Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1/[CH:11]=[CH:12]/[CH:13]=[C:14](/[N:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)\[C:15]([O:17][CH2:18][CH3:19])=[O:16].[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][C:42]=1[OH:49]>C(#N)C>[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([C:45]2[N:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:12][C:11]=2[C:4]2[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[CH:43][C:42]=1[OH:49]
Reactant: CCOC(=O)/C(=C\C=C\c1c(OC)cccc1OC)N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Cl)c(O)c1
Solvent: CC#N
Product: CCOC(=O)c1ccc(-c2c(OC)cccc2OC)c(-c2ccc(Cl)c(O)c2)n1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
Reflux a solution of 7.54 g (14 mmol) of ethyl (2E,4E)-5-(2,6-dimethoxyphenyl)-2-[(triphenylphosphoranylidene)amino]penta-2,4-dienoate and 2.42 g (15.4 mmol) of 4-chloro-3-hydroxybenzaldehyde in 280 mL of anhydrous acetonitrile for 96 h. After cooling to RT, concentrate the reaction mixture under reduced pressure and purify the residue obtained by silica gel column chromatography, eluting with a cyclohexane/ethyl acetate (EtOAc) gradient from 0 to 30% of EtOAc. After concentration under reduced pressure, we obtain 2.4 g of ethyl 6-(4-chloro-3-hydroxyphenyl)-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylate in the form of white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[O:10][C:11]([C:14]3[N:15](C(OC(C)(C)C)=O)[C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[C:14]1[C:11]1[O:10][C:9]([NH:8][C:4]2[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=2)=[N:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cnc(Nc3cccc(O)c3)o2)cc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1cccc(Nc2ncc(-c3cc4ccccc4[nH]3)o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
To a stirred solution of tert-butyl 2-(2-((3-hydroxyphenyl)amino)oxazol-5-yl)-1H-indole-1-carboxylate 22 (0.125 g, 0.319 mmol) in anhydrous CH2Cl2 (20 mL) was added 1:1 mixture of CH2Cl2:Trifluoroaceticacid (5 mL) at 0° C. Reaction was stirred for 1 hour at ambient temperature. It was quenched with aq. saturated NaHCO3 and CH2Cl2 layer was separated. After evaporation of solvent, crude product was purified using preparative-TLC to obtain 3-((5-(1H-indol-2-yl)oxazol-2-yl)amino)phenol 23 (0.027 g, 16% yield).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[C:18]1([C:15]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][N:8]([CH3:7])[C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH2:17][CH2:16]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CNCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)N(C)CCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reaction time: 1 h
Yield: 89.4 %

Procedure:
Diketene (0.98 mL, 12.7 mmol, 1.50 equiv) was added at 0° C. to a stirred solution of 1-[3-(N-methylamino)propyl]-4,4-diphenylpiperidine (2.61 g, 8.46 mmol, 1.00 equiv) in anhydrous toluene (30 mL) under argon, and stirring was continued for 1 hour. After removal of the solvent, the residue was purified by flash chromatography (SiO2, EtOAc-MeOH-isopropylamine 9:1:0 to 6:1:0.1) to afford 2.97 g (89%) of brown oil, which was characterized spectroscopically.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[OH-].[Na+].[O:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][OH:20].Cl>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:20][CH2:19][CH:15]1[CH2:16][CH2:17][CH2:18][O:14]1
Reactant: OCC1CCCO1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OCC2CCCO2)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of 2-bromo-1-fluoro-4-nitro-benzene (5.0 g, 22.72 mmol) in DMSO (40 mL) was added NaOH (1.36 g, 34.09 mmol) and (tetrahydrofuran-2-yl)methanol (3.47 g, 34.09 mmol) at 0° C. The mixture was stirred at RT for 1 h, then poured into H2O (50 mL), the pH adjusted ˜7 with 1M HCl and extracted with EtOAc (2×250 mL). The combined organics were washed with H2O, brine, dried (Na2SO4), filtered and concentrated in vacuo to obtain i (6.50 g, 95%). 1HNMR (CDCl3, 400 MHz): δ 8.46 (d, J=2.40 Hz, 1H), 8.20 (dd, J=2.40 and 9.20 Hz respectively, 1H), 6.98 (d, J=9.20 Hz, 1H), 4.36 (m, 1H), 4.16 (m, 2H) 3.97 (m, 1H) 3.86 (m, 1H) 2.07 (m 2H) and 1.95 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](C[C@H]4C[O:21]C(=O)N4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.N(C1C=CC(C[C@@H:32]2[CH2:36][O:35][C:34](=[O:37])[NH:33]2)=CC=1)N.O.CN1CC=C(C2C3C(=CC=C(C[C@@H]4COC(=O)N4)C=3)NC=2)CC1.Cl>>[OH2:21].[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C@@H:32]4[CH2:36][O:35][C:34](=[O:37])[NH:33]4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CC=C(c2c[nH]c3ccc(C[C@H]4COC(=O)N4)cc23)CC1
