Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)=[CH:6][CH:5]=[C:4]([Cl:14])[C:3]=1[CH2:15][C:16]([NH:18][C:19]1[N:20]=[CH:21][S:22][C:23]=1[C:24]([O:26][CH3:27])=[O:25])=[O:17].[H-].[Na+].FC(F)(F)S(O[CH2:36][CH:37]([F:39])[F:38])(=O)=O>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)=[CH:6][CH:5]=[C:4]([Cl:14])[C:3]=1[CH2:15][C:16]([N:18]([CH2:36][CH:37]([F:39])[F:38])[C:19]1[N:20]=[CH:21][S:22][C:23]=1[C:24]([O:26][CH3:27])=[O:25])=[O:17]
Reactant: COC(=O)c1scnc1NC(=O)Cc1c(Cl)ccc(-c2ccc(Cl)s2)c1Cl
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1scnc1N(CC(F)F)C(=O)Cc1c(Cl)ccc(-c2ccc(Cl)s2)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under an atmosphere of argon, 300 mg (0.65 mmol) of methyl 4-({[2,6-dichloro-3-(5-chloro-2-thienyl)phenyl]acetyl}amino)-1,3-thiazole-5-carboxylate were dissolved in 15 ml of tetrahydrofuran, and 23 mg (0.97 mmol) of sodium hydride were added at room temperature. The reaction mixture was stirred at RT for 5 min, and a solution of 167 mg (0.78 mmol) of 2,2-difluoroethyl trifluoromethanesulfonate in 6 ml of THF was then added over a period of 10 min. The mixture is then stirred at RT for 12 h. The THF is removed under reduced pressure and the residue is taken up in water. The aqueous phase is extracted with dichloromethane and the organic phase is dried and concentrated by evaporation. The residue is chromatographed (acetonitrile/water (0.05% trifluoroacetic acid 20/80 to 100/0)). This gave 120 mg of methyl 4-[{[2,6-dichloro-3-(5-chloro-2-thienyl)phenyl]acetyl}(2,2-difluoroethyl)amino]-1,3-thiazole-5-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9]([CH2:12][N:13]=[C:14]=[O:15])([OH:11])=[O:10].O1CCOC[CH2:17]1>>[C:9]([CH2:12][NH:13][C:14]([N:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][C:4]1=[O:8])=[O:15])([O:11][CH3:17])=[O:10]
Reactant: C1COCCO1
Reactant: O=c1cc(O)cc[nH]1
Reactant: O=C=NCC(=O)O
Product: COC(=O)CNC(=O)n1ccc(O)cc1=O
Yield: 54 %

Procedure:
To 50 ml of a suspension of 2.00 g of 4-hydroxy-2-pyridone in dioxane was added 2.49 g of carboxymethylisocyanate and the resultant mixture was refluxed at 80° C. for 2 hours. After completion of the reaction, the dioxane was distilled off and diethylether was added to the residue to produce 2.20 g of the title compound in the form of solid in a yield of 54%.
Reaction SMILES: [CH3:1][Mg]Cl.[C:4](=[S:6])=[S:5].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C1COCC1>[C:4]([S:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[S:5])[CH3:1]
Reactant: S=C=S
Reactant: C[Mg]Cl
Reactant: BrCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=S)SCc1ccccc1
Temperature: 40 °C

Procedure:
Methyl magnesium chloride (10 mL, 3M solution in THF) was diluted with THF (10 mL) and the resulting solution warmed to 40° C. Carbon disulfide (2.28 g, 0.03 mol) was added over 10 minutes while maintaining the reaction temperature at 40° C. The reaction was cooled to room temperature before adding benzyl bromide (5.1 g, 0.03 mol) over 15 minutes. The reaction temperature was increased to 50° C. and maintained for a further 45 minutes. Water (100 mL) was added and the organic products extracted with n-hexane (3×60 mL). The combined organic extracts were washed with water, brine and dried over anhydrous magnesium sulfate. After removal of solvent and column chromatography (Kieselgel-60, 70-230 mesh, 5% diethyl ether in n-hexane eluent), pure benzyl dithioacetate was obtained as a golden oil (3 g, 55% yield). 1H-nmr (CDCl3) d(ppm): 2.90 (s, 3H); 4.46 (s, 2H) and 7.31 (m, 5H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10]1.Br[CH2:19][CH2:20][CH2:21][CH2:22][Cl:23]>>[Cl:23][CH2:22][CH2:21][CH2:20][CH2:19][C:9]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)C1CCC1
Reactant: ClCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCOC(=O)C1(CCCCCl)CCC1
Temperature: 0 °C

