Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[C:2]1([CH2:8][CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH:34]1([CH:46]=O)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CCOCC>[C:2]1([CH2:8][CH:9]=[CH:46][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CC1CCCCCCCCCCC1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: C(=CC1CCCCCCCCCCC1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To 11.4 g (25.5 mmol) of phenylethyl triphenylphosphonium bromide in 50 mL of dry ether at 0° C. is added 10.2 mL (25.5 mmol) of 2.5M butyllithium. The suspension is stirred at 0° C. for 1 hour followed by the addition of 5.0 g (25.5 mmol) of cyclododecane carboxaldehyde. The mixture is stirred at room temperature for 3 hours after which time no starting material is evident by TLC. The reaction mixture is quenched with 1N HCl. The layers are separated and the aqueous layer is washed twice with ethyl ether. The combined organic layers are dried over a MgSO4 and the ether is evaporated. The residue is flash chromatographed on silica gel using hexanes to give 6.4 g of a colorless oil: NMR (CDCl3) δ 1.0-1.6 (m, 10H), 2.6 (m, 1H), 3.4 (d, 2H, J=8 Hz,), 5.3 (t, 1H, J=7 Hz), 5.45 (q, 1H, J=7 Hz), 7.2 ppm (m, 5
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:12][CH2:11]2)[C:3]=1[C:4]#[N:5].[C:13]([N:21]=C=O)(=[O:20])C1C=CC=CC=1.[OH-].[Na+]>O1CCOCC1>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[CH:10]2[CH2:11][CH2:12]2)[NH:1][C:13](=[O:20])[N:21]=1
Reactant: N#Cc1c(N)cccc1C1CC1
Reactant: O=C=NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1nc(=O)[nH]c2cccc(C3CC3)c12
Temperature: 75 °C
Reaction time: 2 h
Yield: 12.4 %

Procedure:
A solution of 2-amino-6-cyclopropylbenzonitrile (Example 92a) (1.0 eq., 1.0 mmol, 158 mg) and benzoyl isocyanate (90% pure, 1.0 eq., 1.0 mmol, 1.171 g/mL, 140 μL) in dioxane (15 mL) was stirred at room temperature. After 2 hours, the volatiles were removed on a rotary evaporator. The resulting crude N-benzoyl urea was suspended in EtOH (10 mL, 200 proof) and NaOH (2.5 eq., 2.5 mmol, 1N, 2.50 mL) was added. The reaction was heated to 75° C. with stirring for 7 hours. The solvent were evaporated and the residue diluted with water (10 mL). The reaction mixture was acidified with 10% citric acid/water solution and carefully titrated to pH 7-8 with saturated NaHCO3 solution. The precipitated product was collected by vacuum filtration, washing with water. The residue was suspended in EtOH (3 mL, 200 proof) and HCl was added (12.1N, 3 mL). The mixture was heated to 90° C. for 1 hour. The reaction mixture was cooled to room temperature and diluted with water (20 mL), filtered (0.45 μm PTFE frit), and the filtrate concentrated on a rotary evaporator. The residue was further purified by preparative TLC (1000 μm, 10/90 MeOH/DCM) and trituration with methanol at room temperature. The reaction gives 25 mg (12.4%) of the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.802 (m, 2H), 1.086 (m, 2H), 2.345 (m, 1H), 6.922 (d, J=8 Hz, 1H), 7.000 (d, J=8 Hz, 1H), 7.253 (br. s, 1H), 7.397 (t, J=8 Hz, 1H), 8.022 (br. s, 1H), 10.644 (s, 1H). MS 202 