Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:9]1[C:13]2=[C:14]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:15]=[C:16]([C:18]#[N:19])[CH:17]=[C:12]2[CH:11]=[C:10]1[CH3:30])[CH:7]=[CH2:8].CN(C)[CH:33]=[O:34]>ClCCl>[CH2:6]([N:9]1[C:13]2=[C:14]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:15]=[C:16]([C:18]#[N:19])[CH:17]=[C:12]2[C:11]([CH:33]=[O:34])=[C:10]1[CH3:30])[CH:7]=[CH2:8]
Reactant: CN(C)C=O
Reactant: C=CCn1c(C)cc2cc(C#N)nc(N3CCc4ccccc4C3)c21
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: C=CCn1c(C)c(C=O)c2cc(C#N)nc(N3CCc4ccccc4C3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.3 %

Procedure:
Phosphorus oxychloride (425 μl, 4.56 mmol) was added at room temperature to a solution of 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile (1 g, 3.04 mmol) prepared in Step 3 in a mixture of anhydrous dichloromethane (20 ml) and N,N-dimethylformamide (353 μl, 4.56 mmol). The reaction mixture was refluxed for 3 hours, cooled to room temperature, and then filtered. The resulting solid was washed with water and 1M sodium acetate (30 ml) was added thereto. The reaction mixture was stirred for 1 hour at room temperature and then filtered. The resulting solid was washed with water and then dried to give 350 mg of the titled compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]2[CH2:7][S:8][C@H:9]([CH:10]=[O:11])[C@H:4]2[O:3]1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[O:6][C@H:5]2[CH2:7][S:8][C@H:9]([CH2:10][O:11][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@H:4]2[O:3]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)O[C@H]2[C@H](CS[C@@H]2C=O)O1
Solvent: c1ccncc1
Product: CC1(C)O[C@H]2[C@H](CS[C@@H]2COC(=O)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.9 %

Procedure:
To a solution of 111 (2.1 g, 11.1 mmol) in pyridine (20 mL) was added benzoyl chloride (1.9 g, 13.4 mmol) at 0° C. and the reaction mixture was stirred for 6 h at room temperature before being quenched with methanol. The reaction mixture was evaporated under reduced pressure. The residue was then taken up in diethyl ether (50 mL), and the pyridinium salt was filtered and washed with diethyl ether. The combined organic layer was concentrated and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=4:1) to afford the benzoate 112 (3.2 g, 99%) as a colorless oil: 1H NMR (CDCl3) δ 1.26 (s, 3H, CH3), 1.47 (s, 3H, CH3), 2.87 (dd, 1H, J=13.2, 1.5 Hz, 6-CHH), 3.11 (dd, 1H, J=13.2, 4.9 Hz, 6–CHH), 3.57 (m, 1H, 4-H), 4.25 (dd, 1H, J=11.5, 8.0 Hz, BzOCHH), 4.35 (dd, 1H, J=11.4, 5.8 Hz, BzOCHH), 4.72 (dd, 1H, J=5.6, 1.2 Hz, 6a-H), 4.91 (td, 1H, J=4.4, 1.2 Hz, 3a-H), 7.35–7.99 (m, 5H, Ph); FAB-MS m/z 294 (M+); Anal. Calcd for C15H18O4S: C, 61.20; H, 6.16; S, 10.89. Found: C, 60.99; H, 6.42; S, 10.77.
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.CC1(C)S[C@@H]2[C@H]([NH:54][C:55]([C@H:57](N)[C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)=O)C(=O)N2[C@H]1C(O)=O.[NH4+].[Cl-].[NH4+].[OH-].C1(CC(=O)[C:81]([O-:83])=[O:82])C=CC=CC=1.[Na+].OC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O>>[NH2:54][C@H:55]([C:81]([OH:83])=[O:82])[CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: O=C([O-])C(=O)Cc1ccccc1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Agent: [Cl-]
Product: N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 6 h
Yield: 33 %

