Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:7]([OH:8])[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[CH2:16]([O:23][C:24](=[O:27])[NH:25]O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ClC(Cl)(Cl)C(O)=O>C(Cl)Cl>[CH2:16]([O:23][C:24](=[O:27])[NH:25][O:8][CH:7]1[CH2:1][CH2:2][O:3][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[NH:6]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Reactant: O=C(NO)OCc1ccccc1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(NOC1CCOP(=O)(N(CCCl)CCCl)N1)OCc1ccccc1
Reaction time: 72 h

Procedure:
750 mg (2.7 mmol) of 4-hydroxycyclophosphamide and 450 mg (2.7 mmol) of benzyl-hydroxycarbamate are dissolved in 6 ml of methylene chloride free of alcohol. A small amount of trichloroacetic acid is added thereto and the solution is allowed to stand at -25° C. in a refrigerator for 3 days. The resulting solution is filtered off, the mother liquor is diluted with 5 ml of chloroform, then is diluted with water and thereafter is washed with a dilute solution of NaHCO3 and with water. The washed solution is dried over sodium sulfate and is evaporated in a vacuum. The oily residue thereafter is recrystallized from acetic acid ethyl ester containing a small amount of methanol.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]([C:9]1[CH:37]=[CH:36][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH:31]4[CH2:35][CH2:34][S:33][CH2:32]4)=[O:29])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].ClC1C=C(C=CC=1)C(OO)=[O:45]>ClCCl>[F:5][C:4]([F:7])([F:6])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH:31]4[CH2:35][CH2:34][S:33](=[O:45])[CH2:32]4)=[O:29])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[CH:36][CH:37]=1)([OH:8])[C:2]([F:38])([F:1])[F:39]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1)NC1CCSC1
Solvent: ClCCl
Product: O=C(Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1)NC1CCS(=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
To an ice-cooled solution of 1-(4-((1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperidin-4-yl)methyl)phenyl)-3-(tetrahydrothiophen-3-yl)urea (0.243 mmol, 140 mg) in dichloromethane was added 3-chloroperoxybenzoic acid (0.243 mmol, 54.5 mg) and the resulting mixture was stirred for 30 minutes. Additional 3-chloroperoxybenzoic acid (0.243 mmol, 54.5 mg) was added and reaction stirred for 1.5 hours. The reaction was concentrated under vacuum. The residue was purified by silica column chromatography (eluent: 2% methanol in dichloromethane-7% methanol in dichloromethane) and SCX chromatography to give the title compound (77.1 mg).
Reaction SMILES: [C:1]1([N:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[N:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:12][CH:11]2[CH2:29][CH2:30]O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:38]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[C:1]1([N:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[N:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:12][CH:11]2[CH2:29][CH2:30][Br:38])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)C(CCO)C1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)C(CCBr)C1
Yield: 86 %

Procedure:
A solution of 312 mg (0.61 mmol) of (RS)-1-(N,N-diphenylcarbamoyl)-2-(2-hydroxyethyl)-4-(N,N-dipentylcarbamoyl)piperazine and 362 mL (0.86 mmol) of dibromotriphenylphosphorane in 15 mL of acetonitrile was stirred under nitrogen at 82° C. for 2 hours. The yellow solution was cooled and concentrated in vacuo. Flash chromatography on 35 g of silica gel using 1:1 v/v ethyl acetate/hexane as the eluant afforded 300 mg (85%) of a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][OH:10])[N:3]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>CCOC(C)=O.O>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][OH:10])[N:3]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(CN)cc1
Reactant: OCCc1cccc(Cl)n1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CNc2cccc(CCO)n2)cc1

Procedure:
Chloropyridine 30-2 (150 mg, 0.95 mmol) and 4-methoxybenzylamine (4 mL, 31 mmol) were combined neat and heated in a sealed tube at 160° for 4 days. After diluting with EtOAc and water the pH was adjusted to 7 phases separated and the organic phase was washed with brine, dried (MgSO4) and concentrated. Flash chromatography (twice on silica, 50% and 40% EtOAc/hexane) provided 30-3 as a yellow semi-solid.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[C:12]([C:13](O)=[O:14])=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[N:10]=[C:9]([CH3:25])[CH:8]=1)[CH2:4][CH3:5])[CH3:2].CSC>C1COCC1>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[NH:16][C:11]1[C:12]([CH2:13][OH:14])=[C:7]([O:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:8]=[C:9]([CH3:25])[N:10]=1
Reactant: CCC(CC)Oc1cc(C)nc(Nc2ccc(Cl)cc2Cl)c1C(=O)O
Solvent: CSC
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc(Nc2ccc(Cl)cc2Cl)c1CO
Reaction time: 0.5 h

