Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[CH3:29][C:30]1[N:34]=[CH:33][N:32]([C:35]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][C:36]=2[O:37][CH2:38][CH2:39][CH2:40][NH2:41])[N:31]=1>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:41][CH2:40][CH2:39][CH2:38][O:37][C:36]2[CH:42]=[C:43]([N+:46]([O-:48])=[O:47])[CH:44]=[CH:45][C:35]=2[N:32]2[CH:33]=[N:34][C:30]([CH3:29])=[N:31]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)c(F)c1
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCN)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCNc2nc(Cl)nc3c2CCC3c2ccc(F)cc2F)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.4 %

Procedure:
To a solution of 2,4-dichloro-7-(2,4-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation T, 0.717 g, 2.38 mmol) in acetonitrile (40 mL) was added diisopropylethylamine (0.420 g, 3.25 mmol) followed by 3-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)propan-1-amine (Preparation K, 0.60 g, 2.164 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was taken in dichloromethane (10 mL) and silica (2 g). The resultant slurry of the compound on silica was subjected to flash chromatography using a Teledyne Isco instrument (12 g RediSep silica column, 50% ethyl acetate in pet-ether) to get 2-chloro-7-(2,4-difluorophenyl)-N-(3-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)propyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (0.65 g, 55.4%) as a light yellow solid. LC-MS (M+H)+=542.0. 1H NMR (400 MHz, CDCl3) δ ppm 8.95 (1H, s), 8.05-7.93 (3H, m), 6.95-6.77 (3H, m), 4.86 (1H, br s), 4.86-4.85 (1H, m), 4.37-4.34 (2H, m), 3.75-3.75 (2H, s), 2.69-2.50 (3H, m), 2.50 (3H, s), 2.29-2.26 (2H, m), 2.01-1.98 (1H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][CH:16]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([NH2:25])[C:18]=2[O:17]1>>[CH3:15][CH:16]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([NH:25][C:8]3[CH:7]=[CH:6][C:5]4[C:4]([NH2:1])=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=3)[C:18]=2[O:17]1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: CC1Cc2cccc(N)c2O1
Product: CC1Cc2cccc(Nc3ccc4c(N)cccc4n3)c2O1

