Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN.[NH2:3][C:4]1[C:9]([C:10]2[O:11][C:12]3[C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:8][C:7]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[CH:26]=2)=[CH:6][N:5]=1.F[P-](F)(F)(F)(F)F.[CH3:47][N:48](C(=[O+]N1C2=NC=CC=C2N=N1)N(C)C)C>CO.CN(C=O)C>[NH2:3][C:4]1[N:5]=[CH:6][C:7]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[CH:26]=2)=[CH:8][C:9]=1[C:10]1[O:11][C:12]2[C:18]([C:19](=[O:20])[NH:48][CH3:47])=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5cccc(C(=O)O)c5o4)c3)cn2)CC1
Reactant: CN(C)C(=[O+]n1nnc2cccnc21)N(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)c1cccc2nc(-c3cc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc3N)oc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.8 %

Procedure:
A 2M solution of methylamine in methanol (0.535 ml) was added to a mixture of 2-[2-amino-5-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]-3-pyridyl]-1,3-benzoxazole-7-carboxylic acid (270 mg) and bis(dimethylamino)methylene-(triazolo[5,4-b]pyridin-3-yl)oxonium hexafluorophosphate (285 mg) dissolved in DMF (1 ml). The resulting solution was heated at 25° C. for 1 day. A 2N solution of methylamine (0.535 ml) in methanol was added and the mixture was stirred at 25° C. in a sealed tube for 3 days. The mixture was evaporated to dryness and adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 20 to 50% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-[4-[6-amino-5-[7-(methylcarbamoyl)-1,3-benzoxazol-2-yl]-3-pyridyl]pyrazol-1-yl]piperidine-1-carboxylate (210 mg) as a pale yellow solid. NMR Spectrum: (DMSOd6) 1.43 (s, 9H), 1.80 (dd, 1H), 1.85 (dd, 1H), 2.01-2.11 (m, 2H), 2.94 (bs, 2H), 2.96 (d, 3H), 4.00-4.13 (m, 2H), 4.36-4.46 (m, 1H), 7.51 (dd, 1H), 7.65 (bs, 2H), 7.82 (dd, 1H), 7.93 (s, 1H), 7.98 (dd, 1H), 8.30 (s, 1H), 8.43 (q, 1H), 8.54 (d, 1H), 8.57 (d, 1H); Mass spectrum: M+H+ 518.
Reaction SMILES: [CH2:1]([NH:6][C:7](=[O:18])[C@@H:8]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH3:10])[CH2:2][CH2:3][C:4]#[CH:5].I[C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22].C(NCC)C>[Cu](I)I>[NH2:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[C:5]#[C:4][CH2:3][CH2:2][CH2:1][NH:6][C:7](=[O:18])[C@@H:8]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH3:10]
Reactant: Nc1ccccc1I
Reactant: C#CCCCNC(=O)[C@H](CC)NC(=O)C(F)(F)F
Agent: I[Cu]I
Solvent: CCNCC
Product: CC[C@H](NC(=O)C(F)(F)F)C(=O)NCCCC#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 50 mL round bottom flask was charged with (S)—N-(pent-4-ynyl)-2-(2,2,2-trifluoroacetamido)butanamide (110 mg, 0.42 mmol), 2-iodoaniline (89.0 mg, 0.41 mmol), copper iodide (13.0 mg, 0.068 mmol), palladium tetrakistriphenylphosphine (47 mg, 0.041 mmol), and diethylamine (12.6 mL). The resulting mixture was stirred at room temperature for 4 h, concentrated in vacuo and the resulting residue purified via flash silica gel chromatography (Analogix IF-280, SF25-40 g column, gradient 90:10-10:90 Heptane:EtOAc) to yield N-[5-(2-aminophenyl)pent-4-ynyl]-2-(S)-(2,2,2-trifluoroacetylamino)butyramide. 1H NMR (300 MHz, CDCl3) δ 7.21-7.24 (m, 1H), 7.07-7.12 (m, 1H), 6.64-6.71 (m, 1H), 6.42-6.46 (m, 1H), 4.38-4.45 (m, 1H), 3.39-3.53 (m, 2H), 2.53 (t, J=6.8 Hz, 2H), 1.67-1.96 (m, 4H), and 0.88-0.93 (m, 3H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]CC)=[O:22])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][N:28]=2)[CH2:6][C@@H:5]1[CH3:35])(=[O:3])[CH3:2].[OH-].[Li+]>CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][N:28]=2)[CH2:6][C@@H:5]1[CH3:35])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(C#N)cn2)C[C@H](C)N3C(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1c2ccc(-c3ccc(CC(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 40 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of ethyl 2-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)acetate (for a preparation see Intermediate 8) (300 mg, 0.640 mmol) in methanol (5 mL) was added lithium hydroxide solution (0.768 mL, 0.768 mmol). The resulting mixture was stirred at 40° C. for 2 h, whereupon it was concentrated under vacuum to give the crude lithium carboxylate of 2-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)acetic acid (286 mg, 100%) as a white solid which was used in the next step without further purification. LCMS (Formate, 2 min), Rt=1.10 min, MH+=433.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@@H:12]2[CH2:16][C@H:15]([S:17][C:18]3[C@H:19]([CH3:42])[C@@H:20]4[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]4[C:22]=3[C:23]([O:25]CC3C=CC([N+]([O-])=O)=CC=3)=[O:24])[CH2:14][N:13]2[CH3:43])=[O:11])[CH2:6][CH2:5]1.O1CCCC1.[ClH:49]>O>[ClH:49].[OH:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]([C@@H:12]2[CH2:16][C@H:15]([S:17][C:18]3[C@H:19]([CH3:42])[C@@H:20]4[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]4[C:22]=3[C:23]([OH:25])=[O:24])[CH2:14][N:13]2[CH3:43])=[O:11])[CH2:8][CH2:9]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(CCO)CC4)N(C)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@H]3C[C@@H](C(=O)N4CCN(CCO)CC4)N(C)C3)[C@H](C)[C@H]12

