Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([O:29]C)=[O:28])[CH:22]=2)[C:8]2[C:13]([C:14]=1[CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+]>C1COCC1.CO.O>[C:16]([CH2:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([OH:29])=[O:28])[CH:22]=2)[C:6]=1[C:4]([OH:5])=[O:3])([OH:18])=[O:17]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)n(-c2cccc(C(=O)OC)c2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1c(C(=O)O)n(-c2cccc(C(=O)O)c2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of 3-ethoxycarbonylmethyl-1-(3-methoxycarbonyl-phenyl)-1H-indole-2-carboxylic acid ethyl ester (1.31 g, 3.2 mmol) in THF-methanol (2:1, 25 mL) was added a solution of NaOH (0.64 g, 16.0 mmol) in H2O (5 mL). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with H2O (50 mL) and washed with diethyl ether (50 mL). The aqueous layer was acidified with concentrated HCl to pH=1. The white precipitated was filtered off and dried in vacuo to afford 1.08 g of white solid (quantitative yield): 1H NMR (DMSO-d6) δ 4.13 (s, 2H), 7.05 (d, 1H), 7.21 (t, 1H), 7.31 (t, 1H), 7.62–7.71 (m, 2H), 7.76–7.82 (m, 2H), 8.01–8.05 (m, 1H); 13C NMR (DMSO-d6) 31.0, 111.1, 119.0, 121.2, 121.4, 126.2, 127.4, 127.8, 128.3, 128.7, 129.9, 132.2, 138.9, 139.3, 162.6, 167.0, 172.5. Anal: Calcd for C18H13NO6: C, 63.72; H, 3.86; N, 4.13. Found: C, 63.32; H, 4.08; N, 3.97.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[N:2]1.[CH3:14]COCC.Cl>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:2]1
Reactant: CCOCC
Reactant: O=C(O)Cc1noc2ccccc12
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1noc2ccccc12

Procedure:
A solution of 1,2-benzisoxazole-3-acetic acid (prepared according to G. Casini et al, J. Het. Chem. 6, 1969, 279) (18 g), ether saturated with dry HCl (150 ml) and methanol (200 ml) was stirred for 2 h at room temperature. Removal of the volatiles in vacuo gave methyl 1,2-benzisoxazole-3-acetate (17 g) as an oil. The oil was dissolved in tetrahydrofuran (100 ml) and added dropwise to a suspension of lithium aluminium hydride (6 g) in tetrahydrofuran (200 ml) at 0-10° C. followed by stirring for 30 min at 15° C. Usual work-up gave 2-(1,2-benzisoxazol-3-yl)ethanol (13 g) as an oil.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@:14]([F:26])([CH3:25])[C:13](=[O:27])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].CCOC(C)=O>C1COCC1>[C:1]([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@:14]([F:26])([CH3:25])[C@H:13]([OH:27])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]1(F)C(=O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@]1(F)[C@H](O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
To a 5 L of dry three-neck round-bottomed flask fit with a mechanical stirrer, addition funnel and thermometer was charged the lactone ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)methyl benzoate) (1a, 379 g, 1.018 mol). The solid was dissolved in anhydrous THF (1.75 L) and cooled to −30° C. under a nitrogen atmosphere. A solution of lithium tri-tert-butoxyaluminohydride (1.0 M in THF, 1.527 L) was added to the lactone solution while stirring over 1 h and maintaining the −30° C. temperature. After finishing the addition, the temperature was slowly increased and the reaction was followed by TLC (lactol Rf 0.4, 30% EtOAc in hexanes). The reaction was complete after 1 h 15 min (temperature reached −10° C.). The reaction was quenched by addition of Ethyl acetate (900 mL) via addition funnel. Sat. NH4Cl (40 mL) was added at 0° C. The cloudy mixture was decanted into a 10 L round-bottomed flask. The solid residue left behind was filtered and washed with ethyl acetate (2×200 mL). The filtrate was combined with the decanted solution and the combined solution was concentrated under reduced pressure. The oily residue was dissolved in ethyl acetate (2 L) and washed with 3 N HCl (600 mL). The aqueous layer was back-extracted with ethyl acetate (3×400 mL). The combined organic layer was washed with water (3×800 mL), sat. NaHCO3 (400 mL) and brine (400 mL). The organic solution was dried over MgSO4, filtered and concentrated under reduced pressure to afford a light brown oily residue. The residue was purified by plug column (2.2 kg of 40-63 micron silica gel, packed in a 6 L sintered glass funnel, 22 cm length of silica gel, diameter 15 cm) using suction and a step-gradient of 5%, 10%, 20%, and 30% ethyl acetate in hexanes—ca 5 L of each). The product containing fractions were combined and concentrated under reduced pressure to a colorless, very thick liquid (310.