Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]=[C:11]([C:20]([NH:22][CH2:23][CH2:24][O:25][CH3:26])=[O:21])[N:10]=1.[N:27]#[C:28]Br.O>O1CCCC1.C(N(CC)CC)C>[C:28]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]=[C:11]([C:20]([NH:22][CH2:23][CH2:24][O:25][CH3:26])=[O:21])[N:10]=1)#[N:27]
Reactant: COCCNC(=O)c1nc(N[C@H]2CCCC[C@H]2N)c2cc(C)ccc2n1
Reactant: N#CBr
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCNC(=O)c1nc(N[C@H]2CCCC[C@H]2NC#N)c2cc(C)ccc2n1
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
In an argon atmosphere, to a solution of 3.30 g of 4-{[(1S,2R)-2-aminocyclohexyl]amino}-N-(2-methoxyethyl)-6-methylquinazolin-2-carboxamide in 80 ml of tetrahydrofuran, 1.54 ml of triethylamine and 978 mg of cyanogen bromide were sequentially added at −20° C., and the mixture was stirred at the same temperature for 0.5 hour. Water was added to the reaction solution, and the mixture was subjected to an extraction with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform:methanol=50:1), whereby 1.96 g of a desired compound was obtained as a pale yellow crystal.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22](=[N:28]O)[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1.CN(C=O)C>[F:13][C:2]([F:1])([F:14])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][C:10]1[O:12][N:28]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc(Cc2cccc(C(F)(F)F)c2)n1
Yield: 3.5 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-(3-(trifluoromethyl)phenyl)acetic acid (0.773 g; 3.78 mmol) and oxalyl chloride (0.352 mL; 4.16 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (6 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.040 g (4%) of ethyl 5-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:13])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=O)([O-:3])=[O:2].Cl.[CH:15](N)=[NH:16]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:7]([C:8](=[O:10])[NH:16][CH:15]=[N:13]2)=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: N=CN
Agent: Cl
Product: O=c1[nH]cnc2cc([N+](=O)[O-])ccc12
Reaction time: 1 h
Yield: 44.3 %

Procedure:
4-Nitroanthranilic acid (10.0 g, 54.9 mmol) and formamidine hydrochloride (6.63 g, 82.4 mmol) were ground together in a mortar and pestle to produce a fine, intimate mixture. The mixture was placed in a 250 mL round-bottom flask, and spread evenly over the surface. The flask was placed in an oilbath at 200° C. The solid underwent a color change, and a distillate was seen on the side of flask, but did not really melt. After 30 min the flask was removed from the heating bath. 0.3M sodium hydroxide solution (150 mL) was added to the cooled flask, the black solid mass was broken up with a spatula, and stirred for 1 h. The solid was filtered off and washed with water. The filtrate was discarded. The black solid was suspended in dichloromethane/methanol (10:1) and filtered through a plug of silica, eluting with the same solvent until no more product came off. The material was one spot by TLC, plus black baseline material, but was poorly soluble, so a large volume of solvent was needed. The filtrate was evaporated to dryness and the solid residue triturated with a little methanol and filtered to give 7-nitroquinazoline-4-one (4.65 g, 44%).
Reaction SMILES: N1CCCC1.Cl.C[N:8]1[C:16]2[N:11]([CH:12]([CH3:25])[N:13]=[C:14]([NH:17][CH2:18][C:19]3C=CC=[CH:21][CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1>>[CH3:25][C:12]1[N:11]2[CH2:10][CH2:9][N:8]=[C:16]2[CH:15]=[C:14]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[N:13]=1
Reactant: CC1N=C(NCc2ccccc2)C=C2N(C)CCN21
Agent: Cl
Solvent: C1CCNC1
Product: CC1=NC(N2CCCC2)=CC2=NCCN12

