Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21]([C:23]3([C:26](O)=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:31][CH2:32][C:33]1[CH:34]=[C:35]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH:46]3[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]3)[CH:40]=2)[CH:36]=[CH:37][CH:38]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21]([C:23]3([C:26]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH:46]6[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C1(C(=O)NCc2cccc(-c3cccc(CC4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropanecarboxylic acid (100 mg, 0.241 mmol), 1,1-dimethylethyl 4-{[3′-(aminomethyl)-3-biphenylyl]methyl}-1-piperidinecarboxylate (70.9 mg, 0.241 mmol), HBTU (110 mg, 0.289 mmol) and Et3N (0.101 mL, 0.722 mmol) in DCM (3 mL) was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give the crude residue. It was then purified with a Gilson HPLC (with 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were dried under GeneVac and then combined to give the intermediate 1,1-dimethylethyl 4-[(3′-{[({1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropyl}carbonyl)amino]methyl}-3-biphenylyl)methyl]-1-piperidinecarboxylate. It was then dissolved in 2 mL of 25% TFA in DCM and stirred at room temperature for 3 h. The crude products were purified with a Gilson HPLC (with 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined and washed with 1 N NaOH and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-{[3′-(4-piperidinylmethyl)-3-biphenylyl]methyl}-1,1-cyclopropanedicarboxamide as a solid (32 mg, 19.6%). LC-MS m/z 678 (M+H)+, 0.79 min (ret time).
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[C:31]([C:36]([O:38]C)=[O:37])[CH:30]=[CH:29]4)=[CH:22][CH:21]=2)[CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>C(OCC)(=O)C.CO>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[C:31]([C:36]([OH:38])=[O:37])[CH:30]=[CH:29]4)=[CH:24][CH:25]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CCC4)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CCC4)cc3)ccc2n1
Temperature: 120 °C
Yield: 77.9 %

Procedure:
To a solution of methyl 6-[4-({[5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (67 mg, 0.12 mmol) in 2:1 tetrahydrofuran:methanol (1.5 mL) was added 1 N sodium hydroxide (0.18 mL, 0.18 mmol). The solution was heated in a microwave reactor at 120° C. for 500 seconds. The solution was concentrated and water was added followed by 1 N hydrochloric acid (0.18 mL, 0.18 mmol). Ethyl acetate was added. The layers were separated and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and concentrated to afford of 6-[4-({[5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid as a solid (51 mg, 78%). 1H-NMR (400 MHz, DMSO-d6) δ 13.38 (br s, 1H), 8.52 (d, J=8 Hz, 1H), 8.27 (s, 1H), 8.15-8.08 (m, 3H), 7.73 (d, J=9 Hz, 2H), 7.62-7.51 (m, 3H), 6.92 (d, J=9 Hz, 2H), 4.84 (s, 2H), 4.07-3.94 (m, 1H), 2.43-2.33 (m, 4H), 2.11-2.03 (m, 1H), 1.94-1.90 (m, 1H). HRMS (ESI) C30H22Cl2N2O4 calculated: 545.1029 (M+H)+, found: 545.1026 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[N:20](C)[CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14]4)(=[O:3])[CH3:2].Cl[C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28])=[O:24]>C1C=CC=CC=1.CCOCC.C(=O)([O-])[O-].[K+].[K+]>[Cl:28][C:27]([Cl:30])([Cl:29])[CH2:26][O:25][C:23]([N:20]1[CH2:19][CH2:18][C@@:15]23[C:16]4[CH:17]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=4[CH2:8][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)=[O:24]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C)CC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)OCC(Cl)(Cl)Cl)CC3
Yield: 66.1 %

Procedure:
To a mixture of 2.7 g of (-)-3-acetyl-N-methylmorphinan, 50 ml of benzene and 20 mg of potassium carbonate, was added dropwise 2.11 g of 2,2,2-trichloroethyl chloroformate in 10 ml of benzene. The reaction mixture was stirred at reflux temperature for 48 hours and after cooling it was diluted with 100 ml ether. The ether solution was extracted with 1 N hydrochloric acid (2×30 ml) and dried over magnesium sulfate. Removal of the solvent gave 2.8 g (66%) of crude (-)-3-acetylmorphinan-17-carboxylic acid (trichloroethyl)ester. For analysis, a sample of this compound was distilled, bp 230°-240° (0.1 mm), [α]25D-127.21° (c 1.11, MeOH).
Reaction SMILES: [CH2:1]=[C:2]1[C@H:7]([C:8]([O:10]C(C)(C)C)=[O:9])[N:6]2[C:15](=[O:27])[C@@H:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:5]2[S:4][CH2:3]1.Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]=[C:2]1[C@H:7]([C:8]([OH:10])=[O:9])[N:6]2[C:15](=[O:27])[C@@H:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:5]2[S:4][CH2:3]1
Reactant: C=C1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: C=C1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 60.2 %