Procedure:
The title compound, MS: m/e=292.0 (M+H+), was prepared in accordance with the general method of example 1 from 5-nitro-2-chloroquinoline and 2,3-dihydro-2-methyl-7-benzofuranamine (CAS 26210-74-2).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[S:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([S:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([CH3:23])=[CH:13][C:12]=1[CH3:24].ClC1C=CC=C(C(OO)=[O:35])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].CCCCCC>C(Cl)(Cl)Cl.C(OCC)(=O)C>[F:26][C:2]([F:1])([F:25])[S:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([S:17]([CH2:18][C:19]([F:20])([F:21])[F:22])=[O:35])[C:14]([CH3:23])=[CH:13][C:12]=1[CH3:24]
Reactant: Cc1cc(C)c(SCC(F)(F)F)cc1OCCCCCCSC(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(S(=O)CC(F)(F)F)cc1OCCCCCCSC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
In 40 ml of chloroform was dissolved 1.36 g (3.23 mmol) of 6-trifluoromethylthiohexyl-[2,4-dimethyl-5-(2,2,2-trifluoroethylthio)phenyl]ether. Thereto was added 0.67 g (2.72 mmol) of 3-chloroperbenzoic acid (purity: about 70%) under ice cooling, and the mixture was stirred for 30 minutes at room temperature. Then, saturated aqueous solution of sodium thiosulfate was added to the reaction mixture to decompose excess peroxide. Thereafter, the solvent was distilled off under reduced pressure, and extraction was conducted by adding ethyl acetate and water. The organic phase obtained was washed by aqueous potassium carbonate solution and saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=5:1), to obtain 0.87 g (yield: 62%) of an intended product.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[N+](=[CH2:31])=[N-].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1>C1COCC1.CCOCC>[CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([O:7][CH3:31])=[O:6]
Reactant: C=[N+]=[N-]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Chenodeoxycholic acid (0.5 g, 1.3 mmol) in THF (10 ml) at 0° C. was treated dropwise with freshly prepared diazomethane in ether (prepared in the usual manner from diazald) until the yellow colour persisted. After 15 minutes at 0° C. the solvent was evaporated to yield a white foam (0.55 g). The compound would not recrystallise, although gas chromatography showed the product to be 97% pure. The product was further purified by preparative silica tlc. (solvent system: EtOAc/CH2Cl2 /AcOH--10:10:1) to afford pure methyl chenodeoxycholate3 (0.42 g, 81%) as a foam: 1H NMR (60 MHz; CDCl3) δ0.65 (3H, s, 18-CH3), 0.91 (3H, s, 19-CH3), 1.85 (2H, s [exchanges on adding D2O], 3α and 7α OH's), 3.1-3.7 (1H, m, 3β-H), 3.64 (3H, s, --OMe), 3.7-3.9 (1H, m, 7β-H); IR (nujol mull) 3384 (OH's), 1740 (C=O) cm-1 ; MS: Found m/z 406.3077; C25H42O4 (M) requires 406.3083.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([CH:11]([CH3:15])[CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:16][C:17]1[C:22]([C:23](O)=[O:24])=[C:21]([CH3:26])[N:20]=[CH:19][N:18]=1>>[O:4]1[C:5]2([CH2:6][CH2:7][N:8]([CH:11]([CH3:15])[CH2:12][CH2:13][NH:14][C:23]([C:22]3[C:17]([CH3:16])=[N:18][CH:19]=[N:20][C:21]=3[CH3:26])=[O:24])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: Cc1ncnc(C)c1C(=O)O
Reactant: CC(CCN)N1CCC2(CC1)OCCO2
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC2(CC1)OCCO2
Yield: 69.7 %

Procedure:
Using general procedure E with 3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-butylamine (4.50 g, 21.0 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (3.20 g, 21.0 mmol), followed by purification by column chromatography on silica gel (2-10% MeOH/CH2Cl2) gave 4,6-dimethyl-pyrimidine-5-carboxylic acid [3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-butyl]-amide (5.10 g, 73%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH2:23][OH:24])[C:19](=[O:22])[O:20][CH3:21])=[C:14]([CH3:25])[CH:13]=1.S(=O)(=O)(O)O.[C:31]1([CH:38]=CC(O)=[CH:34][CH:33]=1)O>C(O)CCC.S([O-])(O)(=O)=O.[Na+]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH2:23][O:24][CH2:38][CH2:31][CH2:33][CH3:34])[C:19](=[O:22])[O:20][CH3:21])=[C:14]([CH3:25])[CH:13]=1
Reactant: COC(=O)N(CO)c1ccc(OCc2nc3ccccc3s2)cc1C
Reactant: Oc1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: CCCCOCN(C(=O)OC)c1ccc(OCc2nc3ccccc3s2)cc1C
Temperature: 85 °C
Reaction time: 1 h
Yield: 9330.4 %

