Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][C:13]#[CH:14])[CH2:8][CH2:9][C:10]=2[N:11]=1.Br[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.CC(C)=O>C(NCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][C:13]#[C:14][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: C#CCN1CCc2nc(N)sc2CC1
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CC(C)=O
Product: N#Cc1ccc(C#CCN2CCc3nc(N)sc3CC2)cc1

Procedure:
Prepared analogously to Example 10 from 2-amino-6-propargyl-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine, 4-bromo-benzonitrile and copper(I)iodide/bis(triphenyl-phosphine)palladium dichloride in diethylamine for 6 hours at ambient temperature. Yield: 46% of theory, Melting point: 174°-176° C. (acetone).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]2[CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[CH:5][CH:4]=1.[I:30]N1C(=O)CCC1=O>CC#N.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([I:30])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]2[CH2:19][O:20][Si:21]([C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:22])[CH3:23])=[CH:28][CH:29]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc(Cn2cc(-c3ccccc3)nc2CO[Si](C)(C)C(C)(C)C)cc1
Solvent: CC#N
Solvent: CCOCC
Product: COc1ccc(Cn2c(CO[Si](C)(C)C(C)(C)C)nc(-c3ccccc3)c2I)cc1
Yield: 85 %

Procedure:
Treat a solution of 1-(4-methoxybenzyl)-2-tert-butyldimethylsilyloxymethyl-4-phenylimidazole (2.08 g, 5.09 mmol) in MeCN (25 mL) with N-iodosuccinimide (NIS) (1.35 g, 6.00 mmol) at room temperature for 24 hours. Dilute the mixture with Et2O (100 mL), wash with saturated NaHCO3 (25 mL), dry (Na2SO4), and concentrate in vacuo. Purify the residue by flash chromatography (SiO2, hexane/EtOAc 20:1→9:1) to provide 2.30 g (85% yield). MS (ES+): m/z 535 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:9]=[C:10]([Br:13])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[C:15]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:13][C:10]1[C:11]([CH3:12])=[C:2]([NH:1][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:3]([CH3:14])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCCC1
Reactant: COC(=O)c1cc(Br)c(C)c(N)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Br)c(C)c(NC2CCCC2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2,4-dimethylbenzoate (1.4 g, 5.42 mmol) and cyclopentanone (2.4 mL, 27.13 mmol) in methanol (20 mL), acetic acid (0.650 g, 10.84 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (0.85 g, 13.56 mmol) was added and reaction was stirred for overnight. On completion, solvent was removed water was added and compound was extracted with ethyl acetate. Combined organic layer was collected, dried over Na2SO4 and concentrate under reduced pressure and crude material was purified by column chromatography to afford the desired compound (1.2 g, 68%).
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@@H:13]([C:14]([OH:16])=[O:15])[C:12]([CH3:18])([CH3:17])[S:11][CH2:10]1)=[O:8])(=O)C.N>O.C(OCC)(=O)C>[SH:4][CH2:5][CH2:6][C:7]([N:9]1[C@@H:13]([C:14]([OH:16])=[O:15])[C:12]([CH3:18])([CH3:17])[S:11][CH2:10]1)=[O:8]
Reactant: CC(=O)SCCC(=O)N1CSC(C)(C)[C@@H]1C(=O)O
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)SCN(C(=O)CCS)[C@H]1C(=O)O
Yield: 100.3 %

