Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([C@@H:15]2[CH2:17][C@H:16]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32]([NH2:34])=[O:33])[CH2:27][CH2:26]1>CN1C(=O)CCC1.CS(C)=O.CO>[CH3:11][C:9]1[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([C@@H:15]3[CH2:17][C@H:16]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:14])[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][CH:28]([NH:31][C:32]([NH2:34])=[O:33])[CH2:27][CH2:26]3)[N:7]2[N:8]=1
Reactant: Cc1cc2nc(NC(=O)[C@@H]3C[C@H]3c3ccccc3)cc(Cl)n2n1
Reactant: NC(=O)NC1CCNCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1cc2nc(NC(=O)[C@@H]3C[C@H]3c3ccccc3)cc(N3CCC(NC(N)=O)CC3)n2n1
Temperature: 25 °C
Yield: 59.3 %

Procedure:
The title compound was prepared by combining (1R,2R)—N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-phenylcyclopropanecarboxamide (8D, 0.08 g, 0.245 mmol) and the 1-(piperidin-4-yl)urea hydrochloride (0.088 g, 0.490 mmol) in NMP (0.816 ml) and heating the mixture at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by 40-60% preparatory HPLC (ACN/MeOH)/H2O+0.01% TFA). Lyophilization of the combined fractions gave 63 mg (59%) of the titled compound as a yellow solid. Melting point (160.1-165.7° C.). 1H NMR (DMSO-d6) δ: 10.95 (s, 1H), 7.24-7.35 (m, 3H), 7.14-7.24 (m, 3H), 6.08 (s, 3H), 4.24 (d, J=13.1 Hz, 2H), 3.66 (br. s., 2H), 3.17 (dd, J=23.7, 12.1 Hz, 2H), 2.39-2.47 (m, 1H), 2.26-2.38 (m, 4H), 1.90 (d, J=13.1 Hz, 2H), 1.34-1.59 (m, 4H); [α]D20=−202° (c=0.714, MeOH). ESI-MS: m/z 434.0 (M+H)+. Melting point (160.1-165.7° C.).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([C:30]1[S:34][C:33]([NH2:35])=[N:32][N:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([C:30]1[S:34][C:33]([NH:35][C:18]([C:17]2[CH:21]=[CH:22][C:14]([CH:11]3[CH2:10][CH2:9][CH:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12]3)=[CH:15][CH:16]=2)=[O:19])=[N:32][N:31]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1nnc(Cc2ccccc2)s1
Reactant: CC(C)(C)OC(=O)C1CCC(c2ccc(C(=O)O)cc2)CC1
Product: CC(C)(C)OC(=O)C1CCC(c2ccc(C(=O)Nc3nnc(Cc4ccccc4)s3)cc2)CC1

Procedure:
This compound is obtained according to Preparation 11.5. 85 mg of tert-butyl 4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl]cyclohexanecarboxylate are obtained from 4-(4-tert-butoxycarbonylcyclohexyl)benzoic acid and 5-benzyl-1,3,4-thiadiazol-2-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]3[CH2:16][C@H:15]3[NH:17]C(=O)OC(C)(C)C)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[ClH:25]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]3[CH2:16][C@H:15]3[NH2:17])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[ClH:25]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(-c2cccc(Cl)c2)cc1
Agent: Cl
Solvent: CCOCC
Product: N[C@@H]1C[C@H]1c1ccc(-c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled solution of tert-butyl(trans)-2-(3′-chlorobiphenyl-4-yl)cyclopropylcarbamate (3 g) in Et2O (15 mL) at 0° C. was added HCl in Et2O (15 mL), stirred for 16 h at RT. The progress of the reaction was monitored by TLC. After completion, the solvent was evaporated, residue was triturated with. Et2O to get (Trans)-2-(3′-chlorobiphenyl-4-yl)cyclopropanamine as HCl salt (2.3 g, 95.8%) as a white solid. The HCl salt was made free base by using NaHCO3 solution and used in next reaction.
Reaction SMILES: C([C:3]1[C:11]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])C.[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH:14]1([CH2:13][O:12][C:11]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCc1c(OCC2CCCCC2)cccc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(OCC2CCCCC2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 101.9 %

