Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19].[H][H]>C(O)C.[Pd]>[Br: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][OH:19]
Reactant: [H][H]
Reactant: OCCCCCC=CCCCCCCCCCCBr
Agent: [Pd]
Solvent: CCO
Product: OCCCCCCCCCCCCCCCCCBr
Yield: 76.8 %

Procedure:
17-Bromoheptadec-6-en-l-ol (33.8 g) was subjected to hydrogenation in a Paar hydrogenation apparatus (50 psi initial hydrogen pressure), using ethanol as solvent and 10% palladium on charcoal as catalyst, to yield 17-bromoheptadecan-1-ol (26.1 g, 76% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=[C:8]2[CH:7]=1.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[NH2:37][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:39]=1[CH:40]=[N:41][N:42]2[CH2:47][C:48]1[CH:49]=[C:50]([CH:55]=[CH:56][CH:57]=1)[C:51]([O:53][CH3:54])=[O:52]>CCOC(C)=O.CN1C(=O)CCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([NH:37][C:38]3[CH:46]=[CH:45][CH:44]=[C:43]4[C:39]=3[CH:40]=[N:41][N:42]4[CH2:47][C:48]3[CH:49]=[C:50]([CH:55]=[CH:56][CH:57]=3)[C:51]([O:53][CH3:54])=[O:52])=[O:17])=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: COCCOc1ccn2c(C(=O)O)cnc2c1
Reactant: COC(=O)c1cccc(Cn2ncc3c(N)cccc32)c1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COCCOc1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3cccc(C(=O)OC)c3)cnc2c1
Temperature: 80 °C
Yield: 80.1 %

Procedure:
To a vial was added 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (0.260 g, 1.05 mmol) and NMP (3.5 mL). Triethylamine (0.243 mL, 1.74 mmol) was added and the mixture was stirred until homogeneous. 2,4,6-Trichlorobenzoyl chloride (0.153 mL, 0.975 mmol) was added and the mixture was stirred at ambient temperature for 0.5 hours. Methyl 3-((4-amino-1H-indazol-1-yl)methyl)benzoate (0.196 g, 0.697 mmol) was added as a NMP solution (1.2 mL), and the reaction mixture was sealed in the vial and warmed to 80° C. with stirring overnight. The reaction mixture was cooled and diluted with EtOAc (20 mL), and then filtered to remove white solids. The solids were washed with EtOAc and the filtrate was concentrated under vacuum until only DMA was left. The concentrated solution diluted with water/saturated aqueous NaHCO3 (25 mL, 1:1) forming a precipitate. The precipitate was isolated by filtration and the solid was washed with water, Et2O, and hexanes, then dried under vacuum at 40° C. for 4 hours to provide 0.279 g (74%) of the title compound. MS (ES+APCI) m/z=500 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH:6]=1.[Br:16]Br>Br.CC(O)=O>[Br:16][CH2:14][C:13]([C:10]1[CH:11]=[N:12][C:7]([N:5]2[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]2)=[CH:8][CH:9]=1)=[O:15]
Reactant: BrBr
Reactant: CC(=O)c1ccc(-n2cnc(C)c2)nc1
Agent: Br
Solvent: CC(=O)O
Product: Cc1cn(-c2ccc(C(=O)CBr)cn2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 124.9 %

Procedure:
Compound 19 (6.1 g, 30.30 mmol) was suspended in 30% HBr/AcOH (75 ml). Bromine (4.82 g, 30.30 mmol) was added dropwise over 1 h. The reaction was stirred for 2 h at room temperature. The reaction mixture was poured into 600 mL of ice water and stirred rapidly for 15 min. The resulting precipitate was collected on a filter and washed with water. The compound was air dried to yield 20 as a yellow solid (10.6 g, 80%). LC/MS: [M+1]+=281.1. C11H10BrN3O:2HBr=442.0. 1H NMR (DMSO-d6) 300 MHz δ2.36 and 2.37 (6H, two s), 5.06 (2H, s), 8.16 (1H, d, J=9.0 Hz), 8.29 (1H, s), 8.69 (1H, d, J=9.0 Hz), 9.15 (1H, s), 9.93 (1H, s).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[C:12]([Cl:21])[CH:11]=2)=[CH:6][N:5]=[C:4]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:34])OC(C)(C)C)[CH3:26])[CH:3]=1.[C:35](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]I>[Cl:21][C:12]1[CH:11]=[C:10]([C:9]2[O:22][C:2]3[CH:3]=[C:4]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:34])[CH3:35])[CH3:26])[N:5]=[CH:6][C:7]=3[N:8]=2)[CH:15]=[CH:14][C:13]=1[O:16][CH2:17][CH:18]1[CH2:19][CH2:20]1
Reactant: C[C@@H](COc1cc(Cl)c(NC(=O)c2ccc(OCC3CC3)c(Cl)c2)cn1)NC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCC4CC4)c(Cl)c3)nc2cn1
Temperature: 160 °C
Reaction time: 5 h
Yield: 11.1 %

