Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15]C2C=CC(C3ON=CC=3)=CC=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[CH3:30][N:31]1[C:35]([C:36]2[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=2)N)=[N:34][N:33]=[N:32]1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:38]2[CH:40]=[CH:41][CH:42]=[C:36]([C:35]3[N:31]([CH3:30])[N:32]=[N:33][N:34]=3)[CH:37]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: Cn1nnnc1-c1cccc(N)c1
Product: Cn1nnnc1-c1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)ncc2C(N)=O)c1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-(1-methyl-1H-tetrazol-5-yl)aniline in step 1. MS: 409.5 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:12])=[CH:4][C:3]=1[Cl:20].Cl[CH2:22][CH2:23][CH2:24][O:25][CH3:26].C(N(CC)CC)C>CN(C)C=O>[ClH:20].[NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH2:16][CH2:15]2)=[O:12])=[CH:4][C:3]=1[Cl:20]
Reactant: Nc1c(Cl)cc(C(=O)NC2CCNCC2)c2c1CCO2
Reactant: COCCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCCN1CCC(NC(=O)c2cc(Cl)c(N)c3c2OCC3)CC1
Product: Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
A mixture of 4-amino-5-chloro-2,3-dihydro-N-(4-piperidinyl)-7-benzofuran-carboxamide(0.01 mol), 1-chloro-3-methoxypropane (0.012 mol), N,N-diethyl-ethanamine (2.1 ml) and KI (catalytic amount) in N,N-dimethylformamide (75 ml) was stirred overnight at 50° C. The reaction mixture was cooled. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CHCl3 /(CH3OH/NH3)97/3). The pure fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanol and converted into the hydrochloric acid salt (1:1) with HCl/2-propanol. The precipitate was filtered off and dried (vacuum; 80° C.), yielding 1.40 g (35%) of 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide monohydrochloride (comp. 1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:21][CH:20]2[CH2:44][OH:45])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:47]([O-:49])=O.[NH3:50]>O1CCCC1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:21][CH:20]2[CH2:44][O:45][C:47](=[O:49])[NH2:50])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: O=C([O-])Cl
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(COC(N)=O)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 150(a), from tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 148(h)] there was synthesized the corresponding chloroformate, reaction of which with a solution of ammonia in tetrahydrofuran gave tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-carbamoyloxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 672 (M+NH4)+.
Reaction SMILES: S(Cl)(Cl)=O.CC1C(C)=CC=CC=1C(O)=O.CC1C(C)=CC=CC=1C(Cl)=O.[CH3:27][C:28]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=1[C:35]([N:37]=[C:38]=[S:39])=[O:36].[Cl:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][C:47]=1[O:48][C:49]1[C:58]2[C:53](=[CH:54][C:55]([O:61][CH3:62])=[C:56]([O:59][CH3:60])[CH:57]=2)[N:52]=[CH:51][CH:50]=1)[NH2:44]>C(O)C.C1(C)C=CC=CC=1>[Cl:40][C:41]1[CH:42]=[C:43]([NH:44][C:38]([NH:37][C:35](=[O:36])[C:29]2[CH:30]=[CH:31][CH:32]=[C:33]([CH3:34])[C:28]=2[CH3:27])=[S:39])[CH:45]=[CH:46][C:47]=1[O:48][C:49]1[C:58]2[C:53](=[CH:54][C:55]([O:61][CH3:62])=[C:56]([O:59][CH3:60])[CH:57]=2)[N:52]=[CH:51][CH:50]=1
Reactant: Cc1cccc(C(=O)N=C=S)c1C
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: Cc1cccc(C(=O)Cl)c1C
Agent: Cc1cccc(C(=O)O)c1C
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4C)cc3Cl)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2,3-dimethylbenzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2,3-dimethyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 2,3-dimethyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 2,3-Dimethyl-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (76 mg, yield 96%).
Reaction SMILES: CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[C:20]([O:24][C:25]([NH:27][CH2:28][C@H:29]1[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:31]([C:41]([OH:43])=O)[CH2:30]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[CH:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]2[CH:56]=[CH:55][C:54]([NH2:57])=[CH:53][CH:52]=2)=[CH:46][CH:45]=1.ON1C2C=CC=CC=2N=N1>O1CCCC1.CN(C)C=O>[O:50]([C:51]1[CH:52]=[CH:53][C:54]([NH:57][C:41](=[O:43])[C@@H:31]2[CH2:30][C@@H:29]([CH2:33][NH:32][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:28][N:27]2[C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])=[CH:55][CH:56]=1)[C:47]1[CH:48]=[CH:49][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 63.4 %

