Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH:24]=O)[CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:27]1([C:33]2([OH:39])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[BH3-]C#N.[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH2:24][N:36]2[CH2:37][CH2:38][C:33]([OH:39])([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:34][CH2:35]2)[CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=CCC(CC(=O)N1CCCc2ccccc21)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CC(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.3 %

Procedure:
1-[3-(3,4-dichlorophenyl)-1,5-dioxopentyl]-1,2,3,4-tetrahydroquinoline (900 mg), in MeOH/THF (1:1, 20 mL) was treated sequentially with molecular sieves 3A (767 mg), 4-phenyl-4-hydroxypiperidine HCl (767 mg) and NaBH3CN (150 mg). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was with quenched with water (20 mL) and diluted with CH2Cl2 (50 mL). The organic layer was separated and the aqueous layer extracted with CH2Cl2 (3×50 mL) The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give the crude oil. Silica gel chromatography eluting with 1-2% MeOH/CH2Cl2 gave the title compound (750 mg). Mass spectrum (FAB): 537.2081.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)=[C:34]=[O:35]>ClCCl>[N:38]1[CH:39]=[CH:40][CH:41]=[C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])[CH:37]=1
Reactant: O=C=Nc1cccnc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccnc1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (20 mg, 0.19 mmol) (Aldrich), followed by the addition of 3-isocyanato-pyridine (19 mg, 0.16 mmol) (Oakwood). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid pyridine-3-yl-amide as a white solid. (Yield 30 mg, 45%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH:4]=[CH:5][CH:6]=[CH2:7].[CH3:9][C:10]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:30]=[CH:29][C:25]([CH:26]=[N:27][OH:28])=[CH:24][CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1>>[CH3:1][O:2][C:3](=[O:8])[CH:4]=[CH:5][CH:6]1[O:28][N:27]=[C:26]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=[C:10]([CH3:9])[CH:19]=3)=[CH:30][CH:29]=2)[CH2:7]1
Reactant: C=CC=CC(=O)OC
Reactant: Cc1cc(COc2ccc(C=NO)cc2)c2ccccc2n1
Product: COC(=O)C=CC1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Yield: 73 %

Procedure:
Following a procedure analogous to that used in Example step 1c, but using penta-2,4-dienoic acid methyl ester and 4-(2-methyl-quinolin-4-ylmethoxy)-benzaldehyde oxime from step 1b, the crude reaction was partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give 3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-acrylic acid methyl ester (2.57 g, 73%) as a white powder. MS found: (M+H)+=403.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:12](O)[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.S(Br)([Br:17])=O>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C@@H:12]([Br:17])[CH3:13])[CH:3]=1
Reactant: C[C@H](O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: O=S(Br)Br
Solvent: ClCCl
Product: C[C@H](Br)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethanol (150 mg, 0.56 mmol) in dichloromethane (3 mL) at 0° C. was added thionyl bromide (0.086 mL, 1.12 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was warmed to reflux and held there for 1 h. The reaction was treated with a second portion of thionyl bromide (0.086 mL, 1.12 mmol) and the reaction held at reflux for 2 h. The reaction was cooled to 0° C., quenched by addition of water, and diluted with pentane. The organics were washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (100% hexanes) gave 78 mg (42%). 1H NMR (500 MHz, CDCl3) δ ppm 7.76 (s, 1H), 7.68 (s, 1H), 7.60 (s, 1H), 5.12 (q, J=7.0 Hz, 1H), 2.03 (d, J=7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 146.4, 133.5, 132.9 (q, J=32.6 Hz), 128.4 (q, J=3.8 Hz), 123.0, 123.0 (q, J=273 Hz), 122.6 (q, J=3.8 Hz), 46.1, 26.6.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7](=O)[C:8]3[CH:13]=[C:12]([CH3:14])[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[C:8]3[CH:13]=[C:12]([CH3:14])[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(s1)Oc1cc(F)ccc1NC2=O
Reactant: CN1CCNCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1cc2c(s1)Oc1cc(F)ccc1N=C2N1CCN(C)CC1

