Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C@@H:2]([C:4]([OH:6])=O)[CH3:3].[NH2:17][CH2:18][C:19]([OH:21])=[O:20].[CH2:22](N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C@@H:2]([C:4]([NH:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:6])[CH3:3]
Reactant: NCC(=O)O
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCN(CC)CC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Yield: 84.4 %

Procedure:
A solution of Z-D-Ala (2.23 g, 10 mmol) and Gly.OMe.HCl (1.26 g, 10 mmol) in THF (50 ml) was chilled to 0° C. and triethylamine (1.01 g, 10 mmol), HOBt (1.35 g, 10 mmol) and DCC (2.06 f, 10 mmol) was added successively at 0° C. with stirring. After stirring for 4 hrs at 0° C., the reaction mixture was stirred at room temperature overnight and the precipitated crystals were filtered and the filtrate was evaporated in vacuo. The residue was extracted with ethyl acetate and the extract was washed with 5% citric acid, 5% NaHCO3 and water successively, and dried over anhyd. Na2SO4. The solvent was removed in vacuo and the resulting solid was recrystallized from ethyl acetate-hexane to give Z-D-Ala-Gly-OMe (26) (2.48 g, 84.4%) as colorless needles, mp 96°-97° C.; [α]D22 23.3° (c=1.0, MeOH): NMR (CDCl3)δ:1.39 (3H, d, J=8 Hz, CH3), 3.76 (3H, s CH3O), 4.03 (2H, d, J=6 Hz, CH2NH), 4.15-4.50 (1H, m, --CH--NH), 5.15, (2H, s, CH2O), 5.58 (1H, d, J=7 Hz, NH), 6.70-6.95 (1H, br, NH), 7.42 (5H, s, Ar--H). Rf (I)=0.62, Rf (VI)=0.38.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[ClH:18].[N:19]1(C(=N)N)[CH:23]=[N:22]C=N1>CN(C)C=O.CCOCC>[ClH:18].[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([C:23](=[NH:19])[NH2:22])[CH2:5]1
Reactant: CC1CNCC(C)O1
Reactant: N=C(N)n1cncn1
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(C(=N)N)CC(C)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.3 %

Procedure:
A mixture of 2,6-dimethylmorpholine (6.16 ml, 50.0 mmol) (Fluka, a 2.5:1 mixture of cis:trans isomers), diisopropylethylamine (8.73 ml, 50.0 mmol) and 1H-1,2,4-triazole-1-carboximidamide hydrochloride (6.11 g, 55 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 24 hours. The suspension was diluted with ether (50 ml) and the reaction mixture was stirred at room temperature for 10 minutes. The ether layer was decanted off. Ether (50 ml) was added and the process repeated twice. The solid was collected, washed with ether and dried to give the title compound as a colourless solid (7.1 g, 73%) as a 2.3:1 mixture of cis:trans isomers. LC/MS [M+H]+=158.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH2:14][O:15][CH3:16])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1>CCCCO.CCOC(C)=O>[Br:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH2:14][O:15][CH3:16])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCCC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: COCCC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 160 °C
Reaction time: 24 h

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxypropanamide (110 mg, 0.348 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (279 mg, 1.39 mmol) in n-BuOH (5 mL) was stirred at 160° C. for 24 hours. The mixture was diluted with EtOAc (100 mL) and washed with brine (1×20 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by C-18 reverse phase chromatography (Biotage 25M+ column) on Biotage SP4 unit eluting with 10-85% CH3CN gradient (25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(3-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate as a solid. This material was dissolved in TFA (3 mL) and stirred at room temperature for 20 minutes. TFA was then removed in vacuo, and the residue was dissolved in a few drops of methanol and purified by C-18 reverse phase chromatography (Biotage C-18, 12M+ column) on Biotage SP4 unit eluting with 1-50% CH3CN/water gradient (14 CV). The product isolated was dissolved in CH2Cl2 (1 mL), and 2M HCl in ether (2 mL) was added. The solid was dissolved in MeOH, evaporated from CH2Cl2 (3×2 mL) and dried under high vacuum to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxypropanamide hydrochloride (28 mg, 20% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.80 (s, 1H), 9.34 (s, 1H), 8.23 (br s, 4H), 7.57 (br s, 1H), 3.64 (t, 2H), 3.55-3.49 (m, 2H), 3.42-3.55 (m, 2H), 3.27 (s, 3H), 3.08-3.03 (m, 1H), 2.62 (t, 2H), 2.15-2.09 (m, 1H), 1.88-1.81 (m, 1H), 1.75-1.67 (m, 1H), 1.53-1.45 (m, 1H); LCMS (APCI+) m/z 396, 398 (M+H)+, Retention time=2.09 minutes (Method 2).
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C(N(CC)CC)C.[CH3:16][C:17]([O:20][C:21](ON=C(C1C=CC=CC=1)C#N)=[O:22])([CH3:19])[CH3:18]>O1CCOCC1>[C:17]([O:20][C:21]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[O:22])([CH3:19])([CH3:18])[CH3:16]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCCCCC(=O)O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CCCCC(=O)O
Yield: 52.7 %

