Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14](=[O:33])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH:11]=[C:10]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:9]=2[O:41]CCCCC(OCC)=O)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>C1COCC1.CO>[N:24]1([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:14](=[O:33])[C:12]2[CH:13]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:9]([OH:41])=[C:10]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[CH:11]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25]1
Reactant: CCOC(=O)CCCCOc1c(-c2cccc(Cl)c2)cc(C(=O)NCCCCCCCCn2ccc3ccccc32)cc1-c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCCCCCCCCn1ccc2ccccc21)c1cc(-c2cccc(Cl)c2)c(O)c(-c2cccc(Cl)c2)c1
Reaction time: 18 h
Yield: 74.2 %

Procedure:
A mixture of 5-[3,3″-Dichloro-5′-(8-indol-1-yl-octylcarbamoyl)-[1,1′;3′,1″]terphenyl-2′-yloxy]-pentanoic acid, ethyl ester (0.409 g, 0.573 mmol) and 1N KOH (1.15 ml) in THF (6 ml) and methanol (3 ml) was stirred under nitrogen. After 18 h, the reaction mixture was concentrated in vac. The residue was suspended in water (25 ml) and acidified with 2 N HCl (1.15 ml) then extracted with EtOAc (3×25 ml). The combined organics were washed with water (3×10 ml), brine (2×10 ml), dried over Na2SO4, filtered and the filtrate concentrated in vac and dried. The residue was purified by preparatory plate chromatography (50% EtOAc/Hex) to give the title compound as a light yellow foam (0.249 g, 63%); dec. >50° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.12-1.32 (m, 12H), 1.44-1.53 (m, 2H), 1.67-1.76 (m, 2H), 1.87 (t, J=7.0 Hz, 2H), 3.16-3.27 (m, 4H), 4.12 (t, J=7.0 Hz, 2H), 6.37-6.38 (m, 1H), 6.94-6.99 (m, 1H), 7.06-7.10 (m, 1H), 7.31 (d, J=3.1 Hz, 1H), 7.40-7.52 (m, 6H), 7.56-7.59 (m, 2H), 7.66-7.69 (m, 2H), 7.87 (s, 2H), 8.52 (t, J=5.7 Hz, 1H), 11.85 (s, 1H); IR (KBr) 3400, 2940, 1710, 1630, 1550, 1220 cm−1; mass spectrum [(+)APCI], m/z 685 (M+H)+; Anal. Calcd. for C40H42Cl2N2O4: C, 70.07; H, 6.17; N, 4.09, Found: C, 69.66; H, 6.17; N, 3.85.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][CH2:27][NH2:28])[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][CH2:27][NH:28][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: CCCCCCCCOc1ccc(C=O)cc1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Product: CCCCCCCCOc1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1

Procedure:
The same procedure as employed in the preparation of Example 394 (step b) but using 4-(octyloxy)benzaldehyde and 2-(3,4-dichlorophenyl)ethylamine gave the title compound as an oil. HPLC (Condition A), Rt: 4.69 min (HPLC purity: 71.8%).
Reaction SMILES: [Si]([O:8][C:9]1[S:17][C:16]2[CH2:15][CH2:14][N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[CH2:12][C:11]=2[CH:10]=1)(C(C)(C)C)(C)C.O.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:13]1[CH2:14][CH2:15][CH:16]2[S:17][C:9](=[O:8])[CH2:10][C:11]2=[CH:12]1.[CH3:37][C:27]1[CH:32]=[CH:31][C:30]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc2c(s1)CCN(Cc1ccccc1Cl)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: O=C1CC2=CN(Cc3ccccc3Cl)CCC2S1
Temperature: 40 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
A mixture of 8.23 g of 2-(tert-butyldimethylsilyloxy)-5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 4.31 g of p-toluenesulfonic acid monohydrate and 40 ml of methylene chloride was stirred at 40° C. for 2 hours to obtain precipitated crystals. The obtained precipitated crystals were filtered, washed with 20 ml of methylene chloride and dried under reduced pressure to obtain 7.85 g of 5-(2-chlorobenzyl)-5,6,7,7a-tetrahydrothieno[3,2-c]-pyridin-2-one-p-toluenesulfonate.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:16][C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([CH2:25][O:26][C:27]4[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=4)[N:22]([CH3:35])[C:21]=3[CH:36]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[S:37]1[CH2:41][C:40](=[O:42])[NH:39][C:38]1=[O:43].N1CCCCC1>C(O)C>[C:12]([C:9]1[CH:8]=[C:7]([S:16][C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([CH2:25][O:26][C:27]4[CH:34]=[CH:33][C:30]([CH:31]=[C:41]5[S:37][C:38](=[O:43])[NH:39][C:40]5=[O:42])=[CH:29][CH:28]=4)[N:22]([CH3:35])[C:21]=3[CH:36]=2)[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cn1c(COc2ccc(C=O)cc2)nc2ccc(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cc21
Reactant: O=C1CSC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cn1c(COc2ccc(C=C3SC(=O)NC3=O)cc2)nc2ccc(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cc21
Yield: 86 %