Procedure:
A solution of 700 mg of 4-nitrobenzyl (1R,5S,6S)-2-{(2S,4S)-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-1-methylpyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] in 60 ml of a 1:1 by volume mixture of tetrahydrofuran and water was mixed with 1.15 ml of 1N aqueous hydrochloric acid, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 1000 mg of 10% w/w palladium-on-charcoal. At the end of this time, the catalyst was removed by filtration, and the filtrate was extracted with diethyl ether. The remaining aqueous layer was concentrated by evaporation under reduced pressure, and the residue was subjected to column chromatography through a Lobar column (Merck, LiChroprep RP-8, size B). The column was eluted with 1.5% v/v aqueous methanol and those fractions containing the title compound were combined, concentrated by evaporation under reduced pressure and lyophilized, to give 300 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9]C)[C:6]([I:11])=[CH:5][N:4]=1.[OH-].[Na+]>CO>[I:11][C:6]1[C:7](=[O:9])[NH:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=1
Reactant: COc1ncc(I)c(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ncc(I)c(=O)[nH]1

Procedure:
2,4-Dimethoxy-5-iodopyrimidine Z (2.54 g, 9.6 mmol) was added to 26 ml of 5N sodium hydroxide in 50% aqueous methanol and the resulting solution was refluxed overnight. The reaction mixture was evaporated to dryness under reduced pressure, diluted to 25 ml with water and neutralized to ph ˜6 with 1N hydrochloric acid. The precipitate was filtered off, washed with water (2×10 ml), methanol (2×10 ml) and diethyl ether to give 0.55 g of pure product. The filtrate was concentrated under reduced pressure and kept overnight at 4° C. The crystals of the product were filtered off washed as above to give additional 0.3 g of pure product as a colorless crystals (total yield 0.85 g, 35%). 1HNMR (DMSO-d6, 300 MHz) δ 8.14 (s, 1H) 3.82 (s, 3H); 3.3 (broad s, 1H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[S:6]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7]1.[BH3-]C#N.[Na+]>CO.CC(O)=O>[CH3:1][N:2]([CH2:11][C:8]1[CH:9]=[CH:10][S:6][CH:7]=1)[CH2:3][CH2:4][OH:5]
Reactant: O=Cc1ccsc1
Reactant: CNCCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(CCO)Cc1ccsc1
Reaction time: 18 h
Yield: 94.4 %

