Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[NH2:29][CH2:30][C@@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35](Cl)[CH:34]=1)[OH:32]>>[OH:32][C@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30][NH:29][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NC[C@H](O)c1cccc(Cl)c1
Agent: Cl
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4ccccc4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and (1R)-2-amino-1-(3-chloro-phenyl)-ethanol (which was obtained in Example 1) according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.55–1.75 (m, 2 H), 2.06 (s, 3 H), 2.00–2.15 (m, 2 H), 2.50–3.20 (m, 5 H), 3.55–3.70 (m, 2 H), 4.90–5.00 (m, 1 H), 6.00–6.20 (brs, 1 H), 6.80 (d, J=9.0 Hz, 2 H), 6.89 (d, J=9.0 Hz, 2 H), 7.25–7.52 (m, 5 H), 7.59 (d, J=8.7 Hz, 2 H), 7.70 (d, J=8.7 Hz, 2 H), 10.41 (s, 1 H); MS (ES) m/z: 509.2 (MH+); HRMS Calcd. for C27H33N4O4S (MH+): 509.2223. Found: 509.2194.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([S:18](O)(=[O:20])=[O:19])=[CH:16][CH:17]=1>CCO.O=[Pt]=O>[C:12]1([CH3:11])[CH:17]=[CH:16][C:15]([S:18]([O:10][CH2:9][CH2:8][CH2:7][CH:4]2[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCCc1ccncc1
Agent: O=[Pt]=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OCCCC2CCNCC2)cc1
Reaction time: 6 h
Yield: 112.1 %

Procedure:
To a solution of 3-(4-pyridyl)propan-1-ol (15.13 g, 0.1103 mol) in EtOH (100 mL) was added p-TsOH (20.98 g, 0.1103 mol) and PtO2 (1.5 g, 6.6 mmol). The resulting mixture was placed on a Parr apparatus and hydrogenated at 55 p.s.i. After 6 hr, the mixture was filtered (EtOH wash) and the filtrate concentrated in vacuo, giving 36.78 g (>100%) of the desired piperidine; 1H NMR (300 MHz, CDCl3) δ 7.7 (d, 2H), 7.2 (d, 2H), 3.55 (t, 2H), 3.3 (m, 4H), 2.95 (bt, 2H), 2.38 (s, 3H), 1.95 (bd, 2H), 1.58 (m, 2H), 1.3 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[C:6]([C:8]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=1[C:10](O)=[O:11])=O.O.[NH2:25][NH2:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[C:8]3[C:9](=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:10](=[O:11])[NH:26][N:25]=2)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: COc1cc(OC)cc(C(=O)c2ccc(OC)cc2C(=O)O)c1
Reactant: NN
Solvent: O
Product: COc1cc(OC)cc(-c2n[nH]c(=O)c3cc(OC)ccc23)c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 2-(3,5-dimethoxybenzoyl)-5-methoxybenzoic acid with hydrazine hydrate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].C(N(CC)CC)C>C(#N)C>[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:15]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)c1ccc(NC(=O)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.2 %