Procedure:
A mixture of 4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazole-2-ylmethoxy]benzaldehyde (502 mg), thiazolidine-2,4-dione (234 mg), piperidine (170 mg ) and ethanol (60 ml) was heated at reflux for 19 hours. The reaction mixture was evaporated to dryness and to the residue was added water and insoluble product was isolated by filtration and washed with water and diisopropyl ether to give the title compound (517 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH3:17])=[O:15].CC(O)=O>C(OCC)(=O)C.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH3:17])=[O:15])=[C:2]([F:1])[CH:7]=1
Reactant: CNC(=O)CCCc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CNC(=O)CCCc1ccc(N)cc1F
Temperature: 21 °C
Yield: 95.1 %

Procedure:
A solution of compound 4-(2-Fluoro-4-nitrophenyl)-N-methylbutanamide (81) (18 mg, 0.07 mmol), Fe (30 mg, 0.52 mmol) and AcOH (1 mL) in ethyl acetate (3 mL) was heated under reflux for 2 h. The reaction mixture was allowed to cool to 21° C. and then filtered. The organic layer was concentrated and the residue was purified with silica gel column chromatography (dichloromethane:acetone, 9:1) to give desired 4-(4-Amino-2-fluorophenyl)-N-methylbutanamide (80) (14 mg, 86%): 1H NMR δ 6.92 (dd, 1H, J=8.3, 8.2 Hz), 6.39 (dd, 1H, J=8.3, 2.0 Hz), 6.33 (dd, 1H, J=13.3, 2.0 Hz), 5.48 (br s, 1H), 3.69 (br s, 2H), 2.79 (d, 3H, J=4.8 Hz), 2.55 (t, 2H, J=7.4 Hz) 2.16 (t, 2H, J=7.5 Hz) 1.85-1.94 (m, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH:9]([C:12]1[N:17]=[C:16]2[S:18][C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[N:20][C:15]2=[CH:14][CH:13]=1)[C:10]#[N:11].[NH2:26][NH2:27]>CCO.CC(O)=O>[NH2:11][C:10]1[NH:27][N:26]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[C:9]=1[C:12]1[N:17]=[C:16]2[S:18][C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[N:20][C:15]2=[CH:14][CH:13]=1
Reactant: NN
Reactant: CC(C)Nc1nc2ccc(C(C#N)C(=O)c3ccccc3F)nc2s1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)Nc1nc2ccc(-c3c(-c4ccccc4)n[nH]c3N)nc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 1.4 %