Procedure:
2-(Methylamino)-ethanol (0.047 mol, 3.5 g) and 3-thiophenecarboxaldehyde (0.047 mol, 5.3 g) were dissolved in 50 mL of MeOH and 10 mL of AcOH. NaCNBH3 (0.023 mol, 1.5 g) was added portionwise, and the resulting mixture was stirred for 18 h. The solvent was removed in vacuo, and the residue was taken up in 1N KOH and extracted with EtOAc. The organics were dried and concentrated to give an oil which was filtered through a six inch silica gel plug using 1:1 hexanes:ethyl acetate to give 7.6 g of product. 1H NMR (300 MHz) CDCl3: 7.3 (m, 1H), 7.12 (s, 1H), 7.05 (d, 1H), 3.6 (m, 4H), 2.57 (t, 2H), 2.25 (s, 3H).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][C:32]([F:35])([F:34])[F:33].C(OCC)(=O)C>CN(C=O)C>[F:33][C:32]([F:35])([F:34])[CH2:31][CH2:30][CH2:29][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: FC(F)(F)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCN(CCCC(F)(F)F)C3)nc1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.350 g, 1.24 mmol), K2CO3 (0.427 g, 3.09 mmol), and 4-bromo-1,1,1-trifluorobutane (0.248 g, 1.30 mmol) in DMF (6.2 mL). Beat at 95° C. for 5.5 hours, then at 50° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL) and brine (1×30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 20% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+394.2 (M+H)+, HRMS calcd for C20H23N3O2F3 394.1742 (M+H)+, found 394.1733, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=10.1 min, 100% purity.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:16]=[CH:15][C:8]([CH:9]=[CH:10][C:11](OC)=[O:12])=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18].CO.O>C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:16]=[CH:15][C:8]([CH:9]=[CH:10][CH2:11][OH:12])=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18]
Reactant: COCOc1ccc(C=CC(=O)OC)cc1[N+](=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: COCOc1ccc(C=CCO)cc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
Under a current of argon, a solution of 710 mg of methyl 4-methoxymethoxy-3-nitrocinnamate in 6 ml of toluene and 4.4 ml of diisobutyl aluminum hydride (1.5M toluene solution) added thereto at -78° C. were stirred for 30 minutes. The produced reaction solution was combined with methanol at -78° C. to effect decomposition of excess diisobutyl aluminum hydride and then the resultant mixture and water added thereto at 0° C. were stirred for a while. Subsequently, the mixture was filtered with sellaite and wased with ethyl acetate and the filtrate was extracted from ethyl acetate. The consequently separated organic layer was washed with saturated saline solution and then with anhydrous sodium sulfate and concentrated under a vacuum. The resultant concentrate was subjected to silica gel column chromatography. From the hexane-ethyl acetate (1:1 V/V) eluate, 560 mg of 4-methoxymethoxy-3-nitrocinnamyl alcohol was obtained in the form of a yellow oily substance. The yield was 88%.
Reaction SMILES: C(OC([C:11]1[NH:12][C:13]2[CH2:14][CH2:15][C:16]([CH3:23])([CH3:22])[C:17](=[O:21])[C:18]=2[C:19]=1[CH3:20])=O)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:20][C:19]1[C:18]2[C:17](=[O:21])[C:16]([CH3:23])([CH3:22])[CH2:15][CH2:14][C:13]=2[NH:12][CH:11]=1
Reactant: [H][H]
Reactant: Cc1c(C(=O)OCc2ccccc2)[nH]c2c1C(=O)C(C)(C)CC2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c[nH]c2c1C(=O)C(C)(C)CC2
Reaction time: 0.5 h