Procedure:
To a solution of 4-(1-ethyl-propoxy)-6-methyl-2-(2,4-dichloro-phenylamino)-nicotinic acid in dry THF was added BH3.DMS. The resulting mixture was heated at reflux overnight. The mixture was quenched with dilute HCl and stirred for 30 min, adjusted pH to 7.5-8.5, then extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a golden oil. After silica gel column chromatography, the Ute compound was obtained as a golden oil. 1H NMR(CDCl3) d 8.44(d,1H), 8.18(s,1H), 7.32(d,1H), 7.179d,1H), 6.28(s,1H), 4.82(s,2H), 4.21(m,1H), 2.42(s,3H), 1.6-1.8(m,4H), 0.94(t,6H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][N:6]=[CH:5]2.[H-].[Na+].C([Li])(C)(C)C.CCCCC.S([O-])(O)(=O)=O.[K+].[C:30](=O)(O)[O-:31].[Na+]>CO.O.C(OCC)C.CN(C)C=O.O1CCCC1>[Cl:11][C:9]1[CH:10]=[C:2]([CH:30]=[O:31])[CH:3]=[C:4]2[C:8]=1[NH:7][N:6]=[CH:5]2
Reactant: Clc1cc(Br)cc2cn[nH]c12
Reactant: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCCCC
Product: O=Cc1cc(Cl)c2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-Bromo-7-chloroindazole (2.0 g, 8.7 mmol) and sodium hydride (221 mg, 1.1 equiv) were weighed into a flame-dried round-bottom flask containing a magnetic stir bar. Under a nitrogen atmosphere at room temperature, dry tetrahydrofuran (30 mL) was added. The mixture was stirred at room temperature for 15 min, during which time it became homogeneous. The stirred mixture was cooled to −78° C. and a solution of tert-butyllithium in pentane (1.7 M, 10.5 mL, 2.0 equiv) was added over several minutes. After 30 min at −78° C., the reaction was gradually warmed to −50° C., kept there for 15 min, and recooled to −78° C. Dimethylformamide (2.8 mL) was slowly added and the mixture allowed to warm to −50° C. The solution was quickly transferred to a separatory funnel containing diethyl ether and water. The aqueous was made acidic by the addition of 1 M potassium hydrogen sulfate and neutralized by the addition of sodium bicarbonate. The aqueous was extracted with diethyl ether (3×) which was washed with water, then brine, dried over magnesium sulfate, and concentrated to give 1.7 g (100%) of nearly pure material. An analytically pure sample was obtained by recrystallization from hot methanol. 1H-NMR (CDCl3, 500 MHz) δ 7.97 (s, 1H), 8.20 (s, 1H), 8.30 (s, 1H), 10.02 (s, 1H). Mass spec.: 181.09 (MH)+.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]1[CH:15]=[C:14]([OH:16])[C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][C:6]=1[OH:17])C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1(=O)CCCC1.[I-].[K+]>[CH2:26]([O:16][C:14]1[CH:15]=[C:5]([C:4]([OH:3])=[O:18])[C:6]([O:17][CH2:7][CH2:6][CH2:5][CH2:15][CH3:14])=[CH:7][C:8]=1[C:9]([OH:11])=[O:10])[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCBr
Reactant: CCOC(=O)c1cc(O)c(C(=O)OCC)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O=C1CCCC1
Product: CCCCCOc1cc(C(=O)O)c(OCCCCC)cc1C(=O)O
Temperature: 25 °C
Yield: 140.2 %

Procedure:
A mixture of 25.4 g of 2,5-dihydroxy terephthalic acid diethyl ester, 30.0 g potassium carbonate, 1 g potassium iodide and 31.5 g 1-bromopentane was heated to boiling-point in cyclopentanone for at least 24 hours. The solvent was withdrawn and 250 ml of 5 wt % caustic potash and 20 ml ethanol was added to the residue, which was then heated to boiling-point for at least 24 hours. After cooling to room temperature the product was precipitated by acidifying with hydrochloric acid and was recrystallized from methylene chloride. 23.7 g of 2,5-bis(pentyloxy) terephthalic acid was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:8][C:4]1[CH:3]=[C:2]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cccc(Br)c2)cc1
Yield: 65.1 %