Procedure:
under an N2 atmosphere, 4-aminobenzoic acid (2.50 g, 18.2 mmol) was dissolved in acetonitrile (100 ml) and treated with 2-chlorobenzoyl chloride (2.43 ml, 19.1 mmol). Triethylamine (2.66 ml, 19.1 mmol) was added and the reaction was allowed to stir at room temperature for four hours. The reaction was concentrated in vacuo, and the resulting solid was partitioned between Et2O and 0.5N NaOH. The layers were separated and the organic layer was discarded. The aqueous layer was acidified to pH 2 with HCl and the aqueous layer was extracted with ethyl acetate. The organic layer was dried Na2SO4, filtered and concentrated in vacuo. The resulting solid was triturated with Et2O, and the solid was collected by filtration to afford 4-(2-chlorobenzamido)benzoic acid (2.72 g, 54.2% yield). ESI m/z=276.1 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.Cl.Cl[CH2:46][C:47]1[CH:48]=[N:49][CH:50]=[C:51]([F:53])[CH:52]=1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[F:53][C:51]1[CH:52]=[C:47]([CH2:46][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])[CH:48]=[N:49][CH:50]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: Fc1cncc(CCl)c1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Agent: Cl
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Product: O=C1N(Cc2cncc(F)c2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 3-(chloromethyl)-5-fluoropyridine hydrochloride (Carlson et al., Acta Pharmaceutica Suecica, 1972, 9, 411-414) to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 1′-[(5-fluoropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (71%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.45-8.38 (m, 2H), 7.37-7.34 (m, 1H), 7.24-7.14 (m, 2H), 7.04-7.00 (m, 1H), 6.78-6.75 (m, 1H), 6.46 (s, 1H), 6.17 (s, 1H), 5.03-4.85 (m, 3H), 4.64-4.61 (m, 1H), 4.16-4.04 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.6, 155.3, 144.7, 144.6, 141.4, 138.4, 138.1, 137.8, 132.1, 129.0, 124.3, 123.9, 122.1, 121.9, 120.6, 111.4, 108.8, 99.5, 80.1, 64.5, 63.9, 58.0, 41.1; MS (ES+) m/z 405.0 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23](=[O:25])[O:24][C:20]=3[CH:19]=2)[CH2:14][CH2:13]1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:28](=O)[CH3:29].Cl>>[CH2:28]([N:11]([C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23](=[O:25])[O:24][C:20]=3[CH:19]=2)[CH2:16][CH2:17]1)[CH3:29]
Reactant: CC=O
Reactant: C[C@H](CCc1ccccc1)N[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Agent: Cl
Product: CCN([C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1)[C@H](C)CCc1ccccc1

Procedure:
Coupling of 6-{trans-4-[(R)-1-methyl-3-phenylpropylamino]cyclohexyl}-3H-benzoxazol-2-one (370 mg, 1.01 mmol) and acetaldehyde (44 mg, 1.01 mmol) following the procedure described in Example 24, followed by formation of the HCl salt, gave 6-(trans-4-{ethyl-[(R)-1-methyl-3-phenylpropyl]amino}-cyclohexyl)-3H-benzoxazol-2-one (70 mg, 25%), as a pale yellow solid (a mixture of diastereomers): mp 139-158° C.; IR (KBr): 2941, 1772, 1497, 1451 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 11.52 (s, 2H), 9.11 (s, 2H), 7.35-7.21 (m, 10H), 7.18 (m, 4H), 7.00 (s, 2H), 3.20 (m, 2H), 2.81 (m, 2H), 2.54 (m, 2H), 2.20-1.51 (m, 28H), 1.44 (d, J=7 Hz, 3H), 1.32 (d, J=7 Hz, 3H), 1.26 (m, 6H); API-MS (methane) (m/z): 393 [M+H]+; calcd for C25H32N2O2, 393.2542; found, 393.2540; HPLC: method C, 5.77 minutes (97.4%), method D, 11.47 minutes and 11.57 minutes (98.1%); Anal. Calcd for C25H32N2O2HCl.0.5H2O: C, 68.55; H, 7.82; N, 6.40. Found: C, 68.67; H, 8.03; N, 6.27.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([OH:17])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C1(=O)O[CH2:21][CH2:20][O:19]1>[I-].C([N+](CC)(CC)CC)C.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:15])[CH3:16])[C:9]=2[O:17][CH2:21][CH2:20][OH:19])=[CH:6][CH:7]=1
Reactant: CC(C)c1cccc(-c2ccc(F)cc2)c1O
Reactant: O=C1OCCO1
Agent: CC[N+](CC)(CC)CC
Agent: [I-]
Solvent: ClCCl
Product: CC(C)c1cccc(-c2ccc(F)cc2)c1OCCO
Temperature: 155 °C
Yield: 26 %

Procedure:
A mixture of 4'-fluoro-3-(1-methylethyl)[1,1'-biphenyl]-2-ol (1.84 g), ethylene carbonate (0.78 g) and tetraethylammonium iodide (0.68 g) was heated in an oil bath at 155° C. for 2 hours, then was cooled and taken up in dichloromethane. The solution was washed in turn with water, 1N sodium hydroxide, 1N hydrochloric acid and brine, then was dried (MgSO4) and evaporated. The residual material was chromatographed over 70 g of silica gel (ethyl acetate-hexane; 3:7) to provide 0.57 g of 2-[4'-fluoro-3-(1-methylethyl)[1,1'-biphenyl]-2-yloxy]ethanol. The compound was crystallized from hexane to give the analytical sample, mp 77°-78° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([OH:11])[CH2:8][C@H:7]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>ClCCl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:8][C@H:7]1[CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(O)C[C@H]1COc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CC(OS(C)(=O)=O)C[C@H]1COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 96.6 %