Procedure:
Ethyl 3-cyclohexylmethoxy benzoic acid (1.8 g, 6.7 mmol) was dissolved in ethanol (50 ml) and THF (50 ml), wereupon NaOH (4 N, 10 ml) was added, and the solution was stirred overnight at 20° C. To the reaction mixture was added HCl (2 N, 200 ml), and the resulting solution was extracted with DCM (3×100 ml). The combined organic extracts were washed with water (100 ml), dried (MgSO4) and evaporated to give 1.6 g of the title compound. LC-MS (m/z): 236 (M+2).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][NH:7][C:6]2=[S:11].[CH:18]1C2N(C=NC=2)C(=S)NN=1>>[Cl:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][N:7]=[C:6]2[S:11][CH3:18]
Reactant: S=c1[nH]ncc2cncn12
Reactant: S=c1[nH]ncc2c(Cl)nc(-c3ccccc3)n12
Product: CSc1nncc2c(Cl)nc(-c3ccccc3)n12

Procedure:
The procedure of Example 29 is repeated substituting an equimolar amount of 8-chloro-6-phenyl-imidazo[1,5-d]-as-triazine-4(3H)-thione for the imidazo[1,5-d]-as-triazine-4(3H)-thione employed in that example. There is thus obtained the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=2[NH:10][C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([N:32]1[CH2:35][CH:34](O)[CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:19]([N:32]1[CH2:35][CH:34]([O:17][C:16]2[C:11]3[NH:10][C:9](=[O:18])[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:33]1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=c1[nH]c2c(O)cccc2n1Cc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1[nH]c2c(OC3CN(C(c4ccccc4)c4ccccc4)C3)cccc2n1Cc1ccccc1
Yield: 39.3 %

Procedure:
To a suspension of 1-benzyl-4-hydroxy-1,3-dihydro-benzoimidazol-2-one (0.104 g., 0.433 mmol) and 1-benzhydryl-azetidin-3-ol (0.114 g., 0.477 mmol) in 0.5 mL anhydrous THF was added triphenyl phosphine (0.125 g., 0.477 mmol) and diisopropyl azodicarboxylate (0.093 mL, 0.477 mmol). The reaction mixture was refluxed for 2 hours, then concentrated in vacuo and purified by preparative TLC (2% methanol in dichloromethane) to give 78 mg (0.17 mmol, 39.5%) of 4-(1-benzhydryl-azetidin-3-yloxy)-1-benzyl-1,3-dihydro-benzoimidazol-2-one as a yellow glass. MS: 462 (M+H)+.
Reaction SMILES: C(N)=S.C(Cl)Cl.[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][NH:18][C:19](=S)[SH-:20][CH2:21]C2C=CC=CC=2)=[CH:8]1.CCCCCCS/C(/S)=N\CC1NC2C=CC=CC=2C=1>CC#N.O>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]2[N:18]=[CH:19][S:20][CH:21]=2)=[CH:8]1
Reactant: S=C(NCCc1c[nH]c2ccccc12)[SH-]Cc1ccccc1
Agent: CCCCCCS/C(S)=N\Cc1cc2ccccc2[nH]1
Agent: NC=S
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: c1ccc2c(Cc3cscn3)c[nH]c2c1
Yield: 71 %

Procedure:
The general method was used with thioformamide to afford a 71% yield (Londergan et al. (1953) J. Am. Chem. Soc., 75:4456-8). 1H NMR (CDCl3) δ 8.76 (d, 1H, SCHN, J=2.0 Hz), 8.11 (br s, 1H, NH), 7.52 (d, 1H, ArH, J=7.6 Hz), 7.36 (d, 1H, ArH, J=8.0 Hz), 7.18 (t, 1H, ArH, J=7.1 Hz), 7.08 (t, 2H, ArH, J=7.4 Hz), 6.90 (s, 1H, ArH), 4.34 (s, 2H, ArCH2). 13C NMR (CDCl3) δ 157.5, 152.5, 122.5, 122.1, 119.4, 119.1, 113.8, 113.5, 111.2, 27.6. IR (CH2Cl2) vmax cm−1: 3626, 3470, 3051, 2987, 1420, 1264. GC: r.t.=15.05 min. EI-MS m/z (%) 214 (100, M+), 213 (86), 186 (15), 154 (14), 130 (51). RP-HPLC (1/1 CH3CN/H2O+0.1% TFA) r.t.=4.408 min.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:32](=[O:33])[N:5]2[C:6]([C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[S:17])=[C:7]([CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH2:8][S:9][C@H:4]12.[C:34]([NH:53][C:54]1[S:55][CH:56]=[C:57](/[C:59](=[N:63]/[O:64][C:65]([C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)/[C:60](O)=[O:61])[N:58]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:34]([NH:53][C:54]1[S:55][CH:56]=[C:57](/[C:59](=[N:63]/[O:64][C:65]([C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)([C:72]2[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=2)[C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=2)/[C:60]([NH:2][CH:3]2[C:32](=[O:33])[N:5]3[C:6]([C:16]([O:18][CH:19]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[S:17])=[C:7]([CH:10]4[CH2:11][CH2:12][O:13][CH2:14][CH2:15]4)[CH2:8][S:9][C@H:4]23)=[O:61])[N:58]=1)([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(C3CCOCC3)CS[C@H]12
Reactant: O=C(O)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Product: O=C(NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(C3CCOCC3)CS[C@H]12)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 77.4 %