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5](N)=[C:4]([C:9]2[CH2:13][CH2:12][O:11][N:10]=2)[C:3]=1[CH3:14].[CH3:15][S:16]SC.N([O-])=O.[Na+].S(=O)(=O)(O)O.Cl>[Cu].O>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]([C:9]2[CH2:13][CH2:12][O:11][N:10]=2)[C:5]([S:16][CH3:15])=[CH:7][CH:8]=1
Reactant: CSSC
Reactant: Cc1c(Br)ccc(N)c1C1=NOCC1
Agent: [Cu]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: CSc1ccc(Br)c(C)c1C1=NOCC1
Reaction time: 1 h
Yield: 58 %

Procedure:
10 g (35.3 mmol) of 4-bromo-2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline, 67.3 mg of copper powder and 58.5 ml of dimethyl disulfide are initially charged, and the mixture is stirred for one hour. At 50° C., 9.05 g of a 40.4% strength aqueous sodium nitrite solution are added. At 63-65° C., 6.96 g of 25% strength sulfuric acid are then metered in, and the mixture is stirred at 65° C. for 3 hours. At 20-25° C., 15 ml of conc. hydrochloric acid are added, and the mixture is stirred for one hour. 15 ml of water are added, and the phases are then separated. Washing is repeated twice. The organic phase is concentrated, giving 6.7 g of a brown solid (yield: 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:25][OH:26])[C:11]([CH3:24])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:29]([O:31][C:32](=[O:37])[C:33](Br)([CH3:35])[CH3:34])[CH3:30]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:29]([O:31][C:32](=[O:37])[C:33]([O:26][CH2:25][C:10]1[C:11]([CH3:24])=[N:12][C:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:9]=1)([CH3:35])[CH3:34])[CH3:30]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)c(-c2ccc(Cl)cc2)cc1CO
Reactant: CCOC(=O)C(C)(C)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)OCc1cc(-c2ccc(Cl)cc2)c(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 500 mg of [5-(4-Chloro-phenyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol in 6 ml of DMF were added 264 mg of sodium hydride (60% in mineral oil) at room temperature. After 15 min 449 mg of tetrabutylammonium iodide and 1.0 g of 2-Bromo-2-methyl-propionic acid ethyl ester were added and the reaction mixture was stirred for 16 h at room temperature. After dilution with saturated aqueous sodium hydrogen carbonate solution, the reaction mixture was filtered through a chem Elut® cartridge by eluting with ethyl acetate The solvents were removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 400 mg.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]1[CH:12]2[C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=3[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:11]2[CH2:10][CH2:9][N:8]1[CH2:26][C:27](OCC)=[O:28].[Cl-].[NH4+]>O1CCCC1>[CH2:7]1[CH:12]2[C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=3[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:11]2[CH2:10][CH2:9][N:8]1[CH2:26][CH2:27][OH:28]
Reactant: CCOC(=O)CN1CCN2c3ccccc3Cc3ccccc3C2C1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A suspension of 0.251 g of lithium aluminum hydride in 20 ml of tetrahydrofuran was added, whilst ice-cooling, over a period of 10 minutes to a solution of 2.22 g of ethyl (1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepin-2-yl)acetate [prepared by the same procedure as described in Example 3(b)] dissolved in 15 ml of tetrahydrofuran, under an atmosphere of nitrogen. The mixture was then stirred at 0° C. for 30 minutes and at room temperature for 2 hours, after which 2 ml of a saturated aqueous solution of ammonium chloride were added. The mixture was filtered, and the filtrate was extracted with ethyl acetate. The extract was washed with water and concentrated by evaporation under reduced pressure, to afford 1.65 g (yield 85%) of the title compound, melting at 123°-125° C.