Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][C:11]([CH3:30])([CH2:13][CH2:14][S:15]([CH2:18][C@@H:19]1[C@@H:24]([OH:25])[C@H:23]([OH:26])[C@@H:22]([OH:27])[C@@H:21]([O:28][CH3:29])[O:20]1)(=[O:17])=[O:16])[CH3:12])C1C=CC=CC=1>CO.[Pd]>[NH2:10][C:11]([CH3:30])([CH3:12])[CH2:13][CH2:14][S:15]([CH2:18][C@@H:19]1[C@@H:24]([OH:25])[C@H:23]([OH:26])[C@@H:22]([OH:27])[C@@H:21]([O:28][CH3:29])[O:20]1)(=[O:16])=[O:17]
Reactant: CO[C@H]1O[C@H](CS(=O)(=O)CCC(C)(C)NC(=O)OCc2ccccc2)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Pd]
Solvent: CO
Product: CO[C@H]1O[C@H](CS(=O)(=O)CCC(C)(C)N)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 3 h
Yield: 101 %

Procedure:
Under a nitrogen atmosphere, 175 mg of 10% Pd on carbon was added to a solution of benzyl(2-methyl-4-((((2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)sulfonyl)butan-2-yl)carbamate (700 mg, 1.5 mmol) in 5 mL of methanol. The resultant mixture was degassed and placed under a hydrogen atmosphere, stirring for 3 hours. The suspension was filtered through a pad of celite, washing with methanol, and the filtrate was concentrated under reduced pressure to give ca 496 mg of white foam (quantitative yield). 1H NMR (400 MHz, CD3OD) δ 1.19 (s, 6H), 1.90-1.95 (m, 2H), 3.13-3.18 (dd, J=8.9, 9.9 Hz, 1H), 3.21-3.30 (m, 2H), 3.4-3.43 (m, 3H), 3.48 (s, 3H), 3.61-3.66 (t, J=9.2 Hz, 1H), 4.04-4.10 (m, 1H), 4.69-4.70 (d, J=3.7 Hz, 1H). 13C NMR (100 MHz, MeOD) δ 27.6, 27.7, 34.8, 48.8, 50.8, 53.9, 54.9, 67.3, 71.9, 72.8, 73.3, 100.1. LRMS (ESI/APCI) m/z 328 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH2:6].C([O-])(=O)C.[K+].[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[O:14]1[C:18]2([CH2:23][CH2:22][CH:21]([NH:6][C@@H:5]([C:4]([O:3][CH3:2])=[O:8])[CH3:7])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1
Reactant: COC(=O)[C@@H](C)N
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@@H](C)NC1CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 67 %