Procedure:
Diphenylmethyl 7-amino-3-(tetrahydropyran-4-yl)thio-3-cephem-4-carboxylate hydrochloride (290 mg) was reacted with (Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (403 mg), followed by purifying the reaction product in accordance with the procedure of Example 1(d), affording the titled compound (500 mg; 88%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([OH:16])=O)=[N:4][C:5]([O:12][CH3:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:17][C:18]([F:34])([F:33])[C:19]([CH3:32])([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:20][NH2:21].CCN(C(C)C)C(C)C>>[NH2:1][C:2]1[C:3]([C:14]([NH:21][CH2:20][C:19]([NH:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)([CH3:32])[C:18]([F:34])([F:33])[F:17])=[O:16])=[N:4][C:5]([O:12][CH3:13])=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: COc1ccc(CNC(C)(CN)C(F)(F)F)cc1
Reactant: COc1nc(C(=O)O)c(N)cc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(C)(CNC(=O)c2nc(OC)c(C(F)(F)F)cc2N)C(F)(F)F)cc1

Procedure:
The title compound was prepared analogously to Example 1 from 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate D) and 3,3,3-trifluoro-N2-(4-methoxybenzyl)-2-methylpropane-1,2-diamine (Intermediate N). DIPEA was used in this reaction. 1H NMR (400 MHz, DMSO-d6) δ 8.27 (1H, m), 7.68 (1H, s), 7.25 (2H, d), 6.83 (2H, d), 6.70 (2H, s), 3.85 (3H, s), 3.75 (2H, m), 3.72 (3H, s), 3.70 (1H, m), 3.47 (1H, m), 2.80 (1H, t), 1.24 (3H, s)
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][NH:8][C:9](=[O:29])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[OH:27])=[CH:16][C:15]=2[F:28])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].Cl.Cl[CH2:34][CH2:35][N:36]([CH3:38])[CH3:37].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:29])[CH:10]([C:14]2[C:15]([F:28])=[CH:16][C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])=[CH:18][C:19]=2[F:20])[O:11][CH2:12][CH3:13])=[CH:30][CH:31]=1)#[N:2]
Reactant: CN(C)CCCl
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(-c2ccccc2O)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(-c2ccccc2OCCN(C)C)cc1F

Procedure:
In analogy to example 16.4, (RS)-N-(4-cyano-benzyl)-2-(3,5-difluoro-2′-hydroxy-biphenyl-4-yl)-2-ethoxy-acetamide (example 256.1) was alkylated with 1-chloro-2-dimethylaminoethane hydrochloride and cesium carbonate in DMF to give (RS)-N-(4-cyano-benzyl)-2-[2′-(2-dimethylamino-ethoxy)-3,5-difluoro-biphenyl-4-yl]-2-ethoxy-acetamide. Colorless solid. MS 494.1 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:14].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[CH2:21]([O:14][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:6]=[CH:7][C:2]=1[Cl:1])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Oc1cc(Nc2nccs2)ccc1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Clc1ccc(Nc2nccs2)cc1OCc1ccccc1
Yield: 53 %