Procedure:
Following the above procedure, but substituting N-methyl benzylamine for pyrrolidine, there was prepared N,5-dimethyl-7-benzylamino-2,3-dihydroimidazo[1,2-c]pyrimidine hydrochloride decomposing at 213° C. after recrystallization from ether.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:12]#[N:13])[CH:6]=[CH:5][C:4]=2[CH2:3]1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][C:26]2=[O:31])=[CH:19][CH:18]=1)([O-:16])=[O:15].C([BH3-])#N.[Na+]>C(O)C.CCOC(C)=O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH:2]3[CH2:11][CH2:10][C:9]4[CH:8]=[C:7]([C:12]#[N:13])[CH:6]=[CH:5][C:4]=4[CH2:3]3)[CH2:27][C:26]2=[O:31])=[CH:21][CH:22]=1)([O-:16])=[O:15]
Reactant: O=C1CNCCN1CCc1ccc([N+](=O)[O-])cc1
Reactant: N#Cc1ccc2c(c1)CCC(=O)C2
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1ccc2c(c1)CCC(N1CCN(CCc3ccc([N+](=O)[O-])cc3)C(=O)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-Oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (24 mg, 0.14 mmol) and 1-[2-(4-nitrophenyl)ethyl]piperazin-2-one (20 mg, 0.070 mmol) was treated with titanium(IV) isopropoxide (0.10 ml, 0.35 mmol) for 30 minutes. Then the reaction was diluted with ethanol (5 mL), and sodium cyanoborohydride (44 mg, 0.70 mmol) was added. The reaction was stirred at RT overnight. The reaction was diluted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated to give the crude residue. The desired product was purified by reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 405 [M+1]+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][CH2:20][NH2:21])=[CH:16][CH:17]=3)[C:12]3[CH:22]=[C:23]([Cl:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[Cl:26][C:23]1[CH:24]=[N:25][C:11]2[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:18]3[C:13]([C:12]=2[CH:22]=1)=[CH:14][C:15]([CH2:19][CH2:20][NH:21][C:34](=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[CH:16][CH:17]=3
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCc1ccc2c(c1)c1cc(Cl)cnc1n2S(=O)(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1ccc2c(c1)c1cc(Cl)cnc1n2S(=O)(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 48 %

Procedure:
To a cooled mixture (0° C.) of 16 (65 mg, 0.17 mmol) in CH2Cl2 (3 mL) were added Et3N (100 μL, 4.2 equiv.) and benzoyl chloride (30 μL, 1.5 equiv.). The mixture was stirred for 12 h at room temperature. The resulting mixture was then quenched at 0° C. with NaHCO3. It was extracted with the mixture of EtOAc. The resulting organic layer was washed with saturated aqueous NaHCO3 solution and brine, dried over MgSO4, filtered and solvents were removed under reduced pressure. The crude product was purified by flash chromatography (EtOAc/PE 1:1) to afford 17 in 48% yield as a white solid, 1H NMR (300 MHz, CDCl3): δ 8.48 (d, 1H, J=2.3 Hz), 8.41 (d, 1H, J=8.5 Hz), 8.13-8.11 (m, 3H), 7.77 (bs, 1H), 7.70 (d, 1H, J=7.5 Hz), 7.57-7.41 (m, 7H), 6.19 (bs, 1H), 3.05 (q, 2H, J=6.9 Hz), 3.09 (t, 2H, J=6.9 Hz); MS (ESI) m/z 490 [M+H+]
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)C(C)C)C>C(Cl)Cl.CCOCC>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(Br)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1cccc(Br)n1
Temperature: 0 °C
Yield: 69.1 %

Procedure:
To an ice cold solution of 6-bromopyridine-2-amine (7 g, 40.5 mmol) in DCM was added pivaloyl chloride (5.23 mL, 42.48 mmol), N-ethyl-N-isopropylpropan-2-amine (13.6 mL, 82.9 mmol) sequentially. The solution was stirred for an hour then diluted with 50 mL of ether. The mixture was washed with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered concentrated. The residue was slowly solidified after scratching in ethyl acetate-hexane mixture to afford 7.2 gm (69.2% yield) of the titled compound. LCMS: m/z=257.0 (M+1).
Reaction SMILES: C[O:2][CH:3]([O:20][CH3:21])[CH2:4][C:5]1[C:17]([CH3:18])=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]([CH3:19])[CH:6]=1.Cl(O)(=O)(=O)=O.[C:27](#N)C>>[CH2:21]([O:20][CH:3]([OH:2])[CH2:4][C:5]1[C:17]([CH3:18])=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]([CH3:19])[CH:6]=1)[CH3:27]
Reactant: CC#N
Reactant: CCOC(=O)COc1cc(C)c(CC(OC)OC)cc1C
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCOC(=O)COc1cc(C)c(CC(O)OCC)cc1C
Yield: 48.8 %