Procedure:
To a solution of 3-(2-fluorophenyl)-2-(2-(isopropylamino)thiazolo[5,4-b]pyridin-5-yl)-3-oxopropanenitrile (0.10 g, 0.282 mmol, 1.0 eq.) in EtOH (1 mL) and HOAc (2 mL) at 0° C. was added hydrazine (0.1 mL, 3.19 mmol, 11.3 eq.). After 10 min., the cold bath was removed, and the reaction mixture was stirred to room temperature for 10 min. It was then heated at 88° C. for 5 hr and at 100° C. overnight. After cooling to room temperature and then to 0° C., water was added followed by concentrated aqueous NH4OH until pH was 10 by litmus paper. The aqueous layer was extracted with EtOAc (3×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. MeOH was added to the residue, and the mixture was subjected to autoprep. The appropriate fractions were collected, and NaHCO3 (s) was added. The solution was then concentrated in vacuo not to dryness and extracted with CH2Cl2 (3×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to give 5-(5-amino-3-phenyl-1H-pyrazol-4-yl) -N-isopropylthiazolo[5,4-b]pyridin-2-amine as a light yellow solid (0.0014 g, 1.3% yield). LC/MS (MH)=369.14.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH:7]=[O:8])[CH2:3][CH2:4][C:5]#[N:6].[O-:10][Mn](=O)(=O)=O.[K+].C(Cl)Cl>CC(O)(C)C>[C:5]([CH2:4][CH2:3][C:2]([CH3:9])([CH3:1])[C:7]([OH:10])=[O:8])#[N:6]
Reactant: CC(C)(C=O)CCC#N
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CC(C)(CCC#N)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4,4-dimethyl-5-oxopentanenitrile (1.0 g, 7.98 mmol) in t-BuOH (2 mL) was cooled to 0° C. and 5% aqueous NaH2PO4 solution (11 mL) was added dropwise. 1M KMnO4 solution (16 mL) was added dropwise to the reaction mixture at 0° C. followed by few drops of CH2Cl2 (0.5 mL). The reaction mixture was allowed to stir at 0° C. for 1 h, and quenched with sodium sulfite. 1.5N HCl was then added to adjust the pH of the solution to ˜3. The organic product was extracted with EtOAc and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure to get 4-cyano-2,2-dimethylbutanoic acid (0.9 g, crude), which was carried through without further purification. 1H NMR (300 MHz, CDCl3) δ 5.55 (br s, 1H), 2.43-2.37 (m, 2H), 1.99-1.94 (m, 2H), 1.28-1.27 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH2:22][CH3:23])=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[C:11]([CH3:19])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:34])[CH:32]=[CH2:33])[CH2:27][CH2:26]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C(#N)C>[CH3:19][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[N:9]=[C:8]([C:6]1[CH:7]=[C:2]([CH2:33][CH2:32][C:31]([N:28]3[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]3)=[O:34])[CH:3]=[CH:4][C:5]=1[O:20][CH2:21][CH2:22][CH3:23])[NH:17][C:16]2=[O:18]
Reactant: CCCOc1ccc(Br)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Reactant: C=CC(=O)N1CCN(C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCOc1ccc(CCC(=O)N2CCN(C)CC2)cc1-c1nc2c(C)cccc2c(=O)[nH]1

Procedure:
A stirred mixture of 2-(5-bromo-2-n-propoxyphenyl)-8-methylquinazolin-4(3H)-one (Preparation 11; 0.5 g, 0.0013 mol), 1-methyl-4-propenoylpiperazine (Makromol. Chem., 1984, 185, 1525; 0.24 g, 0.0015 mol), palladium diacetate (0.175 g, 0.00077 mol), tri-o-tolylphosphine (0.30 g, 0.001 mol), triethylamine (1 ml) and acetonitrile (25 ml) was heated under reflux under a nitrogen atmosphere for 4 days. The cool mixture was filtered and the filtrate evaporated to dryness under vacuum. The residue was suspended in saturated aqueous sodium carbonate solution (25 ml), the resulting solution extracted with dichloromethane (50 ml) and the organic extract washed with brine (2×30 ml), dried (Na2SO4) and evaporated under vacuum. Chromatography of the residue on silica gel (10 g), using a methanol in dichloromethane elution gradient (0-4%), gave the title compound which crystallized from hexane-ethyl acetate as a pale pink solid (0.072 g, 12%), m.p. 184°-185° C. Found: C,89.96; H,6.64; N,12.49. C26H30N4O3 requires C,69.93; N,6.77; N,12.55%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[CH2:15]([O:17][C:18](=[O:28])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:20])[CH3:16].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:15]([O:17][C:18](=[O:28])[C@@H:19]([NH:20][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:16]
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 2.00 g, 10.2 mmol) in DMF (50 mL) was added L-phenylalanine ethyl ester hydrochloride (2.45 g, 10.7 mmol), HOBt (1.37 g, 10.2 mmol) and DIPEA (5.3 mL, 30.5 mmol). After 5 min, EDCI (2.54 g, 13.2 mmol) was added and the reaction mixture stirred at rt for 16 h. The solvent was removed in vacuo and the solid dissolved in ethyl acetate (150 mL) and washed with water (200 mL). The organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with methanol/dichloromethane (3:97) to give the title compound as a pale yellow solid. δH (CD3OD): 1.21 (3H, t), 3.13 (1H, dd), 3.28 (1H, dd), 4.17 (2H, q), 4.86 (1H, m), 7.09 (1H, s), 7.16–7.26 (5H, m), 7.65 (1H, s), 8.55 (1H, s); m/z (ES+)=372 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:3]=1.[NH2:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][CH2:21][OH:22])=[CH:18][CH:17]=1>>[CH:10]1([C:4]2[N:3]=[C:2]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([CH2:20][CH2:21][OH:22])=[CH:18][CH:17]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Nc1ccc(CCO)cc1
Reactant: CCc1cc(Cl)nc(C2CCCC2)n1
Product: CCc1cc(Nc2ccc(CCO)cc2)nc(C2CCCC2)n1
Yield: 62.9 %