Procedure:
49.8 mg of methyl N-hydroxymethyl-N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]carbamate [prepared as described in Example 19] were dissolved in 2 ml of butanol at room temperature, and the pH of the resulting solution was adjusted with concentrated sulfuric acid to pH 3. A catalytic amount of hydroquinone (2 mg) was added to the resulting mixture at room temperature and the mixture was then stirred for 1 hour at 85° C. The reaction mixture was then cooled to room temperature, diluted with aqueous sodium hydrogen sulfate and then extracted with ethyl acetate. The resulting extract was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give a residue which was purified by column chromatography through silica gel using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 702.5 mg (yield 94.1%) of the title compound as an oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:11][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][N:2]([CH3:1])[S:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:20])=[O:19]
Reactant: CNCC(O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(O)c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of α-(methylaminomethyl)benzyl alcohol (1.00 g, 6.61 mmol) in 15 mL of THF was cooled in an ice bath. Benzenesulfonyl chloride (0.886 mL, 1.23 g, 6.94 mmol) and N,N-diisopropylethylamine (2.3 mL, 1.7 g, 13 mmol) were added and mixture was allowed to warm to room temperature. After 30 min, the solvent was evaporated and the residue was partitioned between 50 mL of ethyl acetate and 40 mL of saturated aqueous sodium bicarbonate. The aqueous layer was extracted with 2×50 mL of ethyl acetate. The combined organic layers were washed with 50 mL of brine, dried over sodium sulfate, and evaporated. Purification by flash column chromatography on silica gel, eluting with 20-50% ethyl acetate in hexane, gave the title compound in quantitative yield.
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[CH2:14][CH2:13][O:12][C@@H:11]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[CH:17][CH:16]=3)[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.IC.[CH3:30]C(C)([O-])C.[K+].O>O1CCCC1>[CH3:30][N:21]([C:18]1[CH:19]=[CH:20][C:15]([C@@H:11]2[O:12][CH2:13][CH2:14][N:9]([C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:8])[CH2:10]2)=[CH:16][CH:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(Nc3ccccn3)cc2)C1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N(C)c3ccccn3)cc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.7 %

Procedure:
To a solution of N-(4-((2S)-4-((1R)-1-phenylethyl)morpholin-2-yl)phenyl)pyridin-2-amine (0.57 g, 1.5 mmol) and iodomethane (1.6 g, 11.2 mmol) in tetrahydrofuran (50 ml) was added potassium tert-butoxide (1.6 g, 9.45 mmol). After stirring at room temperature for 4 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated. The crude product was purified by column chromatography on silica gel (hexane-ethyl acetate, 1:1) to afford N-Methyl-N-(4-((2S)-4-((1R)-1-phenylethyl)-morpholin-2-yl)phenyl)pyridin-2-amine (0.57 g, 81%) as a yellow oil.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]([CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:25](=[O:37])[C:26]3[C:31]([C:32]=2/[CH:33]=[CH:34]/[CH:35]=[O:36])=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:19][CH:18]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]([CH2:38][CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:25](=[O:37])[C:26]3[C:31]([C:32]=2/[CH:33]=[CH:34]/[CH:35]([OH:36])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6])=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:19][CH:18]=1
Reactant: O=C/C=C/c1c(-c2ccc(F)cc2)n(CCc2ccccc2)c(=O)c2ccccc12
Reactant: COC(=O)CC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccc(F)cc2)n(CCc2ccccc2)c(=O)c2ccccc12
Temperature: -78 °C

Procedure:
In an atmosphere of argon gas, methyl acetoacetate (0.29 ml) was added to a suspension of sodium hydride (60%, in oil) (129 mg) in anhydrous tetrahydrofuran (15 ml) at 0° C. under stirring, followed by stirring for 10 minutes. After cooling at -78° C., the mixture to which a solution of n-butyllithium in n-hexane (1.6M, 2.7 ml) was added was stirred for 10 minutes. A solution of the compound (748 mg) obtained by Step 2 of Reference Example 13 in anhydrous tetrahydrofuran (7 ml) was added to the mixture, followed by stirring at -78° C. for 30 minutes. The reaction mixture to which aqueous ammonium chloride solution was added was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was subjected to a silica gel column chromatography using ethyl acetate-n-hexane to give the title compound (768 mg) as pale yellow oily substance.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]#[N:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=[CH:30][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:35][OH:36].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25](=[N:35][OH:36])[NH2:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:27]=[C:28]([C:31]([F:33])([F:34])[F:32])[CH:29]=[CH:30][C:16]=3[CH2:15]2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C#N)cc32)cc1
Reactant: NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(N)=NO)cc32)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbonitrile (0.60 g, 1.23 mmol, intermediate 54) in ethanol (6 mL) at rt was added hydroxylamine (0.24 mL of a 50% aqueous solution), and potassium carbonate (0.02 mL of a 0.8 M aqueous solution). After stirring at rt for 45 min, the reaction mixture was heated at 105° C. for 65 min in a microwave reactor. After cooling to rt, the precipitate was collected by filtration to provide the title compound. LC/MS: m/e 520.2 (M+H)+.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[C:33]([CH2:34][NH:35][C:36]3[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:43])=[CH:32][N:31]=[C:30]([S:44][CH3:45])[N:29]=2)[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:53](Cl)(Cl)=[O:54]>O1CCCC1>[Si:1]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([N:27]2[C:28]3=[N:29][C:30]([S:44][CH3:45])=[N:31][CH:32]=[C:33]3[CH2:34][N:35]([C:36]3[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:43])[C:53]2=[O:54])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1ncc(CNc2c(C)cccc2Cl)c(Nc2cccc(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)n1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)N(c1cccc(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c1)C(=O)N(c1c(C)cccc1Cl)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.5 %