Procedure:
To a cold (ice bath) solution of (1R,2R)-2-(4-Chloro-phenoxymethyl)-4-hydroxy-cyclopentanecarboxylic acid ethyl ester (epimeric mixture, 312 mg) and triethylamine (528 mg) in dichloromethane (6 mL) was added methanesulfonyl chloride (580 mg). The reaction mixture was stirred 36 h at room temperature then hydrochloric acid (1N) was added. The reaction mixture was extracted with dichloromethane. The combined organic layers were washed with an aqueous half-saturated solution of sodium carbonate and half saturated brine then dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of cyclohexane/ethylacetate (3:1 to 3:1 v/v) as eluant to afford the title compound (0.380 g, 97%) as a light yellow oil. MS (EI): 377.1 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.C(Cl)(=O)C(Cl)=O.C[N:21](C=O)C>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH2:21])=[O:13]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc2ccccc2c1
Agent: O=C(Cl)C(=O)Cl
Product: NC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-naphthoic acid (25 g, 0.145 mol) in MC (200 ml), oxalyl chloride (38 ml, 0.4356 mol) and a catalytic amount of DMF were added and stirred at room temperature for 2 hrs. After the solvent was evaporated, the crude acyl chloride was diluted with MC (200 ml), to which a solution of ammonium hydroxide in water (160 ml) was dropwise added at an ice bath temperature. After stirring for 1 hr, the precipitated product was collected by suction filtration, triturated in hexane and dried to obtain the title compound, which was used next step without further purification.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH3:11].Cl[O-].[Na+]>O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][NH2:11]
Reactant: N
Reactant: Sc1nc2ccccc2s1
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: NSc1nc2ccccc2s1

Procedure:
2-Benzothiazole sulfenamide was synthesized from the reaction of 2-mercaptobenzothiazole, ammonia, and sodium hypochlorite in water (previously incorporated J. Org. Chem., 14, 921 (1940)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([NH2:12])[CH:9]([NH2:11])[CH3:10])=[CH:4][CH:3]=1.CO[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#N)[CH:25]=1)=[NH:23].C(Cl)(Cl)Cl>CO>[C:22]([C:24]1[CH:25]=[C:26]([C:30]2[NH:11][CH:9]([CH3:10])[C:8]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:12]=2)[CH:27]=[CH:28][CH:29]=1)#[N:23]
Reactant: CC(N)C(N)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: COC(=N)c1cccc(C#N)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC1NC(c2cccc(C#N)c2)=NC1(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14 %

Procedure:
1,1-bis(4-fluorophenyl)-1,2-propanediamine(50 mg) was dissolved in methanol(1 mL), and to the solution was added 3-cyanobenzeneimidic acid methyl ester (75 mg). The mixture was stirred at room temperature for 24 hrs. After chloroform (5 ml) was added to the reaction mixture, insolubles were removed by filtration. After concentrating the filtrate in vacuo, the obtained residue was purified by silica gel column chromatography (C-300; hexane:ethyl acetate=3:1→1:1) to give the objective compound (10 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc2c(cc1O)CCC2=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2c(cc1OCc1ccccc1)CCC2=O

Procedure:
The mixture of 5-Hydroxy-6-methoxy-indan-1-one (2.1 g), K2CO3 (3.3 g), acetone (30 ml) and benzyl bromide was heated to reflux for 5 hours. The mixture was filtered and the filtrate was evaporated to oil. The oil was treated with diethyl ether (50 ml) and the solid was collected to give 5-Benzyloxy-6-methoxy-indan-1-one (3 g). LC-MS: m/e 269 (MH+).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[CH3:20][N:21]([CH3:31])[CH2:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1>C(#N)C>[CH3:31][N:21]([CH3:20])[CH2:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7](=[O:15])[C:6]3=[CH:16][S:17][C:18]([CH3:19])=[C:5]23)=[O:3])[CH2:26]1
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Reactant: CN(C)CCCC1CCCNC1
Solvent: CC#N
Product: Cc1scc2c1N(C(=O)N1CCCC(CCCN(C)C)C1)c1ccccc1NC2=O
Yield: 35 %