Reactant: NNc1ccc(C[C@@H]2COC(=O)N2)cc1
Agent: CN1CC=C(c2c[nH]c3ccc(C[C@@H]4COC(=O)N4)cc23)CC1
Agent: Cl
Solvent: O
Product: CN1CC=C(c2c[nH]c3ccc([C@@H]4COC(=O)N4)cc23)CC1

Procedure:
By steps analogous to steps (a) to (c) of Synthetic Example 14, the product from step (a) was converted to (R)-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridyl)-5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indole hydrate, mp 229°-231° C., [α]D18 +24.9° (c=0.5, 1N aqu. HCl). Elemental analysis and 1H NMR were consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([S:14]([O-:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)[CH2:4]1.[Li+].C1C(=O)N([Cl:25])C(=O)C1.CN1CCC2C(=C(N)C=CC=2)C1>ClCCl>[CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([S:14]([Cl:25])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)[CH2:4]1
Reactant: COC1CCN(c2cccc(S(=O)[O-])c2)C1
Reactant: O=C1CCC(=O)N1Cl
Agent: CN1CCc2cccc(N)c2C1
Agent: [Li+]
Solvent: ClCCl
Product: COC1CCN(c2cccc(S(=O)(=O)Cl)c2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Into a 250 mL round bottom flask was placed a solution of lithium 3-(3-methoxypyrrolidin-1-yl)benzenesulfinate (12 g, 29.15 mmol) in dichloromethane (100 mL). To the above was added NCS (4.48 g, 33.56 mmol) in several batches, while cooling to a temperature of 0° C. over a time period of 10 minutes. The resulting solution was allowed to react, with stirring, for 15 minutes while the temperature was maintained at 0° C. in a bath of H2O/ice, then the ice bath was removed and the solution was allowed to react for an additional 25 minutes at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether 5=1:1). The resulting mixture was washed 2 times with 50 mL of NaHSO3 and 2 times with 50 mL of brine. The mixture was dried over Na2SO4 and concentrated by evaporation under vacuum using a rotary evaporator. The residue was purified by eluting through a column with a 2:3 ethyl acetate/petroleum ether solvent system. This resulted in 6.6 g (82.5%) of 3-(3-methoxypyrrolidin-1-yl)benzene-1-sulfonyl chloride as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].CCN(CC)CC.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:25])=[O:24])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Cl
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(OS(=O)(=O)c2ccccc2)ccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-chloro-3-methylphenol (1.0 g, 7.0 mmol) in dry CH2Cl2 (70 mL) at 0° C. was added Et3N (1.45 mL, 10.5 mmol). After stirring at 0° C. for 20 min, benzenesulfonyl chloride (1.34 mL, 10.5 mmol) was added to the reaction mixture. The reaction was slowly warmed to room temperature and stirring was continued for an additional 18 h. Water was added to quench the reaction and the organic layer was washed with brine and dried over Na2SO4. The solvent was removed in vacuo and resulting crude product was purified by flash column chromatography (silica gel, 10-30% CH2Cl2/hexanes). The desired product was obtained as a white solid (1.9 g, 96%). LC/MS (ES+) m/e 283.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=2)O1>>[O:27]1[CH2:28][CH2:29][N:24]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([N:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]5)[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:38]3[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=3)[N:3]=2)[CH2:25][CH2:26]1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCCCC4)CC3)cc2n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCC(N5CCCCC5)CC4)cc3n2)cn1

Procedure:
1′-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-[1,4′]bipiperidinyl (Example 24) was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine in General Procedure A. Purification on silica yielded 114. NMR (CDCl3): 1.50 (m, 2H, CH2), 1.58-1.70 (m, 6H, 3×CH2), 1.80 (m, 2H, CH2), 2.12 (m, 2H, CH2), 2.30 (m, H, CH), 2.53 (m, 4H, 2×CH2), 3.05 (m, 2H, CH2), 3.82 (s, 2H, CH2), 3.89-3.91 (m, 4H, 2×CH2), 4.03-4.06 (m, 4H, 2×CH2), 5.23 (sbr, 2H, NH2), 7.26 (s, H, ArH), 9.30 (s, 2H, 2×ArH). MS: (ESI+): MH+=495.49