Procedure:
A solution of 3.3 g (5 mmol) of 4-[3-(2-(tert-butyldiphenylsilyloxy)ethyl)phenyl]amino-5-(2-chloro-6-methylanilino)methyl-2-methylthiopyrimidine in 50 ml of tetrahydrofuran was treated with 1.4 ml (10 mmol) of triethylamine and the resulting mixture was added dropwise to a solution of 5 ml (9.6 mmol) of phosgene (20% in toluene) in 30 ml of tetrahydrofuran. The mixture was stirred at room temperature for 24 hours and then heated at reflux for a further 18 hours. The mixture was cooled and evaporated. The mixture was partitioned between 40 ml of dichloromethane and 40 ml of saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 1.58 g (47%) of 1-[3-(2-(tert-butyldiphenylsilyloxy)ethyl)phenyl]-3-(2-chloro-6-methylphenyl)-3,4-dihydro-7-methylthio-pyrimido[4,5-d]pyrimidin-2(1H)-one as a yellow solid. [Mass spectrum (ESI) MH+ =679].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:17]([O:16][C:3]1[CH:4]=[C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:2]=1[C:26]1[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:25]=1[F:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: Brc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(-c2ccc(OCc3ccccc3)cc2OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 90.3 %

Procedure:
Under an argon atmosphere, to a solution of (((4-bromo-1,3-phenylene)bis(oxy))bis(methylene))dibenzene (21.8 g) in toluene (160 mL) were added 2-fluoro-5-methoxyphenylboronic acid (13.8 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (2.23 g), tris(dibenzylideneacetone)dipalladium(0) (1.24 g) and 2.0 M aqueous sodium carbonate solution (81.0 mL), and the mixture was stirred at 80° C. for 14 hr. The reaction mixture was diluted with water, and filtered through celite. The filtrate was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (22.1 g) as a pale-yellow oil.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]([O:14]CC)=[O:13])[N:3]=1.CO.[Li+].[OH-]>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]([OH:14])=[O:13])[N:3]=1
Reactant: CCOC(=O)Cn1nc(I)c2cccnc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cn1nc(I)c2cccnc21