Procedure:
Compound 104b was prepared, likewise the procedure described for 104c, starting from LDA (prepared from BuLi (2.5M in hexanes, 52.8 mL, 132 mmol) and iPr2NH (18.52 mL, 132 mmol, distilled from NaOH)), ethyl 1-cyclobutanecarboxylate (Török, B. et al. J. Chem. Soc. Perkin Trans. 1, 1993, 7, 801-804) (14.05 g, 110 mmol) (the resulting mixture was allowed to warm to 0° C. and cooled again to −60° C.) and 1-bromo-4-chlorobutane (19.1 mL, 165 mmol) to give, after purification by fractional distillation under reduced pressure, 104b (20.53 g, 86%) as a thin, colorless oil. bp: T=64-71° C. (p=0.001 Torr). 1H NMR: δ 4.13 (q, J=7.1 Hz, 2H), 3.51 (t, J=6.8 Hz, 2H), 2.50-2.32 (m, 2H), 1.96-1.70 (m, 8H), 1.40-1.20 (m, 2H), 1.26 (t, J=7.2 Hz, 3H). 13C NMR: δ 176.6, 60.3, 47.6, 44.8, 37.3, 32.8, 30.1 (2×), 22.4, 15.8, 14.4.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:25]2[C:30]([Cl:31])=[CH:29][N:28]=[C:27](F)[CH:26]=2)=[N:4][C:5]([N:8]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][C:19]([CH3:24])([CH3:23])[CH2:18]2)C(=O)OC(C)(C)C)=[CH:6][CH:7]=1.[NH2:33][C@H:34]1[CH2:39][CH2:38][C@H:37](N)[CH2:36][CH2:35]1.CC[N:43](C(C)C)C(C)C>CS(C)=O.O>[NH2:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([C:7]2[CH:6]=[C:5]([NH:8][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][C:19]([CH3:23])([CH3:24])[CH2:18]3)[N:4]=[C:3]([C:25]3[C:30]([Cl:31])=[CH:29][N:28]=[C:27]([NH2:43])[CH:26]=3)[C:2]=2[Cl:1])[CH2:36][CH2:35]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N(CC1CCOC(C)(C)C1)c1ccc(Cl)c(-c2cc(F)ncc2Cl)n1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)CC(CNc2cc([C@H]3CC[C@H](N)CC3)c(Cl)c(-c3cc(N)ncc3Cl)n2)CCO1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3,5′-dichloro-2′-fluoro-2,4′-bipyridin-6-yl((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate (40 mg, 0.083 mmol) in DMSO (0.4 mL) was added trans-1,4-diaminocyclohexane (47 mg, 0.41 mmol) and DIEA (0.029 mL, 0.17 mmol). The mixture was stirred at 120° C. for 2 hr. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was re-dissolved in trifluoroacetic acid (1 mL), stirred for 15 min at ambient temperature, and then concentrated under reduced pressure. The resulting residue was taken up in DCM, washed with saturated aqueous sodium bicarbonate, dried (Na2SO4), filtered, and concentrated to give 39 mg of NT-(trans-4-aminocyclohexyl)-3,5′-dichloro-N6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine. LCMS (m/z): 478.4 (MH+), retention time=0.64 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([O:7]C)=O.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCN2CCCN=C12.BrC1C=CC2N(N=CC=2C(NC2C=C(C(=O)NCC3C=CC=CC=3N3CCN(C)CC3)C=CC=2C)=O)C=1>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([NH:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:7]
Reactant: COC(=O)c1ccc(F)c(N)c1
Reactant: NCc1ccccc1
Agent: C1CN=C2NCCCN2C1
Agent: Cc1ccc(C(=O)NCc2ccccc2N2CCN(C)CC2)cc1NC(=O)c1cnn2cc(Br)ccc12
Product: Nc1cc(C(=O)NCc2ccccc2)ccc1F

Procedure:
The title compound was prepared from methyl 3-amino-4-fluorobenzoate, benzylamine and 2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine analogously to 3-amino-4-methyl-N-(2-(4-methylpiperazin-1-yl)benzyl)benzamide (Intermediate 4A, step 1);
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:28])[C@@H:15]([O:24][CH:25]([CH3:27])[CH3:26])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)C1C=CC=CC=1.[OH:29]O.[OH-].[Li+].O>O1CCCC1>[OH:23][C:19]1[CH:18]=[C:17]([CH2:16][C@H:15]([O:24][CH:25]([CH3:26])[CH3:27])[C:14]([OH:28])=[O:29])[CH:22]=[CH:21][CH:20]=1
Reactant: OO
Reactant: CC(C)O[C@@H](Cc1cccc(O)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)O[C@@H](Cc1cccc(O)c1)C(=O)O
Reaction time: 8 h