Procedure:
To a stirred mixture of D-alanine methyl ester hydrochloride (1, 12 g, 85.9 mmol) in anhydrous dichloromethane (120 mL) was added potassium acetate (8.5 g, 85.9 mmol) and the resulting reaction mixture was stirred at rt for ten minutes. The reaction was then cooled to 10° C. and treated with 1,4-dioxaspiro[4.5]decan-8-one (2, 13.4 g, 85.9 mmol), followed by the addition of sodium triacetoxyborohydride (22.6 g, 106.6 mmol) in portions over a period of ten minutes. The resulting reaction mixture was stirred at rt for 16 h. Saturated aqueous sodium bicarbonate solution was then added to the reaction and the mixture was stirred for another 30 minutes. Dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane (100 mL×3). Organic layers were combined, washed with brine, dried over sodium sulfate, and evaporated to give the crude product as colorless oil (14 g), which was used for next step without any further purifications. 1HNMR (300 MHz, CDCl3): δ 1.22 (d, 3H), 1.40-1.61 (m, 4H), 1.65-1.90 (m, 4H), 2.42-2.55 (m, 1H), 3.42 (q, 1H), 3.72 (s, 3H), 3.98 (s, 4H).
Reaction SMILES: C(NCC)C.[CH2:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:25])[CH2:21]CCCl)=[CH:16][CH:15]=1.O>C(#N)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:25])[CH2:21][CH2:7][CH2:6][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:16][CH:15]=1
Reactant: O=C(CCCCl)c1ccc(Br)cc1
Reactant: CCN(CC)CC
Solvent: O
Solvent: CC#N
Solvent: CCNCC
Product: CCN(CC)CCCC(=O)c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
Diethylamine (180 mL) and triethylamine (90 mL) were added to a solution of 4′-bromo-4-chlorobutyrophenone (18.13 g) in acetonitrile (90 mL), and the mixture was stirred at 100° C. for one hour. The reaction solution was cooled to room temperature and water was added, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1→ethyl acetate:methanol:triethylamine=40:4:1) to give 1-(4-bromophenyl)-4-(diethylamino)butan-1-one as a brown oil (9.02 g, 44%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[CH3:54][N:55]1[CH:59]=[CH:58][C:57]([C:60](Cl)=[O:61])=[N:56]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:60]([C:57]2[CH:58]=[CH:59][N:55]([CH3:54])[N:56]=2)=[O:61])[CH2:48]1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cn1ccc(C(=O)Cl)n1
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc(C(=O)N2CC[C@@H](CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)C2)n1
Yield: 82 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 1-methyl-1H-pyrazole-3-carbonyl chloride as the starting materials in 82% yield. LCMS for C28H29ClN9O2 (M+H)+: m/z=558.1.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([S:20][CH3:21])[N:17]=[C:18](Cl)[C:9]=2[C:8]1=[O:22].[CH3:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1OB(O)O>>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([S:20][CH3:21])[N:17]=[C:18]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH3:32])[C:9]=2[C:8]1=[O:22]
Reactant: Cc1ccccc1OB(O)O
Reactant: CSc1nc(Cl)c2c(n1)NCCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Product: CSc1nc2c(c(-c3ccccc3C)n1)C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 99.9 %

Procedure:
In a similar manner to Reference Example 10, 6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 7; 485 mg) was reacted with 2-methylphenylboric acid (163 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine (540 mg, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[C:18]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:17]=[CH:16][C:3]=1[O:4][CH:5]1[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1.Cl>CO>[NH:7]1[CH2:8][CH:5]([O:4][C:3]2[CH:16]=[CH:17][C:18]([CH2:20][N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[CH:19][C:2]=2[CH3:1])[CH2:6]1
Reactant: Cc1cc(CN2CCOCC2)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Product: Cc1cc(CN2CCOCC2)ccc1OC1CNC1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
A solution of 12A (2.6 g, 7.17 mmol) in MeOH (10 mL) was treated with HCl in MeOH (40 ml, 50 mmol) and stirred at RT over night. The reaction mixture was concentrated and the residue was dissolved in water (15 mL). The solution was washed with EtOAc. DCM (100 mL) was added to the aqueous phase and then aqueous K2CO3 (sat., 20 mL) was added. The two phases were separated and organic solution was filtered through a phase separator. The solvent was removed by evaporation. There was obtained 1.8 g (96%) of 12B as a colorless oil. 1H NMR (600 MHz, CDCl3): δ 2.21 (s, 3H), 2.33-2.48 (m, 4H), 3.38 (s, 2H), 3.63-3.73 (m, 4H), 3.74-3.84 (m, 2H), 3.87-3.96 (m, 2H), 4.91-5.02 (m, 1H), 6.43 (d, 1H), 7.01 (d, 1H), 7.09 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[CH3:11][NH:12][CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[CH3:11][N:12]([CH2:6][C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[C:1]#[N:2])[CH3:13]
Reactant: CNC
Reactant: N#Cc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)Cc1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5.00 g (37.37 mmol) 3-cyanobenzaldehyde and 20.00 ml (40 mmol) dimethylamine (2 molar solution in tetrahydrofuran) are placed in 150 ml of tetrahydrofuran and cooled to 0° C. 12.40 g (81.73 mmol) sodium triacetoxyborohydride are added, then the mixture is stirred for 2 hours at 0° C. and 2 hours at ambient temperature. The reaction mixture is combined with 25 ml of 15% potassium carbonate solution and stirred for 0.5 hours. After the addition of ethyl acetate the mixture is extracted. The organic phase is washed with potassium carbonate solution, dried and evaporated to dryness.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20]([CH:22]2[CH2:24][CH2:23]2)=[O:21])=[C:13]3[NH:25][C:26]2[CH:40]=[CH:39][C:29]([CH2:30][NH:31]C(=O)OC(C)(C)C)=[CH:28][CH:27]=2)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].C(O)(C(F)(F)F)=O>>[NH2:31][CH2:30][C:29]1[CH:39]=[CH:40][C:26]([NH:25][C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:4]4[CH:5]=[C:6]([F:9])[C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=4)[CH:11]=3)[N:16]=[CH:15][C:14]=2[C:20]([CH:22]2[CH2:24][CH2:23]2)=[O:21])=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)cc1
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)cc1
Yield: 52.8 %

