Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:28])[C:15](=[O:27])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([SH:26])[CH:17]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.Br[CH2:32][CH2:33][O:34][CH3:35].CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C(#N)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:28])[C:15](=[O:27])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([S:26][CH2:32][CH2:33][O:34][CH3:35])[CH:17]=2)=[C:4]([O:29][CH3:30])[CH:3]=1
Reactant: COCCBr
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(S)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCCSc1cc(C(=O)N(C)c2cnccc2-c2ccc(F)cc2OC)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-3-mercapto-N-methyl-5-(trifluoromethyl)benzamide (0.065 g, 149 μmol, example 216, intermediate a) in acetonitrile (2 mL) was treated with 1-bromo-2-methoxyethane (24.8 mg, 16.8 μL, 179 μmol) and DIPEA (38.5 mg, 52.0 μL, 298 μmol) and stirred at room temperature for 5 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (0.04 g; 54%). MS (ESI): m/z=495.14 [M+H]+.
Reaction SMILES: [CH:1]1([NH2:6])CCC[CH2:2]1.FC1C=C(C)C=CC=1[N+]([O-])=[O:15].[CH:18]1([NH:23][C:24]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:25]=2[NH2:26])[CH2:22][CH2:21][CH2:20][CH2:19]1.N[C:33]1[S:34]C=[CH:36][N:37]=1>>[CH:18]1([NH:23][C:24]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:25]=2[NH2:26])[CH2:22][CH2:21][CH2:20][CH2:19]1.[CH:18]1([NH:23][C:24]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:25]=2[NH:26][C:36]([NH:37][C:33]2[S:34][CH:2]=[CH:1][N:6]=2)=[O:15])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC1CCCC1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: Nc1nccs1
Agent: Cc1ccc(N)c(NC2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2nccs2)c(NC2CCCC2)c1
Yield: 62 %

Procedure:
2-Cyclopentylamino-4-methyl-aniline (0.64 g, 68%) was prepared from cyclopentylamine (1.0 ml, 10.0 mmol) and 3-fluoro-4-nitrotoluene (0.77 g, 5.0 mmol) following the general procedure W. 1-(2-Cyclopentylamino-4-methyl-phenyl)-3-thiazol-2-yl-urea (195 mg, 62%) was prepared from 2-cyclopentylamino-4-methyl-aniline (190 mg, 1.0 mmol) and 2-aminothiazole (100 mg, 1.0 mmol) following the general procedure D.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7](O)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]>C1COCC1.[Cl-].[Na+].O>[C:10]([NH:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:5])[CH3:6])([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
To a solution of BOC-Leu-OH (15.09 g, 65 mmol, 1 equiv) in THF (150 mL) at 0° C. was added BH3. THF (163 mL of a 1.0 M solution in THF, 163 mmol, 2.51 equiv). The reaction mixture was stirred at 23° C. for 3 h and then cooled to 0° C. Brine (100 mL) was added carefully, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (gradient elution, 25-35% EtOAc in hexanes) to afford BOC-L-Leucinol as a colorless oil (12.59 g, 89%): IR (cm−1): 3434, 1699, 1256, 739; 1H NMR (CDCl3) δ 0.93 (dd, 6H, J=6.6, 1.5), 1.29-1.31 (m, 2H), 1.45 (s, 9H), 1.60-2.05 (m, 2H), 3.47-3.53 (m, 1H), 3.65-3.72 (m, 2H), 4.56 (s, br, 1H); Anal. (C11H23NO3) C, H, N.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:17]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29]Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:7]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCCOCCOCc1ccccc1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Product: O=C(Cc1ccccc1)c1ccc(OCCOCCOCc2ccccc2)cc1