Procedure:
1.535 g of 4 (S)-Benzyl-3-[3-(3-hydroxyphenyl)-2 (S)-isopropoxypropionyl]oxazolidin-2-one was dissolved in 40 ml of tetrahydrofuran, and 3.3 ml of 30% aqueous hydrogen peroxide and 12 ml of 1N aqueous lithium hydroxide were successively added under ice-cooling, and stirring was continued at room temperature overnight. After adding water to the reaction solution, the mixture was extracted with dichloromethane and the aqueous layer was acidified by 1N hydrochloric acid. Following extraction (×3) was conducted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressures, to give 847 mg of 3-(3-hydroxyphenyl)-2(S)-isopropoxypropanoic acid. This product was then dissolved in 10 ml of N,N-dimethylformamide, and 400 mg of potassium hydrogencarbonate and 0.32 ml of ethyl iodide were successively added thereto, and stirring was continued at room temperature for 3 days. The reaction solution was diluted with ethylacetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 567 mg of the title compound as a colorless oil in the 3:1 hexane-ethyl acetate fraction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13](SC)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:19]C(O)(C)C.O[O:25][S:26]([O-:28])=O.[K+]>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:18])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([S:26]([CH3:19])(=[O:28])=[O:25])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)O
Reactant: CSc1ccc(CC(O)c2ccc(F)cc2)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(CC(O)c2ccc(F)cc2)cc1
Reaction time: 72 h

Procedure:
To a suspension of the product of step 1 (42 g, 160 mmol) in a mixture of CH2Cl2 (200 mL), t-BuOH (500 mL) was added a suspension of oxone (144 g, 234 mmol) in 1 L of H2O. The mixture was stirred for 72 h. CH2Cl2 was added until all solid dissolved. The resulting mixture was extracted with EtOAc. The organic extracts were dried (Na2SO4) and concentrated to give 47 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Na+].[I-].CN(C)[C:13]1[C:22]2[C:17](=CC=C[C:21]=2N(C)C)C=CC=1.Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CC#N>[C:32]([O:31][C:29](=[O:30])[CH2:28][N:1]([CH2:28][C:29]([O:31][C:22]([CH3:21])([CH3:13])[CH3:17])=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])([CH3:35])([CH3:34])[CH3:33]
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Nc1ccccc1O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)c1ccccc1O
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A solution of 2-aminophenol (10) (5.0 g, 45.8 mmol) and NaI (3.44 g, 23 mmol) in dry CH3CN (150 mL) was treated with 1,8-bis(dimethylamino) naphthalene (21.6 g, 100.8 mmol) followed by t-butyl bromoacetate (14.2 mL, 96.2 mmol) under an Ar atmosphere and stirred at reflux overnight. After the mixture was cooled to room temperature, the precipitated salts were filtered off and washed with additional EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography, eluting with CH2Cl2/hexane/EtOAc=1:4:0.2 to yield 12.3 g (80%) of the desired product (11) as a light yellow oil. Rf=0.3 (in CH2Cl2/hexane/EtOAc=1:4:0.2); 1H NMR (300 MHz, CDCl3) δ 7.29 (dd, 7.9 and 1.5 Hz, 1H), 7.07 (m, 1H), 6.94 (dd, 8.1 and 1.5 Hz, 1H), 6.79 (m, 1H), 5.30 (s, 1H), 3.74 (s, 4H), 1.46 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 171.2, 153.6, 137.4, 127.3, 126.0, 119.9, 115.6, 81.9, 57.0, 28.0; mass spectrum, calculated for C18H27NO5 (MH+) 338.2, Found 337.9.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH3:13])([O-:3])=[O:2].[CH2:14]=[O:15].[K].Cl.CN1[C:23](=[O:24])CCC1>>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH:13]([CH2:23][OH:24])[CH2:14][OH:15])([O-:3])=[O:2]
Reactant: C=O
Reactant: Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CN1CCCC1=O
Agent: Cl
Agent: [K]
Product: O=[N+]([O-])c1ccc(C(CO)CO)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20 g (106.5 mmol) of 2,4-dinitrotoluene is solubilized in 280 ml of NMP. To the brown solution is added 7.6 g (255.6 mmol) of paraformaldehyde. To the suspension is added 597 mg (5.32 mmol) of potassium tetrabutoxyde. The resulting solution is stirred overnight at RT. The mixture was poured onto 200 ml ice, and neutralized with 2 mL of HCl 25%. The reaction mixture is then partitioned between ethyl acetate and water; the organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The solution is precipitate at RT by adding 150 ml of heptane. The product is filtrated and dried under vacuum at RT to give 16.1 g of 2-(2,4-dinitrophenyl)propane-1,3-diol as a slightly yellow product.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][O:11][C:12](=[O:27])[C:13]1[CH:18]=[C:17](F)[C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=1[N+:24]([O-:26])=[O:25].CC#N>O1CCCC1>[CH3:10][O:11][C:12](=[O:27])[C:13]1[CH:18]=[C:17]([N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[O:3])[C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=1[N+:24]([O-:26])=[O:25]
Reactant: Oc1ccccn1
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COC(=O)c1cc(-n2ccccc2=O)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.7 %