Procedure:
3,5,5-trimethyl-4-oxo-4,5,6,7-tetrahydroindole-2-carboxylic acid benzyl ester from the previous step, 6.60 g (21.20 mmol) and 2.0 g of 10% Pd—C was suspended in ethyl acetate 150 mL and hydrogenated under balloon of hydrogen for 3 hours. The reaction mixture was diluted with methanol 0.5 L and the mixture was stirred under Ar for 30 min to dissolve the precipitated carboxylic acid intermediate. The catalyst was then removed by filtration and the filtrates were evaporated to dryness and dried on highvac. The residue was dissolved in trifluoroacetic acid 40 mL, the solution was stirred on a 45° C. bath for 30 min, then evaporated to dryness. The residue was dried on highvac. The crude material was applied onto a column of silica (60 g) in dichloromethane and eluted with 10:1 dichloromethane-ethyl acetate mixture. Y=3.17 g (84% overall) of 3,5,5-trimethyl-4-oxo-4,5,6,7-tetrahydroindole as a white solid that gradually turns pink on air and light. 1H-NMR (d6-DMSO, 400 MHz): 10.89 (br s, 1H), 6.44 (s, 1H), 2.72 (t, 6.3 Hz, 2H), 2.12 (s, 3H), 1.85 (t, 6.3 Hz, 2H), 1.04 (s, 6H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:44])[CH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)[CH3:25]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:24]([O:26][C:27](=[O:44])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH2:14][S:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:31][CH:30]=1)[CH3:25]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CSCCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3CSCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) as the catalyst and the following starting materials: 5-(4-bromo-phenyl)-3-methyl-4-phenethylsulfanylmethyl-isoxazole and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([N:17]2[CH2:21][C@@H:20]([N:22]([CH2:35][C:36]3[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=3)[C:23]3[N:28]=[CH:27][C:26]([C:29]4[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=4)=[CH:25][N:24]=3)[CH2:19][C@H:18]2[CH2:50][CH3:51])=[N:7][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][CH:10]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:48][C:46]([F:47])([F:49])[C:38]1[CH:37]=[C:36]([CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=1)[CH2:35][N:22]([C:23]1[N:28]=[CH:27][C:26]([C:29]2[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=2)=[CH:25][N:24]=1)[C@@H:20]1[CH2:21][N:17]([C:6]2[C:5]([CH2:3][OH:2])=[CH:10][N:9]=[C:8]([N:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[N:7]=2)[C@H:18]([CH2:50][CH3:51])[CH2:19]1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1c1nc(N2CCCCC2)ncc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1c1nc(N2CCCCC2)ncc1CO
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 17.6 %

