Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:11][C:4]=2[CH:3]=1.O.[NH2:19][NH2:20]>>[NH:19]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:11][C:4]=2[CH:3]=1)[NH2:20]
Reactant: CC(C)(C)C(=O)N1CCc2nnc(Cl)cc2C1
Reactant: NN
Solvent: O
Product: CC(C)(C)C(=O)N1CCc2nnc(NN)cc2C1

Procedure:
11.4 g of 3-chloro-5,6,7,8-tetrahydro-6-pivaloylpyrido[4,3-c]pyridazine and 100 cc of hydrazine hydrate are boiled at reflux at a bath temperature of 110° for 11/2 hours while stirring. The crude title compound is taken up in 100 cc of chloroform, is dried with sodium sulphate, the chloroform solution is again concentrated, and recrystallized from 20 cc of absolute ethanol. The title compound has a M.P. of 158°-160° (decomp.).
Reaction SMILES: C(O)(=O)C.[N+:5](/[CH:8]=[CH:9]/[C:10]1[CH:23]=[CH:22][C:13]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([O-:7])=[O:6].[BH4-].[Na+]>CS(C)=O>[N+:5]([CH2:8][CH2:9][C:10]1[CH:23]=[CH:22][C:13]([CH2:14][NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])/C=C/c1ccc(CNc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(CNc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
To an acetic acid (1.5 mL) and dimethyl sulfoxide (26 mL) solution of (4((E)-2-nitro-vinyl)-benzyl)-phenyl-amine (1.53 g, 6.02 mmol) described in Manufacturing Example 73-1-4 was added sodium borohydride (364 mg, 9.63 mmol) at room temperature while cooling appropriately. This mixture was stirred for 1.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (1.5 g). This compound was used in the subsequent reaction without being purified.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]([CH:17]([CH3:19])[CH3:18])[N:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[C:14]([C:32]3[CH:33]=[CH:34][C:29]([CH3:28])=[CH:30][CH:31]=3)[N:15]([CH:17]([CH3:19])[CH3:18])[N:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(Cc1ccccc1)C2
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2c3c(nn2C(C)C)CN(Cc2ccccc2)CC3)cc1
Yield: 26.1 %

Procedure:
The title compound (67 mg) was prepared according to Example 287 using 300 mg of trifluoro-methanesulfonic acid 6-benzyl-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl ester and 141 mg of 4-methylphenylboronic acid. MS (ESI): exact mass calculated for C23H27N3, 345.22; found, m/z 346.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.60-7.58 (m, 2H), 7.54-7.53 (m, 3H), 7.37-7.35 (m, 2H), 7.28-7.24 (m, 2H), 4.58-4.49 (m, 3H), 4.42-4.33 (m, 2H), 3.81-3.78 (m, 1H), 3.45-3.41 (m, 1H), 2.90-2.82 (m, 2H), 2.41 (s, 3H), 1.42-1.29 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.C(O)(=O)C>O1CCOCC1>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH:14]2[NH:13][CH2:12][C:11]3[C:2](=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=[CH:9][CH:10]=3)[NH:1]2)[CH:16]=1
Reactant: COC(=O)c1cccc(CN)c1N
Reactant: O=Cc1cccnc1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c1NC(c1cccnc1)NC2
Reaction time: 0.33 h
Yield: 53.6 %

Procedure:
A mixture of methyl 2-amino-3-(aminomethyl)benzoate (5.0 g, 27.7 mmol), nicotinaldehyde (3.0 g, 27.7 mmol) and acetic acid (2.0 mL) in dioxane (50 mL) was stirred in the microwave for 20 minutes. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (10% methanol in CH2Cl2) to give methyl 2-(pyridin-3-yl)-1,2,3,4-tetrahydroquinazoline-8-carboxylate (4.0 g, 53% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)[CH:5]=[CH:6][CH:7]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:40])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(-c2cccc3[nH]ccc23)c1
Reactant: CC(=O)O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To the suspension of 4-(3-chloro-phenyl)-1H-indole (1.52 g, 6.68 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (81 mL) was added pyridinium tribromide (90% purity from Aldrich, 7.12 g, 20.0 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (30 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (1.55 g, 95%) as a tan solid
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.C(O)=O.C(N(CC)CC)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:8]([OH:13])[C:9]([CH3:11])([CH3:12])[CH3:10])=[CH:19][CH:20]=1
Reactant: CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CC(C)(C)C(O)C(Oc1ccc(Cl)cc1)n1cncn1
Yield: 61.5 %