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([CH2:12][N:13]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:15]([CH2:16][C@H:17]([C:19]([OH:21])=[O:20])[NH2:18])=[CH:14]2)[CH2:11][CH2:10][CH2:9]1.[CH2:28]([O:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1)[C:29]#[C:30][CH3:31]>O.O1CCOCC1>[CH2:28]([O:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH:18][CH:17]([CH2:16][C:15]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:13]([CH2:12][CH:8]3[CH2:11][CH2:10][CH2:9]3)[CH:14]=2)[C:19]([OH:21])=[O:20])(=[O:41])=[O:40])=[CH:35][CH:34]=1)[C:29]#[C:30][CH3:31]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: N[C@H](Cc1cn(CC2CCC2)c2ccccc12)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CC#CCOc1ccc(S(=O)(=O)NC(Cc2cn(CC3CCC3)c3ccccc23)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Triethylamine (0.275 mL, 1.97 mmol) was added to a solution of crude 1-cyclobutylmethyl-D-tryptophan of Step 2 (0.657 mmol) and 4-but-2-ynyloxy-benzenesulfonyl chloride (0.177 g, 0.723 mmol) in H2O-dioxane (2 mL:3 mL) at room temperature. The reaction mixture was stirred for 20 hours at room temperature. The mixture was then concentrated and acidified with HCl. The mixture was extracted with ethyl acetate (3×10 mL). The organic solution was washed with H2O and brine, dried over Na2SO4, and concentrated. The residue was purified by RP-HPLC to give 0.152 g (48% in 3 steps) of the title compound as a yellow solid. 1H NMR (DMSO-d6): 400 MHz δ 12.57 (bs, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.49 (d, J=7.2 Hz, 2H), 7.37 (d, J=8.0 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.08 (t, J=7.4 Hz, 1H), 7.02 (s, 1H), 6.96-6.88 (m, 3H), 4.77 (q, J=2.4 Hz, 2H), 4.04 (d, J=6.8 Hz, 2H), 3.84 (q, J=6.8 Hz, 1H), 3.02 (dd J=14.4, 6.4 Hz, 1H), 2.82 (dd J=14.4, 8.4 Hz, 1H), 2.67 (p, J=7.6 Hz, 1H), 1.91 (m, 2H), 1.83 (m, 5H), 1.75 (m, 2H); HRMS: calcd for C26H29N2O5S (ESI+, [M+H]1+), 481.1792; found 481.1786; LCMS m/z (ESI) [M+H] 481, retention time=3.22 min.
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[NH2:15][CH2:14][C:8]1([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: N#CC1(Nc2ccccc2)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NCC1(Nc2ccccc2)CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
A solution of 5 g (25 mmol) of 1-phenylaminocyclohexanecarbonitrile in 70 ml of ethyl ether is added drop by drop to 1.13 g (29.8 mmol) of lithium aluminum hydride in 30 ml of ethyl ether at 0° C. The mixture is stirred for 2 hours at 0° C. The reaction is stopped by the addition of 1.1 ml of water, 1.1 ml of 15% sodium hydroxide and then 3.5 ml of water. The medium is then filtered on Celite and the filtrate is evaporated. The residue is purified on silica gel (dichloromethane then dichloromethane/methanol 80/20, v/v). 2 g of (1-aminomethylcyclohexyl)phenylamine are obtained in the form of a brown oil. Yield=39%.
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C@@H:9]12[CH2:15][C@@H:12]([CH2:13][NH:14]1)[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10]2.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:8][C:3]1[C:2]([N:14]2[CH2:13][C@@H:12]3[CH2:15][C@H:9]2[CH2:10][N:11]3[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1ncccc1Br
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Cc1ncccc1N1C[C@@H]2C[C@H]1CN2C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 53.3 %

Procedure:
3-Bromo-2-methylpyridine (258 mg, 1.5 mmol), tert-butyl (1S,4S)-3,6-diazabicyclo[2.2.1]heptane-3-carboxylate (397 mg, 2 mmol), Pd2(DBA)3 (30 mg, 0.033 mmol), sodium tert-butoxide (160 mg, 1.66 mmol), BINAP (60 mg, 0.096 mmol) were placed in anhydrous THF (5 ml), purged with argon and heated under microwave heating at 80° C. in a closed vial for 40 minutes. The mixture was filtered through kieselguhr, concentrated under reduced pressure and purified by column chromatography (silica, gradient from 0 to 50% ethyl acetate in DCM) to yield 230 mg of an orange solid (0.80 mmol, yield 53%). MS (ESI) m/z=290.1 [M+1]+.