Procedure:
Prepared as described for L3 from stirring 5-aminopentanoic acid (3.40 g, 29.1 mmol) in 50% aqueous dioxane with triethylamine (6.0 mL, 43.1 mmol) and BOC-ON (7.91 g, 32.1 mmol) to yield a cream solid (3.10 g, 48.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][NH:22]3)=[O:16])[CH2:7][CH2:6]2.[C:27](Cl)(=[O:29])[CH3:28].C(OCC)(=O)C>N1C=CC=CC=1>[C:27]([N:22]1[C:23]2[C:19](=[C:18]([NH:17][C:15]([NH:14][CH:8]3[C:9]4[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=4)[CH2:6][CH2:7]3)=[O:16])[CH:26]=[CH:25][CH:24]=2)[CH:20]=[N:21]1)(=[O:29])[CH3:28]
Reactant: COc1cc2c(cc1OC)C(NC(=O)Nc1cccc3[nH]ncc13)CC2
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OC)C(NC(=O)Nc1cccc3c1cnn3C(C)=O)CC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 38 %

Procedure:
To the solution of 1-(5,6-dimethoxy-indan-1-yl)-3-(1H-indazol-4-yl)-urea (0.1 g, 0.28 mmol) in pyridine (2 mL) was added acetyl chloride (0.5 mL) and mixture stirred for 15 hours at ambient temperature. The mixture was suspended with ethyl acetate and filtered. The precipitate was triturated with ether twice and dried to obtain 42 mg (38%) of desired product as a yellow solid. NMR (DMSO-d6): 8.98 (s, 1H), 8.72 (s, 1H), 7.60 (d, J 7.5 Hz, 1H), 7.32-7.18 (m, 2H), 6.90 (d, J 8 Hz, 2H), 6.53 (d, J 8 Hz, 1H), 5.16 (m, 1H), 3.76 (s, 3H), 3.72 (s, 3H), 3.00-2.70 (m, 5H), 2.43 (m, 1H), 1.82 (m, 1H). MS (DCI): 395 (M+1). Elemental: Calculated for C18H18N4O2.0.2H2O: C 63.37, H 5.67, N 14.08; Found: C 63.07, H 5.49, N 13.94.
Reaction SMILES: Cl.[CH:2]1([C@H:8]2[CH2:13][NH:12][CH2:11][C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[NH:31][N:30]=[C:29]([CH:32]3[CH2:34][CH2:33]3)[CH:28]=2)[CH:23]=[C:22]([CH3:35])[N:21]=1.ClC1N=C(NC2NN=CC=2)C=C(C)N=1>>[CH:2]1([C@H:8]2[CH2:13][N:12]([C:20]3[N:25]=[C:24]([NH:26][C:27]4[NH:31][N:30]=[C:29]([CH:32]5[CH2:34][CH2:33]5)[CH:28]=4)[CH:23]=[C:22]([CH3:35])[N:21]=3)[CH2:11][C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1cc(Nc2cc(C3CC3)n[nH]2)nc(Cl)n1
Reactant: COC(=O)C[C@@H]1CNC[C@H](C2CCCCC2)C1
Agent: Cc1cc(Nc2ccn[nH]2)nc(Cl)n1
Agent: Cl
Product: COC(=O)C[C@H]1C[C@@H](C2CCCCC2)CN(c2nc(C)cc(Nc3cc(C4CC4)n[nH]3)n2)C1