Procedure:
28.45 g (0.1 mol) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one and 43.25 g (0.1 mol) of formic acid/triethylamine (5:2 addition compound) were heated to 145° to 150° C. for 4.5 to 5 hours. The reaction mixture was allowed to cool and was concentrated in vacuo. The residue was taken up in dilute sodium hydroxide solution and the mixture was extracted with methylene chloride. The organic phase was washed with water, dried over sodium sulphate and concentrated in vacuo. The residue was suspended in hot cyclohexane, the suspension was filtered hot and the solid was dried. 18.2 g (63.6% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol of melting point 114°-116° C. were obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]2)=[N:21][CH:22]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]>>[Cl:37][C:38]1[CH:43]=[C:42]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]3[NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]3)=[N:21][CH:22]=2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]
Reactant: CCC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 56.8 %

Procedure:
Following general procedure II, (R)-tert-butyl (1-(5-((6-chloro-3-propionyl-1,5-naphthyridin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)carbamate (175 mg, 0.34 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (140 mg, 0.51 mmol) to afford the desired product (120 mg, 57%) as a solid: ESI MS m/z 621 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:22])[CH2:17][CH2:16]2)[N:3]=1.[OH-:35].[Na+]>>[OH:35][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:22])[CH2:17][CH2:16]2)[N:3]=1
Reactant: [OH-]
Reactant: CN1CCN(c2nc(Cl)nc(N3CCC(C(=O)NCc4ccccc4C(F)(F)F)CC3)n2)CC1
Agent: [Na+]
Product: CN1CCN(c2nc(O)nc(N3CCC(C(=O)NCc4ccccc4C(F)(F)F)CC3)n2)CC1
Temperature: 80 °C

Procedure:
To ⅕ of the suspension prepared in step b (0.542 mmol, 1.00 equiv) was added 6 N NaOH. The resulting mixture was heated to 80° C. for 1 h. The final solution was directly purified by reverse-phase HPLC (Sunfire, 20-40% CH3CN, H2O, 0.1% TFA, 12 min) to afford 21.2 mg of the title compound. MS (ES+): m/e 480.1 [M+H]+.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1>C(OCC)(=O)C>[ClH:2].[ClH:1].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Temperature: 60 °C
Yield: 88.1 %

Procedure:
To a solution prepared by introducing 7.78 g (213.3 mmol) of hydrogen chloride gas in 45.9 g of ethyl acetate, 176.0 g of a solution containing the obtained (+)-1-[(4-chlorophenyl)phenylmethyl]-4-(tert-butoxycarbonyl)piperazine (optical purity 98.0% ee) was added dropwise at 20° C. over 1 hour. After stirring at that temperature, the mixture was heated up to 60° C. for 30 minutes and was stirred at this temperature for 3 hours. After cooling to 20° C., the crystals formed were collected by filtration and were washed with toluene. The crystals obtained were dried under reduced pressure to yield 8.51 g (23.7 mmol) of (+)-1-[(4-chlorophenyl)phenylmethyl]piperazine dihydrochloride from the (+)-1-[(4-chlorophenyl)phenylmethyl]-4-(tert-butoxycarbonyl)piperazine-2D-(−)-O,O′-dibenzoyltartaric acid salt in a yield of 88.1%. The optical purity of the (+)-1-[(4-chlorophenyl)phenylmethyl]piperazine in the crystals was 98.4% ee.
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1[CH:19]=[C:20]([O:24][CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:21]=[N:22][CH:23]=1)(C1C=CC(C)=CC=1)(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-:55]>C1COCC1>[F:55][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1[CH:19]=[C:20]([O:24][CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:21]=[N:22][CH:23]=1
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OCCCCC#Cc2cncc(OC[C@@H]3CCCN3C(=O)OC(C)(C)C)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(C#CCCCCF)c1
Yield: 97 %