Procedure:
To a suspension of NaH (315 mg, 1.4 eq) in 50 ml of tetrahydrofuran, a solution of 2-hydroxypyridine (801 mg, 1.5 eq) in 5 ml of tetrahydrofuran is added drop-wise. The mixture is stirred at room temperature for 30 min before addition of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester (1.5 g, 5.61 mmol) in 10 ml of tetrahydrofuran. The resulting mixture is stirred at room temperature for 16 hours. The solvent is removed in vacuo and the crude oil is solubilised in ethyl acetate. The organic phase is washed with sat NaHCO3 solution, dried over sodium sulfate and concentrated in vacuo to afford a crude yellow oil. The crude product is purified by flash-chromatography (ethyl acetate/hexane (0:100 to 100:0)) to obtain 2-nitro-5-(2-oxo-2H-pyridin-1-yl)-4-trifluoromethyl-benzoic acid methyl ester as a yellow solid (1.3 g, 68% yield) (ES-MS: m/z 328 [M+H+CH3CN]+, Rt 4.67 min.).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][CH:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Cl.[F:20][CH2:21][CH2:22][NH2:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[F:20][CH2:21][CH2:22][NH:23][CH:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)[CH2:13][CH2:14]1
Reactant: NCCF
Reactant: O=C1CCC(Nc2cccc3cnccc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: FCCNC1CCC(Nc2cccc3cnccc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.1 %