Procedure:
L-phenylalanine was synthesized using cells of E. coli RR1 containing the plasmid pBPDH3. As an NADH regeneration system, enzymes for glycolysis in E. coli were used. The above-mentioned E. coli was inoculated in an LB medium containing 50 μg/ml of ampicillin at a ratio of 1%, and cultured at 37° C. for 6 hours. The 5 ml of the cultured broth was centrifuged to collect cells, which were then washed with a 0.85% NaCl solution. The cells were suspended in 3 ml of a reaction mixture containing 200 μ moles of an NH4Cl-NH4OH buffer (pH 9.0), 109 μ moles of a sodium phenylpyruvate, and 267 μ moles of a lactose, and the suspension was allowed to stand at 30° C. for 24 hours. As a result, 20 mg/ml (yield 33%) of L-phenylalanine was accumulated, as determined by the above-mentioned L-phenylalanine assay procedure.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Li]CCCC.[C:12]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH:31]=[O:32])[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[NH4+].[Cl-]>C1COCC1.CCCCCC.[Cl-].[Na+].O>[C:12]([N:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH:31]([OH:32])[C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)[CH2:23][CH2:24]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C=O)CC1
Reactant: Cn1ccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1ccnc1C(O)c1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 159 %

Procedure:
To a solution of 1-methyl imidazole (350 uL, 4.4 mmol) in 15 mL of THF at −78° C. was added n-BuLi (1.5 mL of a 1.6 M solution in hexane, 2.4 mmol). After stirring for about 30 minutes, the solution was warmed to about 0° C. and then stirred for about 15 minutes. The mixture was then cooled to about −78° C. A solution of N-Boc-4-(2-formylphenyl)-piperazine (580 mg, 1.0 mmol) in 5 mL of THF was added via cannula The solution was allowed to warm slowly to r.t. overnight. After addition of saturated aqueous NH4Cl and brine, the solution was extracted with EtOAc (2×). The combined organic solutions were dried (Na2SO4), filtered and concentrated. Purification by silica gel chromatography (35 g SiO2, 0 to 10% 0.2 M NH3 in MeOH/CH2Cl2 over 30 min at 35 mL/min) afforded about 592 mg (1.59 mmol, 79%) of the alcohol as a colorless oil. LRMS (ESI+): 373.2 (M+1)
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[C:8]([O:29][CH3:30])=[C:9]([O:27][CH3:28])[C:10]2[O:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])([CH3:15])[CH2:12][C:11]=2[C:25]=1[CH3:26])(=O)C.Cl>CO>[OH:6][C:7]1[C:8]([O:29][CH3:30])=[C:9]([O:27][CH3:28])[C:10]2[O:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])([CH3:15])[CH2:12][C:11]=2[C:25]=1[CH3:26]
Reactant: CCOC(=O)CCCCC1(C)Cc2c(C)c(OC(C)=O)c(OC)c(OC)c2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(O)c(C)c2c(c1OC)OC(C)(CCCCC(=O)O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.7 %

Procedure:
An aqueous 1N sodium hydroxide solution (30 ml) was added to a solution of ethyl 5-(5-acetoxy-2,3-dihydro-6,7-dimethoxy-2,4-dimethylbenzofuran-2-yl)valerate (2.3 g) in methanol (20 ml), and the mixture was stirred at room temperature for 2 hours. 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (2.0 g, 96%) as an oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:16])=O>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:16])=[O:6]
Reactant: O=C(O)c1ccccc1C(F)(F)F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccccc1C(F)(F)F