Procedure:
A stirred solution of tert-butyl (4R,6R,7R)-3-methylene-7-phenylacetamido-cepham-4-carboxylate (0.83 g, purity 93.7%, 2.0 mmol) in dichloromethane (80 ml) was cooled to 0° C. Titanium tetrachloride (0.66 ml, 6.0 mmol) was added in 1 min. After stirring for 4 h at 0° C., the suspension was mixed with a chilled 2 M solution of hydrochloric acid in. water (40 ml). The organic phase was separated and washed with a 1 M solution of hydrochloric acid in water (20 ml), water (20 ml), and brine (20 ml). The organic phase was dried over magnesium sulphate and evaporated to give 0.40 g of (4R,6R,7R)-3-methylene-7-phenylacetamido-cepham-4-carboxylic acid (purity 75%, yield 45.1%).
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(=O)O)n[nH]1

Procedure:
5-Nitro-1H-pyrazole-3-carboxylic acid 1 is reduced under standard conditions, such as treatment with hydrogen in the presence of palladium(0) on carbon in a solvent such as methanol, to yield 5-amino-1H-pyrazole-3-carboxylic acid 2. Compound 2 is reacted with di-aldehyde 3, carrying a bromo or chloro substituent at the R1 position, under acid conditions, such as acetic acid, at elevated temperatures to give 6-bromo- or 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (4). A compound of Formula I is prepared from 4 via reaction with an appropriate secondary amine 5 in the presence of a condensation agent, including, for example, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (“TBTU”) or N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]([F:49])([S:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:14]([F:35])([F:34])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21]>C(Cl)Cl>[F:49][C:13]([F:12])([S:36]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:9])[C:14]([F:34])([F:35])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Sc1ccccc1-c1ccccc1
Solvent: ClCCl
Product: O=S(c1ccccc1-c1ccccc1)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 99.7 %

Procedure:
Under ice cooling, 3.57g (14.5 mmol) of m-chloroperbenzoic acid was added little by little to a solution of 8.76 g (14.5 mmol) of 2-(perfluorooctylthio)biphenyl in 50 ml of methylene chloride with stirring. The mixture was stirred overnight at room temperature. The precipitate in the reaction mixture was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using hexane as an eluent to give 8.97 g (100%) of 2-(perfluorooctylsulfinyl)biphenyl as while crystals. The properties of the product were as shown below.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.CN(C)C=O.C(Cl)(=O)C([Cl:19])=O>ClCCl>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([Cl:19])=[O:10])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CC1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CC1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tetrahydro-2H-pyran-4-ylacetic acid (89 mg), N,N-dimethyl formamide (1 μL), and dichloromethane (1 mL) was added oxalylchloride (54 μL), and the mixture was stirred at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure, and then toluene (1 mL) was added thereto, followed by further concentration under reduced pressure, to obtain crude tetrahydro-2H-pyran-4-yl acetyl chloride.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20]([F:32])([F:33])[F:19])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)/C=C/c3ccccc3C(F)(F)F)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-(2-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: Cl.[C:2](=[NH:13])([O:9][CH:10]([CH3:12])[CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[S:22][N:23]([CH3:38])[C:24](=[O:37])[O:25][C:26]1[C:34]2[O:33][C:32]([CH3:36])([CH3:35])[CH2:31][C:30]=2[CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH3:38][N:23]([C:24]([O:25][C:26]1[C:34]2[O:33][C:32]([CH3:36])([CH3:35])[CH2:31][C:30]=2[CH:29]=[CH:28][CH:27]=1)=[O:37])[S:22][N:13]=[C:2]([O:9][CH:10]([CH3:11])[CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)OC(=N)c1ccccc1
Reactant: CN(SCl)C(=O)Oc1cccc2c1OC(C)(C)C2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=NSN(C)C(=O)Oc1cccc2c1OC(C)(C)C2)c1ccccc1