Procedure:
Following general procedure A-2, tert-butyl 4-[6-(3-chloro-5-fluoro-4-hydroxyphenyl)-3-(cyclopropanecarbonyl)quinolin-4-ylamino]benzylcarbamate (0.127 mmol) was reacted with TFA (2 mL) to afford the desired product (31 mg, 53% over two steps) as a yellow solid: 1H NMR (300 MHz, CD3OD+TFA-d) δ 9.44 (s, 1H), 8.24 (dd, J=8.9, 1.9 Hz, 1H), 8.08-7.96 (m, 2H), 7.69 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 7.17-7.06 (m, 1H), 7.06-6.98 (m, 1H), 4.27 (s, 2H), 2.93-2.80 (m, 1H), 1.25-1.11 (m, 4H); ESI MS m/z 462 [C26H21ClFN3O2+H]+; HPLC>99% (AUC), tR=12.22 min.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[C:6](Cl)=[N:5][S:4][N:3]=1.O.[CH3:11][O:12][C:13]1[CH:14]=[C:15](O)[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1.[OH-].[Na+]>C(Cl)Cl.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[C:7](=[O:8])[C:6]([C:15]2[CH:14]=[C:13]([O:12][CH3:11])[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=2)=[N:5][S:4][N:3]=1
Reactant: O=c1c(Cl)nsnc1Cl
Reactant: COc1cc(O)cc(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(OC)cc(-c2nsnc(Cl)c2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1.83 g of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one in 50 ml CH2Cl2 is added a solution of 50 ml of water, 1.54 g of 3,5-dimethoxyphenol, 5 ml of 2N aqueous sodium hydroxide solution and 0.1 g of tetra-n-butylammonium chloride. The two phase mixture is stirred at room temperature for 3 hours. Then the layers are separated, and the organic layer is dried over magnesium sulfate and concentrated. The residue is recrystallized from alcohol to yield white crystals, mp 121°-124°.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[Na+].[Na+]>O>[C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3]
Reactant: O=C([O-])CC(O)C(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CC(O)C(=O)O

