Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:26][C:24]1[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=2)[N:21]=[C:20]([N:18]2[CH:19]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[N:16]=[CH:17]2)[N:25]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.8 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.19 g) in dichloromethane (4 mL) was added TFA (4 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (3 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as an off-white solid (0.13 g, 28%). MS (ISP) 460.2 [(M+H)+]; mp 186° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20].O=CC1C=CC(O)=C(OC)C=1>C(OCC)(=O)C.CCCCCC>[CH:19]([NH:22][C:16](=[O:18])[C@@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:21])[CH3:20]
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)N
Agent: COc1cc(C=O)ccc1O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)NC(=O)[C@H](NC(=O)OCc1ccccc1)C(C)C

Procedure:
Reaction of N-benzyloxycarbonyl-D-valine with isopropylamine by the method of Example 20, Part A afforded a quantitative yield of N-benzyloxycarbonyl-D-valine isopropylamide of Rf 0.61 (TLC, ethyl acetate/hexane, 1:1, vanillin spray).
Reaction SMILES: [ClH:1].Cl.C1(C=[N:10][N:11]2[CH2:15][C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[C:12]2=[O:28])C=CC=CC=1.Cl.[H][H]>[Pd].O>[ClH:1].[NH2:10][N:11]1[CH2:15][C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)[C:12]1=[O:28]
Reactant: CN1CCN(CCCCN2C(=O)CN(N=Cc3ccccc3)C2=O)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Product: CN1CCN(CCCCN2C(=O)CN(N)C2=O)CC1
Reaction time: 2 h

Procedure:
A mixture of 1-phenylmethyleneamino-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4-imidazolidinedione dihydrochloride (8.04 g, 0.0187 mole), 2N HCl (125 ml) and 5% Pd/C:50% H2O (1.5 g, is subjected to hydrogen on a Parr apparatus at 40 psi at ambient temperature. After 2 hours, the catalyst is removed by filtration. The filtrate is divided into two equal portions. Each is concentrated under reduced pressure on a rotary evaporator to an oily residue of 1-amino-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4-imidazolidinedione hydrochloride.
Reaction SMILES: CN1CCN(C)C1=O.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]([NH:19][CH2:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=2)=[O:18])[CH:10]=1.[C:30]1([NH2:37])[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH2:36].CS(O)(=O)=O>O>[NH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[NH:37][C:25](=[O:27])[C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][C:17]([O:16][CH2:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)=[O:18])=[CH:29][CH:28]=1
Reactant: Nc1ccccc1N
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCc1cccnc1
Agent: CS(=O)(=O)O
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: Nc1ccccc1NC(=O)c1ccc(CNC(=O)OCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
7.78 g (48 mmole) of N,N′-carbonyldiimidazole were added to a 1,3-dimethyl-2-imidazolidinone (50 g) suspension including 11.45 g (40 mmole) of 4-[N-(pyridin-3-ylmethoxycarbonyl)aminomethyl]benzoic acid. After stirring at room temperature for 2 hours, 17.30 g (0.16 mole) of 1,2-phenylenediamine were added to the solution. After cooling to 2° C., 9.60 g (0.1 mole) of methanesulfonic acid were added dropwise. After stirring for 2 hours, water was added, and the deposited solid was collected by filtration. Purification was then carried out through silica gel column chromatography to obtain 10.83 g (yield: 72%) of N-(2-aminophenyl)-4-[N-(pyridin-3-ylmethoxycarbonyl)aminomethyl]benzamide.
Reaction SMILES: CS(C)=O.[CH2:5]1[O:13][C:12]2[C:7](=[C:8]([CH2:14][C:15]#[N:16])[CH:9]=[CH:10][CH:11]=2)[O:6]1.[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH3:21].[OH-].[Na+]>O>[CH2:5]1[O:13][C:12]2[C:7](=[C:8]([CH:14]([C:15]#[N:16])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:9]=[CH:10][CH:11]=2)[O:6]1
Reactant: N#CCc1cccc2c1OCO2
Reactant: CCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCC(C#N)c1cccc2c1OCO2
Temperature: 25 °C
Yield: 81.1 %