Procedure:
A mixture of 5-(6-tosyloxy-1-hexynyl)-3-(1-tert-butoxycarbonyl -2(S)-pyrrolidinylmethoxy)pyridine (195 mg, 0.37 mmol) and in 2 mL of 1.0 M solution of TBAF in THF was stirred at room temperature for 15 h. The reaction mixture concentrated. The residue was purified by chromatography with hexane-EtOAc (3:1) to give a viscous oil (135 mg, 97%), [α]D=−58 (c 0.44, CHCl3). 1H NMR (CDCl3) δ 8.21 (m, 2H), 7.23 (br s, 1H), 4.52 (dt, 2H, J=47.3, 6.0 Hz), 4.14 (br s, 2H), 4.05-3.75 (m, 1H), 3.50-3.25 (m, 2H), 2.49 (t, 2H, J=6.9 Hz), 2.08-1.70 (m, 8H), 1.48 (s, 9H); 13C NMR (CDCl3) δ 154.37, 144.82 and 144.57, 137.38 and 137.08, 123.03, 121.03, 83.56 (d, J=165.2 Hz), 79.53, 68.65 and 68.41, 55.99 and 55.62, 46.97 and 46.60, 29.67 and 29.41, 28.51, 28.03, 24.32 (d, J=4.5 Hz), 23.87, 22.82, 19.04; 19F NMR (CDCl3, CFCl3) δ 131.0 (tt, J=47.3, 24.4 Hz).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][CH:25]=[CH:24]4)=[CH:9][N:10](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39].C([O-])([O-])=O.[Na+].[Na+]>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:26]1[C:27]2[C:23](=[CH:22][C:21]([C:8]3[C:6]4=[N:7][C:2]([C:34]5[CH:35]=[C:36]([O:40][CH3:41])[C:37]([O:38][CH3:39])=[C:32]([O:31][CH3:30])[CH:33]=5)=[CH:3][N:4]=[C:5]4[NH:10][CH:9]=3)=[CH:29][CH:28]=2)[CH:24]=[CH:25]1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3nc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc5[nH]ccc5c4)c3n2)cc(OC)c1OC
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-7-(1H-indol-5-yl)-5-tosyl-5H-pyrrolo[3,2-b]pyrazine [Intermediate AV] (65 mg, 0.14 mmol) in CH3CN (1 mL) in a Personal Chemistry microwave reaction vial was added 3,4,5-trimethoxyphenylboronic acid (30 mg, 0.14 mmol), bis(triphenylphosphine)-palladium(II) dichloride (7.0 mg, 0.010 mmol), and 1 M Na2CO3 (1 mL). The resulting mixture was de-gassed with Ar for 10 min, after which it was heated at 150° C. for 10 min in a Personal Chemistry Optimizer. The organic layer was separated, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (3 mL) and acetone (2 mL), and 2 M NaOH (1.5 mL) was added. The resulting mixture was stirred at 65° C. for 30 min, after which it was partitioned between EtOAc and 1 M NaOH. The organic layer was separated, dried over MgSO4, filtered, and stripped to give a residue which was purified by preparatory HPLC to give the title compound as a yellow solid. HPLC retention time: 2.25 minutes; MS ESI (m/z) 401.2 (M+1)+, calc. 400.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N+:9]([O-])=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:18]([O:21]C(=O)C)(=[O:20])[CH3:19]>>[C:18]([O:21][CH:11]1[C:10]2[C:15](=[C:2]([NH2:1])[C:3]3[C:8]([N:9]=2)=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:14](=[O:16])[CH2:13][CH2:12]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c2c([n+]([O-])c3ccccc13)CCCC2=O
Product: CC(=O)OC1CCC(=O)c2c1nc1ccccc1c2N
Reaction time: 1 h
Yield: 52 %

