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([Cl:12])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:26]=[CH:25][C:17]([CH2:18][N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:12][C:5]1[C:6]([N:22]2[CH2:21][CH2:20][N:19]([CH2:18][C:17]3[CH:25]=[CH:26][C:14]([Cl:13])=[CH:15][CH:16]=3)[CH2:24][CH2:23]2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Cl)c(N2CCN(Cc3ccc(Cl)cc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 2-amino-4,5-dichloro-3-nitropyridine (0.038 g, 0.18 mmol) and isopropanol (3 ml) was added 1-(4-chlorobenzyl)piperazine (0.042 g, 0.20 mmol) with the aid of isopropanol (0.5 ml) followed by diisopropylethylamine (0.035 ml, 0.20 mmol). The reaction mixture was heated at 45° C. for 18 h, then allowed to cool to room temperature, and diluted with isopropanol (4 ml). The precipitate was collected by filtration, washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.034 g, 50%); 1H-NMR (500 MHz, DMSO-d6) 2.48 (br s, obscured by DMSO peak, 4H, piperazine N(CH2)2), 3.06 (br s, 4H, piperazine N(CH2)2), 3.52 (s, 2H, NCH2), 6.95 (s, 2H, NH2), 7.35 (d, J=8.50 Hz, 2H) and 7.38 (d, J=8.55 Hz, 2H) (3,5-ArH and 2,6-ArH), 8.06 (s, 1H, 6-H);
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>C([O-])(=O)C.[Na+]>[C:9]([CH:4]1[CH2:3][CH:2]([CH3:1])[CH2:7][CH2:6][C:5]1=[O:8])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CCC(=O)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)C1CC(C)CCC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
40% Boron trifluoride-acetic acid complex, 24 g, was chilled with ice and a mixture of 5.6 g of 4-methylcyclohexanone and acetic anhydride was dropwise added to the complex. After stirring at room temperature for 4 hours, approximately 50 ml of saturated sodium acetate aqueous solution was added to the mixture followed by heating to reflux for 1 hour. After cooling, the reaction mixture was extracted with ether and the extract was washed with a sodium bicarbonate aqueous solution and then water. Thereafter, the system was dried and ether was removed by distillation. The obtained 2-acetyl-4-methylcyclohexanone was used in the whole amount at the following step in a crude state thereof.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:32])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:23](=[O:31])[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:14](=[O:22])[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C>O.C(O)C>[C:16]1([NH:15][C:14]([CH:13]([C:23](=[O:31])[NH:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([OH:32])=[O:6])=[O:22])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CCCCCC(C(=O)Nc1ccccc1)C(=O)Nc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCCC(C(=O)Nc1ccccc1)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
A solution of lithium hydroxide monohydrate (0.17 g, 4.05 mmol) in water (5 mL) was added to a stirred solution of 7,7-bis-phenylcarbamoyl-heptanoic acid ethyl ester (16a) (1.07 g, 2.7 mmol) in ethanol (50 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 16 hours. The solvent was removed under reduced pressure and the resulting residue was taken up in water (50 mL), washed with ethyl acetate (60 mL) and acidified with 1 M hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3×60 mL), and the combined extracts were dried (MgSO4), filtered and organic solvent evaporated to give 7,7-bis-phenylcarbamoyl-heptanoic acid (16b) as a white solid (0.95 g, 95%); Rf=0.25 (3:1, petroleum ether 60-80° C.:ethyl acetate); 1H NMR (300 MHz, CDCl3): δ 9.83 (2H, s, NH), 7.56 (4H, d, J=7.8 Hz, Ar—H), 7.32 (4H, t, J=8.1 Hz, Ar—H), 7.14 (2H, t, J=7.6 Hz, Ar—H), 3.43 (1H, t, J=7.2 Hz, COCH), 2.58 (2H, t, J=7.1 Hz, CH2CO), 1.86 (2H, br m, CHCH2CH2CH2CH2), 1.49 (2H, t, J=7.1 Hz, CHCH2), 1.33 (4H, br m, CHCH2CH2CH2); 13C NMR (75 MHz, CDCl3): δ 172.10 (CO), 170.17 (CO), 137.13 (quaternary Ar—C), 128.73 (Ar—C—H), 124.68 (Ar—C—H), 120.52 (Ar—C—H), 56.32 (COCH), 34.18 (CH2CO), 33.43 (CHCH2CH2CH2), 28.32 (CHCH2), 27.23 (CHCH2CH2), 24.54 (CHCH2CH2CH2CH2).
Reaction SMILES: O[C:2]1[C:3]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[N:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:20][C:21]1[CH:30]=[CH:29]C2C(=CC=CC=2)N=1>>[N:4]1[C:5]2[C:6](=[CH:20][CH:21]=[CH:30][CH:29]=2)[CH:7]=[CH:2][C:3]=1[CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[N:10]1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CC(=O)Nc1ccn(Cc2ncccc2O)n1
Agent: Cl
Product: CC(=O)Nc1ccn(Cc2ccc3ccccc3n2)n1