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:15]2)=[CH:10][C:9]=1[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.Cl[CH2:31][C:32]1[C:33]([C:40]2[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:47])=[N:34][O:35][C:36]=1[CH:37]([CH3:39])[CH3:38].O>CN(C)C=O>[Cl:46][C:45]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:47])[C:40]=1[C:33]1[C:32]([CH2:31][O:29][C:26]2[CH:25]=[CH:24][C:23]([C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:8]=3[F:7])[N:15]=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:13]=[CH:12]4)=[CH:28][CH:27]=2)=[C:36]([CH:37]([CH3:39])[CH3:38])[O:35][N:34]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(O)cc3)c(F)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)c(F)cc2n1
Reaction time: 68 h
Yield: 48.8 %

Procedure:
Cesium carbonate (62.6 mg, 192.2 μmol) was added to ethyl 7-fluoro-6-(4-hydroxyphenyl)-2-quinolinecarboxylate (54.4 mg, 174.7 μmol) and 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (58.6 mg, 192.2 μmol) in N,N-dimethylformamide (1.7 mL) at room temperature. The resulting suspension was stirred for 68 hours, then water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 3:7 ethyl acetate:hexanes to give 49.4 mg (49%) of ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-7-fluoro-2-quinolinecarboxylate as an oil. 1H NMR (400 MHz, d6-DMSO): δ 8.61 (d, J=9 Hz, 1H), 8.23 (d, J=9 Hz, 1H), 8.11 (d, J=9 Hz, 1H), 8.02 (d, J=12 Hz, 1H), 7.65-7.62 (m, 2H), 7.56 (d, J=7 Hz, 2H), 7.56-7.52 (m, 1H), 6.96 (d, J=9 Hz, 2H), 4.90 (s, 2H), 4.42 (q, J=7 Hz, 2H), 3.48 (septet, J=7 Hz, 1H), 1.38 (t, J=7 Hz, 3H), 1.34 (d, J=7 Hz, 6H). ESI-LCMS m/z 579 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]([O:21][CH3:22])=[CH:19][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][CH:13]=3)=[N:9][C:5]=2[CH:4]=1.[OH2:23]>>[CH3:1][O:2][C:3]1[C:20]([O:21][CH3:22])=[CH:19][C:6]2[NH:7][C:8]([S:10]([CH2:11][C:12]3[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][CH:13]=3)=[O:23])=[N:9][C:5]=2[CH:4]=1
Reactant: COc1cc2nc(SCc3cccc(N)n3)[nH]c2cc1OC
Reactant: O
Product: COc1cc2nc(S(=O)Cc3cccc(N)n3)[nH]c2cc1OC

Procedure:
The title compound (600 mg) was prepared by the method of Example 85 using 1.6 g (5.0 mmole) of 6-[[(5,6-dimethoxy-1H-benzimidazol-2-yl)thio]methyl]-2-pyridinamine (see Example 98) instead of 6-[(1H-benzimidazol-2-ylthio)-methyl]-2-pyridinamine. Structure assignment was supported by the nmr spectrum and by elemental analysis. Analysis. Calc'd. for C15H16N4SO3*¼ H2O: C, 53.48; H, 4.90; N, 16.63; S, 9.52. Found: C, 53.54; H, 4.57; N, 16.45; S, 9.79.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[O:5][N:4]=1.C(Cl)(=O)C([Cl:14])=O>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([Cl:14])=[O:10])[O:5][N:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C(=O)O)on1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(C(=O)Cl)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
