Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:35]([OH:36])=[C:34]([C:37]([NH:39][CH3:40])=[O:38])[CH:33]=[CH:32][C:6]=2[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:28]=[CH:27][C:15]3[CH2:16][CH2:17][CH:18]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:19][C:14]=3[C:13]=2[CH2:29][CH2:30][CH3:31])[CH2:3][CH2:2]1.[CH2:41]1COCC1.[OH-].[K+].S(OC)(OC)(=O)=O>C(OCC)(=O)C.CCCCCC.O>[CH:1]1([CH2:4][C:5]2[C:35]([O:36][CH3:41])=[C:34]([C:37]([NH:39][CH3:40])=[O:38])[CH:33]=[CH:32][C:6]=2[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:28]=[CH:27][C:15]3[CH2:16][CH2:17][CH:18]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:19][C:14]=3[C:13]=2[CH2:29][CH2:30][CH3:31])[CH2:3][CH2:2]1
Reactant: CCCc1c(OCCCOc2ccc(C(=O)NC)c(O)c2CC2CC2)ccc2c1OC(CCC(=O)OCC)CC2
Reactant: C1CCOC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: CCCCCC
Product: CCCc1c(OCCCOc2ccc(C(=O)NC)c(OC)c2CC2CC2)ccc2c1OC(CCC(=O)OCC)CC2
Reaction time: 0.17 h

Procedure:
The compound of Example 60 (170 mg, 0.31 mmol) was added to about 5.0 ml of THF. Potassium hydroxide (21.2 mg, 0.38 mmol) was added and the mixture was stirred for 10 min. Dimethyl sulfate (59.6 mg, 0.47 mmol) was added, and the reaction mixture was stirred for 4 hours at room temperature. Water (10 ml) was added to the reaction mixture, and it was extracted three times with ethyl acetate. The combined extracts were filtered, and the solvent was removed under vacuum to give an oil. Chromatography of the oil on silica gel with 40/60 ethyl acetate/hexane gave the product as a colorless oil (160 mg).
Reaction SMILES: S1C(CC2C(=O)OC(C)(C)OC2=O)=CC2C=CC=CC1=2.S1C(CC(C(O)=O)C(O)=O)=CC2C=CC=CC1=2.[F:38][C:39]1[CH:55]=[CH:54][C:42]([CH2:43][CH:44]2[C:49](=[O:50])[O:48]C(C)(C)[O:46][C:45]2=[O:53])=[CH:41][CH:40]=1>>[F:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:43][CH:44]([C:45]([OH:53])=[O:46])[C:49]([OH:50])=[O:48])=[CH:54][CH:55]=1
Reactant: CC1(C)OC(=O)C(Cc2ccc(F)cc2)C(=O)O1
Agent: CC1(C)OC(=O)C(Cc2cc3ccccc3s2)C(=O)O1
Agent: O=C(O)C(Cc1cc2ccccc2s1)C(=O)O
Product: O=C(O)C(Cc1ccc(F)cc1)C(=O)O

Procedure:
The title compound was prepared by substituting 5-(benzo[b]thiophen-2-ylmethyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 39: step a) with 5-(4-fluorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 42: step a) then following the procedure described for the preparation of 2-(benzo[b]thiophen-2-ylmethyl)malonic acid (Intermediate 39: step b).
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.C=[PH3].[CH:14]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)=[CH:15][CH2:16][CH2:17][CH2:18][CH3:19]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[CH:14]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[CH2:1])=[CH:23][CH:22]=1)=[CH:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCC=COc1ccc(C=O)cc1
Reactant: [Li]CCCC
Agent: C=[PH3]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: CCOCC
Product: C=Cc1ccc(OC=CCCCC)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 200 ml three-necked flask in a nitrogen atmosphere, anhydrous diethyl ether (150 ml), methyltriphenylphosphonium bromide (7.5 g, 21 mmol) and a 1.6N solution of n-butyllithium in hexane (13.1 ml, 21 mmol of n-butyllithium) were charged and stirred at room temperature for 5 hours to prepare methylenephosphorane. To the reaction mixture, a solution of 4-(1-hexenyloxy)benzaldehyde (4.08 g, 20 mmol) in anhydrous diethyl ether (20 ml) was dropwise added over 3 minutes. After heating the reaction mixture under reflux for one hour and removing solids by filtration, hexane (150 ml) was added to a filtrate, and an organic phase was washed with water (150 ml×3), followed by evaporating volatile components off to obtain 4-(1-hexenyloxy)styrene (3.0 g) of the formula: ##STR5##
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:10]([C:20](OC)=[O:21])[CH2:9]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C@H:10]([CH2:20][OH:21])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@H](c2ccc(N)nc2)CN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1C[C@@H](c2ccc(N)nc2)C[C@H]1CO
Reaction time: 0.25 h
Yield: 100.8 %

