Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18]([O:20][C:21]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br)[CH3:19].Cl>CN(C)C=O>[C:12]([O:11][C:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:28]([N+:29]([O-:31])=[O:30])[C:21]=1[O:20][CH2:18][CH3:19])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOc1c(CBr)cccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A mixture of iminodicarboxylic acid di-t-butyl ester (3.23 g), dimethylformamide (50 ml) and sodium hydride (0.57 g) was stirred under ice cooling for 1 h and then a mixture of the compound (3.51 g) obtained in Example 417c and dimethylformamide (20 ml) was added under ice cooling. The reaction mixture was stirred at room temperature for 14 h and, after addition of 2 N HCl, subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=1:9) to give 5.09 g of the titled compound (yield, 95%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[C:13](SC)[S:14][CH3:15])[C:11]#[N:12].O.[NH2:19][NH2:20].O>C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:12])=[N:19][NH:20][C:13]=1[S:14][CH3:15]
Reactant: CSC(SC)=C(C#N)c1nc2ccccc2s1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CSc1[nH]nc(N)c1-c1nc2ccccc2s1
Yield: 44 %

Procedure:
To a suspension of 2-benzothiazol-2-yl-3,3-bismethylsulfanylacrylonitrile (50 mg, 0.18 mmol) in ethanol (2 mL) was added hydrazine hydrate (15 μL). The mixture was heated to reflux for 2 hours. The reaction mixture was then cooled and water was added. The resulting precipitate was isolated by filtration to yield 21 mg (44%) of the title compound as a yellow solid. MS (m/z, ES+): 263 (M+1, 100%).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:29])[F:28])[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:32])[C:18](=[O:31])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:28])[F:29])[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:32])[C:18](=[O:31])[NH:19][N:20]=2)[CH2:11]1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4CNC4)cc3N21

Procedure:
A solution of 3-(4(R)-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester ((Enantiomer 2, SFC (Table 1, Method 6), Rt=10.53 min., 0.260 g, 0.57 mmol) in DCM (10 mL) and TFA (2 mL) was stirred at ambient temperature for 1 h. The solvent was removed in vacuo to give 6-(azetidin-3-ylamino)-4(R)-methyl-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as a pale yellow solid (Example #53-2, Enantiomer 2, SFC (Table 1, Method 7), Rt=7.98 min, 0.260 g, 97%). LC/MS (Table 1, Method 5) Rt=2.068 min.; MS m/z: 356 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[CH:4][C:3]1=[O:8].[N+:9]([C:12]1[CH:18]=[CH:17][C:15](N)=[CH:14][CH:13]=1)([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:18]=[CH:17][C:15]([C:4]2[C:3]([N:2]([CH3:1])[C:6](=[O:7])[CH:5]=2)=[O:8])=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: CN1C(=O)C=CC1=O
Reactant: Nc1ccc([N+](=O)[O-])cc1
Product: CN1C(=O)C=C(c2ccc([N+](=O)[O-])cc2)C1=O

Procedure:
A 100 g portion of N-methylmaleimide was reacted with 126.2 g of p-nitroaniline as described in Example 6, giving 78 g of 2-(p-nitrophenyl)-N-methylmaleimide.
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:5][CH:4]([S:6]([O-])(=[O:8])=[O:7])[CH2:3]1.[K+].S(Cl)([Cl:14])=O>CN(C=O)C>[F:1][C:2]1([F:10])[CH2:5][CH:4]([S:6]([Cl:14])(=[O:8])=[O:7])[CH2:3]1
Reactant: O=S(=O)([O-])C1CC(F)(F)C1
Reactant: O=S(Cl)Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)C1CC(F)(F)C1
Temperature: 60 °C
Yield: 100.2 %