Procedure:
Following General Procedure A2, 4-chloro-2-cyclopentyl-6-ethylpyrimidine (0.100 g, 0.47 mmol) was reacted with 4-aminophenethyl alcohol (0.078 g, 0.57 mmol) to afford the title compound (0.092 g, 92%) as an off-white solid. MW=311.42. 1H NMR (DMSO-d6, 500 MHz) δ 14.15 (s, 1H), 11.14 (s, 1H), 7.62 (s, 1H), 7.34-7.17 (m, 2H), 6.75 (s, 1H), 4.63 (s, 1H), 3.61 (t, J=6.9 Hz, 2H), 2.80-2.67 (m, 4H), 2.12-2.00 (m, 2H), 1.93-1.73 (m, 4H), 1.71-1.58 (m, 2H), 1.24 (s, 3H); APCI MS m/z 312 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:39])[C@@H:7]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:11][CH:10]=1)(C)(C)C>FC(F)(F)C(O)=O.O>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([S:29]([NH:28][C@@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]3[NH:26][CH2:25][CH2:24][CH2:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]([OH:39])=[O:5])(=[O:30])=[O:31])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1ccc(Cl)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCOc1ccc(C[C@H](NS(=O)(=O)c2ccc(Cl)cc2)C(=O)O)cc1)NC1=NCCCN1
Reaction time: 2 h

Procedure:
35.7 mg of (2S)-2-(4-chlorobenzenesulfonylamino)-3-{4-[3-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-propoxy]-phenyl}-propionic acid tert-butyl ester were dissolved in trifluoroacetic acid/water (95/5) and stirred for 2 hours. The solvent was removed in vacuo. The residue was dissolved in acetic acid/water and lyophilized. Yield 20.2 mg. MS (ES+): m/e=523.1 (M)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:10]1[CH:11]=[C:12]([NH:25][C:26]([NH:28][C@@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@H:32]([O:39][C:40]3[CH:41]=[CH:42][C:43]4[N:44]([C:46]([N:49]5[C@H:54]([CH3:55])[CH2:53][CH2:52][CH2:51][C@@H:50]5[CH3:56])=[N:47][N:48]=4)[CH:45]=3)[CH2:31][CH2:30]2)=[O:27])[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][OH:24])[CH:16]=2)[N:14]=1)([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:6]([C:10]1[CH:11]=[C:12]([NH:25][C:26]([NH:28][C@@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@H:32]([O:39][C:40]3[CH:41]=[CH:42][C:43]4[N:44]([C:46]([N:49]5[C@H:54]([CH3:55])[CH2:53][CH2:52][CH2:51][C@@H:50]5[CH3:56])=[N:47][N:48]=4)[CH:45]=3)[CH2:31][CH2:30]2)=[O:27])[N:13]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[O:21][CH2:22][CH2:23][O:24][S:2]([CH3:1])(=[O:4])=[O:3])[N:14]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Temperature: 0 °C
Yield: 99.8 %

Procedure:
Methane sulfonylchloride (11.0 μL, 0.13 mmol) was added to an ice cold solution of Intermediate 96e (89.0 mg, 0.13 mmol) and DIPEA (27.0 μL, 0.15 mmol) in DCM (1.5 mL). After 1 hour additional DIPEA (27.0 μL, 0.15 mmol) and methane sulfonylchloride (11.0 μL, 0.13 mmol) was added. After a further 1 hour additional DIPEA (27.0 μL, 0.15 mmol) and methane sulfonylchloride (11.0 μL, 0.13 mmol) was added. After 1 hour the reaction was partitioned between DCM and water. The aqueous layer was then extracted with DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give the title compound (100 mg, 99%). LCMS (Method 1): Rt 3.73 min, m/z 771 [MH+].
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([N:13]2[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14]2)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[NH2:26][NH2:27]>C(O)C(C)C>[F:10][C:9]([F:12])([F:11])[C@H:8]([N:13]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14]1)[C:5]1[CH:6]=[N:7][C:2]([NH:26][NH2:27])=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(Cl)nc2)C(F)(F)F)C1
Reactant: NN
Solvent: CC(C)CO
Product: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Temperature: 25 °C
Yield: 100.6 %