Procedure:
Ethyl (3-Iodo-pyrazolo[3,4-b]pyridin-1-yl)-acetate (11 g, 33 mmol, 1 equiv) was dissolved in 50 mL of THF and 50 mL of MeOH to the solution was added 40 mL of 1N LiOH for 3 h. The organic solvents were evaporated and the remaining aqueous phase was neutralized with 1N HCl to a pH of about 1 which resulted in the precipitation of the desired product as a white solid was filtered and air dried to give (3-iodo-pyrazolo[3,4-b]pyridin-1-yl)-acetic acid.
Reaction SMILES: [CH3:1][N:2]([O:41]CC1C=CC=CC=1)[C:3]([CH2:5][N:6]1[CH2:14][CH2:13][N:12]([CH2:15][C:16](=[O:27])[N:17]([O:19]CC2C=CC=CC=2)[CH3:18])[CH2:11][CH2:10][N:9]([CH2:28][C:29](=[O:40])[N:30]([O:32]CC2C=CC=CC=2)[CH3:31])[CH2:8][CH2:7]1)=[O:4]>[Pd]>[CH3:1][N:2]([OH:41])[C:3]([CH2:5][N:6]1[CH2:7][CH2:8][N:9]([CH2:28][C:29](=[O:40])[N:30]([OH:32])[CH3:31])[CH2:10][CH2:11][N:12]([CH2:15][C:16](=[O:27])[N:17]([OH:19])[CH3:18])[CH2:13][CH2:14]1)=[O:4]
Reactant: CN(OCc1ccccc1)C(=O)CN1CCN(CC(=O)N(C)OCc2ccccc2)CCN(CC(=O)N(C)OCc2ccccc2)CC1
Agent: [Pd]
Product: CN(O)C(=O)CN1CCN(CC(=O)N(C)O)CCN(CC(=O)N(C)O)CC1

Procedure:
From N,N′,N″-Tris[(N-methyl-N-benzyloxycarbamoyl)methyl]-1,4,7-triazacyclononane (1.3.5.1) and H2 and Pd/C.
Reaction SMILES: Cl[C:2]([C@:4]12[CH2:39][CH2:38][C@@H:37]([CH:40]([CH3:42])[CH3:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C@@H:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)=[O:3].[NH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1>ClCCCl.CN(C1C=CN=CC=1)C.O>[CH:40]([C@H:37]1[C@@H:5]2[C@@H:6]3[C@@:19]([CH3:22])([CH2:20][CH2:21][C@@:4]2([C:2](=[O:3])[NH:43][CH2:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)[CH2:39][CH2:38]1)[C@@:18]1([CH3:23])[C@@H:9]([C@:10]2([CH3:36])[C@@H:15]([CH2:16][CH2:17]1)[C:14]([CH3:25])([CH3:24])[C@@H:13]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)[CH2:12][CH2:11]2)[CH2:8][CH2:7]3)([CH3:42])[CH3:41]
Reactant: COC(=O)c1ccc([C@H]2CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)Cl)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Reactant: NCCc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCCl
Product: COC(=O)c1ccc([C@H]2CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)NCCc6ccccn6)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 70 %

Procedure:
To a flask containing methyl 4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-(chlorocarbonyl)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (77 mg, 0.13 mmol) in DCE (2 mL) was added Hunig'sBase (0.068 mL, 0.390 mmol), DMAP (1 mg, 8.19 μmol), and 2-(2-Aminoethyl)pyridine (0.031 mL, 0.260 mmol). The mixture was stirred for 2.5 hours at rt. The reaction was diluted with 5 mL of water and was extracted with dichloromethane (3×5 mL). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by Biotage flash chromatography using a 0-75% ethyl acetate in hexanes gradient. The fractions containing the expected product were combined and concentrated. The expected product, methyl 4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3a-(2-(pyridin-2-yl)ethylcarbamoyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.062 g, 0.091 mmol, 70.0% yield), was isolated as a white foam. LCMS: m/e 679.7 (M−H)−, 3.09 min (method 3).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:25])[C:13]([CH:23]=O)=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].Cl.[NH2:33][OH:34]>C(O)C>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:25])[C:13]([CH:23]=[N:33][OH:34])=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=Cc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=c1c(C=NO)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Temperature: 70 °C
Reaction time: 12 h
Yield: 57.6 %

Procedure:
To 500 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde were added 5 ml of ethanol, 460 mg of sodium acetate and 290 mg of hydroxylamine hydrochloride, followed by stirring at room temperature for 15 hours and at 70° C. for 12 hours. The solvent was evaporated under a reduced pressure, and water was added to the resulting residue, followed by extraction with chloroform and washing with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure to obtain 300 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde oxime.