Procedure:
A suspension of 1,3-dibromobenzene (25.3 g), 4-fluorophenylboronic acid (5.00 g) and 2M aqueous sodium carbonate solution (35.7 ml) in DMF (250 ml) was degassed. Tetrakis(triphenylphosphine)palladium(0) (2.06 g) was added under an argon atmosphere and the mixture was refluxed under heating for 21 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate, washed twice with water and washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and distilled under reduced pressure to give the title compound (5.84 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([O:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=2)[NH2:32])[CH2:25][CH2:24]1>>[CH3:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([O:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[C:29]([N:26]5[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]5)[CH:30]=4)[N:21]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)c1ccc(Oc2cccn3nc(Cl)nc23)cc1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Product: CN1CCN(c2cccc(Nc3nc4c(Oc5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)CC1

Procedure:
[8-(4-Methanesulfonyl-phenoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenoxy)-[1,2,4]triazolo[1,5-a]pyridine (0.070 g, 0.21 mmol) and 3-(4-methylpiperazin-1-yl)aniline (0.056 g, 0.29 mmol) in a manner analogous to Example 2d. Product was isolated as a tan solid (56 mg, 54%). MP=Softened at 114-119° C. then melted at 199-201° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.55 (s, 1H), 8.76 (d, J=6.56 Hz, 1H), 7.89 (d, J=8.00 Hz, 2H), 7.50 (d, J=7.69 Hz, 1H), 7.26 (s, 1H), 7.21 (d, J=8.04 Hz, 2H), 7.10-7.11 (m, 3H), 6.46 (d, J=6.60 Hz, 1H), 3.20 (s, 3H), 3.04 (s, 4H), 2.42 (s, 4H), 2.22 (s, 3H). MS=479 (MH)+.
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([OH:17])=[O:16])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].[CH2:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:8][C:4]([CH3:7])([CH2:5][CH3:6])[C:3](=[O:9])[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:1]
Reactant: OCc1ccccc1
Reactant: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A mixture of (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidine-carboxylic acid (500 mg; 2.07 mmol), benzyl alcohol (335 mg; 3.10 mmol), dicyclohexylcarbodiimide (683 mg; 3.31 mmol), 4-dimethylaminopyridine (84 mg; 0.69 mmol) and camphorsulphonic acid (160 mg; 0.69 mmol) in methylene chloride (30 mL) was stirred overnight under a nitrogen atmosphere. The reaction mixture was filtered through Celite to remove solids and concentrated in vacuo, and the crude material was purified on a flash column (25% ethyl acetate in hexane) to obtain 680 mg of the product as a colorless oil. 1H NMR (CDCl3; 300 MHz) δ 0.85 (t, 3H); 1.19 (s, 3H); 1.22 (s, 3H); 1.61–2.25 (m, 6H); 3.46–3.56 (m, 2H); 4.58 (dm, 1H); 5.18 (d, 2H, 7.35 (br, 5H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]2)[CH2:9][CH2:8]1.N>Cl>[C:22]([C:20]1[CH:19]=[N:18][N:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:10]2[CH2:11][CH2:12][N:7]([C:2]3[N:1]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:8][CH2:9]2)[CH:21]=1)([OH:24])=[O:23]
Reactant: CCOC(=O)c1cnn(CCCCN2CCN(c3ncccn3)CC2)c1
Agent: Cl
Agent: N
Product: O=C(O)c1cnn(CCCCN2CCN(c3ncccn3)CC2)c1
Yield: 84.4 %