Procedure:
To a solution of 4-((2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-2-piperidin-1-yl-pyrimidine-5-carboxylic acid methyl ester (250 mg, 0.33 mmol) in 1.5 mL of THF is added LAH (24 mg, 0.66 mmol). After stirred at room temperature for 3.5 hours, the reaction is quenched by Glauber's salt. The mixture is filtered on celite, and the filtrate is concentrated. The obtained residue is purified by silica gel column chromatography (eluent: hexane/EtOAc) to give [4-((2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-2-piperidin-1-yl-pyrimidin-5-yl]-methanol (40 mg, 20% yields); ESI-MS m/z: 690 [M+1]+, Retention time 5.79 min (condition B).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][NH2:5].[F:8][C@@:9]([CH3:33])([C:13]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH3:24])[C:20]2[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=2[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]1=2)=[O:14])[C:10](O)=[O:11]>>[F:8][C@:9]([CH3:33])([C:10]([NH:5][CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])=[O:11])[C:13]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH3:24])[C:20]2[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=2[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]1=2)=[O:14]
Reactant: NCCC(F)(F)F
Reactant: CN1C(=O)[C@@H](NC(=O)[C@](C)(F)C(=O)O)c2ccccc2-c2ccccc21
Product: CN1C(=O)[C@@H](NC(=O)[C@](C)(F)C(=O)NCCC(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
The title compound [MS m/e (%): 452.3 (M+H+, 100)]was prepared in analogy to example 14 from 3,3,3-trifluoropropylamine and (2S)-2-fluoro-2-methyl-N-((S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamic acid.
Reaction SMILES: [NH2:1][CH:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][SH:5].[CH3:9][S:10](=S)(OC)=O.N[C@H](C(O)=O)CS.N[C@H](C(O)=O)CCS.[Na].N>>[CH3:9][S:10][S:5][CH2:4][CH2:3][CH:2]([C:6]([OH:8])=[O:7])[NH2:1]
Reactant: COS(C)(=O)=S
Reactant: NC(CCS)C(=O)O
Agent: N
Agent: N[C@@H](CCS)C(=O)O
Agent: N[C@@H](CS)C(=O)O
Product: CSSCCC(N)C(=O)O

Procedure:
S-(methylthio)-DL-homocysteine was prepared from DL-homocysteine (Research Organics, Inc., Cleveland, Ohio) and methyl methanethiosulfonate (Fairfield Chemical Company, Blythewood, S.C.) by a modification of the methylthiolation of L-cysteine as described by Smith et al. (Biochemistry, 14, 766-771 (1975)). The L-enantiomorph, L-SMETH, was prepared following reduction of L-homocysteine (Sigma Chemical Company, St. Louis, Mo.) with sodium in liquid ammonia. The excess sodium was removed by the addition of ammonium chloride and the ammonia evaporated at room temperature under nitrogen. The residue was dissolved in oxygen-free water and the solution was neutralized to pH 6.5-7.0 with hydrochloric acid. A 1.25 molar excess of methyl methanethiosulfonate in ethanol was added slowly and the product crystallized after two hours in an ice bath. The crystals were washed with ethanol and peroxide-free ether and dried over phosphorus pentoxide. An analysis was conducted (performed by Atlantic Microlab. Inc., Atlanta, Ga.) for SMETH, which was calculated as C, 33.13; H, 6.12; N, 7.73; and S, 35.37. Similarly, DL-SMETH was calculated as C, 33.21; H, 6.12; N, 7.71; and S, 35.28. L-SMETH was calculated as C, 33.19; H, 6.12; N, 7.68; and S, 35.30. The racemate was resolved into two peaks and the chiral purity of L-SMETH was determined to be at least 99.9% by column chromatography using a resolving column.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>O1CCCC1.O.C(=O)(O)[O-].[Na+]>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:27][CH:26]=2)[CH2:3][CH2:4]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CN1CCC(N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.9 %

Procedure:
To an ice cooled solution of 3.43 g (0.030 mole) of 4-amino-1-methylpiperidine, 4.58 g (0.045 mole) of triethylamine and 75 mL of tetrahydrofuran, was added a solution of 6.44 g (0.0347 mole) of 4-nitrobenzoyl chloride in 25 mL of tetrahydrofuran. The mixture was stirred at room temperature for 6 hours, then diluted with 50 mL of water and 100 mL of saturated sodium bicarbonate. After stirring another 30 minutes, the mixture was extracted twice with 200 mL of ethyl acetate. The ethyl acetate layers were washed with 200 mL of water, 200 mL of brine, combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 4.34 g of N-(1-methyl-piperidin-4-yl)-4-nitro-benzamide as off-white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][C:17](=[O:22])C(Cl)(Cl)Cl)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:26][CH2:25]1>>[CH2:30]([N:27]1[CH2:28][CH2:29][CH:24]([N:23]2[CH:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:15]=3)[NH:16][C:17]2=[O:22])[CH2:25][CH2:26]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)C(Cl)(Cl)Cl
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)N1C1CCN(Cc2ccccc2)CC1