Procedure:
In the same manner as in Example 125 and using 8-fluoro-2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 8-fluoro-2-methyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH3:24]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:15][CH2:23][CH3:24]
Reactant: Oc1cc(Oc2ccccc2)ccc1Br
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc(Oc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-bromo-5-phenoxyphenol (120 mg, 0.45 mmol) in acetone (7 mL) was added potassium carbonate (0.375 g, 2.72 mol) followed by iodoethane (0.0724 mL, 0.905 mol) at rt. The mixture was stirred at rt overnight. Reaction mixture was concentrated down in vacuo and washed with brine extracting with EtOAc. The organics were combined, dried over Na2SO4 and concentrated to afford the title compound which was used for next step without further purification. 1H NMR (400 MHz, CDCl3): δ=1.37 (t, J=6.95 Hz, 3H), 3.95 (q, J=7.07 Hz, 2H), 6.37 (dd, J=8.59, 2.78 Hz, 1H), 6.52 (d, J=2.53 Hz, 1H), 6.90-6.97 (m, 2H), 7.00-7.08 (m, 1H), 7.22-7.30 (m, 2H), 7.36 (d, J=8.59 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[S:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: COc1nc2ccccc2nc1NC(=S)Oc1ccccc1
Product: COc1nc2ccccc2nc1NC(=S)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 65 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)thiocarbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 63 to obtain the titled compound.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[CH3:21][C@H:22]([C@H:34]([CH3:38])[CH2:35][CH2:36][CH3:37])[CH:23]=[N:24][S:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)=[O:26]>C1COCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3]>[C:17]([O:16][C:13](=[O:15])[CH2:14][C@@H:23]([NH:24][S:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)=[O:26])[C@H:22]([CH3:21])[C@H:34]([CH3:38])[CH2:35][CH2:36][CH3:37])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCC[C@@H](C)[C@@H](C)C=NS(=O)c1ccc(C)cc1
Agent: Cl[Ti+3]
Agent: CC(C)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC[C@@H](C)[C@@H](C)[C@@H](CC(=O)OC(C)(C)C)NS(=O)c1ccc(C)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 53.8 %

Procedure:
Butyl lithium (26.3 mL, 42.04 mmol) was added to a solution of diisopropylamine (4.6 g, 45.6 mmol) in dry THF (40 mL) under nitrogen at 0° C. and stirred for 20 minutes. The solution was cooled to −78° C. followed by the addition of t-butyl acetate (4.1 g, 35.0 mmol) and stirred at that temperature for 45 minutes. Chlorotitanium triisopropoxide (9.4 g, 36.2 mmol) was added dropwise and stirring was continued for 30 minutes at −78° C. A −50° C. solution of 4-methyl-benzenesulfinic acid ((2R,3R)-2,3-dimethyl-hexylidene)-amide (3.1 g, 11.7 mmol) in dry THF (10 mL) was added to the reaction and the resulting mixture was stirred at −78° C. for 4 hours. The reaction was quenched with a saturated solution of NaH2PO4 and extracted into ethyl acetate. The solution was dried over MgSO4 and concentrated. The resulting residue was chromatographed on silica, eluting with 15% ethyl acetate in hexane to give the titled compound (2.4 g, 53.9% yield) as white solid: 1H NMR (400 MHz, CDCl3) δ ppm 0.9 (m, 6 H) 1.0 (d, J=6.6 Hz, 3 H) 1.1 (m, 1 H) 1.3 (m, 2 H) 1.4 (m, 9 H) 1.5 (m, 2 H) 2.4 (s, 3 H) 2.6 (m, 2H) 3.8 (m, 1 H) 4.4 (d, J=10.0 Hz, 1 H) 7.3 (d, J=8.1 Hz, 2 H) 7.6 (d, J=8.1 Hz, 2 H). MS, m/z (relative intensity): 382 [M+1H, 100%], 326 [M+1H—C(CH3)3, 50%].
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=[N:3]1.Cl.CN(C)CCCN=C=NCC.[NH:23]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37])[C:30](O)=[O:31])[C:24]([CH3:26])=[O:25].O.NN>CN(C)C=O>[NH:23]([C:27]1[CH:28]=[C:29]([C:30]([NH:2][NH2:3])=[O:31])[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37])[C:24]([CH3:26])=[O:25]
Reactant: COC(=O)c1ccc(C(=O)O)cc1NC(C)=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NN)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
1-Hydroxybenzotriazole (HOBt) (270 mg, 2 mmol) and 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (WSC) (498 mg, 2.6 mmol) were added to a solution of 3-acetamino-4-methoxycarbonylbenzoic acid (474 mg, 2 mmol) in dimethylformamide (10 mL), and the mixture was stirred at room temperature for 3 hours. Hydrazine monohydrate (485 μL, 10 mmol) was further added at 0° C., and the mixture was stirred overnight at room temperature. The precipitated solid was filtered, and then washed with water to obtain 400 mg of the desired product as a white solid (yield 80%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3Cl)=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:24]=[C:25](B(O)O)[S:26][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[F:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([C:25]2[S:26][CH:27]=[C:23]([CH3:22])[CH:24]=2)[C:14]=1[C:10]1[NH:11][C:12](=[O:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:25]3[S:26][CH:27]=[C:23]([CH3:22])[CH:24]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(Br)cc1
Reactant: Cc1csc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1csc(-c2ccc(-n3nc(-c4c(F)cccc4-c4cc(C)cs4)[nH]c3=O)cc2)c1
Yield: 22 %