Procedure:
The S-acetyl derivative E7 (70 mg, 0.24 mmol) was dissolved in water (0.6 ml) and concentrated aqueous ammonia (0.4 ml, sp.gr. 0.88) and stirred at room temperature for 1 hour. The reaction mixture was diluted in ethyl acetate and washed with sufficient dilute hydrochloric acid to acidify the aqueous phase. The two-phase system was treated with saturated brine and the organic layer separated, washed with further brine, dried over sodium sulphate and evaporated to afford the title compound as a colourless oil (60 mg, 100%). νmax (CHCl3) 1744, 1722, 1651, 1410 cm-1. δH (CDCl3) 1.52 (3 H, s), 1.60 (3 H, s), 1.81 (1 H, t, J 8.2 Hz), 2.7-2.9 (4 H, overlapping m), 4.55 (1 H, s), 4.75 (2 H, ABq) ppm. EIMS M+ 249.0496; required for C9H15NO3S2, 249.0493.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:15]1[CH2:16][CH2:17][N:12]([C:2]2[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH:3]=2)[CH2:13][CH2:14]1
Reactant: C1COCCN1
Reactant: COC(=O)C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COC(=O)C1CC=C(N2CCOCC2)CC1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
In a round-bottom flask equipped with a Dean-Starke trap, 15.6 g of methyl 4-oxocyclohexanecarboxylate, 0.1 mol), morpholine (9.63 mL, 0.11 mol) and p-toluenesulfonic acid (5 mg) in benzene (42.3 mL) was heated up to reflux. Water was removed and the reaction was continued at reflux for 8 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo to give crude product as a yellow oil (20 g), which was used for next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1.C(N([CH2:18][CH3:19])CC)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH:19]2[CH2:18][CH2:1][O:2][CH2:3][CH2:4]2)=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(S)cc1
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(SC2CCOCC2)cc1
Reaction time: 0.25 h
Yield: 159.4 %

Procedure:
(4-Mercapto-phenyl)-acetic acid methyl ester (1.8 g, 9.89 mmol) was dissolved in DMF (20 ml) at 0° C. Triethylamine (1.5 g, 14.83 mmol) was added and stirred for 15 minutes followed by addition of 4-iodo-tetrahydropyan (3.14 g, 14.83 mmol). The reaction mixture was stirred overnight at room temperature. Solvent was removed under reduced pressure, the resulting residue was taken into water and extracted with ethyl acetate (50 ml×2) washed with water and brine (50 ml each) dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product which was purified by column chromatography over silica gel using 15% ethyl acetate in hexanes as eluent to provide [4-(Tetrahydro-pyran-4-ylsulfanyl)-phenyl]acetic acid methyl ester (2.1 gm).
Reaction SMILES: [CH2:1]([C:9]1[C:10]([C:22]([F:25])([F:24])[F:23])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].C(N(C(C)C)CC)(C)C>C1COCC1>[Si:30]([O:29][CH2:28][CH2:27][CH:21]1[N:14]2[C:15]3[C:11]([CH:12]=[CH:13]2)=[C:10]([C:22]([F:25])([F:24])[F:23])[C:9]([CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:17][C:16]=3[CH2:18][NH:19][CH2:20]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: FC(F)(F)c1c(CCc2ccccc2)cc2c3c1ccn3CCNC2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCCC1CNCc2cc(CCc3ccccc3)c(C(F)(F)F)c3ccn1c23
Temperature: 80 °C
Yield: 81.9 %