To a solution of 3-methoxyisoxazole-5-carboxylic acid (420 mg, 3 mmol) in THF (15 mL) and DMF (5 drop) was added dropwise oxalyl chloride (650 μL, 7 mmol) at 0° C. The mixture was then stirred at room temperature for 3 hours. The solution was concentrated in vacuo to yield the title compound as a light yellow oil (430 mg).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:50]=[CH:51][CH:52]=1)[CH2:13][N:14]1[CH:18]=[C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:28]4[CH:29]=[N:30][C:31]([N:34]5[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]5)=[CH:32][CH:33]=4)[CH:26]=3)[N:21]([S:40]([C:43]3[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[CH:20]=2)[CH:16]=[N:15]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:53][C@H:54]1[CH2:56][O:55]1.CCN(C(C)C)C(C)C>C(O)C>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:50]=[CH:51][CH:52]=1)[CH2:13][N:14]1[CH:18]=[C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH2:35][CH2:36][N:37]([CH2:53][C@@H:54]([OH:55])[CH3:56])[CH2:38][CH2:39]5)=[N:30][CH:29]=4)[CH:26]=3)[N:21]([S:40]([C:43]3[CH:44]=[CH:45][C:46]([CH3:47])=[CH:48][CH:49]=3)(=[O:41])=[O:42])[CH:20]=2)[CH:16]=[N:15]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(OCc5ccccc5)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(OCc5ccccc5)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-(benzyloxy)benzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (200 mg. 0.273 mmol) was alkylated using (S)-2-methyloxirane (48 mg, 0.819 mmol), DIPEA (211 mg, 1.638 mmol) and ethanol (20 mL) to get 200 mg (crude) of the titled compound. MS: m/z=754.3 (M+1).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([CH2:17][CH2:18][N:19]3[C@H:24]4[CH2:25][CH2:26][C@@H:20]3[CH2:21][CH:22]([N:27]3[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[N:29]=[C:28]3[CH3:36])[CH2:23]4)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:7]=[C:8]([F:10])[CH:9]=1.C(N(CC)CC)C.[CH3:44][C:45]([CH3:50])([CH3:49])[C:46](Cl)=[O:47]>ClCCl>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([CH2:17][CH2:18][N:19]3[C@H:24]4[CH2:25][CH2:26][C@@H:20]3[CH2:21][CH:22]([N:27]3[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[N:29]=[C:28]3[CH3:36])[CH2:23]4)[CH2:12][CH2:13][N:14]([C:46](=[O:47])[C:45]([CH3:50])([CH3:49])[CH3:44])[CH2:15][CH2:16]2)[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cc(F)cc(Cl)c2)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cc(F)cc(Cl)c2)CCN(C(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
A mixture of 1-((1R,5S)-8-{2-[4-(3-chloro-5-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.2 g, 0.39 mmol), triethylamine (0.11 mL, 0.78 mmol) and trimethylacetyl chloride (0.053 mL, 0.43 mmol) in dichloromethane (4 mL) was stirred at rt for 1 h before the reaction mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated, dried, concentrated and purified by two successive chromatographies on silica gel using a dichloromethane to methanol:dichloromethane 1:20 gradient to give 1-((1R,5S)-8-{2-[4-(3-chloro-5-fluorophenyl)-1-(2,2-dimethylpropanoyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole as a glass (0.06 g, 27%). 1H NMR (400 MHz, CDCl3) δ 7.67 (m, 1H), 7.29 (m, 1H), 7.17 (m, 2H), 7.09 (m, 1H), 7.00 (m, 1H), 6.93 (m, 1H), 4.72 (m, 1H), 3.90 (m, 2H), 3.37 (m; 4H), 2.61 (s, 3H), 2.47 (m, 2H), 1.89-2.11 (m, 8H), 1.78 (m, 6H), 1.27 (s, 9H). HRMS C33H42ClFN4O m/z 565.3109 (M+H)Cal., 565.3095 (M+H)Obs..