Procedure:
The title compound was prepared according to the procedure described in Example-2 using 2-(4-bromophenyl)-5-(2-chloro-6-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-1, 0.100 g, 0.271 mmol), (4-methylthiophen-2-yl)boronic acid (0.059 g, 0.407 mmol), K2CO3 (0.112 g, 0.81 mmol), tetrakistriphenyl phosphine palladium (0) (0.062 g, 0.054 mmol) and DMSO (3.0 mL) to afford 0.020 g of desired product. 1H NMR (300 MHz, CDCl3): δ 2.29 (s, 6H), 6.86 (s, 1H), 6.91 (s, 2H), 7.13 (s, 1H), 7.21 (d, J=9.3 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.48-7.55 (m, 1H), 7.61 (d, J=8.1 Hz, 2H), 7.92 (d, J=9.0 Hz, 2H), 9.27 (br s, 1H). MS (m/z): 384.88 (M−H)−.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]([NH:13][CH:14]=O)=[CH:9][CH:8]=1>C1COCC1.C(OCC)(=O)C>[C:7]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:8]=[CH:9][C:10]([NH:13][CH3:14])=[CH:11][CH:12]=1
Reactant: O=CNc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
LAH (96 mg, 2.5 mmol) was added portionwise to a cold (at 0° C.) solution of N-biphenyl-4-yl-formamide (100 mg, 0.5 mmol) in THF (2 mL) and the stirring was continued at the same temperature for 30 minutes. After completion of the reaction, the reaction mixture was quenched with 3% aq NaOH solution, the precipitate obtained was filtered, the filtrate was collected was concentrated under reduced pressure to get a residue. The residue was diluted with ethyl acetate, the organic layer was washed with brine solution and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford 85 mg (91.39% Yield) of biphenyl-4-yl-methyl-amine.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].N[CH:15]([C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C@H:24]([CH2:25][C@@H:26]([OH:36])[CH2:27][CH2:28]2)[CH2:23][CH2:22]3)[CH2:19][CH2:18]1)[CH3:16]>N1C=CC=CC=1>[OH:36][C@H:26]1[CH2:27][CH2:28][C@@:29]2([CH3:30])[C@@H:24]([CH2:23][CH2:22][C@@H:21]3[C@@H:31]2[CH2:32][CH2:33][C@@:34]2([CH3:35])[C@H:20]3[CH2:19][CH2:18][C@@H:17]2[C:15](=[O:4])[CH3:16])[CH2:25]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(N)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 52.9 %