Procedure:
A solution of tert-butyl (S)-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (68.5 g, 180.4 mmol) and anhydrous hydrazine (56.61 mL, 1804 mmol) in i-BuOH (80 mL) was stirred at 106° C. in a sealed flask for 16 hours. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residue was partitioned in ethyl acetate (800 mL) and water (100 mL). The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (68.1 g, 95.6%) as white foam solid. Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexane/10% (1:1 MeOH/EtOH) at 1.0 mL/min, >99% d.e. (R,S)-diastereomer).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.[Cl-].[NH4+:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH2:38])=[O:25]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: [NH4+]
Agent: [Cl-]
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(N)=O)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with ammonium chloride.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1.NC(O)CC>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Agent: CCC(N)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 182.5 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. The above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Triethylamine (7.9 ml) is added to the bottle, and DL-aminopropanol (7.0 ml) is added thereto under the temperature. The above mixture is reacted under the temperature for 1 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amounts of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum at 50° C. for 5 h to obtain solid purin (11.6 g). The yield is about 70.4%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[Cl:9].[Cl:18]C1C=C(C=CC=1)C(OO)=[O:23]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([S:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:23])[CH:6]=[CH:7][C:8]=1[Cl:9].[ClH:18]
Reactant: Clc1ccc(SCc2ccccn2)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: O=S(Cc1ccccn1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of 2-(((3,4-dichlorophenyl)thio)methyl)pyridine, hydrochloride (2.0 g) in methylene chloride (50 ml) at 0° C. was treated with a solution of m-chloroperoxybenzoic acid (1.5 g) in methylene chloride (25 ml). The mixture was allowed to warm to ambient temperature and was stirred for 5 hours. The solution with washed with saturated sodium carbonate solution and water, then dried (MgSO4). The residue was dissolved in acetone and converted into the hydrochloride with ethereal HCl. N.m.r. showed approximately 35% of starting material remaining so the material was suspended in methylene chloride (50 ml) and treated with further m-chloroperoxybenzoic acid (2×500 g). The solution was washed with saturated sodium carbonate solution and water, dried (MgSO4), evaporated and the residue was dissolved in acetone and the hydrochloride precipitated with ethereal HCl solution. Recrystallisation from propan-2-ol/ether gave the title compound, hydrochloride (0.6 g) mp 178° C. decomp (Found: C44.7; H,3.2; N,4.2. C12H9Cl2NOS.HCl requires C,44.7; H,3.1; N,4.3%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:9]([OH:11])=O)[NH:7][N:8]=2)[CH2:3][CH2:2]1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.[C:30]([O:34][C:35](=[O:48])[NH:36][CH:37]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([NH2:47])[CH:42]=1)[CH2:38][CH2:39][OH:40])([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[C:30]([O:34][C:35](=[O:48])[NH:36][CH:37]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([NH:47][C:9]([C:6]2[NH:7][N:8]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[CH:5]=2)=[O:11])[CH:42]=1)[CH2:38][CH2:39][OH:40])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC(CCO)c1cccc(N)c1
Reactant: O=C(O)c1cc(C2CC2)n[nH]1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CCO)c1cccc(NC(=O)c2cc(C3CC3)n[nH]2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
529 mg (3.4 mmol) 5-Cyclopropyl-2H-pyrazole-3-carboxylic acid were suspended in 9 ml THF and 834 mg (3.4 mmol) EEDQ were added. The mixture was stirred for 10 min at room temperature and subsequently 900 mg (3.4 mmol) [1-(3-Amino-phenyl)-3-hydroxy-propyl]-carbamic acid tert-butyl ester dissolved in 9 ml THF were added. The mixture was stirred overnight at room temperature, evaporated to dryness. The residue was dissolved in ethyl acetate and washed with 1 N NaOH, 10% citric acid and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. 1.37 g, clear oil.