Procedure:
Into 5 ml of dimethylsulfoxide, was added 0.26 g (1.6 mmol) of 2,3-methylenedioxyphenylacetonitrile, then, 0.24 g (1.6 mmol) of n-pentyl bromide and a 50% aqueous solution of sodium hydroxide were added dropwise thereinto simultaneously under cooling with ice. After 30-minute stirring at room temperature, the mixutre was added with water and extracted with ether. The ether extract was dried over magnesium chloride and then the solvent was evaporated off to obtain 0.30 g of oily 1-(2,3-methylenedioxyphenyl)hexane carbonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[Sn](C)(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([O:28][CH2:29][CH2:30][CH2:31][OH:32])[CH:22]=[CH:21]2>CN(C=O)C.Cl[Pd-2](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>[OH:32][CH2:31][CH2:30][CH2:29][O:28][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[C:19]([C:9]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:12]=[CH:11][CH:10]=1)=[CH:18][CH:27]=[CH:26]2
Reactant: OCCCOc1ccc2cc(Br)ccc2c1
Reactant: CC(C)(C)OC(=O)n1cccc1[Sn](C)(C)C
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cccc1-c1cccc2cc(OCCCO)ccc12
Temperature: 70 °C
Yield: 60 %

Procedure:
To N-tert-butoxycarbonyl-2-trimethylstannylpyrrole (3.0 g) and 6-bromo-2-(3-hydroxypropyloxy)naphthalene (2.55 g) in 20 ml of DMF was added dichloro bis(triphenylphosphino)palladium(II) (64 mg) under an argon atmosphere. The mixture was heated at 70° C. for 16 h. After cooling the mixture was washed with diethyl ether and water. The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude product was purified by column chromatography (silica, hexane/dichloromethane, 2/98, v/v) to give a pure oil in 60% yield [2-(6-(3-hydroxypropyloxy)-naphthyl)-N-tert-butoxycarbonylpyrrole]. To this oil (0.5 g) in 10 ml of DMF was added dropwise phophorusoxychloride (0.42 g) at 0° C. under an argon atmosphere. The mixture was heated at 60° C. for 2 h. After cooling the mixture was neutralized with aqueous sodium hydroxide (1 M) and heated at 80° C. for 1 h. After cooling the precipitate was filtered off and purified by column chromatography (silica, methanol/dichloromethane, 1/99,v/v) to give a 75% yield of 5-formyl-2-(6-(3-chloropropyloxy)-naphthyl)-N—H-pyrrole.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=3)[CH:9]=2)[C:4](=[O:20])[CH2:3]1.C([O-])([O-])=[O:23].[K+].[K+].CS(C)=O>O>[CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]([NH2:17])=[O:23])=[CH:14][N:13]=3)[CH:9]=2)[C:4](=[O:20])[CH2:3]1
Reactant: CC1(C)CC(=O)c2ccc(Oc3ccc(C#N)cn3)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)CC(=O)c2ccc(Oc3ccc(C(N)=O)cn3)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 188.3 %