Procedure:
A mixture of 6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (prepared as described in Example 2 above, 100 mg, 0.26 mmol), 2-bromoethoxy t-butyl(dimethyl)silane (63 mg, 0.26 mmol) and diisopropylethylamine (0.09 mL, 0.53 mmol) in THF was heated at 80° C. for 5 h. The solvent was evaporated to yield 2-(2-((tert-butyldimethylsilyl)oxy)ethyl-6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (107 mg, MS m/z 503 (MH+)).
Reaction SMILES: [CH2:1]([CH:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:8][C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1C(=O)N([Br:29])C(=O)C1.C(=O)([O-])O.[Na+]>C1COCC1>[Br:29][C:10]1[S:11][CH:12]=[CH:13][C:9]=1[CH2:8][CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCC(CCCCCC)Cc1ccsc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCC(CCCCCC)Cc1ccsc1Br
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 3-(2-hexyldecyl)thiophene (10 g, 32.4 mmol) and THF (100 ml) were added and then cooled to 0° C. NBS (5.75 g, 32.4 mmol) was slowly added, and the temperature was increased to room temperature. The mixture was then stirred overnight. Then, a saturated sodium hydrogen carbonate aqueous solution (50 ml) was added to the reaction solution, followed by extraction with hexane, and an organic layer was washed with a saturated saline solution and water. The organic layer was dried with anhydrous magnesium sulfate, and, after filtration, the solvent was distilled off under reduced pressure. By separating and purifying the obtained reaction mixture by silica gel column chromatography in which hexane was used as a mobile phase, 2-bromo-3-(2-hexyldecyl)thiophene (A2) was obtained as clear oil (12.4 g, 99% yield). The product (A2) obtained was identified using a 1H-NMR method. 1H-NMR (400 MHZ, CDCl3, TMS) δ 7.17 (d, J=5.4 Hz, 1 H), 6.75 (d, J=5.4 Hz, 1 H), 2.49 (d, J=7.0 Hz, 2 H), 1.25 (m, 25 H), 0.88 (m, 6 H)
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13](Cl)=[O:14])[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Li+]>O1CCCC1.C(OCC)(=O)C>[C:1]1([C:7]2[N:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccnc(-c2ccccc2)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1ccnc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
To a solution of 145 mg of 2-phenyl-4-pyrimidinecarboxylic acid chloride in 5 mL tetrahydrofuran was added excess lithium borohydride. The reaction mixture was stirred at room temperature for 10 minutes then diluted with 25 mL of ethyl acetate and filtered. The filtrate was washed successively with 25 mL aliquots of 1N sodium hydroxide and brine. The solvent was removed by evaporation under reduced pressure to yield 100 mg of 2-phenyl-4-hydroxymethylpyrimidine as a white solid.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]2[C:15]3=[N:16][C:17]([Sn](C)(C)C)=[CH:18][N:19]=[C:14]3[NH:13][CH2:12][C:11]2=[O:24])[CH2:5][CH2:4]1.Br[C:26]1[C:27]([CH3:34])=[CH:28][C:29]([C:32]#[N:33])=[N:30][CH:31]=1.C(N(CC)CC)C.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]2[C:11](=[O:24])[CH2:12][NH:13][C:14]3[N:19]=[CH:18][C:17]([C:26]4[C:27]([CH3:34])=[CH:28][C:29]([C:32]#[N:33])=[N:30][CH:31]=4)=[N:16][C:15]2=3)[CH2:5][CH2:4]1
Reactant: Cc1cc(C#N)ncc1Br
Reactant: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc([Sn](C)(C)C)nc32)CC1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C#N)cc4C)nc32)CC1
Temperature: 100 °C

Procedure:
1-(((trans)-4-Methoxycyclohexyl)methyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.721 g, 1.64 mmol), 5-bromo-4-methylpicolinonitrile (0.323 g, 1.64 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.150 g, 0.164 mmol), triethylamine (0.687 mL, 4.93 mmol), tri-ortho-toylphosphine (0.100 g, 0.328 mmol) and dimethylformamide (8 mL) were combined in a sealed reaction vessel. Nitrogen was bubbled through the reaction for 5 min and reaction was heated at 100° C. for 3 h. Reaction is filtered, concentrated and purified by silica gel column chromatography (0-80% ethyl acetate in hexanes). Fractions were combined and concentrated to afford the crude title compound used directly for next step (0.607 g, 1.55 mmol, 94% yield). MS (ESI) m/z 393.5 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20]1([CH:23]=O)[CH2:22][CH2:21]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:23][CH:20]2[CH2:22][CH2:21]2)[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=CC1CC1
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Br)cc(N(CC2CC2)C2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.7 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (1 g, 3.04 mmol) and cyclopropanecarbaldehyde (1.06 g, 15.24 mmol) in methanol (15 mL), acetic acid (0.456 g, 7.6 mmol) was added The reaction mixture was stirred at room temperature for 8 h. Sodium cyanoborohydride (0.488 g, 7.62 mmol) was then added at 0° C. and reaction mixture stirred overnight at room temperature. The solvent was then removed under reduced pressure and the crude product purified by column chromatography to afford methyl 5-bromo-3-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (0.275 g, 23.70%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(I)c1
Reactant: OB(O)c1cccnc1
Product: Brc1cccc(-c2cccnc2)c1