Procedure:
Ethyl 2-[4-(2,2-dimethoxyethyl)-2,5-dimethylphenoxy]acetate (43 g) was dissolved in acetonitrile (190 g) while stirring. To the resulting solution was added 10% perchloric acid (216 g), and the mixture was stirred for an hour at room temperature. The reaction mixture was partitioned between toluene (340 g) and water (200 g). The organic layer was washed with water, an aqueous solution of sodium bicarbonate and brine successively, and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was dissolved in ethanol (180 g), and the solvent was removed under reduced pressure. The residue was dissolved with hexane (86 g) and ethanol (37 g). After seed crystals were added, the solution was stirred at 0-10° C. for 2 hours. Hexane (220 g) was added, and the resulting suspension was stirred at 0-10° C. for 2 hours. The precipitated crystals were filtered to give ethyl 2-[4-(2-ethoxy-2-hydroxyethyl)-2,5-dimethylphenoxy]acetate (21 g).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[C:16]1[N:17]([CH3:21])[N:18]=[CH:19][CH:20]=1.[H][H]>CO.[Pd]>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:16]1[N:17]([CH3:21])[N:18]=[CH:19][CH:20]=1
Reactant: CN(C)CCCOc1ccc([N+](=O)[O-])cc1-c1ccnn1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Yield: 100.2 %

Procedure:
Dimethyl-{3-[2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenoxy]-propyl}-amine (1.4047 g, 4.62 mmol) and 5% Pd/C (114 mg) were stirred in methanol (50 mL) under 1 atm of hydrogen for 75 minutes. The suspension was filtered through celite and dried in vacuo to afford 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine as an orange oil (1.27 g, 100%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH3:4].O.C(=O)(O)[O-].[Na+].[C:19](Cl)(=[O:21])[CH3:20]>C(OCC)(=O)C>[C:19]([NH:1][CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[CH3:4])(=[O:21])[CH3:20]
Reactant: COc1ccc(C(C)CN)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C(C)CNC(C)=O)cc1
Yield: 99.8 %

Procedure:
A mixture of 19.8 g of 1-amino-2-(4-methoxyphenyl)propane, 200 ml of ethyl acetate, 200 ml of water and 84 g of sodium bicarbonate is cooled at 5° to 10° C. under stirring, and 18.8 g of acetyl chloride in 100 ml of ethyl acetate are added dropwise thereto at the same temperature. After the reaction, the ethyl acetate layer is separated therefrom, washed, dried and then condensed to dryness under reduced pressure. 24.8 g of 1-acetylamino-2-(4-methoxyphenyl)propane are obtained as oil.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.[NH2:23][NH:24][C:25](=O)[CH2:26][N:27]([CH3:29])[CH3:28].C(N(CC)CC)C>C(O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:6][C:25]([CH2:26][N:27]([CH3:29])[CH3:28])=[N:24][N:23]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:17][CH:18]=1
Reactant: CN(C)CC(=O)NN
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)Cc1nnc(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)[nH]1
Temperature: 75 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (200 mg, 0.62 mmol), N-amino-2-(dimethylamino)acetamide (147.5 mg, 0.95 mmol), and molecular sieves in ethanol was added triethylamine (0.25 mL, 1.86 mmol). The reaction was allowed to stir under a nitrogen atmosphere at 75° C. overnight. The reaction was filtered using a fritted funnel and the filtrate was concentrated. This was purified by semi-preprative HPLC. The material was taken up in ethyl acetate and washed with aqueous sodium bicarbonate. This organic layer was dried with magnesium sulfate, filtered and concentrated to yield the title compound (192 mg, 23% yield). 1H NMR (CD3OD) δ 8.7 (s, 1H), 8.0-8.1 (m, 3H), 7.7 (d, 1H), 7.25 (t, 2H), 4.5 (s, 2H), 3.0 (s, 6H), ES-MS (m/z) 337 [M+1]+.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].COC([C:11]1[NH:12][C:13]2[CH:14]=[C:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:16]=[C:17]3[C:23](=[O:24])[NH:22][N:21]=[CH:20][C:19]=1[C:18]=23)=O.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:33]([O:37][C:38]([N:40]1[CH2:41][CH:42]=[C:43]([C:11]2[NH:12][C:13]3[CH:14]=[C:15]([NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH:16]=[C:17]4[C:23](=[O:24])[NH:22][N:21]=[CH:20][C:19]=2[C:18]=34)[CH2:44][CH2:45]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COC(=O)c1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cc2c3c(c(C4=CCN(C(=O)OC(C)(C)C)CC4)[nH]c3c1)C=NNC2=O
Temperature: 80 °C
Yield: 94 %