Procedure:
20-Amino-3β-hydroxy-5α-pregnane was first concentrated from dry pyridine. Trifluoroacetic anhydride (3.0 mL) was then carefully added to 3.04 mmol of crude 20-amino-3β-hydroxy-5α-pregnane resuspended in 5.0 mL dry pyridine. After stirring the reaction mixture at room temperature for 3.5 h, the reaction mixture was partitioned between diethyl ether and 1N aqueous HCl, shaken and separated. The organic layer was successively washed with 1N aqueous HCl, water, saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was refluxed in 15.0 mL methanol for 26 h and then concentrated. The residue was purified by flash chromatography on a 25 mm column using first one column volume of methylene chloride, then one column volume of 5% ethyl acetate in methylene chloride, and then 10% ethyl acetate in methylene chloride as eluants. Isolation and concentration of the product afforded 668 mg (52.9% yield over three steps, from 3β-hydroxy-5α-pregnan-20-one) of product.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[N:13]([CH2:14][CH3:15])[C:12](=[O:16])[NH:11][C:10](=[O:17])[C:9]=1[NH:18][C:19](=O)[CH:20]([CH3:22])[CH3:21].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1.C(Cl)C1C=CC=CC=1.Cl>>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:11]2[C:10](=[O:17])[C:9]3[NH:18][C:19]([CH:20]([CH3:22])[CH3:21])=[N:7][C:8]=3[N:13]([CH2:14][CH3:15])[C:12]2=[O:16])=[CH:27][CH:26]=1
Reactant: CCn1c(N)c(NC(=O)C(C)C)c(=O)[nH]c1=O
Reactant: ClCc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: ClCc1ccccc1
Product: CCn1c(=O)n(Cc2ccc(Cl)cc2)c(=O)c2[nH]c(C(C)C)nc21
Reaction time: 3 h
Yield: 56.7 %

Procedure:
3.17 g (28.2 mM) of potassium t-butoxide (t-BuOK) were added to a solution of 6.11 g (27.5 mM) of 6-amino-1-ethyl-5-isobutyrylamino-uracil. At 0° C., 4.90 g (30.4 mM) of 4-chlorobenzylclhloride were added. After 3 hours at 0-5° C., further 1.22 g t-BuOK and 2.45 g of 4-chloro-benzylchloride were added. After further 3 hours another 2.45 g of benzylchloride are supplemented. After 3 days, the solution was neutralized with 1N HCl and the solvents evaporated. The residue was suspended in water, the solid collected and washed. The crude intermediate amide was heated under reflux in 100 ml of 1N NaOH and 10 ml of 1-propanol. After 1 hour, the mixture was neutralized to pH 7 and extracted with chloroform. Crystallization from dichloromethane (mainly evaporated)--methanol gave 2.99 g (31.3%) of the title xanthine, mp 194-5° C. The mother liquors gave 6.33 g of impure material which was separated on 15 g of silica gel elutions with dichloromethane and gave additional 0.78 g (8.2%) of the xanthine.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]([CH3:18])[C:6]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)=[O:7])[CH2:2][CH3:3].[CH3:19][C@@H:20]([CH2:32][CH3:33])[CH2:21][O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)=[O:24].C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:4][C@@H:5]([CH3:18])[C:6]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C:28]2[CH:29]=[CH:30][C:25]([C:23]([O:22][CH2:21][C@@H:20]([CH3:19])[CH2:32][CH3:33])=[O:24])=[CH:26][CH:27]=2)=[O:14])=[CH:16][CH:17]=1)=[O:7])[CH2:2][CH3:3]
Reactant: CC[C@H](C)COC(=O)c1ccc(O)cc1
Reactant: CCCO[C@@H](C)C(=O)Oc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCO[C@@H](C)C(=O)Oc1ccc(C(=O)Oc2ccc(C(=O)OC[C@@H](C)CC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.1 %

