Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22]C(=O)OC(C)(C)C)=[CH:18][CH:17]=3)=[CH:12][N:11]=1)[CH2:2]2.FC(F)(F)C(O)=O>>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([O:9][C:10]1[N:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[CH:12][N:11]=1)[CH2:2]2
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cnc(O[C@H]3CN4CCC3CC4)nc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2cnc(O[C@H]3CN4CCC3CC4)nc2)cc1

Procedure:
The product of Example 19B (150 mg, 0.38 mmol) was treated with trifluroacetic acid (2 mL) according to the procedure of Example 18C. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.07) as solid (30 mg, yield, 26%). 1H NMR (300 MHz, MeOH-d4) δ 1.88-2.22 (m, 3H), 2.31-2.45 (m, 1H), 2.56-2.64 (m, 1H), 3.27-3.51 (m, 5H), 3.84-3.96 (m, 1H), 5.36-5.45 (m, 1H), 6.87 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 8.77 (s, 2H) ppm. MS (DCl/NH3) m/z 297 (M+H)+.
Reaction SMILES: OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[CH3:23][NH:24][C:25](=[S:28])[NH:26][NH2:27].[C:29]1([C:39](O)=O)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]=1>CN(C)C=O.C(N(CC)CC)C>[C:29]1([C:39]2[N:24]([CH3:23])[C:25]([SH:28])=[N:26][N:27]=2)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]=1
Reactant: O=C(O)c1nccc2ccccc12
Reactant: CNC(=S)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(S)nnc1-c1nccc2ccccc12
Temperature: 25 °C
Yield: 78.6 %

Procedure:
Hydroxybenzotriazole (0.078 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.11 g) and triethylamine were added successively to a cooled solution (0° C.) of 4-methyl-3-thiosemicarbazide (0.061 g) and 1-isoquinoline carboxylic acid (0.10 g) in dimethylformamide (3 ml). Following addition the cooling bath was removed and the mixture was stirred at room temperature over night and then the reaction mixture was evaporated to dryness. To the residue was added sodium hydroxide solution (0.5 M, 5 ml) and the mixture was stirred at 80° C. for 3 h. The mixture was cooled to room temperature and the pH adjusted to pH 6 using hydrochloric acid solution (2M) and the resulting precipitate was filtered and dried in vacuo to give the title compound (0.11 g, 78%) as an off-white solid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:53][C:54]1[CH:66]=[CH:65][CH:64]=[CH:63][C:55]=1[O:56][CH:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>CN(C=O)C.O>[Cl:53][C:54]1[CH:66]=[CH:65][CH:64]=[CH:63][C:55]=1[O:56][CH:57]1[CH2:62][CH2:61][N:60]([C:18](=[O:20])[CH2:17][NH:16][C:14](=[O:15])[C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:13][CH:12]=2)[CH2:59][CH2:58]1
Reactant: Clc1ccccc1OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(Nc2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1ccc(Nc2ccccc2)nc1
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a stirred solution of [(6-phenylamino-pyridine-3-carbonyl)-amino]-acetic acid (0.035 g, 0.00013 mol) in DMF (1 mL) was added DIPEA (0.05 g, 0.00039 mol), HOBt (0.0209 g, 0.00015 mol) and EDCI.HCl (0.029 g, 0.0001549 mol) at ambient temperature. After 2 minutes 4-(2-chloro-phenoxy)-piperidine hydrochloride (0.0382 g, 0.00015 mol) and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (70% ethyl acetate in hexane) to afford 0.037 g (62%) of N-{2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-6-phenylamino-nicotinamide. LCMS: 465.16 (M+1)+, 96.6%, 1H NMR (DMSO-d6): δ 9.4 (s, 1H), 8.8 (s, 1H), 8.4 (t, 1H), 8.0 (dd, 1H), 7.7 (d, 2H), 7.45 (d, 1H), 7.4 (m, 4H), 7.0 (d, 2H), 6.8 (d, 1H), 4.7 (m, 1H), 4.25 (m, 2H), 3.7 (m, 2H), 3.5 (m, 2H), 2.0 (m, 2H), 1.7 (q, 2H).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[S:3]Cl.[NH2:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1.[OH-].[Na+]>ClCCl.O>[NH2:7][C:8]1[C:12]([S:3][C:2]([F:6])([F:5])[F:1])=[CH:11][N:10]([CH3:13])[N:9]=1
Reactant: Cn1ccc(N)n1
Reactant: FC(F)(F)SCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cn1cc(SC(F)(F)F)c(N)n1
Temperature: 25 °C