Procedure:
To a solution of (2S,4R)-1-tert-butyl 2-methyl 4-(6-aminopyridin-3-yl)pyrrolidine-1,2-dicarboxylate (250 mg, 0.778 mmol) in 2-methyl THF (18 mL) was added LiAlH4 (59 mg, 1.56 mmol). After 15 min, the reaction was quenched by the sequential addition of water (60 μL), 1 N NaOH aqueous solution (60 μL) and water (60 μL). The mixture was stirred vigorously for 5 min, and then filtered over Celite, rinsing with 2-methyl THF. The organics were concentrated to provide (2S,4R)-tert-butyl 4-(6-aminopyridin-3-yl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (230 mg, 100% yield). LCMS (m/z): 294.1 (MH+), 0.49 min.
Reaction SMILES: [F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[CH2:4][N:5]([CH2:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]=1[CH3:17].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:64]([O:66][C:67](=[O:71])[CH2:68][CH2:69][NH2:70])[CH3:65].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[CH2:4][N:5]([CH2:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH:70][CH2:69][CH2:68][C:67]([O:66][CH2:64][CH3:65])=[O:71])=[O:29])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:14])=[O:15])[C:7]=1[CH3:17]
Reactant: CCOC(=O)CCN
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1)Cc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc(NS(C)(=O)=O)c3C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 68C (0.050 g, 0.096 mmoles), 1-hydroxybenzotriazole hydrate (0.015 g, 0.109 mmoles), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.021 g, 0.109 mmoles) in DMF (1.5 mL) were treated with β-alanine ethyl ester hydrochloride (0.121 g, 0.136 mmoles) and triethylamine (0.025 mL, 0.181 mmoles). The reaction mixture was shaken at room temperature overnight. The mixture was diluted with ethyl acetate, washed with H2O, saturated aqueous NaHCO3 (2×), 1N H3PO4 (2×), and brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by preparative HPLC (CH3CN:0.1% trifluoroacetic acid in H2O) on a YMC ODS Guardpak column to provide the title compound. 1H NMR (300 MHz, CDCl3) δ7.73 (d, 2 H), 7.25 (m, 2 H), 7.15 (m, 2 H), 6.95 (m, 6 H), 6.75 (m, 2 H), 6.15 (s, 1 H), 4.18 (q, 2 H), 4.13 (s, 2 H), 4.11 (s, 2 H), 3.73 (dd, 2 H), 2.96 (s, 3 H), 2.65 (t, 2 H), 2.30 (s, 3 H), 1.28 (t, 3 H); MS (ESI+) m/z 652 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)[CH:18]=[CH:19][N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[C:25]1([NH:31]N)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: NNc1ccccc1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Solvent: CO
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1ccccc1
Yield: 14.2 %

Procedure:
To a solution of 1-[3-(difluoromethoxy)phenyl]-3-[3-(dimethylamino)prop-2-enoyl]pyridazin-4(1H)-one (crude, 993 mg, 2.96 mmol) in 20 mL of methanol was added phenylhydrazine (480 mg, 4.44 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-[3-(difluoromethoxy)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (160 mg, 14% for two steps) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]([CH:21]=O)=[CH:17][CH:18]=[CH:19][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)cc1