Procedure:
N-Methylmorpholine (60 mL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (94 mg) were added to a solution of trans-4-(N-tert-butoxycarbonylaminomethyl)-N-tert-butoxycarbonyl-L-proline (Compound D109 (D), 206 mg), 4-aminodiphenylether (104 mg), and 1-hydroxybenzotriazole (70 mg) in tetrahydrofuran (6 mL) and N,N-dimethylformamide (2 mL) at room temperature. After stirring at room temperature for 13 hr, the reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with saturated sodium carbonate and then brine. After drying over anhydrous sodium sulfate, the organic layer was concentrated in vacuo. The residue was washed with hexane to give the title compound (182 mg) as colorless plates: 1H NMR (400 MHz, CDCl3) δ 1.44-1.49 (18 H), 1.70 (br s, 1H), 2.54 (br s, 2 H), 3.08 (br s, 1H), 3.20 (br s, 2 H), 3.52 (br s, 1 H), 4.52 (br s, 1 H), 4.64 (br s, 1 H), 6.96 (d, J=7.8 Hz, 4 H), 7.07 (t, J=7.3 Hz, 1H), 7.31 (t, J=7.8 Hz, 2 H), 7.47 (d, J=9.3 Hz, 2 H), and 9.49 (br s, 1 H); mass spectrum (EI+) m/e 511 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1Br.C(N([CH2:16][CH3:17])CC)C.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.NN>[F:9][C:4]1[C:3]([CH:20]=[CH:19][C:18]([O:22][CH2:16][CH3:17])=[O:21])=[C:2]([CH:20]=[CH:19][C:18]([O:22][CH2:23][CH3:24])=[O:21])[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: Fc1cc(F)c(Br)c(Br)c1
Reactant: CCN(CC)CC
Reactant: C=CC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=Cc1cc(F)cc(F)c1C=CC(=O)OCC
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 126.7 %

Procedure:
A mixture of 1,2-dibromo-3,5-difluorobenzene (24.7 g, 91.6 mmol), bis(triphenylphosphine)palladium(II) chloride (2.57 g, 3.66 mmol) and triethylamine (51.0 mL, 366 mmol) in 300 mL of DMF was stirred under argon at approximately 85° C. for 15 minutes. Hydrazine hydrate (366 μL, 7.54 mmol) was added and the mixture was stirred for an additional 10 minutes. Ethyl acrylate (39.7 mL, 366 mmol) was added and the mixture was stirred under argon at approximately 85° C. for approximately 144 hours. The solvents were removed by evaporation under reduced pressure and the residue was dissolved in 1.0 L of ethyl acetate. The ethyl acetate solution was washed 3 times with water and dried over magnesium sulfate. Evaporation of the solvent gave crude ethyl 3-{3,5-difluoro-2-[2-(ethoxycarbonyl)vinyl]phenyl}acrylate (36 g).
Reaction SMILES: [I-].[I-].[CH3:3][N+:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([O:12][C:13]2[CH:30]=[CH:29][C:28]3[C@@H:27]4[C@H:18]([C@H:19]5[C@@:23]([CH2:25][CH2:26]4)([CH3:24])[C@@H:22]([O:31][C:32](C4C=[N+](C)C=CC=4)=[O:33])[CH2:21][CH2:20]5)[CH2:17][CH2:16][C:15]=3[CH:14]=2)=[O:11])[CH:5]=1.C1([CH2:47][N:48]2[CH:53]=[CH:52][C:51](C(N)=O)=[CH:50][CH2:49]2)C=CC=CC=1>C(#N)C.C(Cl)Cl>[CH3:3][N:4]1[CH:9]=[CH:8][CH2:7][C:6]([C:10]([O:12][C:13]2[C:14]3[C@@H:27]4[C@H:18]([C@H:19]5[C@@:23]([CH2:25][CH2:26]4)([CH3:24])[C@@H:22]([O:31][C:32]([C:52]4[CH2:51][CH:50]=[CH:49][N:48]([CH3:47])[CH:53]=4)=[O:33])[CH2:21][CH2:20]5)[CH2:17][CH2:16][C:15]=3[CH:28]=[CH:29][CH:30]=2)=[O:11])=[CH:5]1
Reactant: C[n+]1cccc(C(=O)Oc2ccc3c(c2)CC[C@@H]2[C@@H]3CC[C@]3(C)[C@@H](OC(=O)c4ccc[n+](C)c4)CC[C@@H]23)c1
Reactant: NC(=O)C1=CCN(Cc2ccccc2)C=C1
Agent: [I-]
Solvent: CC#N
Solvent: ClCCl
Product: CN1C=CCC(C(=O)Oc2cccc3c2[C@H]2CC[C@]4(C)[C@@H](OC(=O)C5=CN(C)C=CC5)CC[C@H]4[C@@H]2CC3)=C1
Temperature: 0 °C