Procedure:
A suspension of tert-butyl ((2S)-1-((4-chloro-5-((3-chloro-4-(cyclopropylmethoxy)benzoyl)amino)pyridin-2-yl)oxy)propan-2-yl)carbamate (1.02 g), potassium carbonate (0.552 g) and copper(I) iodide (38.0 mg) in DMF (10 mL) was stirred at 160° C. for 5 hr under microwave irradiation. To the reaction mixture was added water, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and to the obtained residue was added 2 M hydrogen chloride/methanol (5 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (5 mL) and acetic anhydride (5 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (92.4 mg). 1H NMR (300 MHz, CDCl3) δ 0.38-0.48 (2H, m), 0.64-0.77 (2H, m), 1.30 (3H, d, J=6.4 Hz), 1.33-1.44 (1H, m), 1.97 (3H, s), 3.99 (2H, d, J=6.8 Hz), 4.25-4.51 (3H, m), 6.01 (1H, d, J=6.0 Hz), 6.91 (1H, s), 7.02 (1H, d, J=8.7 Hz), 8.06 (1H, dd, J=8.7, 1.9 Hz), 8.24 (1H, d, J=2.3 Hz), 8.53 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:18][CH:19]=[CH2:20])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=O)[CH:5]=[CH:6][CH:7]=1.[CH3:21][C:22]([S@:25]([NH2:27])=[O:26])([CH3:24])[CH3:23]>C1COCC1.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH2:18][CH:19]=[CH2:20])[C:9](=[N:27][S@@:25]([C:22]([CH3:24])([CH3:23])[CH3:21])=[O:26])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: C=CCC(C(=O)c1ccc(Cl)cc1)c1cccc(Cl)c1
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@@H](C(=N[S@](=O)C(C)(C)C)c1ccc(Cl)cc1)c1cccc(Cl)c1

Procedure:
2-(3-Chlorophenyl)-1-(4-chlorophenyl)pent-4-en-1-one (Example 418, Step A, 48 g, 157 mmol), titanium(IV) ethoxide, technical grade (65.9 mL, 315 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (Combi-Blocks, San Diego, Calif., 33.1 g, 267 mmol) were dissolved in 400 mL of THF. The mixture was heated with stirring under reflux for eighteen hours. The reaction was cooled and poured into brine. The resulting white solid was removed by filtration, rinsing with ethyl acetate. Ethyl acetate was added to the biphasic filtrate and the layers separated. The organic layer was washed with brine, then dried with anhydrous magnesium sulfate and concentrated. The crude product was purified by three chromatographies (330 g RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.), eluting with hexane:ethyl acetate, 95:5 to 85:5) to afford the title compound eluting second on silica gel TLC in hexane/ethyl acetate, the diastereomer (R)—N-((S)-2-(3-chlorophenyl)-1-(4-chlorophenyl)pent-4-en-1-ylidene)-2-methylpropane-2-sulfinamide eluting third on silica gel TLC in hexane/ethyl acetate, and some starting ketone eluting first on silica gel TLC in hexane/ethyl acetate.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH:11](C2(O)CCCCC2)[C:12]2[CH:17]=[CH:16][C:15]([O:18]CC3C=CC=CC=3)=[C:14]([Cl:26])[CH:13]=2)[CH2:6][CH2:5]1.[CH2:34]([O:41][C:42]1[CH:47]=[CH:46][C:45](C(C2(O)CCCCC2)C(N2CCC(NC(=O)OC(C)(C)C)CC2)=O)=[CH:44][C:43]=1[Cl:72])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[ClH:26].[ClH:72].[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2([CH:16]([C:45]2[CH:46]=[CH:47][C:42]([O:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:43]([Cl:1])[CH:44]=2)[CH3:17])[OH:18])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)C(c2ccc(OCc3ccccc3)c(Cl)c2)C2(O)CCCCC2)CC1
Reactant: NC1CCN(CC(c2ccc(OCc3ccccc3)c(Cl)c2)C2(O)CCCCC2)CC1
Agent: Cl
Product: CC(c1ccc(OCc2ccccc2)c(Cl)c1)C1(O)CCCCC1N1CCC(N)CC1