Procedure:
To a suspension of potassium 3,3-difluorocyclobutane-1-sulfonate (0.250 g, 1.189 mmol) in thionyl chloride (2.60 mL, 35.7 mmol) was added DMF (3 drops). The reaction was heated to about 60° C. for about 21 h. The solvent was removed under reduced pressure and the residue was used in the next reaction without further workup or purification to afford crude 3,3-difluorocyclobutane-1-sulfonyl chloride (0.227 g, 100%) as product. 1H NMR (400 MHz, CDCl3) δ 4.33-4.17 (m, 1H), 3.28 (dd, J=11.1, 7.6 Hz, 2H), 3.21-3.05 (m, 2H).
Reaction SMILES: C([C:4]1[C:5](=[O:26])[N:6]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:7]([CH3:19])=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([CH3:18])[CH3:17])(=O)C.OO.F[C:30](F)(F)[C:31]([O:33]C(=O)C(F)(F)F)=[O:32]>C(Cl)Cl.O>[C:31]([O:33][C:4]1[C:5](=[O:26])[N:6]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:7]([CH3:19])=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([CH3:17])[CH3:18])(=[O:32])[CH3:30]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)Cn1c(C)cc(-c2ccccc2C(C)C)c(C(C)=O)c1=O
Agent: OO
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)cc(-c2ccccc2C(C)C)c(OC(C)=O)c1=O

Procedure:
To a stirred solution of 3-acetyl-4-(2-isopropylphenyl)-6-methyl-1-ethoxycarbonylmethyl-2-pyridinone from step 3 above (0.65 g, 1.8 mmol) in CH2Cl2 (150 mL) at 0° C. was added 30% aqueous H2O2 (0.94 mL, 9 mmol) and trifluoroacetic anhydride (1.8 mL, 14 mmol). The resulting solution was refluxed for 1 h and then diluted with CH2Cl2 and water. The organic phase was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (0.325 g; NMR: OCOCH3 peak at 2.05 ppm; HPLC RT=22.81 min, method B).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[CH3:25])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:26]([O:28]C)=[O:27])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+].O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[CH3:25])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:26]([OH:28])=[O:27])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]ncc4c3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
To a solution of methyl 2-(1H-indazol-5-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate (69 mg, 0.18 mmol) in MeOH (20 mL) was added sodium hydroxide (21.6 mg, 0.54 mmol) and water (2 mL). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (5 mL) and adjusted pH to 5 with hydrochloric acid (1N). The solids were collected by filtration to afford 2-(1H-indazol-5-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylic acid as a yellow solid (29 mg, 43%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]([S:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:27])=[O:26])=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:40]=[N+:41]=[N-:42])(C)C>CO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:42][N:41]=[N:40][N:24]=3)=[CH:15][CH:16]=2)[C:8]([S:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:27])=[O:26])=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nnc(S(=O)(=O)Cc2ccc(Cl)cc2)n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: CO
Product: CCCCc1nnc(S(=O)(=O)Cc2ccc(Cl)cc2)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 17 %