Procedure:
In some embodiments, the process further comprises: reacting 1-bromo-3-iodobenzene with 3-pyridine boronic acid to form 3-(3-bromophenyl)pyridine.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2.[Se](=O)=[O:16]>>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:14]=[O:16])=[N:7]2
Reactant: O=[Se]=O
Reactant: COc1ccc2nc(C)ccc2c1Br
Product: COc1ccc2nc(C=O)ccc2c1Br
Yield: 75 %

Procedure:
The title compound was prepared from 5-bromo-6-methoxy-2-methylquinoline (6b) and selenium dioxide using methods as described in the literature for similar compounds (Mathes et al., 1957) in 75% yield. 1H NMR (DMSO-d6, HMDSO), δ: 4.07 (3H, s); 7.92 (1H, d, J=9.0 Hz); 8.03 (1H, d, J=9.2 Hz); 8.29 (1H, d, J=9.2 Hz); 8.58 (1H, d, J=9.0 Hz), 10.09 (3H, s).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])[CH2:4][CH2:3]1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C>[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[O:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(CN2CCC(O)CC2)c(OC(C)C)c1
Reactant: Cc1cccc(C)c1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN2CCC(Oc3c(C)cccc3C)CC2)c(OC(C)C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.3 %

Procedure:
To a solution of methyl 4-[(4-hydroxypiperidin-1-yl)methyl]-3-isopropoxybenzoate (0.72 g, 2.34 mmol), 2,6-dimethylphenol (0.43 g, 3.51 mmol) and tributylphosphine (0.88 mL, 3.51 mmol) in anhydrous tetrahydrofuran (14 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.89 g, 3.51 mmol), and the mixture was stirred at room temperature for 12 hr. To the reaction mixture were added reagents (2,6-dimethylphenol, tributylphosphine and 1,1′-(azodicarbonyl)dipiperidine) in the same amount as mentioned above, and the mixture was further stirred for 12 hr. Diethyl ether (40 mL) was added to the reaction solution, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/1) to give the title compound (0.35 g, yield 36%) as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:9]=1.[CH3:23][O:24][C:25]1[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][C:26]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:23][O:24][C:25]1[CH:30]=[C:29]([NH:31][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[O:21])=[CH:9][CH:10]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:28]=[CH:27][C:26]=1[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCCCCC(=O)c1ccc(C(=O)NCCC(=O)OC)cc1
Reactant: COc1cc(N)ccc1-c1ccccc1
Product: CCCCCC(Nc1ccc(-c2ccccc2)c(OC)c1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compound is prepared by the general method exemplified in Example 1 using 3-(4-hexanoyl-benzoylamino)-propionic acid methyl ester (Preparation 5) and 2-methoxy-biphenyl-4-ylamine as starting materials. MS (ES): 475.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([N+:23]([O-])=O)=[CH:4][CH:3]=1>[Pd].C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:23])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: O=[N+]([O-])c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
A mixture of 9-chloro-1-(2,4-dichlorophenyl)-6-nitro-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (123 mg, 0.308 mmol) and, 10% palladium on carbon (12 mg) in acetic acid (5.0 mL) was stirred under hydrogen atmosphere at room temperature for 8 hr. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (51 mg, 0.139 mmol, 45%) as an oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][OH:13])[CH2:3][CH2:2]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[CH3:14][S:15]([O:13][CH2:12][CH2:11][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][CH2:3]1)(=[O:17])=[O:16]
Reactant: OCCN1CCOc2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCN1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 61.4 %