Procedure:
One gram (1.31 mmol) of the product of Example 71 was dissolved in 100 mL of dry acetonitrile. To that solution, which was flushed with nitrogen, 0.28 g (1.31 mmol) of 1-(phenylmethyl)-4-(aminocarbonyl)-1,2-dihydropyridine was added, and the reaction mixture was stirred at 0° C. for l hour. Removal of the solvent under reduced pressure afforded a solid, which was suspended in methylene chloride and removed by filtration. The filtrate was chromatographed several times on a neutral alumina column prepared with methylene chloride. Purification and evaporation of the solvent in vacuo gave a solid foam. The product had the formula ##STR106## as confirmed by UV, NMR and elemental analyses.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O-:17])=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH2:26]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:18][CH:19]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C([O-])c1ccc(CCCc2ccccc2O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Reaction time: 18 h

Procedure:
To a solution of 4-[3-(2-hydroxyphenyl)propyl]benzoate (1.0 g) in DMF (20 ml) was added potassium carbonate (0.76 g) and benzyl bromide (0.66 ml). The mixture was stirred for 18 hours, poured into water (100 ml) and ethyl acetate (100 ml). The ethyl acetate solution was washed with water (3×100 ml), dried (magnesium sulphate), filtered and evaporated. The residue was purified by subjecting to chromatography on silica gel using diethyl ether: hexane (1:9) as eluant. There was thus obtained methyl 4-[3-(2-benzyloxy-phenyl)propyl]benzoate (0.7 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH3:15])=[CH:10][CH:9]=2)[CH2:6][N:5]=[C:4]2[S:16][CH:17]=[CH:18][C:3]=12.[CH2:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1N=C=O)[CH3:20].[N-:30]=[C:31]=[O:32]>>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([N:14]([C:31]([NH:30][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH2:19][CH3:20])[CH:22]=3)=[O:32])[CH3:15])=[CH:12][CH:13]=2)[CH2:6][N:5]=[C:4]2[S:16][CH:17]=[CH:18][C:3]=12
Reactant: CNc1ccc(N2CN=c3sccc3=C2N)cc1
Reactant: CCc1ccccc1N=C=O
Reactant: [N-]=C=O
Product: CCc1cccc(NC(=O)N(C)c2ccc(N3CN=c4sccc4=C3N)cc2)c1