Procedure:
A solution of 9-amino-3,4-dihydroacridin-1(2H)-one N-oxide (5.4 g) and acetic anhydride (60 ml) was heated to reflux and then concentrated. The residue was stirred in saturated sodium bicarbonate solution for one hr. The mixture was filtered and the filter cake was washed with water and dried under vacuum at 40° C. for three hrs to yield 1.93 g of product, mp 208° C. (dec). An additional 1.38 g, mp 208° C. (dec), of product was obtained by extraction of the tiltrate with ethyl acetate, evaporation of ethyl acetate extract, and trituration of the residue with diethyl ether; total 52% yield.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:7][CH:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][Cl:10].S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[CH:1]1([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][CH:8]([CH3:7])[CH2:9][Cl:10])=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1=CCCCC1
Reactant: CC(CCl)Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CC(CCl)Cc1ccc(C2CCCCC2)cc1
Reaction time: 14 h
Yield: 70 %

Procedure:
33 parts by weight of cyclohexene are added dropwise to a mixture of 67 parts by weight of 2-methyl-3-phenylpropyl chloride and 40 parts by weight of 96% strength sulfuric acid at 10° C. Stirring is continued for 14 hours at room temperature. The crude product is dissolved in CHCl3 and the solution is thoroughly washed with ice water, dried over Na2CO3 and distilled. 70 parts by weight of 3-(4-cyclohexylphenyl)-2-methylpropyl chloride are obtained; boiling point 130°-2° C./0.1 mm Hg, yield 70% (based on 2-meythyl-3-phenylpropyl chloride).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]([CH3:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1)=O.[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:25][C:26]2[C:31]([CH3:33])([CH3:32])[CH2:30][CH2:29][CH2:28][C:27]=2[CH3:34])C=CC=CC=1>>[CH3:34][C:27]1[CH2:28][CH2:29][CH2:30][C:31]([CH3:33])([CH3:32])[C:26]=1/[CH:25]=[CH:1]/[C:3]1[CH:4]=[C:5]([CH:9]([CH3:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CC1=C(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)C(C)(C)CCC1
Reactant: CCOC(=O)CC(C)c1cccc(C=O)c1
Agent: [Br-]
Product: CCOC(=O)CC(C)c1cccc(/C=C/C2=C(C)CCCC2(C)C)c1

Procedure:
Coupling of ethyl 3-(3-formylphenyl)butanoate with Wittig reagent 24 following the method used in Example 1 gave (E)-ethyl 3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)butanoate as a colorless oil. Yield (0.383 g, 81%): 1H NMR (500 MHz, CDCl3) δ 7.25 (m, 3H), 7.07 (m, 1H), 6.66 (dd, J=16.3, 0.68 Hz, 1H), 6.31 (d, J=16.3 Hz, 1H), 4.09 (q, J=7.0 Hz, 2H), 3.28 (m, 1H), 2.65-2.52 (m, 2H), 2.04 (t, J=6.2 Hz, 2H), 1.76 (s, 3H), 1.64 (m, 2H), 1.49 (m, 2H), 1.30 (d, J=6.9 Hz, 3H), 1.20 (t, J=7.0 Hz, 3H), 1.06 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1.[BH4-].[Na+]>CCO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([O:10][C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1OC(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(Br)cc1OC(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-bromo-2-(trifluoro-methoxy)benzaldehyde (5.0 g, 19 mmol) from Step 1 above in EtOH (100 mL) at 0° C. was added NaBH4 (0.88 g, 23 mmol). The mixture was stirred for 1 h at 0° C., the cooling bath was removed, and the solution was stirred at ambient temperature for 14 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (150 mL) and saturated aqueous NaHCO3 (75 mL). The organic phase was separated, dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 5-10% EtOAc:hexanes. 4-Bromo-2-(trifluoromethoxy)benzyl alcohol was obtained as an amorphous solid by evaporation from CH2Cl2 (TLC Rf =0.25 (10% EtOAc:hexanes); HPLC retention time=8.8 min (method A)).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:15][CH2:16][CH2:17][CH3:18].O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][O:9][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1
Reactant: CCCCI
Reactant: OCCOc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
In DMF (150 ml) was dissolved 2-(4-bromophenoxy)-1-ethanol (15.7 g). To the mixture was added under ice-cooling 65% sodium hydride (4.3 g),and the mixture was stirred at room temperature for 2 hours. To the mixture was added dropwise iodobutane (17.3 g), and the mixture was stirred for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=4/1) to give 1-bromo-4-(2-butoxyethoxy)benzene (12.6 g).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2:5].C1(C)C(C)=CC=CC=1.[B:14]([OH:17])([OH:16])[OH:15]>O>[B:14]([O-:17])([O-:16])[O-:15].[Ca+2:5].[B:14]([O-:17])([O-:16])[O-:15].[Ca+2:5].[Ca+2:5]
Reactant: OB(O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: Cc1ccccc1C
Product: [O-]B([O-])[O-]
Temperature: 95 °C