Procedure:
Title compound was prepared by a method analogous to that described for Intermediate 41 using Intermediate 1 (150 mg, 1.199 mmol), replacing 2-(Bromomethyl)-3-pyridinol hydrobromide with 2-(chloromethyl)quinoline hydrochloride (ALDRICH). Title compound was obtained (90 mg, 0.338 mmol, 28.2% yield). 1H NMR (300 MHz, CDCl3) δ ppm: 8.10 (d, 1H), 8.07 (d, 1H), 7.79 (d, 1H), 7.74 (m, 1H), 7.55 (m, 1H), 7.46 (d, 1H), 7.07 (d, 1H), 6.76 (d, 1H), 5.49 (s, 2H), br s 2.14 (s, 3H). [ES+MS] m/z 267 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])=[O:9])=[CH:4][C:3]=1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[H-].[Na+].I[CH3:31].Cl>O1CCCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([OH:14])=[O:13])=[O:9])=[CH:4][C:3]=1[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH3:31]
Reactant: CI
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(N)c(NC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(C(=O)c2ccccc2C(=O)O)ccc1N
Reaction time: 1.1 h

Procedure:
Methyl 2-{[4-amino-3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)phenyl]carbonyl}benzoate (0.217 g, 0.586 mmol) was dissolved in tetrahydrofuran (3 mL) and cooled in an ice bath. Sodium hydride (60 wt. % dispersion in oil; 0.024 g, 0.600 mmol) was added followed by dropwise addition of iodomethane (0.037 mL, 0.594 mmol). The mixture was stirred for 1.1 h and then iodomethane (0.100 mL, 1.61 mmol) was added dropwise. The mixture was stirred for a further 1 h and then sodium hydride (60 wt. % dispersion in oil; 0.019 g, 0.475 mmol) was added and the mixture was stirred for a further 0.25 h. The mixture was quenched with 1 N hydrochloric acid. The aqueous portion was extracted with ethyl acetate (2×). The combined organic portion was washed with saturated sodium bicarbonate solution. The ethyl acetate portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford a mixture of 4:1 mono-N-methylated: di-N-methylated material (0.115 g). The aqueous portion was acidified with 1 N hydrochloric acid and extracted with ethyl acetate (2×). The organic portion was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-({4-amino-3-[{[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]phenyl}carbonyl)benzoic acid as an orange oil which was dissolved in methanol (0.5 mL) and toluene (4.5 mL), cooled in an ice-bath and treated with (trimethylsilyl)diazomethane (2.0M solution in hexanes; 0.200 mL, 0.400 mmol). The mixture was stirred for 0.1 h and then was quenched with 0.5 N hydrochloric acid and partitioned with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow foam (0.120 g). This yellow foam was combined with the 4:1 mixture of mono- and di-methylated material isolated above (0.115 g) and was purified by column chromatography (ethyl acetate-hexanes 1:1) to afford methyl 2-({4-amino-3-[{[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]phenyl}carbonyl)benzoate as a yellow foam (0.167 g, 0.435 mmol, 74% yield). 1H NMR (4100 MHz, CDCl3): 8.02 (dd, 1H), 7.65-7.30 (m, 5H), 6.69 (d, 1H), 4.24 (s, 2H), 3.65 (s, 3H), 3.13 (s, 3H), 1.56 (s, 9H); MS (EI) for C21H24N2O5: 407 (MNa+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9]Br)[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[OH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][N:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]2=[O:13])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1ccc(CCBr)cc1Br
Reactant: Oc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ccc(CCn2ccccc2=O)cc1Br
Temperature: 80 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
Into a 100 mL round bottom flask was added 2-bromo-4-(2-bromo-ethyl)-1-methoxy-benzene (I-165, 1.82 g, crude), 2-hydroxypyridine (258 mg, 2.72 mmol), K2CO3 (625 mg, 4.53 mmol), and DME (20 mL). After stirring for 18 hours at 80° C. the suspension was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography eluting with 25-50% acetone/hexanes to afford 221 mg of I-166 as a brown oil in 40% yield (2 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:42])([C:18]2[N:19]=[CH:20][N:21]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:22]=2)[C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11](F)[CH:10]=2)=[CH:4][CH:3]=1.[Cl:43][C:44]1[CH:45]=[C:46]([OH:50])[CH:47]=[CH:48][CH:49]=1.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>CC#N>[Cl:43][C:44]1[CH:45]=[C:46]([CH:47]=[CH:48][CH:49]=1)[O:50][C:11]1[CH:10]=[C:9]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([OH:42])[C:18]2[N:19]=[CH:20][N:21]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:22]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: N#Cc1ccc(C(O)(c2ccc(Cl)cc2)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1F
Reactant: Oc1cccc(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(C(O)(c2ccc(Cl)cc2)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1Oc1cccc(Cl)c1