Procedure:
A mixture of 4.4 g (12.2 mmol) of ethyl 1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl}-1H-pyrazole-4-carboxylate in 50 ml of 2N HCl is refluxed for 4 hours. The mixture is cooled in an ice bath, neutralised with ammonia and extracted with chloroform. 3.4 g of 4-carboxy-1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl}-1H-pyrazole with a melting point of 104°-105° C. are thus obtained.
Reaction SMILES: [CH3:1][C:2]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)(=[O:6])=[O:5])[CH3:3].[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:23]([N:20]1[CH2:21][CH2:22][CH:17]([C:2]([CH3:1])([S:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)(=[O:5])=[O:6])[CH3:3])[CH2:18][CH2:19]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C1CCNCC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C1CCN(C(=O)c2ccccc2)CC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 10 ml vial was added 4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine (33 mg, 0.098 mmol), benzoic acid (10 mg, 0.082 mmol), Bop reagent (43.5 mg, 0.098 mmol), diisopropylethyl amine (0.029 ml, 0.164 mmol) and 2 ml dimethylformamide. The resulting solution was stirred at room temperature for 10 minutes. LC-Mass showed clean desired product. The reaction mixture was diluted with 1 ml dimethyl sulfoxide, 1 ml water and 0.03 ml of trifluoroacetic acid. This mixture was loaded on a reverse phase column and purified on HPLC eluted with water/acetonitrile gradient solvent. Desired fraction was collected and lyophilized to give the title compound as a fluffy white solid.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10](Cl)[C:5]=2[S:4][CH:3]=1.[CH:12]([C:15]1[N:19]=[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[O:17][N:16]=1)([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C.[OH-].[NH4+]>C(O)(C)C>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:23]3[CH2:22][CH2:21][CH:20]([C:18]4[O:17][N:16]=[C:15]([CH:12]([CH3:14])[CH3:13])[N:19]=4)[CH2:25][CH2:24]3)[C:5]=2[S:4][CH:3]=1
Reactant: CC(C)c1noc(C2CCNCC2)n1
Reactant: Clc1ncnc2c(Br)csc12
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)c1noc(C2CCN(c3ncnc4c(Br)csc34)CC2)n1
Temperature: 100 °C
Reaction time: 12 h
Yield: 61.1 %

Procedure:
7-bromo-4-chlorothieno[3,2-d]pyrimidine (100 mg) was added to isopropyl alcohol (3 mL), and 4-(3-isopropyl-[1,2,4]-oxadiazol-5-yl)piperidine (100 mg) and diisopropylethylamine (200 μL) were further added thereto. The reaction mixture was stirred at 100° C. for 12 hours. Then, the reaction mixture was mixed with saturated ammonium hydroxide solution and extracted twice with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a foamy residue. The residue was crystallized in the presence of diethyl ether to obtain the title compound (100 mg) as a whitish solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:54][CH2:55][C@@H:56]([OH:58])[CH3:57]>O.CN(C)C=O>[OH:58][C@@H:56]([CH3:57])[CH2:55][NH:54][C:18](=[O:20])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)=[CH:4][C:3]=3[O:2][CH3:1])=[N:16][CH2:15]1
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: C[C@H](O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)NC[C@H](C)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 40 h
Yield: 68.2 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (300 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (190 mg), 1-hydroxybenzotriazole (130 mg), (2S)-1-aminopropan-2-ol (100 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 40 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was washed with ethyl acetate-diethyl ether to give pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (230 mg, 68%) as colorless prisms. MS 519 (MH+). mp 185-186° C.
Reaction SMILES: P(OC)(OC)OC.C(N(CC)CC)C.[CH2:15]1[CH2:42][O:41][C:17]([C@@H:19]2[C@:36]3([CH3:37])[C@H:22]([C@H:23]4[C@H:33]([C:34](=[O:38])[CH2:35]3)[C@:31]3([CH3:32])[C@H:26]([CH2:27][C:28](=[O:40])[C@@H:29]([CH3:39])[CH2:30]3)[CH2:25][CH2:24]4)[CH2:21][CH2:20]2)([CH3:18])[O:16]1>C(O)(C)C.O.Cl.Cl.Cl[Ir](Cl)(Cl)Cl>[CH2:42]1[CH2:15][O:16][C:17]([C@@H:19]2[C@:36]3([CH3:37])[C@H:22]([C@H:23]4[C@H:33]([C:34](=[O:38])[CH2:35]3)[C@:31]3([CH3:32])[C@H:26]([CH2:27][C@H:28]([OH:40])[C@H:29]([CH3:39])[CH2:30]3)[CH2:25][CH2:24]4)[CH2:21][CH2:20]2)([CH3:18])[O:41]1
Reactant: C[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C5(C)OCCO5)[C@@]4(C)CC(=O)[C@@H]32)CC1=O
Agent: Cl[Ir](Cl)(Cl)Cl
Agent: COP(OC)OC
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C5(C)OCCO5)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Yield: 63.3 %