Procedure:
To a solution of isopropyl benzimidate hydrochloride (18.0 g, 90 mmoles) in methylene chloride (100 ml) at 0° under an atmosphere of dry nitrogen is added a solution of triethylamine (28 ml, 200 mmoles) in a small stream with stirring. To this mixture is added a solution of 2,3-dihydro-2,2-dimethyl-7-benzofuranyl N-chlorothio(methyl)carbamate (26 g, 90 mmoles) in methylene chloride (80 ml) in a dropwise fashion. The reaction mixture is stirred for two hours at 0° and then washed in turn with water, 2N hydrochloric acid and saturated sodium bicarbonate. The organic phase is dried over anhydrous magnesium sulfate and the solvent is removed under reduced pressure. The residue is poured onto a column of silica gel. Elution of the column with a solvent consisting of 15 parts ether and 85 parts Skellysolve B gives from the appropriate fraction isopropyl N-[[methyl[[[2,3-dihydro-2,2-dimethyl-7-benzofuranyl]oxy]carbonyl]amino]thio]benzimidate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([Cl:9])[C:7]=1F.[C:12]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[H-].[Na+].C(O)(=O)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([Cl:9])[C:7]=1[CH:13]([C:12]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: Fc1nc(F)c(Cl)c(F)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)c1c(Cl)c(F)nc(F)c1Cl
Reaction time: 17 h
Yield: 107.5 %

Procedure:
3,5-dichloro-2,4,6-trifluoropyridine (25 g, 15.4 mL, 123.7 mmol) and dibenzyl malonate (35.8 g, 31.5 mL, 126 mmol, Aldrich) were dissolved in anhydrous DMF (240 mL) under nitrogen atmosphere. The mixture was then cooled in an ice bath. To a stirred mixture, was added 60% sodium hydride (10 g, 250 mmol) portionwise (2 g) for 2 hr. The mixture was then stirred in a water bath for ca. 17 hr. Glacial acetic acid was added and the mixture was partitioned between ether and water. Ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and dried in vacuo to give 62 g of dibenzyl 2-(3,5-dichloro-2,6-difluoropyridin-4-yl)malonate as a yellow oil. dibenzyl 2-(3,5-dichloro-2,6-difluoropyridin-4-yl)malonate (62 g) was then dissolved in dimethyl sulfoxide (DMSO) (120 mL) and stirred with water (10 mL) in an oil bath (130-140° C.) for 3 hr. After cooling to room temperature, water was added to the mixture and the product was extracted with ether (Sometimes addition of EA is necessary to dissolve product completely). The ether layer was washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a light yellow solid. The crude product was recrystallized from MC/Hexane three times to afford 30.9 g (75% for two steps) of benzyl 2-(3,5-dichloro-2,6-difluoropyridin-4-yl)acetate as a white solid. m.p. 98-101° C. 1H NMR (200 MHz, CDCl3) δ 4.11 (2H, s), 5.19 (2H, s), 7.30-7.38 (5H, m).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:20])[CH:17]=2)[C:12]1=[O:21])(=[O:3])[CH3:2].[CH3:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][Br:26]>>[Br-:26].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:22][C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[CH3:25])[CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:20])[CH:17]=2)[C:12]1=[O:21])(=[O:3])[CH3:2]
Reactant: Cc1ccccc1CBr
Reactant: CC(=O)c1cnccc1CC1Cc2cc(Cl)ccc2C1=O
Product: CC(=O)c1c[n+](Cc2ccccc2C)ccc1CC1Cc2cc(Cl)ccc2C1=O
Product: [Br-]

Procedure:
The title compound 136 is prepared according to the procedure reported in Example 38.1 with compound 110 (90 mg, 0.3 mmol) and 2-methylbenzyl bromide (68 μL, 0.51 mmol) as reactants. White solid. (Yield 119.2 mg, 82%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([CH:26]2[O:28][CH2:27]2)=[CH:24][CH:23]=1>CO>[CH2:1]([N:8]([CH2:27][CH:26]([OH:28])[C:25]1[CH:29]=[CH:30][C:22]([Cl:21])=[CH:23][CH:24]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CCNCc2ccccc2)cc1OC
Reactant: Clc1ccc(C2CO2)cc1
Solvent: CO
Product: COc1ccc(CCN(Cc2ccccc2)CC(O)c2ccc(Cl)cc2)cc1OC