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C@H:12]3[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14][CH2:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl.N1C=CC=CC=1.ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C@H:12]3[CH2:13][CH2:14][C@H:15]([NH:18][C:19](=[O:21])[CH3:20])[CH2:16][CH2:17]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: N[C@H]1CC[C@H](Oc2ccc3cnccc3c2)CC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N[C@H]1CC[C@H](Oc2ccc3cnccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.4 g (34.7 mmol) of 4-(isoquinolin-6-yloxy)-cyclohexylamine (15) were dissolved in 100 ml of dichloromethane/pyridine (4:1). At 0° C. a solution of 3.27 g (41.6 mmol) of acetyl chloride in 10 ml of dichloromethane was added and the reaction mixture was stirred at room temperature. After 2 h, the solution was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. After washing twice with 2 N HCl, the product was transferred to the aqueous phase. The HCl-layers were adjusted to alkaline pH by addition of solid NaOH and extracted three times with dichloromethane. Drying the organic layers with magnesium sulfate and evaporation of the solvent gave 7.69 g of the crude product. After silica gel chromatography 4.48 g of the title compound were isolated. Rt=0.87 min (Method A). Detected mass: 285.2 (M+H+).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21][CH3:22])=[CH:10][CH:9]=2.C(N(CC)CC)C.Cl[CH2:33][CH2:34][CH2:35][C:36](Cl)=[O:37]>ClCCl>[CH3:22][O:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:23])[N:6]([CH3:24])[C:5]([CH2:4][CH2:3][N:2]1[CH2:33][CH2:34][CH2:35][C:36]1=[O:37])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)CCCCl
Reactant: COc1ccc2c(=O)n(C)c(CCN)c(-c3ccccc3)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(=O)n(C)c(CCN3CCCC3=O)c(-c3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-(2-aminoethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one hydrochloride (125 mg, 0.362 mmol) in 15 mL of dichloromethane was added triethylamine (0.202 mL, 1.45 mmol), followed by 4-chlorobutanoyl chloride (0.045 mL, 0.40 mmol). After 45 minutes, the mixture was concentrated in vacuo. Tetrahydrofuran was added (15 mL), and the solution was cooled to 0° C. Sodium hydride was added (58 mg, 60% dispersion in mineral oil, 1.45 mmol). The reaction mixture was stirred at 0° C. for 30 minutes, at room temperature for 16 hours, then at 50° C. for 2 hours. The solution was partitioned between EtOAc and saturated NaHCO3 solution, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC to provide the titled product. Proton NMR for the product was consistent with the titled compound. ESI+MS: 377.27 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:9][CH:8]2[CH2:10][NH:11][C:12]([C:14]2[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[C:1]1([CH:7]2[CH2:9][CH:8]2[CH2:10][NH:11][C:12]([C:14]2[N:15]=[N:16][C:17]([N:24]3[CH2:25][CH2:26][N:21]([C:27](=[O:28])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:38])([F:36])[F:37])[CH2:22][CH2:23]3)=[CH:18][CH:19]=2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(NCC1CC1c1ccccc1)c1ccc(Cl)nn1
Product: O=C(NCC1CC1c1ccccc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-phenylcyclopropylmethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (25% yield). 1H NMR (400 MHz, CDCl3) δ 8.09-8.03, 7.76, 7.64, 7.57, 7.36, 7.28-7.21, 7.17-7.12, 7.07-6.96, 4.09-3.32, 1.92-1.86, 1.47-1.38, 1.01-0.96. MS (ES+) m/z 510.4 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:9][CH:8]=[CH:7][CH:6]=2.[C:21](OC)(OC)(OC)[CH2:22][CH2:23][CH3:24]>C1(C)C=CC=CC=1.Cl.N1C=CC=CC=1>[CH2:22]([C:21]1[N:12]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]2[C:10]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:23][CH3:24]
Reactant: CCCC(OC)(OC)OC
Reactant: CCOC(=O)CCCNc1c(N)cnc2cccnc12
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCc1nc2cnc3cccnc3c2n1CCCC(=O)OCC
Temperature: 25 °C

Procedure:
The preparation of ethyl 4-[(3-amino[1,5]naphthyridine-4-yl)amino]butyrate is described in Parts A-B of Example 4. Trimethyl orthobutyrate (9.1 mL, 57.2 mmol) and pyridine hydrochloride (110 mg, 0.95 mmol) were added to a solution of ethyl 4-[(3-amino-[1,5]naphthyridine-4-yl)amino]butyrate (13.08 g, 47.7 mmol) in toluene (190 mL) and heated at reflux for 3 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (200 mL) and washed with saturated aqueous sodium bicarbonate (150 mL). The aqueous layer was extracted with dichloromethane (2×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 14.9 g of ethyl 4-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-butyrate as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[F:10][C:11]([F:17])([F:16])[CH2:12][CH2:13][CH2:14][OH:15].[F:18][C:19]([F:25])([F:24])S(O)(=O)=O>O>[Br:1][C:2]1[C:3]([O:15][CH2:14][CH2:13][CH2:12][C:19]([F:25])([F:24])[F:18])=[N:4][C:5]([O:15][CH2:14][CH2:13][CH2:12][C:11]([F:17])([F:16])[F:10])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: OCCCC(F)(F)F
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: FC(F)(F)CCCOc1ncc(Br)c(OCCCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
3.19 g (14 mmol) of 5-bromo-2,4-dichloropyrimidine is mixed with 8.06 g (63 mmol) of 4,4,4-trifluorobutanol, and 0.74 ml (8.4 mmol) of trifluoromethanesulfonic acid is slowly added to it. The reaction mixture is stirred overnight at room temperature and then poured into water. The mixture is extracted by means of ethyl acetate, the combined organic phases are dried on MgSO2, and the solvent is evaporated by means of underpressure. The product is always contaminated with varying amounts of 2,4-bisalkoxypyrimidine. The remaining material is therefore purified by means of gradient chromatography with silica gel as a carrier medium (eluant: hexane and hexane/ethyl acetate at a 9:1 ratio). This process results in a yield of 1.70 g (38%) and also yields 1.93 g (34%) of 5-bromo-2,4-bis-(4,4,4-trifluorobutoxy)pyrimidine (starting compound).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])C.N[C@H:11](C(O)=O)CC1C=CC(O)=CC=1>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:4][CH3:6])[CH3:11]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)O

Procedure:
0.94 (1), Leu; 5.10 (5), Tyr; 0.74 (1),
Reaction SMILES: O.[CH3:2][C@@:3]12[C:11](=[O:12])[CH2:10][CH2:9][C@H:8]1[C@@H:7]1[CH2:13][CH2:14][C:15]3[C@@H:21]([C@H:6]1[CH2:5][CH2:4]2)[CH2:20][CH2:19][C:17](=[O:18])[CH:16]=3.Cl[CH2:23][CH2:24]Cl>>[CH3:2][C@@:3]12[C@:11]([OH:12])([C:23]#[CH:24])[CH2:10][CH2:9][C@H:8]1[C@@H:7]1[CH2:13][CH2:14][C:15]3[C@@H:21]([C@H:6]1[CH2:5][CH2:4]2)[CH2:20][CH2:19][C:17](=[O:18])[CH:16]=3
Reactant: ClCCCl
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Solvent: O
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C

Procedure:
A water-jacketed glass column of 2.7 cm inner diameter is packed with a suspension of 50.0 g of basic alumina (sold by Shokubai Kasei Kogyo Co. Ltd. under trade name of ACBR-3, calcined at a temperature above 500° C. and pulverized to about 50 mesh) in 100 ml of 1,2-dichloroethane (to a depth of 13.0 cm) and water is passed through the jacket so as to set the temperature at 20° C. In 1400 ml of 1,2-dichloroethane, 20.00 g of crude 19-norethisterone of 91.8% purity which results from ethynylation of 19-norandrost-4-ene-3,17-dione and which contains 1.7% ethynylestradiol in addition to other impurities is dissolved at 20° C. and the resulting solution is introduced on the top of the column at a linear velocity of 2 m/hr using a feed pump. The 1,2-dichloroethane solution passed through the alumina is received in an Erlenmeyer flask. After the solution of 19-norethisterone in 1,2-dichloroethan has been passed, 500 ml of 1,2-dichloroethane is further passed through the alumina to wash it. The two liquids are combined and concentrated to dryness at reduced pressure with 1,2-dichloroethane being distilled off.