Procedure:
The title compound was prepared by the similar manner described in Example 1 using methyl (cis-5-cyclohexylpiperidine-3-yl)acetate hydrochloride instead of (S)-3-(tert-butoxycarbonylamino)piperidine, and 2-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-6-methylpyrimidin-4-amine prepared in Referential Example 2 instead of 2-chloro-6-methyl-N-(1H-pyrazol-5-yl)pyrimidin-4-amine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1C=CC=CC=1.C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C.[NH2:40][CH2:41][C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([NH:40][CH2:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[O:21])=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[CH3:2]
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: CCN1CCN(c2nc(C)c(C(=O)O)s2)C1=O
Product: CCN1CCN(c2nc(C)c(C(=O)NCc3cccnc3)s2)C1=O
Yield: 16 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-ethyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 16% yield: mp 163-164° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.56-8.48 (m, 2H), 7.66 (d, J=7.8 Hz, 1H), 7.28-7.17 (m, 1H), 6.23 (t, J=5.7 Hz, 1H), 4.55 (d, J=5.7 Hz, 2H), 4.12-4.03 (m, 2H), 3.58-3.53 (m, 2H), 3.35 (q, J=7.2 Hz, 2H), 2.58 (s, 3H), 1.18 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 162.7, 157.5, 155.1, 153.6, 149.2, 148.8, 135.6, 133.9, 123.6, 116.6, 42.0, 41.5, 41.3, 38.5, 17.2, 12.5; MS (ES+) m/z 346.3 (M+1).
Reaction SMILES: [C@@H:1]12[CH2:7][NH:6][C@@H:5]1[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([N:6]2[CH2:7][C@@H:1]3[C@H:5]2[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]3)[CH:20]=1
Reactant: O=C(OCc1ccccc1)N1C[C@@H]2CN[C@@H]2C1
Reactant: Brc1cccnc1
Product: O=C(OCc1ccccc1)N1C[C@@H]2CN(c3cccnc3)[C@@H]2C1
Yield: 61 %

Procedure:
The product of Example 52D (230 mg, 1.0 mmol) and 3-bromopyridine were processed according to the procedure described in Example 1E. The crude product was purified by chromatography (SiO2, CH2Cl2:methanol, 95:5, Rf, 0.3) to provide the title compound (190 mg, 61% yield). 1H NMR (MeOH-d4, 300 MHz) δ 3.24 (dd, J=12.6, 4.1 Hz, 1H), 3.30 (m, 1H), 3.40 (m, 1H), 3.64 (dd, J=7.8, 3.4 Hz, 1H), 3.92-4.08 (m, 3H), 4.70 (m, 1H), 5.10 (m, 2H), 6.90 (m, 1H), 7.24 (m, 3H), 7.35 (m, 2H), 7.73 (d, J=2.7 Hz, 1H), 7.86 (d, J=4.7 Hz, 1H); MS (DCI/NH3) m/z 310(M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][C@H:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3]1.Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:24]=[CH:25][C:18]=12.CCN(CC)CC>CN(C=O)C.O>[CH3:1][C@@H:2]1[CH2:7][N:6]([C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:24]=[CH:25][C:18]=23)[CH2:5][C@H:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3]1
Reactant: C[Si](C)(C)CCOCn1ncc2c(Cl)ncnc21
Reactant: C[C@@H]1CNC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(c2ncnc3c2cnn3COCC[Si](C)(C)C)C1
Temperature: 80 °C