Procedure:
The title compound was prepared from 3-n-butyl-5-(4-chlorobenzylsulfonyl)-4-[(2'-cyanobiphenyl- 4-yl)methyl]-4H-1,2,4-triazole (Step A) according to the procedure of Example 15, Step E, except that 3.5 equivalents of trimethyltin azide were added at the start, and the column was eluted with a gradient of 0-10% methanol in CH2Cl2. The product was obtained in 17% yield as a glass, which was transformed to a powder upon scraping: mp 180°-182° C. dec.; homogeneous by TLC in 4:1CH2Cl2 --MeOH; mass spectrum (FAB) m/e 548 (M+1)+.
Reaction SMILES: F[C:2](F)(F)[C:3]([O-])=[O:4].[F:8][C:9]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[N:30]3[CH:31]=[CH:32][CH:33]=[C:29]3[C:28](=[O:34])[NH:27][CH:26]=2)=[CH:20][C:10]=1[C:11]([N:13]1[CH2:19][CH2:18][CH2:17][NH2+:16][CH2:15][CH2:14]1)=[O:12].N1C=CC=CC=1.CC(OC(C)=O)=O>CO.O.CC#N>[C:3]([N:16]1[CH2:17][CH2:18][CH2:19][N:13]([C:11]([C:10]2[CH:20]=[C:21]([CH:22]=[CH:23][C:9]=2[F:8])[CH2:24][C:25]2[N:30]3[CH:31]=[CH:32][CH:33]=[C:29]3[C:28](=[O:34])[NH:27][CH:26]=2)=[O:12])[CH2:14][CH2:15]1)(=[O:4])[CH3:2]
Reactant: O=C([O-])C(F)(F)F
Reactant: O=C(c1cc(Cc2c[nH]c(=O)c3cccn23)ccc1F)N1CCC[NH2+]CC1
Solvent: CO
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1CCCN(C(=O)c2cc(Cc3c[nH]c(=O)c4cccn34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Example 1 in MeOH was charged on SCX cartridge and washed with MeOH. The free base was then eluted with 2M NH3 in MeOH and the solvent removed under reduced pressure. The resulting amine was dissolved in THF and pyridine (2 eq) and Ac2O (1 eq) were added. The mixture was stirred for 1 h at RT and then the solvent was evaporated under reduced pressure and the product was isolated by purification at prep RP-HPLC using H2O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column). The desired fractions were lyophilized to afford the title compound. 1H NMR (400 MHz, DMSO-d6+TFA) δ: 10.53-10.44 (1H, m), 7.51-7.36 (1H, m), 7.34-7.18 (3H, m), 6.91-6.87 (1H, m), 6.54-6.44 (2H, m), 4.09-4.02 (2H, m), 3.85-3.05 (8H, m, partially overlapped with D2O signal), 2.03-1.72 (3H, m), 1.43-1.15 (2H, m). MS (ES) C22H23FN4O3 requires: 410, found: 411 (M+H)+.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].[C:16](O)([CH3:19])([CH3:18])[CH3:17]>C(O)(C(F)(F)F)=O.O>[C:16]([C:13]1[CH:14]=[C:9]([C:1]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:2])[CH3:3])[CH:10]=[CH:11][C:12]=1[OH:15])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)O
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Yield: 54 %

Procedure:
4-t-octylphenol (160 g, 0.78 mole) was dissolved in 400 ml anhydrous TFA. T-butyl alcohol (94.3 g, 1.27 mole) was added with stirring. The mixture was stoppered and stirred for 24 hours at ambient (~22° C.) temperature. This solution was diluted with 600 ml water, and the resulting upper organic layer was isolated in a separatory funnel. The crude product, 2-t-butyl-4-t-octylphenol, was dried over anhydrous magnesium sulfate and purified by eluting 35 g of the mixture with 70:30 hexanes:dichloromethane (v/v) in a 5×20 cm silica column, then eluted with 300 to 700 ml of solvent and collected in aliquots of 50 ml. Aliquots showing a single spot by TLC on silica eluted with 70:30 hexanes:dichloromethane (v/v) were combined and rotoevaporated to a thick syrup for a yield of 54%.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[C:7]([CH3:8])=[CH:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([S:13]([NH2:16])(=[O:15])=[O:14])[C:4]=2[O:3]1.N12CCCN=C1CCCCC2.[CH3:29][O:30][C:31]1[N:36]=[C:35]([CH3:37])[N:34]=[C:33]([N:38](C2C=CC=CC=2)[C:39](=O)[O-:40])[N:32]=1>O1CCOCC1.C(#N)C>[O:17]=[S:2]1(=[O:1])[C:7]([CH3:8])=[CH:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([S:13]([NH:16][C:39]([NH:38][C:33]3[N:32]=[C:31]([O:30][CH3:29])[N:36]=[C:35]([CH3:37])[N:34]=3)=[O:40])(=[O:14])=[O:15])[C:4]=2[O:3]1
Reactant: COc1nc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Reactant: CC1=Cc2cccc(S(N)(=O)=O)c2OS1(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Solvent: CC#N
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2OS(=O)(=O)C(C)=C3)n1
Reaction time: 1 h
Yield: 97.1 %