Procedure:
A solution of chloroiridic acid (10 mg.) and trimethyl phosphite (1.5 ml.) in aqueous 90% isopropanol (20 ml.) was heated under reflux for 17 hours. The solution was then neutralised with triethylamine, 20,20-ethylenedioxy-2β-methyl-5α-pregnane-3,11-dione (0.66 g.) was added, and the mixture was heated under reflux for 48 hr. The reaction mixture was cooled and partitioned between methylene chloride and water. The organic layer was dried (MgSO4) and evaporated in vacuo. The residue (0.69 g.) was purified by preparative layer chromatography and crystallised from methyl acetate/petroleum ether (b.p. 60°-80°) to give 20,20-ethylenedioxy-3α-hydroxy-2α-methyl-5α-pregnan-11-one (0.42 g.), m.p. 167°-168°, [α]D + 68°.
Reaction SMILES: O1CCCC1.C1(C)C=CC=CC=1.[Cl-].[F:14][C:15]1[CH:20]=[CH:19][C:18]([Zn+])=[CH:17][CH:16]=1.I[C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][Si:32]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([CH2:35][CH2:36][CH3:37])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1.[Cl-].[NH4+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:23]2[CH:24]=[CH:25][C:26]([CH:29]3[CH2:30][CH2:31][Si:32]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([CH2:35][CH2:36][CH3:37])[CH2:33][CH2:34]3)=[CH:27][CH:28]=2)=[CH:17][CH:16]=1
Reactant: CCC[Si]1(c2ccccc2)CCC(c2ccc(I)cc2)CC1
Reactant: Fc1ccc([Zn+])cc1
Agent: [Pd]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC[Si]1(c2ccccc2)CCC(c2ccc(-c3ccc(F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 15 ml tetrahydrofuran-toluene (1:1) solution of 1.0M 4-fluorophenyl zinc chloride was dripped into a mixture of 4.20 g of 4-(4-iodophenyl)-1-phenyl-1-n-propyl-1-silacyclohexane, 30 mg of tetrakis (triphenylphosphine) palladium(0) and 30 ml of tetrahydrofuran. After stirring for 8 hours at room temperature, the mixture was poured into a saturated aqueous solution of ammonium chloride and extraction was conducted using ethyl acetate. Using conventional washing, drying and concentration processes, 4-(4-(4-fluorophenyl)phenyl)-1-phenyl-1-n-propyl-1-silacyclohexane was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.ClC(Cl)(Cl)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH:23]=[N:22][CH:21]=[CH:20]2)=[O:13].C1CCN2C(=NCCC2)CC1>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:12]([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[CH:23]=[N:22][CH:21]=[CH:20]3)=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc2ccncc12)C(Cl)(Cl)Cl
Reactant: NCc1ccc(Br)cc1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCc1ccc(Br)cc1)Nc1cccc2ccncc12

Procedure:
The title compound was prepared using 4-bromobenzylamine, the product from Example 57D, DBU and the procedure described in Example 1B. MS (ESI+) m/z 356 (M+H)+; 1H NMR (DMSO-d6) δ 9.52 (s, 1H), 9.15 (s, 1H), 8.49 (d, 1H), 8.11 (d, 1H), 7.77 (d, 1H), 7.67 (t, 1H), 7.55 (m, 3H), 7.32 (d, 2H), 7.25 (t, 1H), 4.34 (d, 2H); Anal. Calcd for C17H14BrN3O.0.25H2O.0.16 MeOH: C, 56.34; H, 4.17; N, 11.49. Found C, 56.32, H, 4.45, N, 11.70.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2ccccc2)n1
Yield: 69.9 %

Procedure:
2-Amino-6-bromopyridine 10 g (58 mmol), phenylboronic acid 8.5 g (70 mmol) and tetrakis(triphenylphosphine)palladium 1.3 g (1.2 mmol) were dissolved in 60 mL of 1,2-dimethoxyethane. A 2.0M sodium carbonate aqueous solution 30 mL was added thereto, and the solution was refluxed for 8 hours under argon atmosphere by heating. After finishing the reaction, the aqueous layer was removed. The organic layer was dried on anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was refined by silica gel chromatography to obtain 6.9 g (yield: 70%) of 2-amino-6-phenylpyridine.