Procedure:
is prepared according to example 4c starting from 1-(4-hydroxyphenyl)-2-phenyl ethanone (prepared according examples 4a-b) (10.0 g, 47.1 mmol) and 2-(2-benzyloxyethoxy)ethyl chloride (11.0 g, 51.8 mmol). The product was triturated three times with warm heptane to remove byproducts. Yield 9.6 g, 52%.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[NH2:30][CH2:31][CH2:32][C:33]#[N:34].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[C:31]([CH2:32][CH2:33][NH:34][C:20]([C:19]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1/[CH:11]=[CH:10]/[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:1])[F:29])[C:5]=1[O:23][CH2:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:21])#[N:30]
Reactant: N#CCCN
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)NCCC#N)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (80 mg, 0.189 mmol) with 3-aminopropanenitrile (14.56 mg, 0.208 mmol) in the presence of EDCI hydrochloride (72 mg, 0.378 mmol), DMAP (21 mg, 0.189 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 60 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.08 (s, 9H), 2.82-2.86 (m, 2H), 3.52-3.60 (m, 4H), 7.16 (t, J=73.5 Hz, 1H), 7.18-7.30 (m, 2H), 7.37-7.52 (m, 2H), 7.72-7.88 (m, 2H), 8.00-8.06 (m, 1H), 8.59 (br s, 1H); APCI-MS (m/z) 475.28 (MH)+.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([C:29](Cl)([CH3:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1)C1C=CC=CC=1.[Cl-].[NH4+]>CCOCC>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([CH3:30])([CH3:31])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:24]=1)[C:11]1[CH:10]=[CH:9][CH:14]=[CH:13][CH:12]=1
Reactant: CCCCCC[Mg]Br
Reactant: CC(C)(Cl)c1cccc(OCc2ccccc2)c1
Reactant: CCCCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1cccc(OCc2ccccc2)c1
Reaction time: 0.08 h
Yield: 35 %

Procedure:
To a 0° C. mixture of 10.1 mmole of n-hexyl magnesium bromide in 5 ml. of hexane is added dropwise a solution of 2.0 g (7.69 mmole) of 2-(3-benzyloxyphenyl)-2-chloropropane in 14 ml. of hexane. The reaction mixture is stirred 5 minutes longer and then added to 500 ml. of saturated ammonium chloride and 300 ml. ether. The organic extract is dried over magnesium sulfate and evaporated to an oil. The oil is purified via column chromatography on 150 g. silica gel eluted with hexane to yield 841 mg. (35%) of the title compound as an oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C([Li])CCC.CCCCCC.[CH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[O:30][CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:23].[Cl-].[NH4+]>O1CCCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][C:25]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[OH:23])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Brc1ccc(C2CC2)cc1
Reactant: C[Si](C)(C)CCOCOc1cnccc1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)CCOCOc1cnccc1C(O)c1ccc(C2CC2)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 4-cyclopropylbromobenzene (synthesized as described in WO0268439; 2.5 g, 0.0127 mol) in tetrahydrofuran (20 ml), a 1.58 mol/L n-butyllithium/n-hexane solution (8.4 ml, 0.0133 mol) was added dropwise at −70° C. over 8 minutes. After stirring at −70° C. for 1 hour, a tetrahydrofuran solution of 4-formyl-3-[2-(trimethylsilyl)ethoxymethoxy]pyridine (4.2 g, 0.0165 mol) was added over 5 minutes and stirred at −70° C. for 2.5 hours. After addition of saturated aqueous ammonium chloride, the reaction mixture was warmed to room temperature and extracted twice with ethyl acetate. The organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50) to give (4-cyclopropylphenyl)-[3-[2-(trimethylsilyl)ethoxymethoxy]pyridin-4-yl]-methanol (2.5 g, 53%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2([CH2:18][OH:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[O:35][CH:36]=[CH:37][N:38]=2)=[CH:30][CH:29]=1.BrC1C=CC(CN(C2(CO)CCCCC2)S(C2C=CC(Cl)=CC=2)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:12]2([CH2:18][OH:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[O:35][CH:36]=[CH:37][N:38]=3)=[CH:32][CH:33]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(-c2ncco2)cc1
Reactant: O=S(=O)(NC1(CO)CCCCC1)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(Br)cc1)C1(CO)CCCCC1
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)cc1)C1(CO)CCCCC1
Yield: 82.8 %