Procedure:
In an analogous manner to Example 1, step 2 {2-(4-aminopiperidin-1-yl)-1-[4-(benzyloxy)-3-chlorophenyl]ethyl}cyclohexanol dihydrochloride was prepared from tert-butyl {1-[[4-(benzyloxy)-3-chlorophenyl](1-hydroxycyclohexyl)acetyl]piperidin-4-yl}carbamate. MS (ESI) m/z 443; HRMS: calcd for C26H35ClN2O2+H+, 443.24598; found (ESI, [M+H]+), 443.2461.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=2)[C:13]#[N:14])[CH:8]=1.[N+:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32](O)=[O:33])=[CH:26]2)([O-:22])=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:19][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:32]([C:27]2[NH:28][C:29]3[C:25]([CH:26]=2)=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:31][CH:30]=3)=[O:33])=[CH:8][C:7]=1[O:9][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2cc(CNC(=O)c3cc4cc([N+](=O)[O-])ccc4[nH]3)ccc2Cl)c1
Yield: 36.7 %

Procedure:
N-({4-Chloro-3-[(3-chloro-5-cyanophenyl)oxy]phenyl}methyl)-5-nitro-1H-indole-2-carboxamide was prepared in a similar manner as described herein from 3-{[5-(aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.025 g, 0.085 mmol), 5-nitro-1H-indole-2-carboxylic acid, (0.025 g, 0.13 mmol), HATU (0.05 g, 0.13 mmol), DIPEA (0.025 mL, 0.13 mmol) and DMF (1 mL). The crude material was purified by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were neutralized and extracted with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (0.015 g, 36%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.36 (s, 1H), 9.34 (t, 1H), 8.67 (d, 1H), 8.04 (dd, 1H), 7.76 (t, 1H), 7.60 (d, 1H), 7.55 (d, 1H), 7.43 (dd, 1H), 7.41 (s, 1H), 7.35 (t, 1H), 7.28 (dd, 1H), 7.25 (d, 1H), 4.50 (d, 2H). MS: m/z 481.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:20][O:21][CH2:22][CH2:23]Br>>[CH3:20][O:21][CH2:22][CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COCCBr
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Product: COCCOc1cc(OCc2ccccc2)cc(C(=O)OC)c1

Procedure:
The subtitle compound was prepared from the product of step (i) (2.31 g) and 2-bromoethyl methyl ether 90.92 ml) by the method of example 11 step (i). Yield 2.74 g.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:7]([CH2:14]C)[CH2:6][C:5]1([CH2:18]C)[CH2:16]C.C[O:21][C:22](=O)[CH:23]=[CH2:24].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>C(=O)([O-])[O-].[Zn+2].CO>[C:22]([O:1][CH2:2][CH2:3][N:4]1[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:7]([CH3:14])[CH2:6][C:5]1([CH3:16])[CH3:18])(=[O:21])[CH:23]=[CH2:24]
Reactant: CCC1CC(CC)(CC)N(CCO)C2CCCCC12
Reactant: C=CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [Zn+2]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CO
Product: C=CC(=O)OCCN1C2CCCCC2C(C)CC1(C)C
Temperature: 87 °C
Reaction time: 96 h

Procedure:
Following the method described in U.S. Pat. No. 3,872,161, the title compound was prepared by reacting 1 mole of 1-(2-hydroxyethyl)-2,2,4-triethyldecahydroquinoline (hereinafter referred to as HETDQ) with 3 moles methylacrylate in the presence of 0.8 gram phenothiazine and 13 grams zinc carbonate. The above mixture was heated to 87° C. in a 1 liter 3-necked flask equipped with a fractionating column. The pot temperature was gradually increased to a maximum of 164° C. while methanol and other lower boiling point liquid fractions were collected. The reaction took four days.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:18]3[CH:19]=[C:20]([F:24])[CH:21]=[C:22]([F:23])[C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25].O1CCOCC1>C(Cl)Cl>[ClH:25].[F:24][C:20]1[CH:21]=[C:22]([F:23])[C:17]2[O:16][N:15]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:18]=2[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2noc3c(F)cc(F)cc23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Fc1cc(F)c2onc(N3CCNCC3)c2c1
Temperature: 25 °C