Procedure:
A mixture of tert-butyl (3R,5S)-5-methylpiperidin-3-ylcarbamate (150 mg, 0.7 mmol), 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (200 mg, 0.7 mmol) and Et3N (195 μL, 1.4 mmol) in DMF (5 mL) was heated at 80° C. for 16 h. The solution was cooled, diluted with water, extracted with EtOAc, washed with aq. citric acid and aq. NaHCO3, dried (Na2SO4), filtered, and concentrated in vacuo to afford a residue, which was purified by column chromatography (silica gel, gradient EtOAc in hexanes).
Reaction SMILES: [H-].[Na+].N[C@H:4]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[C:18]([CH2:24][CH3:25])[CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[O:26]=[C:27]1[N:33]([CH:34]2[CH2:39][CH2:38][N:37]([C:40](Cl)=[O:41])[CH2:36][CH2:35]2)[CH2:32][CH2:31][C:30]2[CH:43]=[CH:44][CH:45]=[CH:46][C:29]=2[NH:28]1.C1C[O:50]CC1>>[O:26]=[C:27]1[N:33]([CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:50][C@@H:4]([C:5]([O:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:6])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[C:18]([CH2:24][CH3:25])[CH:17]=3)=[O:41])[CH2:36][CH2:35]2)[CH2:32][CH2:31][C:30]2[CH:43]=[CH:44][CH:45]=[CH:46][C:29]=2[NH:28]1
Reactant: CCc1ccc(C[C@@H](N)C(=O)OCc2ccccc2)cc1CC
Reactant: O=C(Cl)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCc1ccc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)OCc2ccccc2)cc1CC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
87 mg (2.0 mmol) sodium hydride (55% in mineral oil) were added to an ice-cooled mixture of 600 mg (1.9 mmol) benzyl (R)-2-amino-3-(3,4-diethyl-phenyl)-propionate and 40 mL THF, stirred for 30 min at RT, cooled in the ice bath and 660 mg (2.1 mmol) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonylchloride in 20 mL THF were added dropwise within 10 min. The reaction mixture was stirred for a further 30 min while cooling with ice and for 1 h at RT and then evaporated down under reduced pressure. The residue was taken up in EtOAc and purified by chromatography on silica gel.
Reaction SMILES: C([Mg]Br)C.C1COCC1.I[C:11]1[N:12]=[CH:13][N:14]2[CH:18]=[CH:17][S:16][C:15]=12.[C:19](=[O:21])=[O:20].[OH-].[Na+]>C1COCC1.CCOCC>[S:16]1[CH:17]=[CH:18][N:14]2[CH:13]=[N:12][C:11]([C:19]([OH:21])=[O:20])=[C:15]12
Reactant: O=C=O
Reactant: Ic1ncn2ccsc12
Agent: CC[Mg]Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)c1ncn2ccsc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
A 0.95 M ethylmagnesium bromide/THF solution (12.6 ml) was added dropwise to a solution (50 ml) of 2.501 g of 7-iodoimidazo[5,1-b]thiazole in THF ac −70° C. The mixture was stirred for 30 min. Carbon dioxide (which had been evolved from about 5 g of dry ice and passed through a calcium chloride tube) was introduced into the reaction solution at the same temperature over a period of 40 min. The reaction solution was allowed to stand at −20° C. overnight, and then added to an ice cold mixed solution composed of an aqueous sodium hydroxide (0.41 g) solution (100 ml) and ether (200 ml) with stirring. The mixture was stirred for one hr. The organic layer was separated and concentrated under the reduced pressure by a minor amount, and the remaining organic solvent was removed by distillation. The residue was adjusted to pH 3.5 by the addition of 2 N hydrochloric acid under ice cooling. The resultant precipitate was washed with a minor amount of cold water, and then dried under the reduced pressure to give 1.407 g of imidazo[5,1-b]thiazole-7-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH2:12]O)[CH:4]=1.C([O-])(O)=O.[Na+].O=S(Cl)[Cl:21]>>[Cl:21][CH2:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)cc2c1OCO2
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(CCl)cc2c1OCO2
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of SOCl2(150 mL) was added (7-methoxybenzo[d][1,3]dioxol-5-yl)methanol (9.0 g, 54 mmol) in portions at 0° C. The mixture was stirred for 0.5 h. The excess SOCl2 was evaporated under reduced pressure to give the crude product, which was basified with sat. aq. NaHCO3 to pH ˜7. The aqueous phase was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated to give 6-(chloromethyl)-4-methoxybenzo[d][1,3]dioxole (10 g 94%), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 6.58 (s, 1H), 6.57 (s, 1H), 5.98 (s, 2H), 4.51 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([O:15][CH3:16])([CH3:14])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[CH2:28]([O:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([O:15][CH3:16])([CH3:14])[CH2:6][CH2:5]2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: ClCc1ccccc1
Reactant: COC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC1(C)CCc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1

Procedure:
A mixture of 70.8 g. of (±)-6-hydroxy-2-methoxy-2,5,7,8-tetramethylchroman, 90.9 g. of anhydrous potassium carbonate, 300 ml. of dimethylsulfoxide and 69 ml. of benzyl chloride was stirred at 23° under N2 for 24 hours. The suspension was poured into water and extracted with ether. The ether solutions were washed with brine, dried over sodium sulfate and stripped of solvent to give (±)-6-benzyloxy-2-methoxy-2,5,7,8-tetramethylchroman as an oil which solidified to a light yellow mass, m.p. 70°-72.5°.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[NH:5][C:4]1=[O:13])[CH3:2].Br[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19]>>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[NH:5][C:4]1=[O:13]
Reactant: CCC1C(=O)Nc2ccc(F)cc21
Reactant: ClCCCCBr
Product: CCC1(CCCCCl)C(=O)Nc2ccc(F)cc21