Procedure:
Add 30% aqueous H2O3 (3.15 ml) to a suspension of 6-(3,3-Dimethyl-1-oxo-indan-5-yloxy)nicotinonitrile (877 mg, 3.15 mmol), K2CO3 (218 mg, 1.57 mmol) and DMSO (10 ml) stirring under nitrogen at ambient temperature. After four hours, dilute the reaction mixture with water (100 ml) and extract with EtOAc (2×). Wash the extract with water and brine, dry (MgSO4) and concentrate on rotary evaporator to yield 876 mg of the title compound as an off-white solid. Mass spectrum (ion spray): m/z=297 (M+1); 1HNMR (CDCl3): 8.62 (s, 1H), 8.24 (d, 1H), 7.75 (d, 1H), 7.24 (s, 1H), 7.14 (d, 1H), 7.07 (d, 1H), 5.91 (broad, 2H), 2.63 (s, 2H), 1.43 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][C:16]([N:18]([C:20]4[CH:25]=[CH:24][N:23]=[C:22](Cl)[N:21]=4)[CH3:19])=[CH:17][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:35]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][C:16]([N:18]([CH3:19])[C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:29][C:30]5[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([S:36]([NH2:39])(=[O:37])=[O:38])[CH:35]=5)[N:21]=4)=[CH:17][C:10]=3[N:9]=2)=[CH:27][CH:28]=1
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Reactant: CN(c1ccc2c(c1)nc(NCc1ccc(Cl)cc1)n2C)c1ccnc(Cl)n1
Product: Cc1ccc(Nc2nccc(N(C)c3ccc4c(c3)nc(NCc3ccc(Cl)cc3)n4C)n2)cc1S(N)(=O)=O
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N2-(4-Chloro-benzyl)-N5-(2-chloro-pyrimidin-4-yl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (103 mg, 0.25 mmol) and 5-amino-2-methyl-benzenesulfonamide (47 mg, 0.25 mmol) as a white solid (106 mg, 71%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 10.17 (br s, 1H), 9.40 (br s, 1H), 8.45 (s, 1H), 7.85 (d, J=6.6 Hz, 1H), 7.62 (m, 2H), 7.49-7.52 (m, 2H), 7.42-7.45 (m, 2H), 7.37 (s, 1H), 7.23-7.31 (m, 4H), 5.75 (m, 1H), 4.72 (d, J=5.7 Hz, 2H), 3.70 (s, 3H), 3.49 (s, 3H), 2.52 (s, 3H). MS (ESI) m/z=561 [M−H]−.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1>C(N)C1C=CC=CC=1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:10][CH2:9][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:7]=3)=[CH:12][NH:11][N:10]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(-c2n[nH]cc2-c2ccnc(Cl)n2)cc1
Solvent: NCc1ccccc1
Product: Fc1ccc(-c2n[nH]cc2-c2ccnc(NCc3ccccc3)n2)cc1
Yield: 95 %

Procedure:
This compound was synthesize by refluxing 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine prepared in accordance with Example A-299 in benzylamine overnight. The product, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-(phenylmethyl)-2-pyrimidinamine, was obtained as a white solid in 95% yield; mp: 216–217° C. Anal. Calc'd for C20H16FN5: C, 69.55; H, 4.67; N, 20.28. Found: C, 69.73; H, 4.69; N, 19.90.
Reaction SMILES: Cl[CH2:2][CH2:3][OH:4].[CH3:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1.[OH-].[K+].C(CN)O.CC1C=CC(CCl)=CC=1>O.C1(C)C=CC=CC=1>[CH3:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:11][CH2:2][CH2:3][OH:4])=[CH:8][CH:7]=1
Reactant: OCCCl
Reactant: Cc1ccc(CN)cc1
Agent: Cc1ccc(CCl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: NCCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(CNCCO)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 35 %

Procedure:
The procedure of Example 7 was repeated using 2-chloroethanol (20.9 g, 0.26 mol, Kodak), 4-methylbenzylamine (32.7 g, 0.27 mol, Aldrich), water (25 mL) and KOH (14.6 g, 0.26 mol). A white solid was crystallized from the concentrated solution. The crystallized product was collected by suction filtration and recrystallized from hexanes. The filtrate was concentrated under reduced pressure and the residue was fractionally distilled using a 7.5 inch vigreux column. The fraction boiling at 140-144° C./9 mm pressure was collected. Total yield 15 g (35% yield). 1H NMR (δ, 360 MHz, CDCl3): 2.32 (s, 3H), 2.51 (broad s, 2H), 2.74 (t, 2H), 3.61 (t, 2H), 3.72 (s, 2H) and 7.142 (m, 4H). 13C NMR (δ, 90 MHz, {1H}, CDCl3): 21.0 (--CH3), 50.5 (--NCH2CH2O--) 53.2 (--NCH2CH2O--), 60.7 (--NCH2Ph), 128.1, 129.1 and 143.0 (--CH2Ph). mp 61-62° C. uncorrected. The title compound was also prepared using the following procedure. In a 2L three-neck flask (equipped with a mechanical stirrer and an addition funnel) ethanolamine (91.6 g, 1.5 mol, Aldrich) and 100 mL of toluene were placed. To this solution was added dropwise 4-methylbenzyl chloride (70.3 g, 0.5 mol, Aldrich). The mixture was stirred for 10 hours at room temperature. Crushed KOH (30.0 g, 0.5 mol) was added and stirring was continued for another 3 hours. Water (300 mL) was added to dissolve all solid. The mixture was poured into a separatory funnel and the toluene layer was separated. The aqueous layer was extracted with 50 mL portions of methylene chloride three times. The combined extracts were dried on anhydrous sodium sulfate and rotovaped to remove the solvents. A white solid was crystallized from the concentrated solution. The crystallized product (34 g) was collected by suction filtration and washed with several mL of toluene. The filtrate was concentrated under reduced pressure and the residue was fractionally distilled using a 7.5 inch vigreux column. The fraction boiling at 140-144° C./9 mm pressure was collected. Total yield isolated 46.5 g (57% yield).
Reaction SMILES: [C:1](Cl)([C:3]([CH3:6])([CH3:5])[CH3:4])=[O:2].N1C=CC=CC=1.[CH2:14]([OH:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].O>C(Cl)(Cl)Cl>[C:1]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][OH:22])(=[O:2])[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: OCCCCCCCO
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)C(=O)OCCCCCCCO
Reaction time: 24 h
Yield: 68 %