Procedure:
128.8 mg of the target compound (0.36 mmol, 65.3%) was obtained using 1-(4-methoxyphenyl)piperazine (212 mg, 1.10 mmol), biphenyl-2-carbaldehyde (100 mg, 0.55 mmol) and NaBH(OAc)3 (355 mg, 1.65 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24].C(N(CC)CC)C.O>C(#N)C>[CH3:19][C:20]1[CH:21]=[C:22]([C:23]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[CH2:10][C@H:9]3[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:4][CH:3]=2)=[O:24])[CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cccc(C(=O)Nc2ccc([C@@H]3C[C@H]3NC(=O)OC(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (100 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (4 mL) were added 3-methylbenzoyl chloride (62.3 mg) and triethylamine (56 μL). The mixture was stirred at room temperature for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (141 mg).
Reaction SMILES: [CH:1]([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])=[CH2:2].[C:9](OC=C)(=[O:11])[CH3:10].Cl>[OH-].[Na+]>[CH:1]([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])=[CH2:2].[CH:9]([OH:11])=[CH2:10]
Reactant: C=COC(C)=O
Agent: C=CN1CCCC1=O
Agent: Cl
Agent: [Na+]
Product: C=CO
Temperature: 60 °C
Reaction time: 2 h

Procedure:
10 g of vinylpyrrolidone/vinyl acetate polymer (Trademark: PVP/VA E-635, GAF Corporation U.S.A.) were introduced into 200 ml of 0.2N NaOH. The mixture was stirred for 2 hours at 60° C., adjusted to neutral with 1N HCl and subjected to ultrafiltration using a thin layer filter (Trademark: UM 10, AMICON, Holland) at 3 atoms. Evaporation under reduced pressure and lyophilization to a temperature of -70° C. to -80° C. gave 8.9 g of vinylpyrrolidone/vinyl alcohol polymer as white powder.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([CH:17]3[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([OH:31])=O)[CH:23]=4)[NH:18]3)[CH:14]=[N:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][S:33]([NH2:36])(=[O:35])=[O:34]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[C:13]([CH:17]3[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([NH:36][S:33]([CH3:32])(=[O:35])=[O:34])=[O:31])[CH:23]=4)[NH:18]3)[CH:14]=[N:15][CH:16]=2)=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)c1ccc(-c2cncc(C3CC(C)(C)c4cc(C(=O)O)ccc4N3)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2cncc(C3CC(C)(C)c4cc(C(=O)NS(C)(=O)=O)ccc4N3)c2)cc1
Yield: 19.9 %

Procedure:
A mixture of 2-[5-(4-tert-butyl-phenyl)-pyridin-3-yl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (200 mg, 0.48 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (130 mg, 0.72 mmol), 4-dimethylaminopyridine (88 mg, 0.72 mmol), methane sulfonamide (140 mg, 1.44 mmol) in dichloromethane (20 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-{2-[5-(4-tert-Butyl-phenyl)-pyridin-3-yl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-methanesulfonamide (47 mg, 20%) as a light yellow solid: MS (ESI) M+1=492.3.
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:16][C:11]=2[N:10]=[CH:9]1)(OC(C)(C)C)=O.C([O-])([O-])=O.[K+].[K+].[C:33]1([CH2:39][CH2:40][CH2:41]Br)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.O>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:17]([CH2:41][CH2:40][CH2:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:15]2[CH:14]=[CH:13][C:12]3[N:8]=[CH:9][NH:10][C:11]=3[CH:16]=2)=[CH:24][CH:23]=1
Reactant: BrCCCc1ccccc1
Reactant: COc1ccc(CNc2ccc3c(c2)ncn3C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(CCCc2ccccc2)c2ccc3nc[nH]c3c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N1-Boc-N-(4-Methoxybenzyl)benzimidazol-5-amine (353 mg; 1 mmol; 1 eq.) was dissolved in DMF (5 ml), treated with K2CO3 (166 mg; 1.2 mmol; 1.2 eq.) and phenylpropylbromide (0.183 ml; 1.2 mmol; 1.2 eq.) and stirred at room temperature for 24 h. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The remains were taken up with THF (5 ml), treated with 5 N NaOCH3 and stirred for 2 h at room temperature. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography on silica using a CHCl3/MeOH gradient. Yield: 0.015 g (4.0%); MS m/z: 372.1 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 1.84-1.90 (m, 2H); 2.62 (t, 2H, 3J=7.6 Hz); 3.39 (t, 2H, 3J=7.6 Hz); 3.39 (s, 3H); 4.45 (s, 2H); 6.71 (br s, 1H); 6.73 (dd, 1H, 4J=2.1 Hz, 3J=8.9 Hz); 6.83-6.85 (m, 2H); 7.12-7.14 (m, 2H); 7.16-7.19 (m, 3H); 7.24-7.27 (m, 2H); 7.36 (d, 1H, 3J=8.9 Hz); 8.08 (s, 1H); HPLC (METHOD [A]): rt 16.97 min (93.2%)
Reaction SMILES: [CH2:1]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[H-].[Na+].Cl[CH2:33][CH:34]([OH:37])[CH2:35][OH:36]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:33][CH:34]([OH:37])[CH2:35][OH:36])=[O:26])=[CH:28][CH:29]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: OCC(O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A solution of 8.05 g. of 4-(n-nonadecylamino)benzoic acid in 25 ml. of hexamethylphosphoramide is treated with sodium hydride and then 1-chloro-2,3-propanediol in the manner described in Example 2 to yield 2,3-dihydroxypropyl 4-(n-nonadecylamino)benzoate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:24].[CH2:25]([C@H:30]1[CH2:35][CH2:34][C@H:33]([C:36](Cl)=[O:37])[CH2:32][CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29].O1CCOCC1.N1C=CC=CC=1>O>[CH2:25]([C@H:30]1[CH2:31][CH2:32][C@H:33]([C:36]([NH:1][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:10][CH:9]=3)[CH:5]=[CH:4][C:3]=2[OH:24])=[O:37])[CH2:34][CH2:35]1)[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCc1ccc(-c2ccc(O)c(N)c2)cc1
Reactant: CCCCC[C@H]1CC[C@H](C(=O)Cl)CC1
Solvent: c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCCCc1ccc(-c2ccc(O)c(NC(=O)[C@H]3CC[C@H](CCCCC)CC3)c2)cc1