Procedure:
Prepared analogously to Example 4 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 3-[3-(dimethylamino)propyl]piperidine in a yield of 35% of theory. Colourless crystals, m.p. 137°-139° C. (acetonitrile).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([OH:24])[CH2:14][NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl.[OH-].[K+]>ClCCl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:14][N:15]([C@@H:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])[C:3](=[O:4])[CH2:2][O:24]2)=[CH:11][CH:12]=1
Reactant: O=C(Cl)CCl
Reactant: C[C@@H](NC[C@@H](O)c1ccc(Br)cc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1C[C@H](c2ccc(Br)cc2)OCC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 115 %

Procedure:
A solution of chloroacetyl chloride (19.5 ml, 245 mmol) in dichloromethane (100 ml) was added dropwise to a ice-cooled solution of (1S)-1-(4-bromophenyl)-2-((1R)-1-phenylethylamino)ethanol (intermediate 11, 71.0 g, 222 mmol) and triethylamine (34 ml, 245 mmol) in dichloromethane (600 ml). After the mixture was stirred for 2 hours, 1 M hydrochloric acid was added and the mixture was partitioned between water and chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in 2-propanol (600 ml). The solution was added with potassium hydroxide (85%, 18.3 g, 278 mmol). The mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure and the residue was added with ethyl acetate. The mixture was partitioned between water and ethyl acetate, and the organic layer was washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give (6S)-6-(4-bromophenyl)-4-((1R)-1-phenylethyl)morpholin-3-one (intermediate 12, 92 g) as a brown oil. This crude product was used for next reaction without purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:31][CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[NH:27][C:26]1=[O:36])=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:31][CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[N:27]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]#[N:16])=[CH:5][CH:4]=2)[C:26]1=[O:36])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccccc2NC1=O
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Product: CC(C)(C)OC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C#N)cc2)C1=O

Procedure:
Prepared from 4'-bromomethyl-1,1'-biphenyl-2-nitrile (prepared by the method of M. Fisher, et al, U.S. Pat. No. 5,206,235) and 3(R)-t-butoxycarbonylamino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Step A) by the procedure described in Example 1, Step Q. 1H NMR (400 MHz, CDCl3): δ 1.39 (s, 9H), 1.90 (m, 1H), 2.40-2.60 (m, 3H), 4.28 (m, 1H), 4.94 (d, 15 Hz, 1H), 5.20 (d, 15 Hz, 1H), 5.43 (d, 7 Hz, 1H), 7.1-7.3 (m, 4H), 7.33 (d, 8 Hz, 2H), 7.35-7.50 (m, 4H), 7.60 (t, 8 Hz, 1H), 7.72 (d, 8 Hz, 1H). FAB-MS: calculated for C29H29N3 O3 467; found 468 (M+H, 15%), 368 (M-BOC, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH:26]([OH:28])[CH3:27])[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:30](OC(=O)C)(=[O:32])[CH3:31]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:30]([O:28][CH:26]([C:23]1[S:24][CH:25]=[C:21]([C:19](=[O:20])[NH:18][C@@H:16]([CH3:17])[CH2:15][N:12]2[CH:13]=[CH:14][C:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=3[CH3:29])=[N:11]2)[N:22]=1)[CH3:27])(=[O:32])[CH3:31]
Reactant: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(C(C)O)n3)n2)ccc(C#N)c1Cl
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC(C)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3C)n2)cs1
Temperature: 0 °C
Yield: 80 %

Procedure:
N—((S)-1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-hydroxyethyl)thiazole-4-carboxamide (0.1 g, 0.233 mmol) and DMAP (2.87 mg, 0.023 mmol) were added into a flask under nitrogen atmosphere. Pyridine was added, the mixture cooled to 0° C. and acetic anhydride (0.023 ml, 0.244 mmol) was added dropwise. The mixture was slowly heated to RT and stirred. After 2.5 h the mixture was evaporated. The product was purified with Flash-chromatography. Yield 80%. 1H-NMR (400 MHz; CDCl3): δ 1.27 (d, 3H), 1.59 (dd, 3H), 2.15 (d, 3H), 2.56 (d, 3H), 4.33 (dd, 1H), 4.43 (dd, 1H), 4.60 (m, 1H), 6.03-6.11 (m, 1H), 6.43 (d, 1H), 7.50-7.58 (m, 3H), 7.77-7.88 (m, 1H), 8.05 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:23]2[N:27]3[CH2:28][CH2:29][NH:30][CH2:31][C:26]3=[N:25][N:24]=2)[NH2:22])=[CH:17][CH:16]=1>>[ClH:1].[ClH:14].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:23]2[N:27]3[CH2:28][CH2:29][N:30]([C:2]4[C:3]5[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=5[N:5]=[CH:6][N:7]=4)[CH2:31][C:26]3=[N:25][N:24]=2)[NH2:22])=[CH:17][CH:16]=1
Reactant: NC(c1ccc(Cl)cc1)c1nnc2n1CCNC2
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Agent: Cl
Product: C[C@@H]1CCc2ncnc(N3CCn4c(nnc4C(N)c4ccc(Cl)cc4)C3)c21
Yield: 64 %