Procedure:
Following the general procedure for O-alkylation, Method B, a mixture of 2-chloro-5-(thiazol-2-ylamino)phenol (50 mg, 0.22 mmol) and Cs2CO3 (72 mg, 0.22 mmol) in acetone (4.4 mL) was treated with benzyl bromide (38 mg, 0.22 mmol) at RT. Reaction control by TLC showed full conversion after 2 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 53% yield (37 mg).
Reaction SMILES: [H-].[Na+].[CH:3](OC)=[O:4].[CH3:7][C@H:8]1[CH2:13][C@H:12]([CH3:14])[CH2:11][N:10]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=2)[CH2:9]1.Cl>O1CCCC1>[CH3:14][C@H:12]1[CH2:13][C@H:8]([CH3:7])[CH2:9][N:10]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH2:26][CH:3]=[O:4])=[CH:21][CH:20]=2)[CH2:11]1
Reactant: COC=O
Reactant: CC(=O)c1ccc(OCCCN2C[C@@H](C)C[C@H](C)C2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1C[C@H](C)CN(CCCOc2ccc(C(=O)CC=O)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (82 mg, 60% in paraffin) are added methyl formate (150 μL) and a solution of trans-3,5-dimethyl-1-[3-(4-acetylphenoxy)propyl]piperidine (610 mg) in tetrahydrofuran (0.4 mL). The mixture is stirred for two hours at room temperature then hydrolysed with a 1N aqueous hydrochloric acid solution keeping the pH alkaline. The solution is extracted twice with ethyl acetate. The extracts are pooled, dried over magnesium sulphate, concentrated under reduced pressure and purified by chromatography over silica gel with a gradient dichloromethane/methanol from 100/0 to 95/5. Fractions containing the expected product are pooled, concentrated under reduced pressure to give 100 mg of trans-3,5-dimethyl-1-{3-[4-(3-oxopropanoyl)phenoxy]propyl}piperidine as a pale yellow oil that is used rapidly, without further purification in the next step.
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[O:48][C:47]([CH3:49])=[C:46]([C:50](=O)[CH3:51])[CH:45]=2)=[CH:40][CH:39]=1.[OH-].[K+]>C(O)C>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[O:48][C:47]([CH3:49])=[C:46]([C:50]3[CH:51]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:18]5[N:22]([CH:23]6[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]6)[C:21]6[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=6[N:19]=5)[CH:14]=4)[N:9]=3)[CH:45]=2)=[CH:40][CH:39]=1
Reactant: CC(=O)c1cc(-c2ccc(Cl)cc2)oc1C
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2ccc(Cl)cc2)cc1-c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1
Yield: 59 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-[5-(4-chloro-phenyl)-2-methyl-furan-3-yl]-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (83 mg, 59% yield). MS: 562.21 (M+H+); HPLC Procedure B, retention time=8.99 min.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13]([N:15]1[CH2:25][CH2:24][CH:18]([C:19](OCC)=[O:20])[CH2:17][CH2:16]1)=[O:14])[CH3:11].[H-].[Na+]>C1(C)C=CC=CC=1>[CH2:10]([O:12][C:13]([N:15]1[CH2:25][CH2:24][CH:18]([C:19]([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]#[N:9])=[O:20])[CH2:17][CH2:16]1)=[O:14])[CH3:11]
Reactant: N#CCc1ccccc1
Reactant: CCOC(=O)C1CCN(C(=O)OCC)CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(C(=O)C(C#N)c2ccccc2)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 61.9 %

Procedure:
Phenylacetonitrile (5.8 g), ethyl 1-ethoxycarbonylisonipecotate (11.5 g), sodium hydride (purity 60%, 2.0 g) and toluene (25 mL) were mixed, and the mixture was stirred at 80° C. for 3 hrs. After the completion of the reaction, the reaction mixture was cooled to room temperature, and the insoluble material was washed by decantation. The insoluble material was dissolved in water, and acetic acid was added to acidify the mixture, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was evaporated. The obtained residue was subjected to silica gel column chromatography, and the fraction eluted with hexane:ethyl acetate=2:1 was concentrated to give α-(1-ethoxycarbonylpiperidin-4-yl)carbonylphenylacetonitrile (9.2 g) as an oil.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])=[N:18][C:12]=2[O:11][C@@H:10]([CH2:24][O:25][CH3:26])[CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:33]>CO.[OH-].[OH-].[Pd+2]>[ClH:33].[CH3:26][O:25][CH2:24][C@H:10]1[CH2:9][NH:8][CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:23])[CH:20]([CH3:21])[CH3:22])=[N:18][C:12]=2[O:11]1
Reactant: COC[C@H]1CN(Cc2ccccc2)Cc2ncc(N(C)C(C)C)nc2O1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC[C@H]1CNCc2ncc(N(C)C(C)C)nc2O1
Temperature: 50 °C
Reaction time: 7 h
Yield: 61 %