Procedure:
The compound was prepared following the procedure described in Example 429, substituting 4-amino-3-(4-(methylamino)phenyl)-thieno[2,3-d]pyrimidine as the amine and using 2-ethyl-phenyl isocyanate as the isocyanate of choice. MH+=404.
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:15]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])=[O:16])=[CH:10]2)(=O)C.C(O)CC.Cl>O>[NH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:15]([NH:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:17])=[O:16])=[CH:10]2
Reactant: CC(=O)Nc1cccc2cc(S(=O)(=O)NCc3ccccc3)ccc12
Agent: Cl
Solvent: O
Solvent: CCCO
Product: Nc1cccc2cc(S(=O)(=O)NCc3ccccc3)ccc12
Temperature: 25 °C
Yield: 74.4 %

Procedure:
5-Acetylamino-N-benzylnaphthalene-2-sulfonamide (compound No. 5-1; 175 mg, 0.494 mmol) was suspended to a mixed solvent of 1-propanol (3.0 ml) and water (1.5 ml). Concentrated hydrochloric acid (1.5 ml) was added to the suspension and the mixture was refluxed for 1 hour. After cooling to room temperature, the separated crystal was collected and washed with 1-propanol and isopropyl ether to give the title compound as a light yellow crystal (128 mg, 74.4%).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=1.C(N(C(C)C)C(C)C)C.[Cl:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][C@H:33]2[C@:31]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=3)([CH2:32]2)[CH2:30]1>CC#N.CS(C)=O>[ClH:25].[CH3:15][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[N:11]([CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][C@H:33]3[C@:31]([C:35]4[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:37][CH:36]=4)([CH2:32]3)[CH2:30]2)[CH:12]=1
Reactant: Cc1ccccc1-c1c[nH]c(=O)[nH]c1=O
Reactant: FC(F)(F)c1ccc([C@]23C[C@H]2CN(CCCCl)C3)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccccc1-c1cn(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)c(=O)[nH]c1=O
Product: Cl
Yield: 62.5 %

Procedure:
5-Phenyl-1H-pyrimidine-2,4-dione (Prep53, 52 mg, 0.25 mmol) was dissolved in MeCN-DMSO (3:1, 3 mL). Ethyl-diisopropyl-amine (132 μl, 0.8 mmol) and (1S,5R)-3-(3-chloro-propyl)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep13, 69 mg, 0.3 mmol) were added. The mixture was placed in a microwave oven and then irradiated at 150° C. for 6 hours (3 cycles×1 h). A second run was performed on 5-Phenyl-1H-pyrimidine-2,4-dione (Prep53, 123 mg, 0.43 mmol), ethyl-diisopropyl-amine (0.2 μl, 1.2 mmol) and (1S,5R)-3-(3-chloro-propyl)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep13, 130 mg, 0.43 mmol) in the same conditions. The two mixtures were mixed and evaporated under vacuum. The residue was dissolved in ethyl acetate and washed with water. The crude was purified by preparative LC-MS to give 79 mg of the title compound as trifluoroacetate salt. The compound was loaded on SCX cartridge washing with MeOH and then eluting with MeOH/NH3 95:5. The free base obtained was treated with 4N HCl in dioxane (2 eq), to give the title compound as a white powder (32 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:13])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:7]=1.CCN(C(C)C)C(C)C.Cl[C:24]([O:26][CH3:27])=[O:25]>C(Cl)Cl>[NH2:13][C:3]1[N:4]=[CH:5][C:6]([CH:8]2[CH2:12][CH2:11][N:10]([C:24]([O:26][CH3:27])=[O:25])[CH2:9]2)=[CH:7][C:2]=1[Br:1]
Reactant: Nc1ncc(C2CCNC2)cc1Br
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N1CCC(c2cnc(N)c(Br)c2)C1
Reaction time: 0.5 h