Procedure:
The following solutions were prepared: 1 μL of 1M potassium ferricyanide aqueous solution obtained by dissolving potassium ferricyanide (manufactured by Wako Pure Chemical Industries, Ltd.) in pure water; 6.7 μL of 1000 U/mL diaphorase solution obtained by dissolving diaphorase (manufactured by UNITIKA LTD.) in 50 mM phosphate buffer (pH 7.5); 7.8 μL of 4M sodium malate aqueous solution obtained by dissolving sodium malate (manufactured by Wako Pure Chemical Industries, Ltd.) in pure water; 7.8 μL of 4M malic acid aqueous solution obtained by dissolving malic acid (manufactured by Wako Pure Chemical Industries, Ltd.) in pure water; 7.8 μL of 4M potassium malate aqueous solution obtained by dissolving potassium malate (manufactured by KANTO CHEMICAL CO., INC.) in pure water; 1 μL of 5 mM NADP aqueous solution obtained by dissolving NADP (manufactured by ORIENTAL YEAST Co., Ltd.) in pure water; and 1 μL of 25000 U/mL malate dehydrogenase solution containing malate dehydrogenase dissolved in 50% of glycerol (manufactured by Roche Diagnostics, Inc.).
Reaction SMILES: [CH3:1][NH2:2].C(O)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:2][CH3:1])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CN
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
A round bottom flask was charged with methylamine solution 40% (0.88 ml, 26 mmol) in ethanol (10 ml, 171 mmol). The mixture was chilled to 0° C. in an ice bath, with stirring under inert atmosphere. Then 4-fluorobenzenesulfonyl chloride (1.00 g, 5.1 mmol) was added into the mixture. The resulting mixture was allowed to stir at 0° C., while under inert atmosphere for 30 minutes. The progress of the reaction was monitored by LC/MS, which showed mostly desired product peak. The mixture was diluted with DCM and saturated sodium bicarbonate solution, then extracted the organic layer with DCM (3×25 ml). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuo. This gave 4-fluoro-N-methylbenzenesulfonamide (0.918 g, 94% yield) as an off-white crystalline solid. MS (ESI pos. ion) m/z: 190 (MH+). Calc'd exact mass for C7H8FNO2S: 189. 1H NMR (400 MHz, chloroform-d): 2.64-2.71 (m, 3H), 4.63 (s, 1H), 7.18-7.28 (m, 2H), 7.88-7.93 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[C:16]=3[S:17][C:18]=2Br)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[C:16]=3[S:17][C:18]=2[N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1c(Br)sc2c1CCCC2=O
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Product: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1c(N2CCOCC2)sc2c1CCCC2=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2-Bromo-7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonic acid[2-(4-fluorophenyl)-2-hydroxy-ethyl]-methyl-amide (the compound of Preparation Example 58) (80 mg), triethylamine (29 mL) and morpholin (24 μL) were stirred at 60° C. for 3 hours. The residue resulting from the evaporation of the solvent at reduced pressure was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (82 mg) was obtained as a colorless candy-like substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][CH:3]=1.[C:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:21]([O:20][C:18]([N:25]1[CH2:30][CH2:29][CH:28]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][C:9](=[O:17])[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[N:7]=2)[CH2:27][CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cccc(NC(=O)c2ccc(F)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(NC(=O)c3ccc(F)cc3)n2)CC1
Reaction time: 1 h
Yield: 90.4 %

Procedure:
Place N-(6-aminopyridin-2-yl)-4-fluorobenzamide (Preparation 37) (2 g, 8.3 mmol) and 1-boc-4-piperidone (15.0 g, 83 mmol) in 1,2-dichloroethane (20 mL). Stir for 1 hr. then add sodium triacetoxyborohydride (4.38 g, 20.8 mmol). After stirring for 36 hr., quench with 1 N NaOH and dilute with CH2Cl2. Separate and extract the aqueous layer twice with CH2Cl2, combine organics, dry over MgSO4, and concentrate. Take up the residue in CH2Cl2, and place on two 10 g SCX columns. Wash the columns successively with CH2Cl2 and then with methanol. Elute the product with 2M NH3 in methanol. Concentrate and chromatograph on silica gel, eluting with a gradient of 0-10% (2M NH3 in methanol) in CH2Cl2) to give the title intermediate 3.11 g (90%): mass spectrum (ion spray): m/z 415.4 (M+1); mp 82.7° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:11]([F:22])[CH:10]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)[N:3]=1.[H][H]>[Pd].C(O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)=[C:11]([F:22])[CH:10]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=2)[N:3]=1
Reactant: Nc1nc(Nc2ccc(Sc3ccncc3)c(F)c2)cc(-c2cccc([N+](=O)[O-])c2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cccc(-c2cc(Nc3ccc(Sc4ccncc4)c(F)c3)nc(N)n2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.5 %