Procedure:
A mixture of 3.3 g of 2,2-dioxo-3-methyl-1,2-benzoxathiin-8-yl sulfonamide, 1.90 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene, 3.28 g of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)phenylcarbamate in a mixture of 25 ml of dioxan and 10 ml of acetonitrile is stirred at 20° C. to 25° C. for 1 hour. The solvents are evaporated and the residue is triturated with a mixture of 7 ml of 2N hydrochloric acid and 10 ml of water and then with 20 ml of ether. The precipitate is isolated by filtration and dried, affording 5.14 g of N-(2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonyl)-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea of m.p. 203°-205° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=O)=[C:4]([F:15])[CH:3]=1.[NH:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[NH2:17].C(O)(=O)C>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=[N:17][NH:16][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:4]([F:15])[CH:3]=1
Reactant: O=C(c1ccc(Br)cc1F)C1CCOC1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NN=C(c1ccc(Br)cc1F)C1CCOC1
Yield: 91.3 %

Procedure:
A mixture of ((4-bromo-2-fluorophenyl)(tetrahydro-3-furanyl)methanone (Intermediate 7, 850 mg) 1,1-dimethylethyl hydrazinecarboxylate (616 mg) and acetic acid (1 mL) in methanol (5 mL) was stirred at reflux under nitrogen for 20 h. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic phase was washed with sodium bicarbonate (1M, 10 mL), dried using a hydrophobic filter tube and concentrated under vacuum to give the title compound as a brown oil (1.1 g).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15]>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:26]1[CH2:27][CH2:28][CH:23]([C:19]2[CH:18]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([CH3:12])[CH3:29])[CH:22]=[CH:21][CH:20]=2)[CH2:24][CH2:25]1
Reactant: CN(C)c1cccc(C=O)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc(N(C)C)c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-(dimethylamino)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 380.2 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].[C:9](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO.O>CN(C)C=O>[C:9]([O:8][CH2:7][C@H:2]([CH3:1])[C:3]([O:5][CH3:6])=[O:4])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)[C@@H](C)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H](C)COC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Methyl (S)-(+)-2-methyl-3-hydroxypropionate (1.18 g; 10 mmole), trityl chloride (3.1 g; 11.13 mmole) and N,N-dimethylaminopyridine (1.34 g; 11 mmole) were dissolved in dry dimethylformamide (10 ml), and the resultant mixture was stirred at room temperature overnight. Methanol (5 ml) was added thereto to decompose the unreacted trityl chloride, and the resultant mixture was stirred for 3 hours. Water (20 ml) was added to the reaction mixture, which was extracted with toluene (20 ml) three times. The extracts were combined together, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl (S)-3-trityloxy-2-methylpropionate.
Reaction SMILES: Cl[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1.[NH3:18]>C(O)C.CCCCCC.C(OCC)(=O)C>[NH2:18][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1
Reactant: N
Reactant: O=C1NC(=O)C(c2cccc([N+](=O)[O-])c2)=C1Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC1=C(c2cccc([N+](=O)[O-])c2)C(=O)NC1=O

Procedure:
3-chloro-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione (1.0 g, 4 mmol) was suspended in a mixture of ethanol (20 mL) and aqueous 880 ammonia (5 mL) and the mixture heated to 80° C. whilst ammonia gas was bubbled through the mixture for 4 hours. The mixture was cooled and concentrated and the residue chromatographed on silica get using hexane-ethyl acetate (gradient from 1:1 v/v) as eluent to afford the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+].[CH3:36][C:37]([Si:40]([CH3:53])([CH3:52])[O:41][CH2:42][C:43]1[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][CH:48]=1)([CH3:39])[CH3:38]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:39][C:37]([Si:40]([CH3:53])([CH3:52])[O:41][CH2:42][C:43]1[CH:44]=[C:45]([C:2]2[CH:9]=[C:8]([F:10])[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=2)[CH:46]=[CH:47][CH:48]=1)([CH3:36])[CH3:38]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(-c2cc(F)cc(C#N)c2)c1
Temperature: 70 °C