Procedure:
Reaction of 2-trifluoromethylbenzoic acid with thionyl chloride affords 2-trifluoromethylbenzoyl chloride, which, on reaction with diethylamine, affords 2-trifluoro-methyl-N,N-diethylbenzamide. Following a procedure similar to that described in Preparation 5, reaction of the latter with s-butyl lithium and reaction of the resulting lithium salt with sulfur dioxide followed by sodium hydroxylamine-O-sulfonate affords 2-trifluoromethyl-6-aminosulfonyl-N,N-diethylbenzamide, which, on heating in glacial acetic acid, affords 4-trifluoromethylsaccharin.
Reaction SMILES: [CH3:1][C:2]([NH2:8])([CH2:4][CH:5]([OH:7])[CH3:6])[CH3:3].[CH:9](=O)[CH3:10].C1(C)C=CC=CC=1>O>[CH3:9][CH:10]1[NH:8][C:2]([CH3:3])([CH3:1])[CH2:4][CH:5]([CH3:6])[O:7]1
Reactant: CC=O
Reactant: CC(O)CC(C)(C)N
Solvent: O
Solvent: Cc1ccccc1
Product: CC1CC(C)(C)NC(C)O1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
1,170 parts by weight of 2-methyl-2-aminopentan-4-ol is placed in a stirred flask. With external cooling, 440 parts by weight of acetaldehyde is run in over a period of about 40 minutes at 15°-20° C. The reaction mixture is stirred for a further 15 minutes at 20° C. After the addition of 600 parts by volume of toluene, 182 parts by weight of water is separated off over a period of 2 hours by azeotropic distillation. The reaction product is subjected to fractional distillation. After removal of the solvent there is obtained 1,372 parts by weight of 2,4,4,6-tetramethyltetrahydro-1,3-oxazine with a purity (according to gas chromatography) of 98%, equivalent to a yield of 94% of theory, based on 2-methyl-2-aminopentan-4-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][N:22]=[C:23]4[CH2:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][N:22]=[C:23]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(OCC5CC5)c(Cl)c4)n3)cccc12
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCc1nccc2c(-c3noc(-c4ccc(OCC5CC5)c(Cl)c4)n3)cccc12
Reaction time: 2 h
Yield: 77.5 %

Procedure:
A solution of 1,1-dimethylethyl 3-[5-(5-{3-chloro-4-[(cyclopropylmethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]propanoate (D45; 22 mg, 0.043 mmol) in 4N HCl in 1,4-dioxane (4 ml) was allowed to stand at room temperature for 2 h. The solvent was evaporated to give a white solid, which was triturated with dry ether to give a white solid (15 mg). The sample was dissolved in NMP (0.5 ml) and purified by Mass Directed Preparative HPLC (Supelcosil ABZ+Plus column, eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid)). The solvent was evaporated in vacuo to give the title compound (5 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15]([NH2:17])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.N1C=CC=CC=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15]([NH:17][S:26]([CH3:25])(=[O:28])=[O:27])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: CCCN(C)C(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCN(C)C(=O)c1cc(NS(C)(=O)=O)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Dissolve 5-amino-N-methyl-N-propyl-isophthalamic acid methyl ester (1.64 g, 6.55 mmol) in dichloromethane (20 mL) and add pyridine (620 mg, 6.88 mmol) and methanesulfonyl chloride (788 mg, 6.88 mmol). Stir at room temperature for 72 h, dilute with dichloromethane, wash with 0.1 N citric acid and saturated aqueous sodium chloride. Dry (magnesium sulfate) and concentrate to give the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[F:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][C:5]=1[S:13]([Cl:12])(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: O=S(=O)(O)Cl
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)c(F)cc1F
Temperature: 100 °C
Reaction time: 48 h
Yield: 64.7 %

Procedure:
A mixture of 2,4-difluoro-1-nitrobenzene (20 g, 126 mmol) in chlorosulfonic acid (44 g, 378 mmol) was stirred at 100° C. for 48 hours before being poured into ice-water and extracted with EtOAc. The organic extract was dried (Na2SO4) and concentrated, and the residue was triturated with 10% EtOAc-petroleum ether to give 2,4-difluoro-5-nitrobenzenesulfonyl chloride as a brown oil (21 g, 81%) which was used directly in the next step.
Reaction SMILES: [C:1]([NH:11][C@@H:12]1[CH2:17][O:16][C:14](=[O:15])[CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:18][NH:19][CH3:20]>C1COCC1>[CH3:18][N:19]([CH3:20])[C:14](=[O:15])[CH2:13][C@@H:12]([NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:17][OH:16]
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)CO1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)C[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-(S)-((carbobenzyloxy)amino)-γ-butyrolactone (prepared according to the procedure described in McGarvey, G. J.; Williams, J. M.; Hiner, R. N.; Matsubara, Y.; Oh, T. J. Am. Chem. Soc. 1986, 108, 4943-4952, 7.72 g) in THF (100 mL) was saturated with gaseous dimethylamine, stirred at room temperature for 16 hours, and concentrated. The residue was filtered through a plug of silica gel eluting with 50% acetone in hexanes to give the desired product.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]2=[C:4]([C:11]([NH2:13])=[O:12])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.C(N(CC)CC)C.[C:28]([N:32]=[C:33]=[O:34])([CH3:31])([CH3:30])[CH3:29].[OH-].[Na+]>>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:33]([NH:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:10][C:5]2=[C:4]([C:11]([NH2:13])=[O:12])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1
Reactant: CC(C)(C)N=C=O
Reactant: NC(=O)c1c(-c2cccc(F)c2)c(Br)n2c1CNCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)N1CCn2c(Br)c(-c3cccc(F)c3)c(C(N)=O)c2C1
Yield: 51.5 %