Procedure:
Trifluoromethanesulfenyl chloride (11.6 g, 85.0 mmol) was added to a solution of 3-amino-1-methylpyrazole (8.0 g, 82.4 mmol) in 150 mL of dichloromethane with stirring at a rate such that the temperature did not rise above 5° C. When the addition was complete the mixture was allowed to warm to ambient temperature and stir for 18 hours and was then purged with nitrogen gas for 1 hour to remove any unreacted trifluoromethanesulfenyl chloride. The solid that formed during the reaction was collected by filtration and the filtrate was concentrated by evaporation under reduced pressure to obtain additional solids. The combined solids were dissolved in water and the solution was basified with 1N aqueous sodium hydroxide. The resulting mixture was extracted with dichloromethane (2×100 mL) and the extracts were combined, dried over magnesium sulfate, and filtered. The filtrate was concentrated by evaporation under reduced pressure to obtain a solid residue that appeared to be a mixture of two compounds. This solid was recrystalized from methylcyclohexane to obtain 16.2 g (40 percent of theory) of the title compound as a yellow solid melting at 138°-140° C. The impurity was identified as 1-methyl-3-((trifluoromethanesulfenyl)amino)-4-(trifluoromethythio)pyrazole.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:14][C@H:13]3[N:15]([CH3:16])[C@H:10]([CH2:11][CH2:12]3)[C@H:9]2[C:17](OC)=[O:18])=[CH:4][CH:3]=1.[BH4-].[Li+]>C(OCC)C>[OH:18][CH2:17][C@H:9]1[C@@H:8]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)[CH2:14][C@H:13]2[N:15]([CH3:16])[C@@H:10]1[CH2:11][CH2:12]2
Reactant: COC(=O)[C@H]1[C@@H](c2ccc(I)cc2)C[C@@H]2CC[C@H]1N2C
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Product: CN1[C@H]2CC[C@@H]1[C@@H](CO)[C@@H](c1ccc(I)cc1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
As shown in FIG. 1, 5 mmol 3β-(4-iodophenyl)-2β-(carbomethoxy)tropane (β-CIT (1)) is dissolved in 25 ml ethyl ether at 0° C., and 2 equivalents of lithium borohydride (LiBH4) are added. The temperature is raised to room temperature, and stirring is continued for approximately 2 hr. The reaction is quenched with water and the aqueous phase of the mixture is extracted with methylene chloride. The organic phase is collected and dried over magnesium sulfate and the solvent is removed to give 2β-hydroxymethyl-3β-(4-iodophenyl) tropane free base (2) in quantitative yield. 2β-hydroxymethyl-3β-(4-iodophenyl)tropane was fully characterized as D-tartaric acid: mp=90°-92° C., [α]D20 -66.3° C. (c, 0.525, MeOH). 1H NMR (250 MHz, CDCl3): δ 7.59 (d, J=8.4 Hz, 2H); 6.99 (d, J=8.4 Hz, 2H); 3.76 (dd, J=11.06 Hz; 1H); 3.44 (d, J=4.59 Hz, 1H); 3.32 (m, 2H); 3.01 (m, 1H); 2.47 (td; J=2.88 Hz, J=12.74 Hz; 1H); 2.20 (s, 3H); 2.16 (m, 2H); 1.70 (m, 2H); 1.65 (m, 1H), 1.46 (m, 1H). Anal. (C15H20 NO1) (C4H6O6): CHN.
Reaction SMILES: [OH-].[Na+:2].[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[C:21]([CH3:37])=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH2:26][N:25]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH2:24][CH2:23]4)[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4]>C(O)C.O>[Na+:2].[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[C:21]([CH3:37])=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH2:26][N:25]([CH2:30][CH2:31][C:32]([O-:34])=[O:33])[CH2:24][CH2:23]4)[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4]
Reactant: CCOC(=O)CCN1CCc2c(ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)c2C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)ccc2c1CCN(CCC(=O)[O-])C2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2M sodium hydroxide (2 ml) was added to a solution of ethyl 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]propanoate (Preparation 24; 80 mg, 0.17 mmol) in ethanol (2 ml) at 60° C. The reaction mixture was stirred at 60° C. for 2 hours, cooled to room temperature and diluted with water (2 ml). The solid was filtered off, washed with a small amount of water and dried to give the title compound as a colourless solid (55 mg). 1H NMR (400 MHz, d6DMSO) δ: 1.39 (6H, d), 2.08 (2H, t), 2.44 (3H, s), 2.59-2.78 (6H, m), 3.56 (2H, s), 4.98 (1H, m), 7.09 (1H, d), 7.55 (1H, d), 7.65 (1H, d), 8.40 (1H, dd), 8.50 (1H, s). MS m/z 447 [MH]+.
Reaction SMILES: [CH2:1]1[C:6]2([C:15](=[O:16])[NH:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][N:18]=[C:19]=[O:20].N12CCN(CC1)CC2>C1C=CC=CC=1>[CH3:17][NH:18][C:19]([N:14]1[C:15](=[O:16])[C:6]2([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]2)[NH:7][C:8]21[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:20]
Reactant: O=C1NC2(CCCCC2)NC12CCCCC2
Reactant: CN=C=O
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: CNC(=O)N1C(=O)C2(CCCCC2)NC12CCCCC2