Procedure:
3-bromo-5-fluorobenzonitrile (5.00 g, 25.0 mmol), Pd(OAc)2 (0.15 g), PPh3 (0.60 g) and K2CO3 (5.18 g, 37.5 mmol) were dissolved in dioxane (60 mL). The mixture was heated at 70° C. for 30 min, then [3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]boronic acid (7.99 g, 30.0 mmol) was added. The mixture reaction was stirred at reflux overnight. The solvent was removed under reduced pressure, then diluted with CH2Cl2 (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL). And the organic layer was dried over Na2SO4. The product 3′-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-5-fluoro-3-biphenylcarbonitrile (5.10 g, 60%) was purified by flash column chomatography. 1H NMR (400 MHz, CDCl3) δ 7.67 (t, J=5.2 Hz, 1H), 7.54-7.32 (m, 5H), 4.81 (s, 2H), 0.94 (s, 9H), 0.13 (s, 6H).
Reaction SMILES: CN(C=O)C.[C:6](Cl)(=O)[C:7]([Cl:9])=[O:8].[CH3:12][S:13]([C:16]1[CH:17]=C([CH:22]=[CH:23][CH:24]=1)C(O)=O)(=[O:15])=[O:14]>C(Cl)(Cl)Cl>[CH3:12][S:13]([C:16]1[CH:17]=[C:6]([CH:22]=[CH:23][CH:24]=1)[C:7]([Cl:9])=[O:8])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
DMF (0.4 mL) and oxalyl chloride (1.90 g) were added to a solution of 3-(methylsulfonyl)benzoic acid (2.00 g) in CHCl3 (including amylene, 40 mL) in a nitrogen gas flow under ice cooling, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to yield a crude product as a yellow solid, which was used in the subsequent reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)[CH3:11]>>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([O:12][CH2:10][CH3:11])[CH:18]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(Br)ncc1Br
Reactant: CCOc1cccc(B(O)O)c1
Product: CCOc1cccc(-c2cc(C)c(Br)cn2)c1
Yield: 49 %

Procedure:
Obtained (1.14 g, yield 49%) following the procedure described in Intermediate 27, starting with 2,5-dibromo-4-methylpyridine (7.97 mmol, 2.0 g), 3-ethoxyphenylboronic acid (7.97 mmol, 1.32 gl).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[CH:12]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Cl:8][C:7]1[CH:6]=[N:5][C:4]2[NH:9][CH:10]=[CH:11][C:3]=2[C:2]=1[NH:17][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC1CCCC1
Reactant: Clc1cnc2[nH]ccc2c1Br
Product: Clc1cnc2[nH]ccc2c1NC1CCCC1
Temperature: 110 °C

Procedure:
To 4-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (D) was added cyclopentylamine (0.5 mL) in a sealed tube. The mixture was heated to 110° C. for 24-48 h. The mixture was concentrated. Preparative HPLC provided 5-chloro-N-cyclopentyl-1H-pyrrolo[2,3-b]pyridin-4-amine (127)(7.4 mg) as the TFA salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][N:23](CC3C=CC=CC=3)[CH3:24])[C:12]3[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[CH2:37]([O:44][C:45](Cl)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][N:23]([C:45]([O:44][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:46])[CH3:24])[C:12]3[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)Cc3ccccc3)C(=O)[C@@H]2OC(C)=O)cc1
Solvent: c1ccccc1
Product: COc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2OC(C)=O)cc1
Yield: 104.7 %

Procedure:
A mixture of 10.37 g of (-)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 125 ml of benzene is refluxed. A solution of 9 g of benzyloxycarbonyl chloride in 25 ml of benzene is added dropwise to the mixture for 30 minutes, and the mixture is refluxed for 4 hours. Then, the mixture is evaporated under reduced pressure to remove solvent. 11.8 g of (-)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:13][C:14]([NH:16][CH3:17])=O)=[CH:9][CH:10]=2)[NH:5][N:4]=1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:14][NH:16][CH3:17])=[CH:9][CH:10]=2)[NH:5][N:4]=1
Reactant: CNC(=O)C=C(c1ccc2c(OC)n[nH]c2c1)c1ccccn1
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNCCC(c1ccc2c(OC)n[nH]c2c1)c1ccccn1

Procedure:
[3-(3-Methoxy-1H-indazol-6-yl)-3-pyridin-2yl-propyl]-methyl-amine CCXLV was prepared from 3-(3-methoxy-1H-indazol-6-yl)-N-methyl-3-pyridin-2yl-acrylamide using the procedure described for preparation of [3-(1H-Indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (Example 4). MS (M+H)=298.