Procedure:
The title compound was synthesized from 4-chloro-N-(1-(hydroxymethyl)cyclohexyl)benzenesulfonamide (114 mg, 0.38 mmol), cesium carbonate (244 mg, 0.75 mmol), and 2-(4-(bromomethyl)phenyl)oxazole (98 mg, 0.41 mmol) according to the procedure described for N-(4-bromobenzyl)-4-chloro-N-(1-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 39) to give 4-chloro-N-(1-(hydroxymethyl)cyclohexyl)-N-(4-(oxazol-2-yl)benzyl)benzenesulfonamide (145 mg, 84%). 1H NMR (400 MHz, CDCl3) δ ppm 7.99 (2H, d, J=8.06 Hz), 7.77 (2H, d, J=8.56 Hz), 7.69 (1H, s), 7.45 (4H, dd, J=15.36, 8.56 Hz), 7.21 (1H, s), 4.78 (2H, s), 3.86 (2H, br. s.), 2.92 (1H, hr. s.), 1.81-1.90 (2H, m), 1.42-1.54 (5H, m), 1.20-1.31 (2H, m), 0.95-1.07 (1H, m). LC/MS R.T.=2.18 min; [M+H]+=461.08. HRMS [M+H]+ calc'd 461.1302, found 461.1321.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])N2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=O.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1([C:31]#[N:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[C:33](O)(=O)C.ClC(Cl)C.C([BH3-])#N>>[C:31]([C:25]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[CH2:26][CH2:27][N:28]([CH2:1][C:3]2[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[CH:33]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH2:29][CH2:30]1)#[N:32]
Reactant: N#CC1(c2ccccn2)CCNCC1
Reactant: CC(=O)O
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Agent: [BH3-]C#N
Solvent: CC(Cl)Cl
Product: CCOC(=O)C1=CC(CN2CCC(C#N)(c3ccccn3)CC2)=C2C=CC=CC2C1=O
Temperature: 120 °C

Procedure:
In a 10-20 mL Emrys™ process vial, a mixture of the ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (684 mg, 2.79 mmol), 4-pyridin-2-ylpiperidine-4-carbonitrile (627 mg, 3.35 mmol), glacial acetic acid (0.96 mL, 16.7 mmol) and 4.1 mL of dichloroethane was stirred vigorously. To the stirring mixture was added resin-bound MP-cyanoborohydride (2.74 g, 5.58 mmol). The mixture was heated via Emrys Optimizer™ microwave to 120° C. for 30 minutes. Filtration and solvent removal provided material, which was subjected to silica gel chromatography eluting with 55-75% EtOAc in hexanes. Collection of product containing fractions and removal of solvent afforded the ethyl 4-[(4-cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-1-oxo-1,8a-dihydronaphthalene-2-carboxylate.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2)=[O:4].[NH:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>C1COCC1.CCOC(C)=O.C(=O)(O)[O-].[Na+]>[C:26]([O:25][C:23]([C@@H:19]1[CH2:20][CH2:21][CH2:22][N:18]1[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2)=[O:4])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=C(CCl)N1CCSc2cc([N+](=O)[O-])ccc21
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1CC(=O)N1CCSc2cc([N+](=O)[O-])ccc21
Temperature: 55 °C
Reaction time: 17 h

Procedure:
A solution of 2-chloro-1-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethanone (1.0 g, 3.67 mmol) in THF (20 mL) was treated with (S)-tert-butyl pyrrolidine-2-carboxylate (0.942 g, 5.50 mmol), followed by saturated sodium bicarbonate (4 mL). The mixture was heated at 55° C. for 3 hours then stirred at room temperature overnight (17 hours). The mixture was diluted with EtOAc (50 mL) and saturated sodium bicarbonate (10 mL) then stirred for 20 minutes. The contents were poured into a separatory funnel, and the organic layer was separated, dried (Na2SO4), filtered, and concentrated to give a dark yellow residue. This residue was subjected to silica gel chromatography using the Biotage purification system (column: Silicycle 40 g; 20:80 EtOAc:hexanes gradient to 60:40 EtOAc:hexanes over 8 column volumes; flow rate: 35 mL/min; collection wavelength: 254 nm). A yellow residue was obtained (1.47 g, 98%). 1H-NMR (CDCl3) δ 8.09 (d, J=2.4 Hz, 1H), 7.91 (dd, J=2.4, 8.7 Hz, 1H), 7.75 (d, J=9.0 Hz, 1H), 4.10 (brs, 2H), 3.74 (brd, J=13.2 Hz, 1H), 3.40 (brd, J=13.5 Hz, 1H), 3.37-3.21 (m, 3H), 3.12-3.04 (m, 1H), 2.61 (brdd, J=8.1, 16.2 Hz, 1H), 2.21-2.07 (m, 1H), 1.95-1.77 (m, 3H), 1.43 (s, 9H); ESI-MS (m/z, %): 408 (MH+, 50), 352 (100).
Reaction SMILES: Cl[C:2]1[N:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([Cl:11])[CH:7]=[CH:6]2.ClC1N(C2C=CC(Cl)=CC=2)N=C2C=1C=CC=C2.[CH2:36]([O:38][C:39]1[CH:40]=[C:41]([NH2:45])[CH:42]=[CH:43][CH:44]=1)[CH3:37]>CN1CCCC1=O>[Cl:11][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[C:2]([NH:45][C:41]3[CH:42]=[CH:43][CH:44]=[C:39]([O:38][CH2:36][CH3:37])[CH:40]=3)[N:3]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[N:4]=2)[CH:9]=1
Reactant: CCOc1cccc(N)c1
Reactant: Clc1ccc(-n2nc3ccc(Cl)cc3c2Cl)cc1
Agent: Clc1ccc(-n2nc3ccccc3c2Cl)cc1
Solvent: CN1CCCC1=O
Product: CCOc1cccc(Nc2c3cc(Cl)ccc3nn2-c2ccc(Cl)cc2)c1