Procedure:
11.1 Parts of 7,14-diazadispiro[5.1.5.2]pentadecan-15-one, 2.9 parts of methyl isocyanate and a trace of 1,4-diazabicyclo[2.2.2]octane in 80 parts of dry benzene were heated at reflux for 48 hours, cooled and filtered. The filtrate was evaporated to dryness and the residue recrystallised from ethanol, and dried in vacuo to give 9 parts of 14-methylcarbamoyl-7,14-diazadispiro[5.1.5.2]pentadecan-15-one, having a melting point of 98° to 100°C. This material gave the following elemental analysis by weight:
Reaction SMILES: [N:1]1([C:6]2[CH:36]=[CH:35][C:9]([CH2:10][N:11]3[C:19]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:18]4[C:13]([N:14]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:15](=[O:29])[N:16]([CH3:28])[C:17]4=S)=[N:12]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[NH3:37]>CO.Cl[Hg]Cl>[N:1]1([C:6]2[CH:36]=[CH:35][C:9]([CH2:10][N:11]3[C:19]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:18]4[C:13]([N:14]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:15](=[O:29])[N:16]([CH3:28])[C:17]4=[NH:37])=[N:12]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cn1c(=S)c2c(Nc3ccccc3)n(Cc3ccc(-n4cncn4)cc3)nc2n(CC(C)(C)C)c1=O
Reactant: N
Agent: Cl[Hg]Cl
Solvent: CO
Product: Cn1c(=N)c2c(Nc3ccccc3)n(Cc3ccc(-n4cncn4)cc3)nc2n(CC(C)(C)C)c1=O
Temperature: 110 °C
Yield: 90 %

Procedure:
2-(4-(1H-1,2,4-triazol-1-yl)benzyl)-5-methyl-7-neopentyl-3-(phenylamino)-4-thioxo-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one (60 mg, 0.12 mmol) and HgCl2 (65 mg, 0.24 mmol) are suspended in 2 mL of 7N NH3 in methanol. The reaction mixture is heated in a Biotage microwave at 110° C. for 3 hours. After routine workup, the mixture is purified by a semi-preparative HPLC to give 52 mg of pure product as off-white solids (yield: 90%). MS (ESI) m/z 484.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([NH2:22])[C:16]=3[CH:15]=[CH:14]2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([NH:22][S:31]([CH3:30])(=[O:33])=[O:32])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(CC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(CC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reaction time: 2 h

Procedure:
To a solution of the product of Step B (50 mg, 0.16 mmol) and N-methylmorpholine (32 mg, 0.32 mmol) in dichloromethane (2 mL) was added methanesulfonyl chloride (23 mg, 0.24 mmol) at room temperature. The mixture was stirred for 2 h, then diluted with water (15 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by PREP-TLC eluting with PE/EA (2/1, v/v) to give the title compound as a colorless solid. LC/MS m/z=391.0[M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=1.[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=2)=[O:18])=[CH:20][CH:21]=1)([O-:12])=[O:11]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(N)cc1C
Product: Cc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc1C

Procedure:
Using 3,4-xylidine (1.35 g, 11.0 mmol) and 4-nitrobenzoic acid (1.69 g, 10.0 mmol), the procedure of Reference Example 16 was repeated to obtain 2.70 g (quantitative) of the title compound in the form of light yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:15][C:16]2[N:17]([CH3:25])[C:18]([C:21](OC)=[O:22])=[CH:19][N:20]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.CC(C[AlH]CC(C)C)C>C1COCC1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>[Br:1][C:2]1[CH:3]=[C:4]([S:15][C:16]2[N:17]([CH3:25])[C:18]([CH2:21][OH:22])=[CH:19][N:20]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Sc2cc(Br)cnc2Nc2nc(C)cs2)n1C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1csc(Nc2ncc(Br)cc2Sc2ncc(CO)n2C)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 8.6 %