Procedure:
A solution of 200 g of a calcium carbonate overbased alkylsalicylate (TBN 280 mgKOH/g, calcium content; 10.0 wt. %) and 200 g of xylene were put in a 1000-ml four-necked flask fitted with a condenser and heated to 95° C. while agitating. To this mixture was added 20 g of orthoboric acid, and the temperature was gradually increased to 145° C., while the reaction water was removed by azeotropic distillation by spending time for 1.5 hours. Subsequently, the reactor contents were filtered to obtain a filtrate (solution) which was cooled and then centrifuged to remove any residual solids present. Finally, the xylene was removed in vacuo to obtain a calcium borate overbased alkylsalicylate.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:16]1([NH:15][C:12]([CH:10]2[CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:11]2)=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: Nc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(C(=O)Nc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of N-Boc-3-Azetidinecarboxylic acid 46 (0.50 g, 2.48 mmol) and aniline (274 μL, 1.1 eq.) in 5 mL of dry CH2Cl2 was added DCC (730 mg, 1.1 eq.) in one portion at 0° C. The mixture was stirred at room temperature for 3 hours. Filtration and removal of the solvent gave an oily crude product, which was purified by flash column chromatography (silica gel, hexane:ethyl acetate) to afford 1-Boc-Azetidine-3-carboxylic acid phenylamide 47 as a colorless oil (660 mg, 96%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:10][C:7]([CH:4]1[CH2:5][CH2:6][N:1]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:2][CH2:3]1)([CH3:9])[CH3:8]
Reactant: CC(C)(O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 48 h

Procedure:
2-(Piperidin-4-yl)propan-2-ol (1 g) was reacted with 1.1 eq of benzyl chloroformate and 1.3 eq of triethylamine in 30 mL of chloroform. The reaction was halted after 2 days at room temperature and purified by isco (0-60% Hexanes/Ethyl Acetate over 20 minutes) to afford 1.49 g benzyl 4-(2-hydroxypropan-2-yl)piperidine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C([O:12][C:13](=O)[CH2:14][C:15]([CH3:17])=O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:12])[CH2:14][C:15]([CH3:17])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: NNc1ccc(Cl)cc1
Product: CC1=NN(c2ccc(Cl)cc2)C(=O)C1

Procedure:
From the reaction of 4-chlorphenylhydrazine and ethylacetoacetate, 2-(4-chlorphenyl)-2,4-dihydro-5-methyl-3H-pyrazol-3-one is obtained. Subsequent reaction with 2-ethylaniline yields 2-(4chlorphenyl)-4-(2-ethylanilinomethylene)-2,4-dihydro-5-methyl-3H-pyrazol-3-one