Procedure:
To a suspension of 0.24 g (0.71 mmol) of 6-bromo-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide is added 0.30 ml (2.13 mmol) of triethylamine and then, at 0° C., 0.10 ml (0.85 mmol) of tert-butyl isocyanate. After reaction for 1 hour at room temperature, the mixture is treated with aqueous 1N sodium hydroxide solution and the product is extracted with dichloromethane. The organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a column of 40 g of silica gel, eluting with a mixture of 4% methanol in dichloromethane, to give 0.16 g of 6-bromo-7-(3-fluorophenyl)-N2-(tert-butyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a powder after recrystallization from 10 ml of acetonitrile, filtering and drying under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1.[F:25][CH:26](I)[CH3:27].C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:20][CH2:21][N:22]([CH2:27][CH2:26][F:25])[CH2:23][CH2:24]2)[CH2:15][CH2:14]1
Reactant: CC(F)I
Reactant: COc1cc(N2CCC(N3CCNCC3)CC2)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)c(Cl)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
1-{1-[2-Chloro-5-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (0.050 g, 1.41 mmol), 1-fluoroethyliodide (0.229 mL, 2.82 mmol), Na2CO3 (0.179 g, 1.69 mmol) were taken up in acetonitrile (10 mL), heated to 70° C. and stirred overnight. Reaction mixture was cooled and then poured onto prepackaged silica gel cartridge and dried by vacuum suction of air through cartridge and then flash chromatographed to give the title compound of step E (0.370 g, 65%). MS (M+H, ES+) 401.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CCN(CC)CC>C1COCC1.[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:10]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=Cc1ccc(Br)cc1
Reactant: C#CCCCCCCCC
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCC#Cc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
To a solution of 4-bromobenzaldehyde (30.0 g, 162.2 mmol), 1-decyne (26.9 g, 35 mL, 194.6 mmol), CuI (309 mg, 1.62 mmol) and of Et3N (68 mL) in anhydrous THF (450 mL) were added PPh3 (1.7 g, 6.49 mmol) and Pd(OAc)2 (728 mg). The reaction mixture was refluxed under argon for 1 hour. After cooling to rt, the solution was concentrated under reduced pressure and the residual oil was dissolved in hexane (480 mL). The solution was washed with an aqueous solution of HCl (0.1N, 1×), brine (2×), water (2×), dried over MgSO4, filtered and concentrated under reduced pressure to give a brown oil. Purification by chromatography on silicagel (c-Hex/EtOAc 20/1) gave the title compound as a yellow solid (34.7 g, 88%). 1H NMR (CDCl3, 300 MHz) δ 9.97 (s, 1H), 7.78 (d, 2H, J=8.7 Hz), 7.51 (d, 2H, J=8.3 Hz), 2.42 (t, 2H, J=7.0 Hz), 1.67-1.55 (m, 2H), 1.50-1.38 (m, 2H), 1.36-1.21 (m, 8H), 0.87 (m, 31). HPLC (Condition A), Rt: 5.50 min (HPLC purity: 93.2%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([C:12](O)=[O:13])[CH:6]=[CH:7][CH:8]=2)[O:3]1.B.C1COCC1.Cl.[OH-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1.ClCCl>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH:12]=[O:13])[CH:6]=[CH:7][CH:8]=2)[O:3]1
Reactant: CC1(C)CCc2cccc(C(=O)O)c2O1
Agent: B
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1(C)CCc2cccc(C=O)c2O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2,2-Dimethyl-3,4-dihydro-2H-chromene-8-carboxylic acid (300 mg, 1.45 mmol) dissolved in THF (3.60 mL) was cooled to 0° C. and BH3-THF (5.82 mL, 5.82 mmol) was added dropwise via a syringe. The resulting solution was stirred at 65° C. for 1 hour, and then allowed to cool to room temperature before addition of 6 N HCl (2.50 mL). The mixture was again heated at 65° C. for 30 minutes. The solution was cooled to room temperature, made basic with 1N NaOH and extracted with EtOAc (40.0 mL, 3×). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to obtain the crude alcohol as a colorless oil, which was directly used to the next step. The crude alcohol was dissolved in dichloromethane (5.00 mL), and Dess-Martin periodinane (1.23 g, 2.91 mmol) was added in one portion at room temperature. The reaction mixture was stirred for 1 hour at room temperature and concentrated under vacuum on silica gel. The crude residue was purified by silica gel chromatography eluting with 0-15% EtOAc/hexanes to give the desired product as a colorless oil.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[N:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(N(CC)CC)C>C(O)C.O1CCCC1.[C].[Pd]>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([NH:15][C@H:12]2[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]2)[N:17]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2ccc(Cl)nn2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N[C@H]1CC[C@H](Nc2cccnn2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In the mixed solvent of 5 ml of ethanol and 4 ml of tetrahydrofuran were dissolved 168 mg of N-tert-butoxycarbonyl-trans-4-[(6-chloro-3-pyridazinyl)amino]cyclohexylamine (Reference Example 3-46) and 0.5 ml of triethylamine. To the solution was added 50 mg of 10% palladium carbon and the mixture was stirred under hydrogen atmosphere with normal pressure at room temperature for 1 day. After the catalyst was removed by filtration, the solvent was removed, and the residue was stirred in 2 ml of trifluoroacetic acid for 3 hours. The solvent was removed, an aqueous 10% sodium hydroxide solution was added to the residue, the mixture was extracted with chloroform and dried over anhydrous sodium sulfate. Subsequently, the solvent was removed under reduced pressure to obtain 61 mg of trans-4-(pyridazin-3-ylamino)cyclohexylamine (Reference Example 3-48 in Table 5).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:48])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][C@@:34](O[Si](C(C)(C)C)(C)C)([OH:39])[CH2:35][N:36]([CH3:38])[CH3:37])=[CH:28][CH:27]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:48])/[CH:24]=[CH:25]/[C:26]3[CH:27]=[CH:28][C:29]([O:32][CH2:33][C@H:34]([OH:39])[CH2:35][N:36]([CH3:38])[CH3:37])=[CH:30][CH:31]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CN(C)C[C@](O)(COc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)CCO3)cc1)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)C[C@@H](O)COc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)CCO3)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
At 0° C. to a solution (E)-(R)-1-[1-(2,3-dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-(2-(tertbutyldimethylsilanyloxy)-3-dimethylamino-2-hydroxy-propoxy)phenyl)propene-1-one (0.4 g, 0.6 mmol) in 50 mL of anhydrous THF was added tetrabutylammonium fluoride (0.6 mL, 1 equiv., 1 M in THF). The resulting mixture was stirred at rt for one day. Quenching with water, extraction with DCM, washing with brine, drying over MgSO4 and concentration in vacuo gave an oil. Recrystallization from iPrOH:H2O gave the title compound (0.2 g, 62%) as an off-white powder.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:19](OC(Cl)(Cl)Cl)=[O:20]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:3]=1[N:4]=[C:19]=[O:20]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(OCc2ccc(Cl)cc2)cc1F
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(OCc2ccc(Cl)cc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of 5.0 grams (0.02 mole) of 2-fluoro-4-(4-chlorophenylmethoxy)aniline in 150 mL of toluene was stirred and a solution of 3.4 mL (0.02 mole) of trichloromethyl chloroformate in 20 mL of toluene was added slowly. Upon completion of addition, the reaction mixture was stirred at 25° C. for one hour. After this time the reaction mixture was warmed to reflux, where it was stirred for about 18 hours. The reaction mixture was then concentrated under reduced pressure, yielding 5.5 grams of 2-fluoro-4-(4-chlorophenylmethoxy)phenyl isocyanate.