Reaction SMILES: C1(C(=[N:14][C:15]2[N:20]=[C:19]([CH2:21][C:22]([O-:24])=[O:23])[CH:18]=[CH:17][CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[CH2:26]1COCC1.O>>[NH2:14][C:15]1[N:20]=[C:19]([CH2:21][C:22]([O:24][CH3:26])=[O:23])[CH:18]=[CH:17][CH:16]=1
Reactant: O=C([O-])Cc1cccc(N=C(c2ccccc2)c2ccccc2)n1
Reactant: C1CCOC1
Agent: Cl
Solvent: O
Product: COC(=O)Cc1cccc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
{6-[(diphenylmethylidene)amino]pyridin-2-yl}acetate (1.3 g, 3.93 mmol) was dissolved in 1:1 mixture of THF/water (20 mL) and treated with 4.5 mL of a 1N aqueous hydrochloric acid solution. The reaction was allowed to stir at ambient temperature for 30 minutes and then concentrated in vacuo. The crude residue was dissolved in DCM and washed with a saturated aqueous sodium bicarbonate solution. The organic layers were dried over sodium sulfate, filtered and concentrated to afford crude methyl (6-aminopyridin-2-yl)acetate which was used without further purification: LC/MS (M+H)+167.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9](=[O:12])([OH:11])[OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([C:17]([CH3:22])([CH2:20]O)[CH2:18]O)[CH3:16]>>[CH2:15]([C:17]1([CH3:22])[CH2:20][O:11][P:9](=[O:10])([CH2:8][C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[O:12][CH2:18]1)[CH3:16]
Reactant: CCC(C)(CO)CO
Reactant: O=[N+]([O-])c1ccc(CP(=O)(O)O)cc1
Product: CCC1(C)COP(=O)(Cc2ccc([N+](=O)[O-])cc2)OC1

Procedure:
4-Nitrobenzylphosphonic acid and 2-ethyl-2-methyl-1,3-propanediol were treated in the same manner as in Reference Example 20 to yield 5-ethyl-5-methyl-2-(4-nitrobenzyl)-1,3,2-dioxaphosphorinan-2-oxide, which was then recrystallized from ethanol-hexane to yield colorless prisms having a melting point of 184°-185° C.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10](S(C)=O)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2].[CH3:17][O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[O:18][CH3:17])[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2]
Reactant: CCn1c(=O)ccc2cnc(S(C)=O)nc21
Reactant: COc1ccccc1N
Product: CCn1c(=O)ccc2cnc(Nc3ccccc3OC)nc21
Temperature: 175 °C
Yield: 34 %

Procedure:
A mixture of 8-ethyl-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (140 mg, 0.59 mmol) and 500 μL of 2-methoxyaniline was heated at 175° C. for 20 minutes. The reaction mixture was cooled to room temperature and partitioned between chloroform and saturated sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate. Recrystallization from ethyl acetate and hexane provided 60 mg (34%) of 8-ethyl-2-(2-methoxyphenyl-amino)-8H-pyrido[2,3-d]pyrimidin-7-one, mp 126-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]#[N:20])([CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.O1CCC[CH2:22]1.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:11]([CH:10]1[CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([C:19]#[N:20])[CH2:14][CH2:15][C:16]1=[O:18])([O:13][CH3:22])=[O:12]
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(Cl)cc1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)C1CC(C#N)(c2ccc(Cl)cc2)CCC1=O
Yield: 96 %

Procedure:
A reaction mixture consisting of 34.97 gm. (0.108 mole) dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid, (prepared in Part A, above), dissolved in 700 ml. tetrahydrofuran with 24.4 gm. (0.218 mole) potassium tert-butoxide added is heated at the reflux temperature for 41/2 hours. After cooling, the reaction mixture is chilled in an ice-bath and 175 ml. 2.5 N acetic acid is added. The organic and aqueous phases separate and the organic phase is recovered. It is diluted with 600 ml. benzene before being washed successively with aqueous sodium bicarbonate, water, and brine. The organic solvents are then removed by distillation under reduced pressure. There is thus obtained 30.2 gm. (96% yield) of 2-carbomethoxy-4-(p-chlorophenyl)-4-cyanocyclohexanone having a melting point at 139° to 143° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[OH:14])[CH:2]=[CH2:3].C(C1C(C(F)(F)F)=CC=CC=1O)C=C.[H][H]>CO.CCOC(C)=O.[Pd]>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:12])([F:13])[F:11])=[CH:6][C:5]=1[OH:14])[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCc1ccc(C(F)(F)F)cc1O