Procedure:
Methyl 2-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)-1-methyl-1H-imidazole-5-carboxylate (0.076 g, 0.17 mmol) dissolved in THF (5 mL) was cooled to 0° C. DIBAL-H (1M in hexanes, 0.52 mL, 0.52 mmol) was added. After 15 minutes, DIBAL-H (0.52 mL, 0.52 mmol) was added again. The solution was diluted with a saturated solution of Rochelle's Salt (10 mL) and the solution stirred overnight. The material was extracted with dichloromethane and the organic layer was dried, and concentrated. Reverse phase HPLC purification gave the title compound (0.006 g, 9% yield) as a white solid. 1H NMR (DMSO-d6) δ 2.18 (s, 3H), 3.64 (s, 3H), 4.50 (d, 2H), 5.22 (t, 1H), 5.75 (s, 1H), 6.38 (bs, 1H), 7.11 (s, 1H), 8.22 (bs, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[C@H:7]([CH2:22][CH:23]=[CH2:24])[CH2:6][C:5]=2[CH:4]=1.[F:25][C:26]([F:52])([C:42]([F:51])([F:50])[C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45])[CH2:27][CH2:28][CH:29]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]C=C)[C:30]([O:32]CC)=[O:31]>>[OH:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[C@H:7]([CH2:6][CH2:5][CH2:4][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH:29]([CH2:28][CH2:27][C:26]([F:25])([F:52])[C:42]([F:50])([F:51])[C:43]([F:48])([F:49])[C:44]([F:45])([F:47])[F:46])[C:30]([OH:32])=[O:31])[CH2:22][C:23]=2[CH:24]=1
Reactant: C=CC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reactant: C=CCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O)[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
Starting with the 3-methoxy-7α-(2-propenyl)estra-1,3,5(10)-trien-17β-ol prepared in Example 13 and ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-8-nonenoate prepared separately, the same procedure as shown in Example 13 was repeated to give 10-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoic acid.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].C([O-])(=O)C.[Na+].C(O)(=O)C.[N:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]([CH:55]=O)=[CH:47][CH:46]=1.N>C(Cl)Cl.CO>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[CH2:55][C:48]1[C:49]2[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=2)[N:45]=[CH:46][CH:47]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=Cc1ccnc2ccccc12
Agent: CC(=O)[O-]
Agent: N
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN(Cc2ccnc3ccccc23)[C@H](Cc2ccccc2)C1)C(F)(F)F

Procedure:
200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 11 with 88 mg (1.4 mmol) of sodium cyanoborohydride, 115 mg (1.4 mmol) of sodium acetate, 134 μl (2.34 mmol) of acetic acid and 294 mg (1.87 mmol) of quinoline-4-carboxaldehyde to give the product. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.33, FD-MS: M+ =568.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[NH:12]CC(O)COC1C=CC=C2C=1C=C(CC(OCC)=O)N2>C(O)C>[NH2:12][CH:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1
Reactant: CCOC(=O)Cc1cc2c(OCC(O)CNC3CCc4ccccc4C3)cccc2[nH]1
Agent: Cl
Solvent: CCO
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure described in Example 27, but starting from ethyl 4-(2,3-epoxypropoxy)indole-2-acetate (27.5 g), obtained from ethyl 4-hydroxyindole-2-acetate and epichlorohydrin according to the method of Swiss Patent 526,542, and 2-aminotetralin (14.8 g) in ethanol (120 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-ethoxycarbonylmethylindol-4-yloxy)propanamine hydrochloride is obtained ((i): R=H, Ar=radical 16 wherein Z is ethoxy, and the chain is attached to position 2 of the tetralin moiety) which is crystallized from a mixture ethanol/isopropanol 2/1.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:22][C@H:23]1[C@@H:27]([CH3:28])[CH2:26][NH:25][CH2:24]1>N1C=CC=CC=1>[NH2:22][C@H:23]1[C@@H:27]([CH3:28])[CH2:26][N:25]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([F:17])[C:10]=2[F:16])[CH2:24]1
Reactant: C[C@H]1CNC[C@H]1N
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Solvent: c1ccncc1
Product: C[C@H]1CN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H]1N
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
In the same manner as described in Example 5, a mixture of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, cis-3-amino-4-methylpyrrolidine, and pyridine was stirred at 50° C. for 30 minutes to give 7-(cis-3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 264°-265° C.
Reaction SMILES: [OH-].[Na+].Cl.Cl.[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([NH:16][C@@H:17]1[C:23](=[O:24])[N:22]([CH2:25][C:26]([OH:28])=[O:27])[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[S:19][CH2:18]1)[C:11]([O:13]CC)=[O:12]>C(O)(=O)C>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([NH:16][C@@H:17]1[C:23](=[O:24])[N:22]([CH2:25][C:26]([OH:28])=[O:27])[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[S:19][CH2:18]1)[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)[C@H](CCCCN)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: NCCCC[C@H](N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 632.4 %