Procedure:
Piv-Cl (0.12 ml, 1.0 mmol) and pyridine (0.03 ml, 0.4 mmol) were added to a solution of 1,7-Heptanediol (Compound 26-1, 0.28 ml, 2.0 mmol) in CHCl3 (2 ml) at 0° C., and the mixture was stirred for one day. H2O was added to the reaction solution, the organic layer was then separated, and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with a saturated aqueous NaCl solution, and was dried over Na2SO4. After evaporation of the solvent, the residue was purified by column chromatography on silica gel (Hexane:EtOAc=3:1) to yield 7-hydroxyheptyl pivalate (147 mg, 68%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].Br[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Br.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: BrCCOCCBr
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(N2CCOCC2)c1
Temperature: 120 °C
Yield: 100 %

Procedure:
To a solution of 3-nitroaniline (42)(5.52 g, 40.00 mmol) in anhydrous dimethylacetamide (15 ml) was added 2-bromoethylether (7.52 ml, 60.00 mmol) and N,N-diisopropylethylamine (13.94 ml, 80.0 mmol). The mixture was then heated to 120° C. for 6 hours. After this time the reaction was cooled to room temperature which saw the mixture take the form of a slurry. The slurry was dissolved in CH2Cl2 (80 ml) and washed with 0.2 M HCl (3×30 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo to give a brown semi-solid residue that was triturated with Et2O to give the desired product (8.33 g, 79.7%) in suitably clean form to be used without any further purification. m/z (LC-MS, ESP): 209 [M+H]+, R/T=3.46 mins
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH2:37](O)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH3:37])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Yield: 86.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-octadecanol (62 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (83 mg, yield 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[C:15]1([CH2:21][CH2:22][C:23](Cl)=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1(C)C=CC=CC=1.O1CCCC1>[C:15]1([CH2:21][CH2:22][CH2:23][N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:10]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1cccc([C@H]2CCCNC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cccc([C@H]2CCCN(CCCc3ccccc3)C2)c1

Procedure:
The title compound was prepared by acylation of 1.0 g (5.2 mmole) of the (R)(-)-3-(3-methoxyphenyl)piperidine from preparation 7, Part C, with 1.3 g (7.8 mmole) of 3-phenylpropionyl chloride in toluene, followed by reduction with 910 mg (24 mmole) of lithium aluminum hydride in tetrahydrofuran, using the procedure of Preparation 3. This afforded 1.9 g of an oil.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]#[N:23])[CH2:18][CH2:17]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][O-:25].[Na+]>CO>[CH3:24][O:25][C:22]([N:19]1[CH2:18][CH2:17][CH:16]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:21][CH2:20]1)=[NH:23]
Reactant: N#CN1CCC(c2nn(-c3ccccc3)c3ccccc23)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)N1CCC(c2nn(-c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
A mixture of 4-(1-phenyl-1H-indazol-3-yl)piperidine-1-carbonitrile of Example 73 (4.0 g, 0.013 moles) and sodium methoxide (3 ml of 25% sodium methoxide in methanol, 0.013 moles) in methanol (30 ml) was warmed to effect solution and then stirred at ambient temperature for 16 hours. The solvent was removed which left an oil (4.5 g). The oil was dissolved in ether, washed with H2O, and dried (MgSO4) Removal of the ether left an oil which began to crystallize upon standing. Crystallization was enhanced by triturating the oil with hexane which produced 3.5 g of product. The product was recrystallized twice from hexane yielding 2.31 g (52%) of 4-(1-phenyl-1H-indazol-3-yl)piperidine-1-carboximidic acid methyl ester, mp 80°-83° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([O:19][CH2:20][CH2:21][CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([O:19][CH2:20][CH2:21][CH:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)OCCC2CCNCC2)cc1
Reaction time: 0.5 h
Yield: 108.3 %