Agent: [Pd]
Agent: C=CCc1c(O)cccc1C(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1ccc(C(F)(F)F)cc1O
Yield: 87.5 %

Procedure:
A mixture of 2-allyl-5-trifluoromethyl-phenol (60 mg, 12%) and 2-allyl-3-trifluoromethyl-phenol and 10% Pd/C (20 mg) in methanol (4 ml) was hydrogenated under 50 psi hydrogen atmosphere for 1 hour. The mixture was dissolved in EtOAc, filtered through a celite pad. The filtrate was concentrated under reduced pressure, and dried to give 2-propyl-5-trifluoromethyl-phenol (53 mg, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].[H-].[Na+]>CN(C=O)C>[C:20]([Si:17]([CH3:19])([CH3:18])[O:16][CH2:15][CH2:14][CH2:13][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[CH:7]=[CH:8]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1ccc2cc[nH]c2c1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ccn(CCCO[Si](C)(C)C(C)(C)C)c2c1
Reaction time: 2 h
Yield: 101.9 %

Procedure:
To a solution of 6-methoxyindole (10.0 g, 67.9 mmol), and (3-bromo-propoxy)-tert-butyl-dimethylsilane (18.0 g, 71.3 mmol) in DMF (300 mL) was added NaH (0.353 g, 8.82 mmol) as a 60% oil dispersion. The reaction was stirred for 2 h, quenched with saturated aq NaHCO3, diluted with EtOAc (400 mL), washed with saturated aq NaHCO3 and brine, dried (MgSO4), filtered, and concentrated to a transparent oil. The oil was purified by filtration through a plug of silica gel (85% hexane/EtOAc) to give (22.1 g, 100%) of the title compound as a transparent oil. 1H NMR (DMSO-d6) 7.38 (d, J=8.4 Hz, 1H), 7.15 (d, J=3.2 Hz, 1H), 6.92 (d, J=2.0 Hz, 1H), 6.65 (dd, J=2.4, 8.4 Hz, 1H), 6.32 (d, J=3.2 Hz, 1H) 4.16 (t, J=6.4 Hz, 2H), 3.77 (s, 3H), 3.53 (t, J=6 Hz, 2H), 1.90 (apparent quintet, J=6.8 Hz, 2H), 0.87 (s, 9H), 0.01 (s, 6H). MS (electrospray, m/z) 320 (M++1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[CH:2]=1.FC1C=CC(CN2C3C=CC=CC=3N=C2NC2CCN(CC[N:35]=[C:36]=[S:37])CC2)=CC=1>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:36](=[S:37])[NH2:35])[CH:2]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Reactant: NCc1cccnc1
Solvent: C1CCOC1
Product: NC(=S)NCc1cccnc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1 part of 3-pyridinemethanamine, 3.9 parts of 1-(4-fluorophenylmethyl)-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine and 45 parts of tetrahydrofuran was stirred for 4 hours at room temperature. The reaction mixture was evaporated in vacuo. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (94:6 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 2,2'-oxybispropane, yielding 3.4 parts (65.7%) of N-[2-[4-[[1-(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-ethyl]-N'-(3-pyridinylmethyl)thiourea; mp. 147.2° C. (compound 102).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:46])([C:42]([F:45])([F:44])[F:43])[C:24]([F:41])([F:40])[C:25]([F:39])([F:38])[O:26][C:27]([F:37])([F:36])[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br>>[CH2:1]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][CH2:28][C:27]([O:26][C:25]([F:38])([F:39])[C:24]([F:40])([F:41])[C:23]([F:22])([F:46])[C:42]([F:43])([F:44])[F:45])([F:37])[F:36])=[CH:17][CH:16]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: FC(F)(COCCCCCBr)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyl-2-(4-hydroxyphenyl)pyrimidine (6.0 g, 21 mmol) and 5-(2-(nonafluorobutoxy)-2,2-difluoroethoxy)-1-bromopentane (12 g, 23 mmol; prepared by combining 1,5-dibromopentane with 2-(nonafluorobutoxy)-2,2-difluoroethanol). After refluxing overnight, the resulting crude product was isolated by filtration and further purified by recrystallization from ethanol, followed by Kugelrohr distillation (b.p. 190°-200° C. at 0.1 torr; yield of 6.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:22]=[C:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]5[CH:21]=[CH:20][CH:19]=[C:16]([C:17](=[O:18])[N:8]3[C:6]=2[CH:7]=1)[C:15]=45.O1CCCC1.[CH3:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]=[C:47]=[O:48].[N-]=C=O>CCOCC>[CH2:45]([NH:46][C:47](=[O:48])[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:22]=[C:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]5[CH:21]=[CH:20][CH:19]=[C:16]([C:17](=[O:18])[N:8]3[C:6]=2[CH:7]=1)[C:15]=45)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH3:28]