Procedure:
4-[(4-Chloro-phenyl)-hydroxy-(1-trityl-1H-imidazol-4-yl)-methyl]-2-fluoro-benzonitrile (0.337 g, 0.591 mmol), 3-chlorophenol (0.074 mL, 0.709 mmol), 40% KF on alumina (0.182 g), and 18-Crown-6 ether (0.018 g, 0.068 mmol) were refluxed in CH3CN for 40 hr under Ar. The reaction mixture was concentrated in vacuo, diluted with EtOAc, washed with satd. NaHCO3 solution, water, brine and dried (MgSO4). Filtration and concentration gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:24][NH:25][S:26](Cl)(=[O:28])=[O:27].[BH4-].[Na+]>N1C=CC=CC=1>[CH3:24][N:25]1[S:26](=[O:28])(=[O:27])[NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][N:10]=3)[CH:5]=[CH:4][C:3]=2[CH:12]1[C:14]1[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=1
Reactant: Nc1c(C(=O)c2ccc(C(F)(F)F)nc2)ccc2cccnc12
Reactant: CNS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1C(c2ccc(C(F)(F)F)nc2)c2ccc3cccnc3c2NS1(=O)=O
Yield: 51.5 %

Procedure:
In a similar fashion using route 27 general procedure 70, (8-amino-quinolin-7-yl)-(6-trifluoromethyl-pyridin-3-yl)-methanone (Intermediate 371) (100 mg, 0.32 mmol), N-methylsulfamoyl chloride (Intermediate 213) (49 mg, 0.38 mmol) and NaBH4 (12 mg, 0.315 mmol) in pyridine (5 ml) gave the title compound (65 mg, 52%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[S:9][C:10]([NH2:12])=[N:11][C:6]2=[CH:5][CH:4]=1.[CH:13]1([CH2:18][CH:19]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[C:20](Cl)=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14]1>N1C=CC=CC=1>[CH:13]1([CH2:18][CH:19]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[C:20]([NH:12][C:10]2[S:9][C:7]3[C:6]([N:11]=2)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=3)=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Cl)cc1
Reactant: COc1ccc2nc(N)sc2n1
Solvent: c1ccncc1
Product: COc1ccc2nc(NC(=O)C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)sc2n1
Temperature: 25 °C

Procedure:
To a solution of the title A compound, 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine (1.22 mmol, 222 mg) in 3 mL of pyridine at 0° C. is added 3-cyclopentyl-2-(4-methansulfonyl-phenyl)-propionyl chloride (1.02 mmol, prepared as described for the preparation of the title C compound in Example 1). The reaction is allowed to warm to RT over 12 h, then evaporated and the residue is partitioned between MTBE and aqueous 0.1 N HCl. The organic solution is washed with water, saturated aqueous NaHCO3 and brine, dried and evaporated to an oil. Chromatography over silica affords 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-propionamide; 1H NMR δ 9.7 (s, 1H), 7.85 (m, 3H), 7.38 (d, J=8, 2H), 6.83 (d, J=8, 1H), 4.05 (s, 3H), 3.63 (t, J=7.5, 1H); 3.09 (s, 3H), 2.2 (m, 1H), 1.1-1.9 (m, 10H); e/z (ES) 460 (M+1, 100%).
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])[CH2:6][CH2:5]2)[O:3]C1.Cl>C(O)(=O)C.O>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1
Reactant: COc1ccccc1N1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1N1CCC(=O)CC1

Procedure:
A solution of 19 (570 mg, 2.28 mmol) in acetic acid (20 mL), water (20 ml), and concetrated HCl (5 mL) was heated in an oil bath (50° C.) overnight. The solvent was removed in vacuo and the residue dissolved in ether and sodium carbonate solution. The aqueous layer was extracted with two additional portions of ether and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 2 mm, CHCl3) afforded the title compound (20)