Procedure:
In analogy to the procedure described in example 4.1, a mixture of 3,5-dichloro-2-(4-chloro-phenyl)-2H-indazole and 3-chloro-2-(4-chloro-phenyl)-2H-indazole was reacted with 3-ethoxy-phenylamine ([621-33-0]) in N-methyl 2-pyrrolidone for 4 d at 175° C. in a sealed tube to give the title compound after purification by column chromatography (silica gel, iPrOAc/heptane) as yellow foam. MS: m/e=398.1 [M+H+].
Reaction SMILES: S(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[CH:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH3:34])[CH2:29][CH2:28]2)=[CH:25][CH:26]=1)=[O:20])(C)(=O)=O.[I-:35].[Na+].O.C(Cl)(Cl)Cl>CC(C)=O>[I:35][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[CH:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH3:34])[CH2:29][CH2:28]2)=[CH:25][CH:26]=1)=[O:20]
Reactant: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCOS(C)(=O)=O)cn2)CC1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCI)cn2)CC1
Yield: 90.1 %

Procedure:
To a solution of 72 mg of N-(12-mesyloxydodecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide in acetone was added 130 mg of sodium iodide and the mixture was heated under reflux for 10 hours. To the reaction solution were added water and chloroform and extracted with chloroform. The chloroform layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue thus obtained was chromatographed over a silica gel column to afford 69.0 mg of the title compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[C:17]2[N:16]=[C:15]3[N:18]([C:22]4[CH:23]=[N:24][C:25]([N:29]([CH3:31])[CH3:30])=[CH:26][C:27]=4[CH3:28])[CH2:19][CH2:20][CH2:21][N:14]3[C:13]=2[C:12]([CH:32]([OH:35])[CH2:33][CH3:34])=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:1]([O:35][CH:32]([C:12]1[C:13]2[N:14]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]4[CH:23]=[N:24][C:25]([N:29]([CH3:30])[CH3:31])=[CH:26][C:27]=4[CH3:28])[C:15]3=[N:16][C:17]=2[C:9]([Cl:8])=[CH:10][CH:11]=1)[CH2:33][CH3:34])(=[O:3])[CH3:2]
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1cnc(N(C)C)cc1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1cnc(N(C)C)cc1C
Temperature: 25 °C
Reaction time: 19 h
Yield: 76 %

Procedure:
Acetic anhydride (142 μL, 1.50 mmol) was added to a stirred solution of 1-{9-chloro-1-[6-(dimethylamino)-4-methylpyridin-3-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}propan-1-ol (200 mg, 0.500 mmol) in pyridine (1.6 mL) at room temperature, and the mixture was stirred at room temperature for 19 hr. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (168 mg, 0.380 mmol, 76%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O.O1CCCC1>CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)CCC2
Yield: 100 %