Procedure:
A solution of N1-(4-methoxybenzoyl)-N2-[2-[1-(tert-butoxycarbonyl)piperidin-4-yl]ethoxycarbonyl]-1,2-benzenediamine (312 mg, 0.627 mmol) in methylene chloride (3 mL) was treated with trifluoroacetic acid (0.48 mL). After 0.5 h, the mixture was concentrated in vacuo. The residue was treated with 1 N aqueous sodium hydroxide followed by ethyl acetate. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were dried and concentrated in vacuo. The residue was taken up in methanol and treated with hydrochloric acid (gas,1-2 eq) and concentrated in vacuo to yield the hydrochloride salt of the title compound (270 mg).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([Sn](CCCC)(CCCC)CCCC)[CH:4]=[N:3][CH:2]=1.Br[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][C@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[CH2:36][CH:37]1[CH2:39][CH2:38]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>>[CH:37]1([CH2:36][N:32]2[CH2:33][CH2:34][CH2:35][C@@H:31]2[CH2:30][C:24]2[C:23]3[C:27](=[CH:28][CH:29]=[C:21]([C:5]4[CH:4]=[N:3][CH:2]=[N:1][CH:6]=4)[CH:22]=3)[NH:26][CH:25]=2)[CH2:39][CH2:38]1
Reactant: Brc1ccc2[nH]cc(C[C@H]3CCCN3CC3CC3)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncnc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Product: c1ncc(-c2ccc3[nH]cc(C[C@H]4CCCN4CC4CC4)c3c2)cn1

Procedure:
(5-Pyrimidinyl)tri-n-butylstannane (see Preparation 45) and 5-bromo-3-(1-cyclopropylmethylpyrrolidin-2(R)-ylmethyl)-1H-indole (see Preparation 56) were reacted together in the presence of palladium (II) acetate Pd(OAc)2 !, tri-o-tolylphosphine (o-TI)3P! and triethylamine (C2H5)3N! using a procedure similar to that described in Example 1. This yielded the title compound. Found: C,73.72; H,7.53; N,15.84; C21H24N4.1/8CH2Cl2.1/8H2O requires: C,73.47; H,7.15; N,16.23%.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]=2[C:15]([OH:17])=O)[CH2:3][CH2:2]1.Cl.[CH3:19][NH:20][O:21][CH3:22].CN1CCOCC1.CN(C)CCCN=C=NCC.Cl>CN(C)C1C=CN=CC=1.ClCCl.CN(C=O)C>[CH3:22][O:21][N:20]([CH3:19])[C:15]([C:5]1[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:7][O:8][C:4]=1[CH:1]1[CH2:2][CH2:3]1)=[O:17]
Reactant: CNOC
Reactant: O=C(O)c1c(-c2ccccc2)noc1C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1c(-c2ccccc2)noc1C1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A mixture of 5-cyclopropyl-3-phenyl-isoxazole-4-carboxylic acid (3.72 g, 16 mmol), N,O-dimethylhydroxylamine hydrochloride (2.53 g, 26 mmol), N-methylmorpholine (2.85 mL, 26 mmol) and 4-dimethylaminopyridine (198 mg, 2 mmol) in dichloromethane (50 mL) and DMF (10 mL) was cooled to 0° C. Then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3.73 g, 19 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into hydrochloric acid (1 N) and extracted with ethyl acetate. The combined organic layers were then washed with a saturated solution of sodium hydrogen carbonate, brine and then dried over sodium sulphate and evaporated to leave a light yellow oil. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 50:50) afforded the title compound (4.03 g, 91%) which was obtained as a colourles oil. MS: m/e=273.0 [M+H]+.