Procedure:
Step i) In a 50 ml-three-necked flask, 0.70 g (2.15 mM) of 2-amino-4-(4-decylphenyl)phenol, 0.48 g (2.21 mM) of trans-4-pentylcyclohexylcarbonyl chloride and 20 ml of dioxane were placed. To the mixture, 0.77 ml of pyridine was gradually added dropwise at about 87° C. under stirring, followed by heat-stirring for 1.5 hours at about 87° C. After the reaction, the reaction mixture was poured into 150 ml of water to precipitate a crystal. The crystal was recovered by filtration, washed with methanol and recrystallized from toluene to obtain 0.61 g of 2-(trans-4-pentylcyclohexylcarbonylamino)-4-(4-decylphenyl)phenol (yield: 56.1%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:22][CH3:23])[CH:8]=2)[N:3]=1.Cl.[CH3:25][NH2:26].C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[CH3:23][O:22][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:26][CH3:25])[N:11]=[C:10]2[N:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH3:13]
Reactant: CN
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccc(OC)cc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CNc1nc(N(C)c2ccc(OC)cc2)c2cc(OC)ccc2n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
A mixture of (2-chloro-6-methoxy-quinazoline-4-yl)-(4-methoxy-phenyl)-methyl-amine (0.15 g, 0.45 mmol), methylamine hydrochloride (0.3 g, 4.5 mmol), potassium carbonate (0.68 g, 4.4 mmol) in 4 mL of iPrOH in a sealed tube stirred at 90° C. overnight. The reaction mixture was concentrated under reduced pressure, the residue dissolved in chloroform 20 mL, washed with conc. Sodium bicarbonate, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (CHCL3/MeOH/NH4OH=10/1/0.1 as eluent) yielding 45 mg (32%) of the title compound. 1H NMR (DMSO): δ 7.2 (d, 1H), 7.18-7.15 (m, 2H), 7.05-7.02 (d, 1H), 6.99-6.97 (d, 2H), 6.5 (br s, 1H), 6.2 (s, 1H), 3.7 (s, 3H), 3.4 (s, 3H), 3.2 (s, 3H), 2.8 (s, 3H). LC/MS: 325, (M+1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[CH2:7][CH2:8][C:9]32[C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[OH:18][CH:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]2)[CH2:8][CH2:7]1
Reactant: O=C1NC(=O)C2(CCC(=O)c3ccc(F)cc32)N1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1NC(=O)C2(CCC(O)c3ccc(F)cc32)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of 15.5 g. (0.0625 mole) of 3',4'-dihydro-7'-fluorospiro [imidazolidine-4,1'(2'H)-naphthalene]2,4',5-trione in 300 ml. of methanol cooled to 0° C. was added 4.8 g. (0.012 mole) of sodium borohydride over a period of 20 minutes. After stirring for one hour at 0° C. 100 ml. of 10% hydrochloric acid was added and the methanol removed under vacuum. The solid suspension was filtered and the solids dried, 7.3 g. (47% yield).
Reaction SMILES: C([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[N:9]1)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:10]1[C:11]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[CH:12][C:13](=[O:14])[NH:8][N:9]=1
Reactant: O=c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n[nH]1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 84.3 %