Procedure:
4-(5-Isoquinolylamino)-1-cyclohexanone (intermediate 4) (60 mg) and 2-fluoroethylamine hydrochloride (50 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC g [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (18 mg) and a syn-form compound (12 mg).
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(OCC)(=O)C>[CH2:18]([O:17][C:15]([N:7]([CH3:6])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)CNC
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A rapidly stirred mixture of ethyl acetate and saturated aqueous sodium bicarbonate containing commercially available commercially available 2 ethyl 2-(methylamino)acetate (1.91 g, 12.4 mmol, HCl salt) was cooled to 0° C. and treated dropwise with benzyl chloroformate (4.10 mL, 12.3 mmol). After stirring overnight warming to room temperature, the aqueous layer was removed and the organic layer concentrated in vacuo. Purification of the residue by flash chromatography (silica gel, DCM) yielded the product.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH:4]2[CH2:3]1.Cl.O1CCOCC1>ClCCl>[CH2:13]1[N:5]2[C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[NH:8][C:2](=[O:1])[CH2:3][CH:4]2[CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ccccc3NC(=O)CC2C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1CC2CNCCN2c2ccccc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 1C (1.78 g, 5.61 mmol) in dichloromethane (100 mL) was added 4 M HCl/dioxane (14.02 mL, 56.1 mmol). The solution was stirred for 2-4 hours at room temperature, and title compound was collected by filtration as the hydrochloric acid salt. 1H NMR (500 MHz, pyridine-d5) δ ppm 7.34-7.42 (m, 1H), 7.24-7.31 (m, 1H), 7.16-7.23 (m, 1H), 7.11 (d, J=7.02 Hz, 1H), 3.92-4.00 (m, 1H), 3.88 (d, J=11.90 Hz, 1H), 3.80 (d, J=12.82 Hz, 1H), 3.64-3.74 (m, 1H), 3.57 (t, J=11.90 Hz, 1H), 3.11-3.24 (m, 2H), 2.64 (dd, J=13.43, 7.02 Hz, 1H), 2.37 (d, J=12.82 Hz, 1H); MS (ESI) m/z 217.9 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:18]#[N:19])[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[I-].[K+]>>[O:23]1[CH2:24][CH2:25][N:20]([CH2:2][CH2:3][CH2:4][C:5]2([C:18]#[N:19])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:21][CH2:22]1
Reactant: C1COCCN1
Reactant: N#CC1(CCCCl)c2ccccc2-c2ccccc21
Agent: [I-]
Agent: [K+]
Product: N#CC1(CCCN2CCOCC2)c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
9-Cyanofluorene was reacted with sodium amide and 1,3-dichloropropane to give 9-(3-chloropropyl)-9-cyanofluorene. A solution of 10.0 g. of 9-(3-chloropropyl)-9-cyanofluorene in 200 ml. of morpholine containing 2.0g. of potassium iodide was stirred at 160° C. for sixteen hours. After cooling the reaction mixture to room temperature, the solution was diluted with 500 ml. of water, and the aqueous mixture was extracted several times with ethylacetate. The organic extracts were combined, washed with water, and the product was extracted therefrom into 0.6 N hydrochloric acid. The aqueous acid layer was separated and made alkaline by the addition of 10 percent sodium hydroxide solution. The alkaline solution was extracted with fresh ethyl acetate, and the extracts were combined, washed with water and dried. Removal of the solvent by evaporation under reduced pressure provided 9-(3-morpholinopropyl)-9-cyanofluorene.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[Cl:11][C:8]1[N:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([F:23])=[CH:25][CH:26]=2)=[O:35])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Cl)nc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Cl)nc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(6-chloro-3-pyridyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (250 mg, 0.76 mmol) in acetonitrile (15 ml) were added 4-fluoronaphthalenecarboxylic acid (144 mg, 0.76 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (218 mg, 1.14 mmol) and 1-hydroxy-1H-benzotriazole (116 mg, 0.76 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (324 mg, 85%).
Reaction SMILES: [Br:1][C:2]1[C:3](C)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.S(O[CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)(C1C=CC(C)=CC=1)(=O)=O.[C:37](=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[Br:1][C:2]1[C:10]([CH3:37])=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:28][CH2:29]3)[N:7]=2)[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Br)ccc2[nH]ncc12
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2nn(CC3CCN(C(=O)OC(C)(C)C)CC3)cc2cc1Br
Temperature: 80 °C

Procedure:
10.0 g (47.4 mmol) of 5-bromo-4-methyl-1H-indazole and 21.0 g (56.9 mmol) of tert-butyl 4-[(tosyloxy)methyl]piperidin-1-carboxylate were dissolved in 726 ml DMF. To this were added 21.0 g (56.9 mmol) of tetrabutylammonium iodide and 18.5 g (56.9 mmol) of caesium carbonate and the reaction mixture was heated under nitrogen at 80° C. for 1.5 hrs. For the work-up, it was treated with water and ethyl acetate, the organic phase separated and the aqueous phase extracted several times with ethyl acetate. The organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. After purification by column chromatography, this yielded the title compound in 5 g yield.
Reaction SMILES: [C:1]([C:5]#[CH:6])([CH3:4])([CH3:3])[CH3:2].Br[CH2:8][CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.C(OCC)C>O1CCCC1>[CH3:2][C:1]([CH3:4])([CH3:3])[C:5]#[C:6][CH2:8][CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: C#CC(C)(C)C
Reactant: BrCCCOC1CCCCO1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)C#CCCCOC1CCCCO1
Temperature: -78 °C
Yield: 40.7 %

Procedure:
0.81 g of tert-butylacetylene was dissolved in 19 ml of tetrahydrofuran, and 6.1 ml of a 0.55M n-butyllithium-hexane solution was added dropwise with stirring at -78° C. After the mixture was stirred at this temperature for 1 hour, 2.2 g of 3-bromo-1-(2-tetrahydropyranyloxy)propane was added. The solution was warmed to the room temperature, and then heated at 80° C. with stirring for 8 hours. The reaction mixture was poured into the ice water, and ethyl ether was added. The organic layer separated was worked up in a customary manner, and the product was purified by silica gel column chromatography [hexane / ethyl acetate=20 /1] to give 0.90 g of 6,6-dimethyl-1-(2-tetrahydropyranyloxy)-4-heptyne.