Procedure:
Under an argon atmosphere, 2.0 M aqueous Na2CO3 (0.66 mL) was added to a mixture of Intermediate 147(d) of Example 147 (100 mg, 0.265 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic Acid tert-butyl Ester (122 mg, 0.395 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (10.8 mg, 0.013 mmol) in anhydrous N,N-dimethylformamide (5 ml). The mixture was heated at 80° C. for 16 hours. The reaction was filtered through a thin pack of diatomaceous earth, and the volatile components were removed in vacuo. Silica gel chromatography (eluted with 1:1 ethyl acetate:hexane) afforded the title compound (120 mg, 0.249 mmol) as a yellow powder in 94% yield.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14]>>[Cl:10][C:11]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14]
Reactant: NCCc1ccccc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cc1Cl
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3ccccc3)cc2)cc1Cl
Yield: 34 %

Procedure:
Reacting phenethylamine with the compound of Example 245, step 2 under reductive amination conditions (described previously) affords the title compound.
Reaction SMILES: B#B.C(O)(=O)C.C([O:10][C@H:11]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:13]([CH2:14][CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][C@@H:19]([O:32]C(=O)C)[C:20]2=[N:30]O)[CH2:12]1)(=O)C.O>O1CCCC1>[NH2:30][C@H:20]1[C@H:19]([OH:32])[CH2:18][C@H:17]2[C@H:16]3[C@H:25]([CH2:24][CH2:23][C@:21]12[CH3:22])[C@:26]1([CH3:29])[C@H:13]([CH2:12][C@@H:11]([OH:10])[CH2:28][CH2:27]1)[CH2:14][CH2:15]3
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(=NO)[C@H](OC(C)=O)C[C@@H]32)C1
Agent: B#B
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@]12CC[C@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](N)[C@H](O)C[C@@H]12
Temperature: 0 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A solution of diborane in tetrahydrofurane (257 ml; 1 M) was added dropwise to a stirred solution of 3β,16α-bis(acetyloxy)-5α-androstan-17-one oxime acetate (11.7 g) in tetrahydrofuran (257 ml) at 0° C. under a nitrogen atmosphere. The solution was set aside at room temperature overnight, then water (35 ml) was carefully added to the cooled (0° C.), stirred solution. Tetrahydrofuran was distilled off and replaced with ethanol (400 ml) and sodium hydroxide solution (12 ml; 4 N), and the solution was heated under reflux for 3 h. The solution was concentrated and cooled; water (100 ml) and concentrated hydrochloric acid (12 ml) were added and the solution was heated on a water bath for 1 h. Aqueous sodium hydroxide (2 N) was then added to the cooled solution to precipitate the product, which was filtered off, washed with water and dried in vacuo to give 17β-amino-5α-androstane-3β,16α-diol (6.7 g), m.p. 234°-237° C. (decomp.), [α]D -3.8° (c 1.1 in MeOH).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:10]([O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5]1.[C:21]1([N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:21]1([N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28](=[O:29])[O:1][CH2:2][CH2:3][CH:4]2[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)COc1cccc2c1CCC(CCO)C2
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)COc1cccc2c1CCC(CCOC(=O)N(c1ccccc1)c1ccccc1)C2
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 36.4 %