Procedure:
7-Nitrotetralone (2.5 g, 13 mmol) was suspended in 50 mL of methanol and complete dissolution achieved by the addition of 10 mL of tetrahydrofuran. The solution was hydrogenated at room temperature and 20-30 psi over 100 mg of 10% Pd/C for 2 hours. The mixture was filtered through Celite, washed with methanol and evaporated to dryness under vacuum to afford 2.1 g (13 mmol, 100%) of the product. 1H NMR (300MHz, CDCl3): 2.09 (m,2H), 2.60 (t,6Hz,2H), 2.84 (t,6Hz,2H), 6.83 (m,1H), 7.06 (d,8Hz,1H), 7.32 (d,2Hz,1H). FAB-MS: calculated for C10H11NO 161; found 162 (M+H,100%).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@@H:16]([C:28](=[O:43])[N:29]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH2:40][CH2:41][OH:42])[CH3:30])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)C)(C)(C)C.C(=O)([O-])O.[Na+].O>ClCCl>[OH:42][CH2:41][CH2:40][O:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][CH2:31][N:29]([CH3:30])[C:28](=[O:43])[C@H:16]([NH:14][CH3:13])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1
Reactant: CN(CCc1ccccc1OCCO)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1OCCO
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
At 0° C., trifluoroacetic acid (4 ml) was added to a solution of N-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester (986 mg, 1.95 mmol) in dichloromethane (4 ml). The solution was stirred for 3 h at 0° C. Dichloromethane (50 ml) was added. A saturated solution of sodium hydrogen carbonate (30 ml) was added. Solid sodium hydrogen carbonate was added until pH 7 was obtained. Water was added until a clear solution was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (2×20 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 730 mg of (2R)-N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](=O)[CH2:6]Br.[NH2:12][C:13]([NH2:15])=[O:14].C([O-])(=O)C.[NH4+].C(O)(=O)C>O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:12][C:13](=[O:14])[NH:15][CH:6]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: NC(N)=O
Reactant: O=C(CBr)c1cccc(Br)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]cc(-c2cccc(Br)c2)[nH]1
Temperature: 25 °C

Procedure:
To a mixture of 3-bromophenacyl bromide (0.5 g, 1.8 mmol), urea (0.32 g, 5.3 mmol), and ammonium acetate (0.40 g, 5.4 mmol) in water (10 mL) was added glacial acetic acid (0.32 g, 5.4 mmol). The reaction mixture was heated at reflux overnight. After cooling to room temperature, the mixture was extracted with three portions of ethyl acetate, and the combined extracts were dried (magnesium sulfate) and concentrated under reduced pressure to give a brown residue which was triturated with diethyl ether to afford the desired product. LC/MS 238.9 and 240.9 (M+1).
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13](CCl)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:7]=2[CH:25]=1.[I-].[K+].C(N)C=C>O1CCCC1>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:8]1[C:7]2[CH:25]=[CH:3][CH:4]=[CH:5][C:6]=2[N:12]2[CH:13]=[N:14][N:15]=[C:11]2[CH2:10][N:9]=1
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: C=CCN
Product: Clc1ccccc1C1=NCc2nncn2-c2ccccc21

Procedure:
In the manner given in Example 31, 8-(trifluoromethyl)-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine, potassium iodide and allylamine in tetrahydrofuran are reacted to give 8-(trifluoromethyl)-1-(allylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Li]CCCC.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([O:35][CH:36]([CH3:38])[CH3:37])[C:21]([F:34])=[C:22]([CH:33]=1)/[CH:23]=[N:24]/[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1)[CH3:16]>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:24]([CH2:23][C:22]1[CH:33]=[C:18]([O:17][CH2:15][CH3:16])[CH:19]=[C:20]([O:35][CH:36]([CH3:38])[CH3:37])[C:21]=1[F:34])[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1
Reactant: CCOc1cc(/C=N/c2ccc(C#N)cc2)c(F)c(OC(C)C)c1
Reactant: c1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(CN(c2ccc(C#N)cc2)c2nc3ccccc3s2)c(F)c(OC(C)C)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 42.6 %

Procedure:
To a solution of benzothiazole (61.9 mg, 0.458 mmol) in 2 mL THF at −78° C. was added 1.6 M solution of BuLi in THF (315 μL, 0.504 mmol). The mixture was stirred at −78° C. for 45 min, then a solution of Intermediate 7.3 (149 mg, 0.458 mmol) in 0.5 mL THF was added dropwise. The mixture was stirred and allowed to warm to rt overnight, then was quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 50% EtOAc/hexanes gradient) to afford 90 mg of Intermediate 7.4 as a white solid.