Reaction SMILES: [CH2:1]=O.[Cl-].[CH:4]([C:6]1[C:7]([OH:35])=[C:8]([CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[CH:31]=1)[CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5].[OH-].[Na+].Cl>O.CS(C)=O>[N+:32]([C:30]1[CH:31]=[C:6]([CH:4]=[O:5])[C:7]([OH:35])=[C:8]([CH:9]=[CH2:1])[CH:29]=1)([O-:34])=[O:33]
Reactant: O=Cc1cc([N+](=O)[O-])cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1O
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=Cc1cc([N+](=O)[O-])cc(C=O)c1O
Reaction time: 11 h
Yield: 3 %

Procedure:
A 50.1 g (1.67 moles) quantity of paraformaldehyde was dissolved in 60 ml of water with heating, and a solution of 7.04 g (14.7 mmoles) of 3-formyl-2-hydroxy-5-nitrobenzyltriphenylphosphonium chloride in 100 ml of dimethylsulfoxide was added thereto, giving a homogeneous solution. Thereafter, a 12N aqueous solution of sodium hydroxide was gradually added to the solution at room temperature and the reaction was effected for 11 hours. A 260 ml quantity of water was added to the reaction mixture and the precipitated crystals of triphenylphosphine oxide were separated by filtration. The filtrate obtained was neutralized with diluted hydrochloric acid, followed by extraction with ether. The liquid extract was concentrated and the residue was recrystallized using chloroform, giving 1.23 g (yield: 3%) of 5-nitro-3-vinylsalicylaldehyde as yellow crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([NH:20][C:21]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCCNCc1ncccn1
Product: O=C(NC(=S)NCCNCc1ncccn1)c1ccccc1

Procedure:
By the procedure of Example 46, N-(2-pyrimidylmethyl)ethylenediamine is reacted with benzoyl isothiocyanate to give N-benzoyl-N'-[2-(2-pyrimidylmethylamino)ethyl]thiourea.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[NH:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]([O:21][CH3:22])=[O:20].[F:25][C:26]([F:43])([F:42])[C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][N:36]([CH2:39]CO)[CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1.[H-].[Na+]>C1(C)C=CC=CC=1>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[NH:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]([O:21][CH2:22][CH2:39][N:36]1[CH2:35][CH2:34][N:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:43])([F:25])[F:42])[CH:28]=2)[CH2:38][CH2:37]1)=[O:20]
Reactant: OCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: COC(=O)c1sccc1Nc1ccnc2c(C(F)(F)F)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(OCCN1CCN(c2cccc(C(F)(F)F)c2)CC1)c1sccc1Nc1ccnc2c(C(F)(F)F)cccc12
Temperature: 60 °C
Reaction time: 10 h
Yield: 92.3 %

Procedure:
A mixture of 7 g of methyl 3-(8-trifluoromethyl-4-quinolylamino)-2-thiophene-carboxylate, 6.17 g of 4-(3-trifluoromethylphenyl)-1-piperazine-ethanol and 50 ml of anhydrous toluene was refluxed for an hour while passing condensed toluene through a column filled with siliporite and the mixture was cooled to 60° C. 150 mg of sodium hydride were added and the mixture was refluxed with stirring for 10 hours. The toluene was distilled and the residue was extracted with ether, washed with water and dried. The product was crystallized from methylene chloride to obtain 10.9 g of 2-[4-(3-trifluoromethylphenyl)-1-piperazinyl]-ethyl 3-(8-trifluoromethyl-4-quinolylamino)-2-thiophene-carboxylate.