Procedure:
Using the procedure from Example 8, Step 5, using (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine and (4-chlorophenyl)(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)methanamine bishydrochloride (100 mg, 0.30 mmol) to afford (4-chlorophenyl)(7-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)methanamine bishydrochloride (75 mg, 0.19 mmol, 64%): LCMS APCI+(M+H+): 396 (60%), 398 (20%), rt 2.48 min. HPLC purity at 254 nm>99%, rt=1.68 min. 1H NMR (400 MHz, d6-DMSO) □ 9.51 (s, 3H), 8.85 (d, J=9.4 Hz, 1H), 7.61 (d, J=7.0 Hz, 2H), 7.55 (d, J=7.8 Hz, 2H), 6.08 (br d, J=9.0 Hz, 1H), 5.42 (dd, J=26 Hz, 16 Hz, 1H), 5.19 (dd, J=21 Hz, 18 Hz, 1H), 4.55 (m, 1H), 4.29 (m, 1H), 3.79 (m, 1H), 3.14 (m, 1H), 2.96 (m, 1H), 2.32 (m, 1H), 1.82 (m, 1H), 1.15 (t, J=6.8 Hz, 2H), 1.04 (d, J=6.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:29][C:30](=[NH:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>CN(C=O)C>[CH2:31]([C:30]1[N:38]=[C:13]([CH:12]=[CH:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[O:15][N:29]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: N=C(Cc1ccccc1)NO
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C=Cc2nc(Cc3ccccc3)no2)cc1OC
Temperature: 25 °C

Procedure:
3-(3,4-Dimethoxy-phenyl)-acrylic acid (compound of Example 2, Method A, Step 1; 2.0 g, 9.6 mmol) was dissolved in DMF (20 mL) to which 1,1′-carbonyldiimidazole (CDI) (1.71 g, 10.56 mmol) was added and the reaction mixture was stirred at room temperature. At the end of 3 h, N-hydroxy-2-phenyl-acetamidine (1.58 g, 10.56 mmol) was added and the reaction mixture was stirred at room temperature for 8 h. After the completion of the reaction, additional CD (1.71 g, 10.56 mmol) was added and the reaction mixture was refluxed at 110° C. to 120° C. for 8 h to effect cyclodehydration. DMF was evaporated and the residue obtained was cooled to room temperature followed by addition of water (15 mL). The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (2×10 mL) and brine (10 mL). The organic phase obtained was dried over anhydrous sodium sulfate and concentrated to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[N:10]([CH3:16])[C:9]=2[CH3:17])=[CH:4][CH:3]=1.[Br:18]Br.O>C(O)(=O)C>[Br:18][C:12]1[C:13](=[O:14])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:9]([CH3:17])[N:10]([CH3:16])[C:11]=1[CH3:15]
Reactant: Cc1cc(=O)c(-c2ccc(Cl)cc2)c(C)n1C
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(Br)c(=O)c(-c2ccc(Cl)cc2)c(C)n1C

Procedure:
To a stirred solution of 3-(4-chlorophenyl)-1,2,6-trimethylpyridin-4-one (0.5 g) in acetic acid (5 ml) was added dropwise a solution of bromine (0.1 ml) in acetic acid (1 ml). After 5 min the mixture was poured into water. The solid was filtered off, washed with water and recrytallised from ethanol (10 ml) to give the desired compound (0.25 g), m.p. 264°-266°, NMR δH (CDCl3) 7.3-7.4 (2H, m), 7.05-7.2 (2H, m), 6.95-7.12 (4H, m), 3.65 (3H, s), 2.7 (3H, s), 2.2. (3H, s).