Procedure:
Similarly, 5.42 g. (0.02 mol) of N-benzyl-3,4-dimethoxyphenethylamine and 4.64 g. (0.03 mol) of p-chlorostyrene oxide are reacted in methanol to give N-benzyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(4-chlorophenyl) ethylamine. The hydrochloride of this ethylamine is dissolved in methanol and hydrogenated with 0.5 g. of 10% palladium-on-carbon in 10 ml. of ethyl acetate at room temperature and 60 psi. for about 90 minutes. The filtered reaction mixture is evaporated in vacuo to yield N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(4-chlorophenyl)ethylamine hydrochloride, m.p. 167°-171° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][S:2]([O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
Methane sulphonyl chloride (0.11 ml, 1.4 mmol) was added to a solution of tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.25 g, 1.24 mmol) and 4-(dimethylamino)pyridine (0.167 g, 1.4 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 1 hour and then 4-(dimethylamino)pyridine (0.051 g, 0.42 mmol) and methane sulphonyl chloride (0.033 ml, 0.42 mmol) were added and the mixture stirred at room temperature for a further 1 hour. The mixture was purified directly by silica gel chromatography, eluting with a 3:1 to 1:1 mixture of iso-hexane:ethyl acetate to yield tert-butyl (2S)-2-{[(methylsulphonyl)oxy]methyl}pyrrolidine-1-carboxylate (0.325 g, 94% yield):
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[CH:11]=2)[NH:6][C:5]([CH3:22])([CH3:21])[CH:4]=1.CN(C=O)C.[N-:28]=[N+:29]=[N-:30].[Na+]>CCOC(C)=O.O>[N:28]([CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[CH:11]=2)[NH:6][C:5]([CH3:22])([CH3:21])[CH:4]=1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ccc2c(c1)C(CN=[N+]=[N-])=CC(C)(C)N2
Reaction time: 48 h
Yield: 156.9 %

Procedure:
To a round bottom flask equipped with a stir bar was added 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline (see Example 1) (0.36 mmol), DMF (3.6 mL), and NaN3 (0.54 mmol, 1.5 equiv). The reaction was stirred 48 hours under argon, then diluted with EtOAc and water, separated, and the aqueous phase was extracted with EtOAc. The combined organics were washed with water. The water was back-extracted with EtOAc and the combined organics were washed with brine and concentrated in vacuo. The residue was diluted with hexanes and a minimal amount of EtOAc and applied to a silica gel column. Flash chromatography, eluting with 0-30% EtOAc/hexanes provided 181 mg of 4-azidomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline as a brown oil.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)CC>[Br-:23].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: BrCCOCc1ccccc1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CCCO
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCOCc3ccccc3)(CC1)CC2
Product: [Br-]
Temperature: 52.5 °C
Reaction time: 0.67 h
Yield: 87.3 %

Procedure:
A solution of 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (31.7 kg) and benzyl 2-bromoethyl ether (25.7 kg) in n-propanol (257.5 kg) was refluxed for 13 hours. The solution was cooled to 50-55° C. over not less than an hour and stirred for 40 minutes to induce crystallisation. The slurry was cooled to 17-23° C. over not less than 1 hour and stirred for 60 minutes. The slurry was then cooled to 0-5° C. over not less than 1 hour and aged for 2 hours. The product was filtered and washed twice with n-propanol (34.8 kg and 33.8 kg). Drying under vacuum at 50° C. gave a white solid (47.95 kg, 87%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:25][N:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH:31]=O.[C:33]([BH3-])#[N:34].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH3:25][N:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH2:31][N:1]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)=[CH:23][CH:24]=1)[CH2:10][C:9]1[N:34]([CH3:33])[CH:6]=[CH:7][N:8]=1
Reactant: [BH3-]C#N
Reactant: CCCN(CCC)Cc1ccc(NCc2ccc(CN)cc2)cc1
Reactant: Cn1ccnc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1ccc(NCc2ccc(CN(Cc3nccn3C)Cc3nccn3C)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 122.1 %

Procedure:
The compound (57.3 mg) obtained in Example 39-2 was dissolved in methanol (2.5 ml). The solution was added with 1-methyl-2-imidazole carboxaldehyde (158 mg) and then added with sodium cyanoborohydride (68.4 mg). The reaction solution was adjusted to pH 5 by the addition of acetic acid, followed by stirring for 17 hours at room temperature. Then, the reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. After that, the organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After the solvent had been distilled off, a 10% hydrogen chloride/methanol solution was added to the residue, and the solvent was then distilled off. The residue obtained was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining the subject compound (55.2 mg) as a yellow solid.