Procedure:
A dry flask under argon was charged with 10% palladium on carbon (20 mg). A solution of N-[2-amino-6-(3-nitrophenyl)-4-pyrimidinyl]-N-[3-fluoro-4-(4-pyridinylsulfanyl)phenyl]amine (Example 20, 200 mg, 0.46 mmol) in ethanol (12 mL) and EtOAc (1 mL) was added via syringe through a septa to the palladium on carbon. The flask was then fitted with a hydrogen balloon and stirred at room temperature for 48 h. At this time the palladium was filtered through a pad of Celite®. The filtrate was coated on silica and purified on the MPLC (Biotage) with 2-8% MeOH in CH2Cl2 to afford the desired product as a solid (120 mg, 64%). TLC (6% MeOH in CH2Cl2) Rf0.26; MS (ES) 405 [M+H]+; 1H-NMR (DMSO-d6) δ 5.22 (bs, 2H), 6.45 (s, 1H), 6.49 (bs, 2H) 6.62-6.65 (m, 1H), 6.98 (d, J=6.4 Hz, 2H), 7.02-7.16 (m, 3H), 7.43-7.55 (m, 2H), 8.30-8.35 (m, 3H), 9.75 (bs, 1H).
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].[NH2:24][CH2:25][CH:26]1[CH2:28][CH2:27]1.FC(F)(F)C(O)=O>CS(C)=O>[CH:26]1([CH2:25][NH:24][C:2]2[N:23]=[CH:22][CH:21]=[CH:20][C:3]=2[C:4]([NH:6][CH2:7][C:8]2[S:9][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)=[O:5])[CH2:28][CH2:27]1
Reactant: O=C(NCc1ccc(Oc2ccccc2)s1)c1cccnc1Cl
Reactant: NCC1CC1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(Oc2ccccc2)s1)c1cccnc1NCC1CC1
Temperature: 120 °C
Reaction time: 14 h
Yield: 17 %

Procedure:
To a solution of 2-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Preparation Example A+-7 (64 mg, 0.186 mmol) in dimethylsulfoxide (1 mL) was added (aminomethyl)cyclopropane (48 μl, 0.56 mmol), and the solution was stirred for 14 hours at 120° C. The reaction mixture was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and the title compound (15.6 mg, 0.0316 mmol, 17%) was obtained as a trifluoroacetic acid salt.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([BH3-])#N.[Na+].[NH2:12][C@@H:13]1[CH2:30][C@@:28]2([CH3:29])[C@@H:24]([CH2:25][CH2:26][C@@H:27]2[C:31]([O:33][CH3:34])=[O:32])[C@H:23]2[C@H:14]1[C@:15]1([CH3:36])[C@H:20]([CH2:21][CH2:22]2)[CH2:19][C@H:18]([OH:35])[CH2:17][CH2:16]1>C(O)C.C([O-])(O)=O.[Na+]>[CH:1]1([NH:12][C@@H:13]2[CH2:30][C@@:28]3([CH3:29])[C@@H:24]([CH2:25][CH2:26][C@@H:27]3[C:31]([O:33][CH3:34])=[O:32])[C@H:23]3[C@H:14]2[C@:15]2([CH3:36])[C@H:20]([CH2:21][CH2:22]3)[CH2:19][C@H:18]([OH:35])[CH2:17][CH2:16]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@H](N)C[C@]12C
Reactant: O=C1CCCCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@H](NC3CCCCC3)C[C@]12C

Procedure:
Cyclohexanone (2.9 ml) and sodium cyanoborohydride (2.512 g) were added to a stirred solution of methyl 11α-amino-3α-hydroxy-5β-androstane-17β-carboxylate (2.505 g) in ethanol (30 ml). After 5 h the mixture was diluted with 5% NaHCO3 solution and extracted with ether (×2). The extract was washed with water (×2), dried Na2SO4) and evaporated to leave a froth (2.544 g). A sample (0.39 g) was purified by preparative t.l.c. using CHCl3 :MeOH (19:1) to give the title compound [α]D -9°, νmax 1725 cm-1.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[C:18](Cl)=[N:17][C:16]([N:20]([CH3:24])[CH2:21][CH2:22][CH3:23])=[CH:15][N:14]=1)[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][C:13]2[N:14]=[CH:15][C:16]([N:20]([CH3:24])[CH2:21][CH2:22][CH3:23])=[N:17][C:18]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN(C)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(C)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reaction time: 6 h
Yield: 7.4 %

Procedure:
To a solution of 2-[benzyl({3-chloro-5-[methyl(propyl)amino]pyrazin-2-yl}methyl)amino]ethanol (0.75 g) in DMF (4 mL) was added potassium tert-butoxide (0.29 g) at 0° C., and the mixture was stirred for 6 hr. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10→50% ethyl acetate/hexane) to give the title compound (50 mg, 8%) as a pale-yellow oil.