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[C:17]([C:19]4[C:20]5[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:21]=5[N:22]=[CH:23][N:24]=4)[CH:16]=[N:15]3)[CH2:11]2)[CH2:6][CH2:5]1.[F:39][C:40]1[C:48]([C:49]([F:52])([F:51])[F:50])=[N:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C)C=O.CCOC(C)=O>[F:39][C:40]1[C:48]([C:49]([F:52])([F:50])[F:51])=[N:47][CH:46]=[CH:45][C:41]=1[C:42]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:11][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[C:17]([C:19]4[C:20]5[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[C:21]=5[N:22]=[CH:23][N:24]=4)[CH:16]=[N:15]3)[CH2:13]2)[CH2:6][CH2:5]1)=[O:43]
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCN(C(=O)c6ccnc(C(F)(F)F)c6F)CC5)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride (1.22 g, 2.03 mmol), 3-fluoro-2-(trifluoromethyl)isonicotinic acid (460 mg, 2.2 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.07 g, 2.42 mmol), and triethylamine (2.0 mL, 14 mmol) in dimethylformamide (DMF) (20.0 mL) was stirred at room temperature overnight. LS-MS showed the reaction was complete. EtOAc (60 mL) and saturated NaHCO3 aqueous solution (60 mL) were added to the reaction mixture. After stirring at room temperature for 10 minutes, the organic phase was separated and the aqueous layer was extracted with EtOAc three times. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. Purification by flash chromatography provided the desired product {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. LC-MS: 684.3 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:12][NH:13][CH2:14][CH2:15][C:16]1[CH:26]=[CH:25][C:19]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:18][CH:17]=1.[BH4-].[Na+].CC(C)=O>CO>[OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:12][NH:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: CS(=O)(=O)Nc1ccc(CCNCC2CCc3ccccc3C2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: CS(=O)(=O)Nc1ccc(CCNCC2CCc3ccccc3C2O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound (XXI) (0.75 g) was combined with NaBH4 (0.14 g) in MeOH (30 ml) and stirred at ambient temperature for 31/2 hours. A further 0.14 g NaBH4 was added and the reaction was stirred a further 1/2 hour. Acetone (10 ml) was added. After stirring 18 hours, the solvent was evaporated and the residue was partitioned between EtOAc and aqueous NaHCO3. The EtOAc was evaporated, and the residue was chromatographed on a silica column, eluting the product with CH2Cl2 /MeOH as a gummy solid (0.5 g). This was converted to its HCl salt using EtOH/concentrated HCl and recrystallized from EtOH to yield Compound XXII.HCl (0.2 g), m.p. 214°-220° (dec.). The elemental analysis for C, H, and N and mass spectra were consistent with the structure indicated. The NMR spectrum suggested that the 1,2-trans-isomer was the principal constituent, though some of the 1,2-cis-isomer was present also.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].CN(C)C=O.[CH3:16][O:17][CH2:18]Cl>C(OCC)(=O)C.O>[CH3:16][O:17][CH2:18][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[I:3]
Reactant: COCCl
Reactant: Oc1ccccc1I
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccccc1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
216 mg of 60% oily sodium hydride was added to a mixture of 1.65 of 2-iodophenol and 20 ml of N,N-dimethylformamide under ice-cooling followed by stirring at room temperature for 30 minutes. Under ice-cooling, 570 μl of chloromethyl methyl ether was added thereto, followed by stirring for 30 minutes at room temperature. Water and ethyl acetate were added thereto. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed, to give 2.12 g of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[Br:22]Br>ClCCl>[NH2:1][C:2]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH2:9][C:10]([Br:22])([C:12]([O:14][CH3:15])=[O:13])[CH:11]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1=CCC(Br)(C(=O)OC)C=C1N
Temperature: 0 °C
Reaction time: 4 h

Procedure:
10.5 g (50 mmol) dimethyl amino-terephthalate and 8.1 ml (100 mmol) pyridine are dissolved in 175 ml dichloromethane and at −16° C. a solution of 2.7 ml (52.5 mmol) bromine in 25 ml dichloromethane is added dropwise. It is stirred for 4 hours at 0° C. and then heated overnight to ambient temperature. The mixture is added to ice water, washed three times with water and then dried over magnesium sulphate and evaporated down. The crude product is recrystallised from ethanol.