Reactant: Nc1ccc2nc3c4cccc5cccc(c(=O)n3c2c1)c54
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Agent: [N-]=C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCNC(=O)Nc1ccc2nc3c4cccc5cccc(c(=O)n3c2c1)c54

Procedure:
A 5.7 g portion of the 10-amino-benzimidazo[2,1-a]benz[de]isoquinoline-7-one was added to 200 ml of distilled tetrahydrofuran in a 500 ml flask. To this mixture was added 5.9 g of Mondur O (octadecyl isocyanate) and 0.3 g of 1,4-diazobicyclo-octane. The mixture was stirred with a magnetic stirring bar and brought to reflux. The mixture was refluxed until no isocyanate peak was visible at 2240 cm-1 on infrared spectraphotometric analysis (~48-72 hours). It was then cooled and the solvent removed on the rotary evaporator. The solid thus obtained was ground to a fine powder, stirred in ether, filtered and dried in the vaccuum oven. The yield was 10.7 g of 10 octadecylureido benzimidazo [2,1-a]benz[de]isoquinoline-7-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:15]=1.C(O)C.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(Cl)cc2cc[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a mixture of 5-chloro-1H-indole-7-carboxylic acid (500 mg), triphenylphosphine (1.01 g), ethanol (235 mg) and toluene (20 mL) was added dropwise diethyl azodicarboxylate (2.2 M toluene solution, 1.74 mL) at room temperature. After stirring for 2 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain ethyl 5-chloro-1H-indole-7-carboxylate (550 mg) as a white solid.
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]2[C:14](=[O:18])[NH:15][CH2:16][CH2:17][N:6]12)=O.[BH4-].[Li+].O.[H-]>O1CCCC1>[OH:2][CH2:3][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]2[C:14](=[O:18])[NH:15][CH2:16][CH2:17][N:6]12
Reactant: COC(=O)C1c2ccccc2C2C(=O)NCCN21
Agent: [BH4-]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1NCCN2C(CO)c3ccccc3C12
Yield: 55.3 %

Procedure:
A mixture of 1,2,3,4,6,10b-hexahydro-1-oxo-pyrazino[2,1-a]isoindole-6-carboxylic acid methyl ester (0.5 g, described in Example 24) and lithium borohydride (0.044 g) in tetrahydrofuran (25 ml) is refluxed for 18 hr. Water is carefully added to decompose the excess hydride and the tetrahydrofuran is evaporated. Water is added and the solution is continuously extracted with ethyl acetate for 18 hr. The extract is dried and evaporated to give 1,2,3,4,6,10b-hexahydro-6-hydroxymethylpyrazino[2,1-a]isoindol-1-one (0.245 g), nmr (CDCl3) δ2.8(s), 3.2(m), 3.75(m), 4.3(m), 4.9(m), 6.95(s) and 7.2(m).
Reaction SMILES: [CH3:1][NH2:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:10][C:11]1[N:15]([CH3:16])[N:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1>CC(C)=O>[CH3:1][NH:2][CH2:10][C:11]1[N:15]([CH3:16])[N:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1
Reactant: CN
Reactant: Cn1nc([N+](=O)[O-])cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CNCc1cc([N+](=O)[O-])nn1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a stirred solution of MeNH2 (30% wt in H2O) (2.5 g, 20 mmol) in acetone (10 mL) at 0° C. (ice bath) was added K2CO3 (415 mg, 3 mmol), followed by the dropwise addition of a solution of 5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole (220 mg, 1 mmol) in acetone (5 mL). The reaction mixture was then warmed to room temperature and stirred for 3 h. The solvent was removed and the residue was extracted with methylene chloride (15 mL×3), dried over Na2SO4 and concentrated to afford 320a as a yellow oil (170 mg, 99%), which was used in the next step without additional purification. LCMS: (M+H)+ 171