Procedure:
To 4 ml of 1N aqueous sodium hydroxide solution is added 0.2 g of 3(R)-[5-amino-1(S)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid.dihydrochloride as obtained in Example 54, and the mixture is stirred at room temperature for 1.5 hours. Acetic acid (1 ml) is added to the raction solution to make the solution weakly acidified, followed by purification by Amberlite XAD-2 column chromatography (methanol:water=3:7). The eluent is concentrated under reduced pressure, and the residue is lyophilized to give 1.0 g of 3(R)-[5-amino-1(S)-carboxypentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH3:18][O:19][CH:20]([O:24][CH3:25])[CH2:21][NH:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:3]([CH2:2][N:22]([CH2:21][CH:20]([O:24][CH3:25])[O:19][CH3:18])[CH3:23])[C:7]=2[CH:8]=1
Reactant: CNCC(OC)OC
Reactant: CCOC(=O)c1oc2ccc(Cl)cc2c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1oc2ccc(Cl)cc2c1CN(C)CC(OC)OC
Reaction time: 30 h

Procedure:
A mixture of ethyl 3-bromomethyl-5-chloro-2-benzofurancarboxylate (52.75 g, 0.166 mol), methylaminoacetaldehyde dimethyl acetal (19.0 g, 0.167 mol) and potassium carbonate (45 g) in dry acetone (600 ml) was stirred under argon for 30 hours, filtered and the filtrate evaporated. The residue was partitioned between ethyl ether and water and the organic phase was dried with magnesium sulfate, filtered, and concentrated to give ethyl 5-chloro-3-[N-(2,2-dimethoxyethyl)-N-methyl(aminomethyl)]-2-benzofurancarboxylate: mp 58°-60° C.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:8][C@H:7]([C:9]2[N:13]3[CH:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]3=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)[N:10]=2)[CH2:6]1)=[N+]=[N-]>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:1][CH2:4][C@@H:5]1[CH2:6][C@H:7]([C:9]2[N:13]3[CH:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]3=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)[N:10]=2)[CH2:8]1
Reactant: [N-]=[N+]=NC[C@H]1C[C@@H](c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn32)C1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: NC[C@H]1C[C@@H](c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn32)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
cis-3-(3-Azidomethyl-cyclobutyl)-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-8-ylamine (35 mg, 0.082 mmol) was dissolved in ethanol (5 mL) upon heating, the mixture was cooled to rt. and charged with Lindlar catalyst (30 mg). The mixture was hydrogenated at rt overnight. LC-MS showed the reaction was complete and clean. The catalyst was removed by filtration through a pad of celite, the filtrate was concentrated and the residue was purified by mass-directed purification to give a white solid; LC-MS (ES, Pos.): m/z 400 [MH+]; 1H NMR (CD3OD, 400 MHz) δ 2.17-2.24 (m, 2H), 2.56-2.67 (m, 3H), 2.79 (d, J=6.5 Hz, 2H), 3.84 (m, 1H), 5.17 (s, 2H), 6.98 (d, J=5.1 Hz, 1H), 7.15-7.47 (m, 10H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH:4]=[O:5].S([O-])(O)(=O)=O.[Na+].[C-:14]#[N:15].[K+]>O>[F:1][C:2]([F:7])([F:6])[CH2:3][CH:4]([OH:5])[C:14]#[N:15]
Reactant: O=CCC(F)(F)F
Reactant: [C-]#N
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: N#CC(O)CC(F)(F)F
Temperature: 0 °C

Procedure:
3,3,3-Trifluoropropanal was added to a mixture of sodium hydrogensulfate and water, with vigorously stirring at 0° C., followed by further stirring for 10 minutes. An aqueous solution of potassium cyanide was dropwise added, followed by reaction with stirring at 0° C. for 1 hour and then work-up and purification to obtain 4,4,4-trifluoro-2-hydroxybutanenitrile.