Procedure:
To a solution of 2-benzyl-6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3(2H)-one (6.4 g, 15.7 mmol) in toluene (100 mL) at 90° C. was added aluminum chloride (5.23 g, 39.3 mmol) in one portion. After addition, the reaction mixture was stirred at 90° C. for 20 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to reduce the volume to about 50 mL, then water (150 mL) was added. The resulting mixture was sonicated for 5 min, then stirred at room temperature for 10 min. The resulting suspension was filtered, the collected solid was washed with water (20 mL×3), hexanes (20 mL×3) and dried in a 50° C. vacuum oven for 16 h to afford 4.2 g (76%) of the title compound as a white solid. HPLC/MS (method A): retention time=3.27 min, (M+H)+=317.0. 1H NMR (CDCl3, 400 MHz): δ 11.6 (S, 1H), 7.17-7.40 (m, 6H), 6.90-7.10 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[C:6]=1[F:24])[CH3:2].I[C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH2:33][CH3:34])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][CH2:33][CH3:34])[CH:31]=3)[C:13]=2[CH3:23])[C:6]=1[F:24])[CH3:2]
Reactant: CCCn1cc(I)cn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1F
Product: CCCn1cc(-n2c(C)c(Sc3cccc(C(=O)OCC)c3F)c3ccc(Cl)c(F)c32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-2-fluoro-benzoic acid ethyl ester and 4-iodo-1-propyl-1H-pyrazole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([CH2:12]OS(C)(=O)=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.[C-:18]#[N:19].[Na+]>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([CH2:12][C:18]#[N:19])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CS(=O)(=O)OCC1(c2ccccn2)CCCC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCC1(c2ccccn2)CCCC1
Temperature: 140 °C
Yield: 82.1 %

Procedure:
To a stirred solution of methanesulfonic acid 1-pyridin-2-yl-cyclopentylmethyl ester (433) (2 g, 7.843 mmol) in dimethyl sulfoxide (15 mL), KI (0.13 g, 0.784 mmol), NaCN (0.769 g, 15.686 mmol) were added and the reaction was subjected to heating at 140° C. for 5 h. The reaction mixture was quenched with ice cold water (50 mL) and extracted with ethyl acetate (2×70 mL). The combined extracts were washed with brine, dried and concentrated. The resulting crude product was purified by normal silica gel (100-200 mesh) column chromatography using 15% ethyl acetate in hexane as eluent to get (1-pyridin-2-yl-cyclopentyl)-acetonitrile (434) (1.2 g, 82%) as a colorless liquid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9])=O.[N+](=[C:24](P(=O)(OC)OC)C(=O)C)=[N-].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9])#[CH:24]
Reactant: N#Cc1cc(C=O)ccc1Oc1cccc(C(F)(F)F)c1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(Oc2cccc(C(F)(F)F)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-formyl-2-{[3-(trifluoromethyl)phenyl]oxy}benzonitrile (1 g, 3.43 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.326 g, 6.87 mmol) in methanol (45 mL), was added potassium carbonate (2.373 g, 17.17 mmol) under argon. The reaction mixture was stirred for 1 h at rt, concentrated. The residue was dissolved in EtOAc (150 mL), washed with sat. ammonium hydrochloride solution (30 mL×3), water 30 mL, concentrated. Purification via ISCO system (EA/PE=1:20) afforded the title compound as a pale yellow oil. LC-MS (ESI): m/z 288 [M+H]+; 3.71 min (ret time).