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][O:17][C@H:18]1[CH2:25][N:24]2[C:26]3[CH:27]=[C:28]([C:39]([O:41][CH3:42])=[O:40])[CH:29]=[CH:30][C:31]=3[C:32]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[C:23]2[C:22]2[CH:43]=[CH:44][CH:45]=[CH:46][C:21]=2[O:20][CH2:19]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:33]1([C:32]2[C:31]3[CH:30]=[CH:29][C:28]([C:39]([O:41][CH3:42])=[O:40])=[CH:27][C:26]=3[N:24]3[C:23]=2[C:22]2[CH:43]=[CH:44][CH:45]=[CH:46][C:21]=2[O:20][CH2:19][C@@H:18]([O:17][CH2:16][CH:12]2[CH2:13][CH2:14][CH2:15][N:11]2[CH2:10][CH2:9][NH:8][CH3:6])[CH2:25]3)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OCC1CCCN1CCN(C)C(=O)OC(C)(C)C)COc1ccccc1-3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCN1CCCC1CO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A solution of methyl (7S)-7-[(1-{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}pyrrolidin-2-yl)methoxy]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.06 M) in DCM was treated with an excess of TFA (>50 eq). The mixture was stirred at RT for 2 h. Volatiles were removed in vacuo and the residue partitioned between EtOAc and sat. aq. NaHCO3. The aqueous was extracted with EtOAc and the organics combined, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the product (82%). The material was taken on without further purification. (ES+) m/z 546 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([CH3:13])[C:9]=1[C:10]([O-:12])=O)=[O:4].[Li+].Cl.Cl.[CH3:17][N:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]=[C:19]1[CH2:29][CH2:30][NH2:31]>>[CH3:13][N:8]1[C:9]([C:10](=[O:12])[NH:31][CH2:30][CH2:29][C:19]2[N:18]([CH3:17])[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:20]=2)=[C:5]([C:3]([O:2][CH3:1])=[O:4])[N:6]=[N:7]1
Reactant: COC(=O)c1nnn(C)c1C(=O)[O-]
Reactant: Cn1cc(-c2ccccc2)nc1CCN
Agent: Cl
Agent: [Li+]
Product: COC(=O)c1nnn(C)c1C(=O)NCCc1nc(-c2ccccc2)cn1C

Procedure:
The product was obtained starting from lithium 4-(methoxycarbonyl)-1-methyl-1H-1,2,3-triazole-5-carboxylate (150 mg, 785 μmol) and 2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethanamine dihydrochloride (226 mg, 824 μmol, example 7, step 4) according to the method described in example 7, step 5 after aqueous work-up and purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light yellow solid (79 mg, 214 μmol, 27.3%).
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)#[N:2].[N+:8]([O-:11])([OH:10])=[O:9]>S(=O)(=O)(O)O>[C:1]([C:3]1[S:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1)#[N:2].[C:1]([C:3]1[S:4][CH:5]=[C:6]([N+:8]([O-:11])=[O:9])[CH:7]=1)#[N:2]
Reactant: O=[N+]([O-])O
Reactant: N#Cc1cccs1
Agent: O=S(=O)(O)O
Product: N#Cc1cc([N+](=O)[O-])cs1
Product: N#Cc1ccc([N+](=O)[O-])s1
Temperature: 25 °C

Procedure:
To a solution of 10 ml conc. sulfuric acid stirred at 0° C. was added 2-cyano-thiophene (4.0 g, 0.036 mole). Six mililiters of a mixture of 1:1 conc. sulfuric acid and fuming nitric acid was added dropwise to the solution and the temperature was maintained between 10° C. and 15° C. The reaction mixture was allowed to warm-up to room temperature after addition was completed and was stirred for an additional hour. The dark red solution was quenched with 50 ml of ice water and stirred vigorously. A yellow solid precipitated out. The solid was collected on a filter and washed with ice water (2×5 ml). This solid weighed 3.7 g (66%) and is a mixture of 4- & 5-nitro 2-cyano thiophene with 1:2 ratio.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[O:17]=[C:18]1[C:27]2([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26][C:25]2[C:20](=[N:21][CH:22]=[C:23](/[CH:33]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:24]=2)[NH:19]1.C(OCC)(=O)C>ClCCCl.O>[CH3:1][N:30]1[CH2:29][CH2:28][C:27]2([CH2:26][C:25]3[C:20](=[N:21][CH:22]=[C:23](/[CH:33]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:24]=3)[NH:19][C:18]2=[O:17])[CH2:32][CH2:31]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCOC(=O)/C=C/c1cnc2c(c1)CC1(CCNCC1)C(=O)N2
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cnc2c(c1)CC1(CCN(C)CC1)C(=O)N2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (1.2 g, 5.73 mmol) and paraformaldehyde (172 mg, 5.73 mmol) were successively added to a suspension of (E)-ethyl 3-(2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylate (904 mg, 2.87 mmol) in 1,2-dichloroethane (40 mL) at room temperature. The reaction mixture was then heated up to 70° C. and stirred for 2 hours. After cooling down to room temperature, the reaction mixture was diluted by addition of ethyl acetate (50 mL) and water (50 mL). The aqueous layer was separated and extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with a saturated solution of sodium hydrogenocarbonate (3×60 mL), dried over sodium sulfate, filtered and concentrated to dryness. The title product was obtained as a white solid (862 mg, 91%).