Procedure:
The title compound is prepared according to process E starting from 3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1-bromo-4-chloro-butane.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[C:13]([CH2:16][C:17](=[O:19])[CH3:18])(=O)[CH3:14].[NH2:20]/[C:21](/[CH3:28])=[CH:22]\[C:23]([O:25][CH2:26][CH3:27])=[O:24]>N1CCCCC1.C1(C)C=CC=CC=1>[CH2:26]([O:25][C:23]([C:22]1[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=2)[C:16]([C:17](=[O:19])[CH3:18])=[C:13]([CH3:14])[NH:20][C:21]=1[CH3:28])=[O:24])[CH3:27]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(C)NC(C)=C(C(C)=O)C1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
A mixture of 3-trifluoromethylbenzaldehyde (12 g), acetylacetone (6.9 g), and piperidine (15 drops) was stirred at room temperature overnight. The reaction mixture was dissolved in toluene, and the toluene solution was washed with dilute hydrochloric acid, and dried over magnesium sulfate. Evaporation of toluene afforded a thick oily residue. Ethyl 3-aminocrotonate (7.0 g) was added to the residue, and the resulting mixture was heated on a steam bath overnight. The crude product was purified by a preparative HPLC, then recrystallized from toluene to give the titled product (4.1 g), mp 133°-1314.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].[Cs+].O1[CH2:38][CH2:37]OCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:38]3[CH:37]=[CH:16][CH:15]=[CH:14][N:11]=3)=[CH:16][C:15]=2[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CC(c2cc(Br)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2cc(-c3ccccn3)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-[4-bromo-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (100 mg, 0.209 mmol) produced in Example (99a), 2-(tributyltin)pyridine (0.08 mL, 0.25 mmol), cesium fluoride (68 mg, 0.448 mmol) and dioxane (15 mL) was added tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmol), followed by stirring for 3 hours at an external temperature of 90° C under a nitrogen atmosphere. Ethyl acetate was added to the reaction mixture, insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 43 mg of the title compound as light yellow crystals.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[BrH:11].[CH2:12]([N:15]([CH2:28][CH2:29][CH3:30])[CH:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][C:20]([NH2:27])=[C:21]([OH:26])[CH:22]=2)[CH2:17]1)[CH2:13][CH3:14]>C(OCC)C>[BrH:11].[CH2:28]([N:15]([CH2:12][CH2:13][CH3:14])[CH:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][C:20]([NH:27][CH:8]=[O:10])=[C:21]([OH:26])[CH:22]=2)[CH2:17]1)[CH2:29][CH3:30]
Reactant: O=CO
Reactant: CCCN(CCC)C1CCc2cc(O)c(N)cc2C1
Agent: Br
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CCCN(CCC)C1CCc2cc(O)c(NC=O)cc2C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
0.7 ml of acetic anhydride is added to 3 ml of 98% formic acid, kept at 0° C., and the whole is left for 15 minutes at 0° C. 2.2 g of 2-dipropylamino-7-amino-6-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide are then added thereto and the mixture is then stirred for one hour at 0° C. After 50 ml of diethyl ether have been added and the solid has been filtered off, the latter is recrystallised from a 50/50 methanol/ethyl acetate mixture. This gives 1 g of the final product melting at 213° C. (with decomposition).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@H:6]1[NH:10][CH2:9][C@@H:8]([NH:11][C:12]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[OH:24])=[O:13])[CH2:7]1.[CH:25]1([CH:31]=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.COC([C@@H]1C[C@H](N=[N+]=[N-])CN1CC1CCCCC1)=O>>[CH:25]1([CH2:31][N:10]2[C@H:6]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)[CH2:7][C@H:8]([NH:11][C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[OH:24])=[O:13])[CH2:9]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C(N[C@@H]1CN[C@H](c2ncco2)C1)c1ccc2ccccc2c1O
Reactant: O=CC1CCCCC1
Agent: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1CC1CCCCC1
Product: O=C(N[C@H]1C[C@@H](c2ncco2)N(CC2CCCCC2)C1)c1ccc2ccccc2c1O

Procedure:
Hydroxy-naphthalene-2-carboxylic acid ((3S,5S)-1-cyclohexylmethyl-5-oxazol-2-yl-pyrrolidin-3-yl)-amide was prepared from 1-hydroxy-naphthalene-2-carboxylic acid ((3S,5S)-5-oxazol-2-yl-pyrrolidin-3-yl)-amide and cyclohexanecarbaldehyde in a similar fashion as the synthesis of (2S,4S)-4-azido-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester. MS calcd. for C25H30N3O3[(M+H)+] 420, obsd. 419.8.