Procedure:
A mixture of ethyl [5,6,7,8-tetrahydro-6-(2-hydroxyethyl)-1-naphthyloxy]acetate (50 mg), N,N-diphenylcarbamoyl chloride (50 mg), and pyridine (32 mg) was stirred at 100° C. for 1 hour and 40 minutes, cooled to room temperature, and partitioned between ethyl acetate and 1N hydrochloric acid. The ethyl acetate layer was washed successively with water, aqueous sodium bicarbonate, and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (toluene-ethyl acetate) over silica gel to afford 2-[5-(ethoxycarbonylmethoxy)-1,2,3,4-tetrahydro-2-naphthyl]ethyl N,N-diphenylcarbamate (31 mg) as a syrup.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=O)[CH2:18][CH2:17]2)[N:4]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH2:34].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:6]=[C:5]([NH:15][C@H:16]2[CH2:17][CH2:18][C@H:19]([C:22]([NH:34][CH2:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[C:26]([F:25])([F:35])[F:36])=[O:24])[CH2:20][CH2:21]2)[N:4]=1
Reactant: CNc1nc(N[C@H]2CC[C@H](C(=O)O)CC2)nc(-c2ccccc2)n1
Reactant: NCc1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CNc1nc(N[C@H]2CC[C@H](C(=O)NCc3ccccc3C(F)(F)F)CC2)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of trans-4-{[4-(methylamino)-6-phenyl-1,3,5-triazin-2-yl]amino}cyclohexanecarboxylic acid (40 mg, 0.12 mmol) was added 1-[2-(trifluoromethyl)phenyl]methanamine (22 mg, 0.12 mmol), EDCl (24 mg, 0.12 mmol), HOBt (17 mgs, 0.12 mmol), and N-methylmorpholine (13 mg, 0.12 mmol). The mixture was stirred at rt for 20 h. The solvent was removed under vacuum, and the resulting residue was purified by HPLC to provide 20 mg (34% yield) of the desired material. MS (ES+): m/e 485.3 [M+H]+.
Reaction SMILES: C([O:8][C:9](=[O:26])[C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1>[Pd].CO>[C:15]([O:14][C:12]([CH2:11][C@@H:10]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:9]([OH:26])=[O:8])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@@H](Cc1ccccc1)C(=O)O
Yield: 98 %

Procedure:
The diester from Example 98 (1.41 g) and 10% palladium on carbon (0.70 g) in methanol were stirred under a hydrogen atmosphere for 2 h. Filtration and solvent evaporation afforded 1.03 g (98%) of the desired product as an oil. 1H NMR (CDCl3, TMS) δ 7.1-7.4 (m,5H), 2.95-3.15 (m,2H), 2.72 (dd,1H), 2.56 (dd,1H), 2.32 (dd,1H), 1.40 (s,9H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[N:7]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[N:24]=[CH:25][NH:26]C=2)[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4].Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1.CCN(C(C)C)C(C)C.N1CCOCC1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[N:7]([CH2:19][CH2:20][CH2:21][C:22]2[N:26]=[CH:25][N:24]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=3)[CH:23]=2)[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCCc1c[nH]cn1)c(=O)n2CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCCc2cn(Cc3cccc(C(F)(F)F)c3)cn2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 9.3 %

Procedure:
A solution of 3-butyl-8-chloro-1-[4-(1H-imidazol-4-yl)butyl]-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (150 mg, 0.38 mmol) in anhydrous DMF (3 ml) was treated with 1-(chloromethyl)-3-(trifluoromethyl)benzene (65 μl, 0.42 mmol) and DIPEA (73 μl, 0.42 mmol). The mixture was left to stir at rt under nitrogen for 3 days. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The crude product was purified on a silica SPE column using a DCM to load the material onto the column and wash through the impurities then a 0-5% MeOH/DCM gradient to elute the compound. The product fractions were combined and concentrated and the residues dissolved in anhydrous DMF (3 ml). The solution was degassed then Pd(PPh3)4 (30 mg, 0.027 mmol) and morpholine (156 μl, 1.8 mmol) were added and the mixture left to stir at rt under nitrogen for 3 h. The crude product was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities then a 0-5% AcOH/MeOH gradient to elute the product. The product fractions were combined and concentrated by high vacuum to leave the title compound as a white solid (18 mg, 9%).