Procedure:
4-(5,7-Difluoro-benzo[d]isoxazol-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.69 g, 5.0 mmol) was dissolved in CH2Cl2 (30 ml) and 4 N HCl in dioxane (24.9 ml, 100 mmol) was slowly added. The resulting mixture was stirred over night at r.t. After dilution with iPr2O the product was collected by filtration and washed with one portion of iPr2O before drying it under high vacuum at 50° C. to obtain 1.35 g (98%) as a white solid. m/z=240.1 ([M+H]+).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17].O>N1C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:4][O:2][CH3:3])(=[O:14])=[O:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17]
Reactant: CON
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CONS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 76 %

Procedure:
Methoxylamine hydrochloride(0.90 g (10.8 mmol) was suspended in pyridine (3.0 ml). To this, under cooling with ice and with stirring, 4-chloro-3-nitrobenzenesulfonylchloride (2.56 g (10.8 mmol)) was added and the mixture was stirred under cooling with ice for one hour and at room temperature for 3 hours. Water (50.0 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and water successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2.02 g (76%) of 4-chloro-N-methoxy-3-nitrobenzenesulfonamide as pale yellow-white crystals.
Reaction SMILES: CN(C)C1[CH:4]=[C:5]([CH2:9][OH:10])[CH:6]=[CH:7][CH:8]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.CC1(C)C(C)(C)OB(C2C=NNC=2)O1>>[O:10]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:4][N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)[CH2:9]1
Reactant: CN(C)c1cccc(CO)c1
Reactant: c1cn[nH]c1
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: c1cnn(CC2CCCOC2)c1

Procedure:
The title compound was prepared by substituting (tetrahydro-2H-pyran-3-yl)methanol for (3-(dimethylamino)phenyl)methanol and 1H-pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 34A.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].O[N:27]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][C:37]([F:40])([F:39])[F:38])[NH2:29].CCN(C(C)C)C(C)C>>[CH3:13][CH:10]1[CH2:11][CH2:12][CH:8]([CH3:7])[N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]2[O:20][N:29]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][C:37]([F:38])([F:39])[F:40])[N:27]=2)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Reactant: CC1CCC(C)N1c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCC(C)N1c1ccc(-c2nc(-c3ccccc3OC(F)(F)F)no2)cc1[N+](=O)[O-]

Procedure:
Oxalyl chloride (152 μL; 1.2 mmol; 3 eq.), Intermediate 25 (106 mg; 0.4 mmol; 1 eq.), Intermediate 2 (88 mg; 0.4 mmol, 1 eq.) and DIEA (155 μL; 1.2 mmol; 3 eq.) were reacted according to general procedure 2. Purification by crystallisation from ethyl acetate/n-pentane afforded the title compound as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].N1C=CN=C1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O1CCCC1.CO.O.C(OCC)C>[Si:24]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)c1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of 9 (12.0 g, 38.22 mmol) and tert-butyldimethylsilyl chloride (13.07 g, 86.68 mmol) in anhydrous N,N-dimethylformamide (80 mL) was quickly added imidazole (10.62 g, 155.96 mmol). After stirring under argon overnight, the reaction mixture was shaken with diethyl ether (100 mL) and water (300 mL). The ethereal layer was separated and washed with a saturated NaHCO3 solution before drying over anhydrous MgSO4. The crude product resulting from evaporation of the solvent was purified by flash column chromatography on silica gel with methylene chloride: hexanes (1:1) as the eluent to afford a compound with silyl-protected hydroxyl and carboxyl groups. The compound was dissolved in tetrahydrofuran:methanol (120 mL:60 mL) followed by stirring with a solution of 10% K2CO3 aqueous solution (60 mL) for 1 h. The volume of the solution was reduced to 25% via evaporation under reduced pressure. Brine (250 ml; 120 g NaCl in 500 mL H2O) was added to the slurry, and the pH was adjusted to 5.0 with 1 M aqueous solution of potassium hydrogen sulfate, KHSO4. The precipitate was collected by filtration and washed with water followed by drying under vacuum at 70° C. to yield 10 (16.3 g, 99%). 1H NMR spectral data (400 MHz, Acetone-d6): δ 0.03 (s, 6H, —Si(CH3)2), δ 0.86 (s, 9H, —SiCCH3), δ 1.30–1.60 (m, 6H, —CH2—), δ 1.74 (m, 2H, —CH2—), δ 3.59 (t, 2H, —CH2OAr), δ 4.01 (t, 2H, SiOCH2—), δ7.03 (d, 2H, aromatic rings), δ 7.66 (d, 2H, aromatic rings), δ 7.70 (d, 2H, aromatic rings), δ 7.97 (d, 2H, aromatic rings).
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C1CCCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:3]1[C:4]2([CH2:9][CH2:8][C:7]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:6][CH2:5]2)[O:11][CH2:1][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: C1=C(N2CCCC2)CCC2(C1)OCCO2
Yield: 30.2 %