Procedure:
In similar way as in Preparation Example 24, the title compound was synthesized from 5-chloro-2-trichloroacetylaminobenzophenone and 4-amino-1-benzylpiperidine.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14](O)[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH:14]2[C:15]3[C:10](=[N:9][C:8]4[C:3]([C:2]=3[NH2:1])=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:11][CH2:12][CH2:13]2)[CH2:20][CH2:19]1
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Reactant: CN1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CCN(C2CCCc3nc4ccccc4c(N)c32)CC1

Procedure:
9-Amino-1,2,3,4-tetrahydroacridin-1-ol (5.36 g) was refluxed for 48 h in 300 ml of toluene that contained 1-methylpiperazine (5.06 g) and p-toluenesulfonic acid monohydrate (9.5 g). At the end of this time the reaction mixture was distributed between EtOAc and aqueous K2CO3 and then the combined organic phase was concentrated and the residue purified by flash chromatography (5% Et3N/EtOAc) to give, after concentration of the product-containing fractions and recrystallization from EtOAc, 2.30 g of analytically pure product, m.p. 200°-202°.
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:34])[CH2:6][O:7][C:8]1[C:13]([Br:14])=[CH:12][C:11]([C:15]2[C:24]3[C:25]4[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=4[O:27][C:23]=3[C:22]([Br:32])=[C:21]3[C:16]=2[CH:17]=[CH:18][CH:19]=[CH:20]3)=[CH:10][C:9]=1[Br:33]>C1COCC1.CO>[Br:14][C:13]1[CH:12]=[C:11]([C:15]2[C:24]3[C:25]4[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=4[O:27][C:23]=3[C:22]([Br:32])=[C:21]3[C:16]=2[CH:17]=[CH:18][CH:19]=[CH:20]3)[CH:10]=[C:9]([Br:33])[C:8]=1[O:7][CH2:6][C:5]([OH:34])=[O:4]
Reactant: COC(=O)COc1c(Br)cc(-c2c3ccccc3c(Br)c3oc4ccccc4c23)cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)COc1c(Br)cc(-c2c3ccccc3c(Br)c3oc4ccccc4c23)cc1Br
Reaction time: 3 h
Yield: 93.6 %

Procedure:
Potasium hydroxide (1.0 M, 1.60 mL, 1.60 mmol) was added to a stirred solution of [2, 6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]furan-11-yl)-phenoxy]-acetic acid methyl ester (0.90 g, 1.45 mmol) in THF (9 mL) and methanol (5 mL). After 3 h, the solvent was removed, water was added and the reaction mixture was acidified with 10% HCl. After stirring overnight, the solid was filtered and washed with water, triturated with hexane and dried in vacuo at 100° C. to provide the title compound as a white solid (0.821 g, 94%): mp 250-252° C.: NMR (DMSO-d6); δ8.37 (d, J=8 Hz, 1 H), 7.90 (s, 2 H), 7.84 (d, J=8 Hz, 1 H), 7.70 (ddd, J=8, 6, 1 Hz, 1 H), 7.61 (ddd, J=8, 1, 1 Hz, 1 H)), 7.62-7.58 (m, 2 H), 7.31 (ddd, J=8, 7, 1 Hz, 1 H), 6.92 (ddd, J=8, 1,1 Hz, 1 H), 4.75 (s, 2 H); MS (EI): [M+], 3 bromine isotope pattern, 602 (40%), 604 (95%) 606 (100%) 608 (40%); Anal. Calc. for C24H13Br3O4: C, 47.64, H, 2.17, N, 0.00. Found: C, 47.33, H, 1.95, N, 0.04.