Procedure:
To a solution of (6R)-8-benzyl-6-(methoxymethyl)-N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (261 mg) in methanol (7 mL) was added 20% Pd(OH)2/C (40 mg), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 7 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the obtained crude product in ethyl acetate (10 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (200 μL), and the mixture was stirred for 30 min. The reaction mixture was filtered, and the obtained crystals were washed with ethyl acetate to give the title compound (136 mg, 61%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[N:34][CH:33]=[C:32]([CH3:36])[N:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][C:11]1[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]2[N:7]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[N:34][CH:33]=[C:32]([CH3:36])[N:31]=4)[CH:25]=3)[CH2:21][C:20](=[O:37])[NH:19][C:9]=2[CH:10]=1
Reactant: Cc1cncc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(C(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cncc(-c2cccc(C3=Nc4cc(C(F)(F)F)c(C)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (4-methyl-2-{3-[3-(6-methyl-pyrazin-2-yl)-phenyl]-3-oxo-propionylamino}-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M118) (0.39 g, 0.74 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (237 mg, 78%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([CH3:5])=O.[Cl:8][C:9]1[C:10](=[N:15][NH2:16])[NH:11][CH:12]=[CH:13][CH:14]=1>>[F:1][C:2]([F:7])([F:6])[C:3](=[N:16][N:15]=[C:10]1[C:9]([Cl:8])=[CH:14][CH:13]=[CH:12][NH:11]1)[CH3:5]
Reactant: NN=c1[nH]cccc1Cl
Reactant: CC(=O)C(F)(F)F
Agent: NNc1ncccc1Cl
Product: CC(=NN=c1[nH]cccc1Cl)C(F)(F)F
Reaction time: 0.17 h
Yield: 66 %

Procedure:
1,1,1-Trifluoroacetone (7.80 g, 69.6 mmol) was added to 3-chloro-2(1H)-pyridinone hydrazone (alternatively named (3-chloro-pyridin-2-yl)-hydrazine) (10 g, 69.7 mmol) at 20-25° C. After the addition was complete, the mixture was stirred for about 10 minutes. The solvent was removed under reduced pressure and the mixture partitioned between ethyl acetate (100 mL) and saturated aqueous sodium carbonate solution (100 mL). The organic layer was dried and evaporated. Chromatography on silica gel (eluted with ethyl acetate) gave the product as an off-white solid (11 g, 66% yield), m.p. 64-64.5° C. (after crystallization from ethyl acetate/hexanes).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]#[N:15])[C:11]3[N:16]=[N:17][N:18]([CH3:19])[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].CS(O[CH2:29][C@@H:30]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH2:31]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C(OCC)(=O)C>[CH3:19][N:18]1[C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([O:1][CH2:29][C@@H:30]4[CH2:34][CH2:33][N:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=5)[CH2:31]4)=[C:3]([C:20]([F:23])([F:22])[F:21])[CH:4]=3)[N:13]=[C:12]([C:14]#[N:15])[C:11]=2[N:16]=[N:17]1
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(O)c(C(F)(F)F)c3)cc21
Reactant: CS(=O)(=O)OC[C@@H]1CCN(c2ccccn2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nnc2c(C#N)nc(-c3ccc(OC[C@@H]4CCN(c5ccccn5)C4)c(C(F)(F)F)c3)cc21

Procedure:
6-(4-Hydroxy-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (0.235 mmol, 0.075 g), (R)-(1-(pyridin-2-yl)pyrrolidin-3-yl)methyl methanesulfonate (0.282 mmol, 0.072 g), cesium carbonate (0.352 mmol, 0.115 g) and tetrabutylammonium iodide (0.117 mmol, 0.043 g) were stirred in DMF (1 ml) at 50° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with water and dried over Na2SO4. The resulting residue was triturated with ether and filtered. The solid was sonicated in methanol, filtered and dried to afford (R)-1-methyl-6-(4-((1-(pyridin-2-yl)pyrrolidin-3-yl)methoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile. (47 mg)
Reaction SMILES: [C:1]1([N:7]2[C:11](=[S:12])[N:10]([CH2:13]Cl)[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K].O.C(OCC)(=O)C>CN(C)C=O>[C:1]1([N:7]2[C:11](=[S:12])[N:10]([CH2:13][N:19]3[C:18](=[O:20])[C:17]4=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]4[C:15]3=[O:25])[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: S=c1n(CCl)nnn1-c1ccccc1
Agent: [K]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cn1nnn(-c2ccccc2)c1=S

Procedure:
A solution of 1-phenyl-4-chloromethyltetrazoline-5-thione (4.53 g) and potassium phthalimide (4.00 g) in 50 ml dimethylformamide was heated at 55° C. for 2 hours. The solution was poured into water. Ethyl acetate extractive workup gave a colorless solid. Recrystallization from ethanol afforded a colorless solid, m.p. 130°-134° C. (2.75 g).