Procedure:
To a solution of 2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethanol (17.0 g, 94.9 mmol) in pyridine (200 ml) was added methanesulfonyl chloride (16.31 g, 142.0 mmol) dropwise at 0° C. The reaction mixture was stirred for 10 h at 25° C. Ice water (200 ml) was added and the mixture was extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with 2N HCl (3×75 ml), water (75 ml), brine (50 ml) and dried (Na2SO4). The solvent was evaporated under reduced pressure. The residue was triturated with 5% ethyl acetate in pet. ether to afford the title compound (15.0 g, 61%) as brown solid. mp. 92-95° C.
Reaction SMILES: Br[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C:13](=[O:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.O>O1CCCC1>[O:29]1[CH2:30][CH2:31][N:26]([CH2:2][C:3](=[O:25])[C@@H:4]2[C@:21]3([CH3:22])[C@H:7]([C@H:8]4[C@H:18]([C:19](=[O:23])[CH2:20]3)[C@:16]3([CH3:17])[C@H:11]([CH2:12][C:13](=[O:24])[CH2:14][CH2:15]3)[CH2:10][CH2:9]4)[CH2:6][CH2:5]2)[CH2:27][CH2:28]1
Reactant: C1COCCN1
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
A solution of 21-bromo-5α-pregnane-3,11,20-trione (500 mg) in dry tetrahydrofuran was treated at reflux with morpholine (0.5 ml) for 1/2 hour, and poured into water. The oily precipitate was extracted into ether and the extracts were washed with water, dried (Na2SO4) and evaporated to the crude product which was purified by preparative t.l.c. in ethyl acetate and crystallisation from ether to give the title compound (220 mg). m.p. 159°-164°C [α]D +98° (c=1.1%)
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:38]([NH2:40])=[O:39])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH:28]5C5C=CC=CC=5)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].C1([CH:47]2CC[CH2:49][NH:48]2)C=CC=CC=1>>[CH3:47][N:48]([CH3:49])[C@H:29]1[CH2:30][CH2:31][N:27]([CH2:26][C:24]2[S:23][CH:22]=[C:21]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:38]([NH2:40])=[O:39])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]3)[CH:25]=2)[CH2:28]1
Reactant: c1ccc(C2CCCN2)cc1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5c5ccccc5)c4)cc23)CC1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CC[C@H](N(C)C)C5)c4)cc23)CC1
Yield: 18 %

Procedure:
The title compound was prepared according to the general procedure for 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-phenyl-1-pyrrolidinyl)methyl]-3-thienyl}1H-indole-7-carboxamide, substituting (2R)—N,N-dimethyl-2-pyrrolidinamine (114 mg, 1.0 mmol) for 2-phenylpyrrolidine to afford 11 mg of the title compound (18%).
Reaction SMILES: [Mg].[Cl-].[CH3:3][CH2:4][CH2:5][C:6](=[O:11])[CH2:7][CH2:8][CH2:9][CH3:10].[CH2:12](Br)[C:13]#[CH:14].S(=O)(=O)(O)O>CCOCC.C1C=CC=CC=1>[OH:11][C:6]([CH2:12][CH2:13][CH3:14])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:5][C:4]#[CH:3]
Reactant: C#CCBr
Reactant: CCCCC(=O)CCC
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: C#CCC(O)(CCC)CCCC

Procedure:
14 Grams of powdered (50 mesh) magnesium metal is suspended in 80 ml of ether and activated by addition of 200 mg of mercurie chloride. A solution of 38.4 g of 4-octanone and 36.6 g of propargyl bromide in 120 ml of ether and 50 ml of benzene is added dropwise at a rate which produced a gentle reflux. After the addition is complete, the reaction mixture is stirred for several hours and is then poured into 500 ml of cold 5% sulfuric acid. The organic layer is separated, washed with water twice, dried over sodium sulfate and stripped of solvent. The residue is distilled under vacuum to give the title product.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[C:37]1([CH2:43][CH2:44][CH2:45][NH2:46])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:46][CH2:45][CH2:44][CH2:43][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: NCCCc1ccccc1
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCCCc4ccccc4)n3Cc3ccccc32)cc1C

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 3-phenyl-1-propylamine, m.p. 183-184° C. MS [(+)ESI, m/z]: 554 [M+H]+ Anal. Calcd for C37H35N3O2: C, 80.26; H, 6.37; N, 7.59. Found: C, 80.18; H, 6.37; N, 7.51.