Procedure:
In 12 ml of methylene chloride were dissolved 107 mg of 4-[2-(S)-propoxypropanoyloxy]benzoic acid, 95 mg of 4-[(S)-2-methyl butoxycarbonyl]phenol, and 140 mg of dicyclohexylcarbodiimide, and a catalytic amount of 4-dimethylaminopyridine was added to the solution, followed by stirring at room temperature. After 5 hours, diethyl ether was added to the reaction mixture, and any insoluble matter was removed by filtration. The filtrate was washed successively with a 10% hydrochloric acid aqueous solution, a saturated sodium bicarbonate aqueous solution, water, and a saturated sodium chloride aqueous solution, and dried over sodium sulfate. The solvent was removed from the residue by distillation, and the resulting oily substance was purified by silica gel column chromatography to obtain 139 mg of the entitled compound as a transparent oily substance. This compound did not crystalize even when allowed to stand at room temperature or less for a long time. The structure of the compound was confirmed by NMR and IR spectra.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[Br:25]Br.O[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([F:38])[CH:31]=1>C(Cl)Cl>[Br:25][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([F:38])[CH:31]=1
Reactant: BrBr
Reactant: COc1ccc(CCO)cc1F
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCBr)cc1F
Yield: 59.8 %

Procedure:
A mixture of resin bound triphenyl phosphine (polystyrene 2% cross linking, loading =3 mmol/g, 3 g, 9 mmol) and imidazole (0.48 g, 7.1 mmol) in DCM (30 mL) cooled on an ice bath was drop wise added Br2 (1.13 g, 7.1 mmol), whereupon a solution of 4-(2-hydroxy-ethyl) -2-fluoro-1-methoxy-benzene (1.0 g, 5.88 mmol) in DCM (5 mL) was added. The cooling bath was removed and the reaction mixture was stirred for 16 hs before the resin was filtered off. The resin was washed with DCM and the filtrate was concentrated in vacuo. The residue was purified using column chromatography (SiO2, heptane-EtAOc 95:5) to give 0.82 g of 4-(2-bromo-ethyl)-2-fluoro-1-methoxy-benzene
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C@@H:21]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:22]([NH:24][N:25]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:26](=[O:35])[CH2:27][C:28]([N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)=[O:29])=[O:23])[C:11](=[O:20])[NH:12][O:13]C2CCCCO2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[C:45]1([CH3:55])[CH:50]=[CH:49][C:48]([S:51]([OH:54])(=[O:53])=[O:52])=[CH:47][CH:46]=1>CO>[C:45]1([CH3:55])[CH:46]=[CH:47][C:48]([S:51]([OH:54])(=[O:52])=[O:53])=[CH:49][CH:50]=1.[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C@@H:21]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:22]([NH:24][N:25]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:26](=[O:35])[CH2:27][C:28]([N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)=[O:29])=[O:23])[C:11](=[O:20])[NH:12][OH:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CC(=O)n1ccnc1)[C@H](CCCC1CCCCC1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CC(=O)n1ccnc1)[C@H](CCCC1CCCCC1)C(=O)NO
Temperature: 25 °C
Reaction time: 6 h
Yield: 34.1 %

Procedure:
A solution of 0.205 g of 2(R)-(4-Cyclohexyl-1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]butyl]-2′-isobutyl-4-methyl-2′-[2-(1-imidazoyl)acetyl]valerohydrazide in 5 ml of methanol was treated with 0.075 g of p-toluenesulphonic acid monohydrate. The mixture was stirred at room temperature for 6 hours and evaporated. The residue was purified by flash column chromatography on silica gel using methanol/dichloromethane (5:95) as the eluant to give 0.080 g of 2(R)-[4-cyclohexyl-1(S)-(hydroxycarbamoyl)butyl]-2′-isobutyl-4-methyl-2′-(2-(1-imidazoyl)acetyl]valerohydrazide p-toluenesulphonate in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[Cl:18][C:19]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Cl:18][C:19]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:22]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(Cl)cc4Cl)cc23)CC1
Yield: 69.4 %

Procedure:
Beginning with 10 mg (0.0437 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 6.4 μL (0.0458 mMol) 2,4-dichlorobenzoyl chloride, 12.2 mg (80%) of the title compound were recovered.