Procedure:
Reflux a solution of 1,4-cyclohexanedione mono-ethylene ketal (10.4 g, 66.5 mmol) and pyrrolidine (4.96 g, 69.8 mmol) and p-toluenesulfonic acid monohydrate (0.13 g, 0.66 mmol) in 50 mL cyclohexane overnight with a Dean-Stark trap and drying tube. Filter the mixture, wash with Et2O and concentrate the brown filtrate to afford 4.20 g of 1-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-pyrrolidine as brown oil
Reaction SMILES: [C:1]1([CH2:7][C:8]([N:10]2[CH2:16][CH:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[C:14]3[CH:28]=[CH:29][CH:30]=[CH:31][C:13]=3[CH2:12][CH2:11]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]1([CH2:7][CH2:8][N:10]2[CH2:16][CH:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)[C:14]3[CH:28]=[CH:29][CH:30]=[CH:31][C:13]=3[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(OC2CN(CCc3ccccc3)CCc3ccccc32)cc1

Procedure:
A solution of 3-phenylacetyl-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine of Example 9a. (6.5 g, 0.015 mole) in THF (100 ml) was slowly dropped into a refluxing suspension of LiAlH4 (1.2 g, 0.030 mole) in THF (75 ml). After refluxing four hours the mixture was cooled, then quenched by dropwise addition of saturated NH4Cl. The mixture was diluted with ether, filtered, washed twice with water and dried (saturated NaCl, anhydrous MgSO4). The solution was filtered, then concentrated to an oil (6.2 g., 92%). This oil was distilled to yield an oil of 3-(2-phenylethyl)-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine, 220°-235° C./0.1 mm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[CH2:15][C:16]([OH:18])=[O:17])=O.C(C1C=C(OC)C=CC=1CC(O)=O)(=O)C1C=CC=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[CH2:15][C:16]([OH:18])=[O:17]
Reactant: COc1ccc(CC(=O)O)c(C(=O)c2cccc(F)c2)c1
Agent: COc1ccc(CC(=O)O)c(C(=O)c2ccccc2)c1
Product: COc1ccc(CC(=O)O)c(Cc2cccc(F)c2)c1

Procedure:
According to the procedure of Preparation 10(c), except substituting 2-(3-fluorobenzoyl)-4-methoxyphenylacetic acid for the 2-benzoyl-4-methoxyphenylacetic acid, the title compound was obtained as a colorless oil: MS (ES−) m/e 273.2 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][N:33]([CH2:21][CH2:20][CH2:19][C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=2)[CH2:32][CH2:31]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: O=CCCc1cc(-c2ccc(F)cc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-c2cc(CCCN3CCN(c4ccccc4F)CC3)nn2-c2ccccc2)cc1

Procedure:
57 mg (70%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (55 mg, 0.187 mmol), 1-(2-fluorophenyl)piperazine (0.027 mL, 0.170 mmol), DIPEA (0.030 mL, 0.170 mmol) and NaBH(OAc)3 (108 mg, 0.510 mmol).
Reaction SMILES: C[O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:12][CH2:13][C:7]=2[C:6]([O:23]C)=[C:5]([O:25][CH3:26])[C:4]=1[O:27][CH3:28].N1C(C(O)=O)=CC=CC=1C(O)=O.C1COCC1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(=O)(O)[O-].[Na+].O>[CH3:28][O:27][C:4]1[C:3](=[O:2])[C:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:12][CH2:13][C:7]=2[C:6](=[O:23])[C:5]=1[O:25][CH3:26]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOc1ccccn1)CC2
Agent: O=C(O)c1cccc(C(=O)O)n1
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CCC(CCOc3ccccn3)CC2)C1=O
Reaction time: 0.25 h
Yield: 75.9 %

Procedure:
To a mixture of 2-[2-(1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-yl)ethoxy]pyridine (700 mg), pyridine-2,6-dicarboxylic acid (907 mg), THF (14 ml), and water (7 ml) was added an water (7 ml) solution of CAN (3.97 g) with cooling with ice. After being stirred for 15 min, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=1:2) to obtain the entitled compound (490 mg) as an oil.