Procedure:
To 3-bromo-5-(pyrrolidin-3-yl)pyridin-2-amine, (20 mg, 0.083 mmol) in DCM in ice bath was added DIEA (43.3 μl, 0.248 mmol) and methyl chloroformate (6.40 μl, 0.083 mmol). The reaction mixture was stirred in ice bath for 30 min. The reaction mixture was partitioned between DCM and water. The DCM layer was separated and washed with brine, dried over sodium sulfate, filtered off, and evaporated. The crude product was used for next step without purification. LCMS (m/z): 300.0, 302.0 (MH+), 0.421 min.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.[CH:29]1([C:33]2[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:34]=2[O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:32][CH2:31][CH2:30]1.C(O)(=O)C>C1COCC1.O>[Si:36]([O:35][C:34]1[C:43]([F:47])=[C:44]([B:16]([OH:21])[OH:17])[CH:45]=[CH:46][C:33]=1[CH:29]1[CH2:30][CH2:31][CH2:32]1)([C:39]([CH3:42])([CH3:40])[CH3:41])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)Oc1c(F)cccc1C1CCC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1c(C2CCC2)ccc(B(O)O)c1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A 100 mL three neck round-bottomed flask, equipped with a stir bar, temperature probe and nitrogen inlet, was charged with 2,2,6,6-tetramethylpiperidine (1.7 mL, 10 mmol) and THF (10 mL). The mixture was cooled to −78° Celsius and treated with 2.5 M n-BuLi (4.1 mL, 10 mmol). The resultant mixture was stirred for 5 min and then warmed up to 0° Celsius for 40 min. After 40 min the reaction mixture was cooled to −78° Celsius and treated with B(O-iPr)3 (13.0 mL, 10.2 mmol) over the course of 10 min. After stirring for 20 min a solution of (2-cyclobutyl-6-fluorophenoxy)(tert-butyl)dimethylsilane (1.8 g, 6.3 mmol) in THF (4 mL) was added over the course of 2 min. The reaction was stirred at −78° Celsius for 2 hours and then warmed to 0° Celsius. Acetic acid (3.6 mL, 64 mmol) is added and the reaction was warmed to room temperature and diluted with water. The resultant mixture was extracted with ethyl acetate. The organic portion was dried over sodium sulfate and concentrated to dryness to provide (3-((tert-butyldimethylsilyl)-oxy)-4-cyclobutyl-2-fluorophenyl)boronic acid (1.8 g, 86%). 1H NMR (500 MHz, CDCl3), δ 7.39-7.32 (m, 1H), 7.18-7.13 (m, 1H), 5.10-4.97 (m, 2H), 3.82 (t, J=8.8 Hz, 1H), 2.41-2.06 (m, 5H), 2.03-1.95 (m, 1H), 1.03 (s, 9H), 0.19 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:27]([CH2:33][CH3:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(=O)(OCC)OCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10]([CH2:34][CH2:33][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCc1cc2c(s1)-n1c(C)nnc1CN=C2c1ccc(Cl)cc1
Reactant: CCOC(=O)C(Br)CC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(=O)OCC
Product: CCOC(=O)CCCC1(C(=O)OCC)N=C(c2ccc(Cl)cc2)c2cc(CC)sc2-n2c(C)nnc21
Temperature: 25 °C

Procedure:
4-(4-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (6 g) is dissolved in diethyl carbonate (100 ml) under a nitrogen stream, and 60% sodium hydride (1.2 g) is added with stirring at room temperature. The mixture is refluxed under heating for 1 hour and cooled to 50° C. with ice water. Ethyl bromobutyrate (4.3 ml) is added. After stirring at 100° C. for 2 hours, the reaction mixture is poured into ice water (1 l) and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate:methanol=100:l) and crystallized from isopropyl ether to give 3.9 g of (±)-ethyl 4-(4-(4-chlorophenyl)-6-ethoxycarbonyl-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)butyrate as white powdery crystals. (±)-Ethyl 4-(4-(4-chlorophenyl)-6-ethoxycarbonyl-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-6-yl)butyrate (3.5 g) is dissolved in a mixture of ethanol (180 ml) and water (60 ml), and barium hydroxide 8 hydrate (8.4 g) is added. The mixture is refluxed under heating for 4 hours. After the completion of the reaction, ethanol is distilled away under reduced pressure and adjusted to pH 1 with 1N hydrochloric acid. The mixture is stirred for 30 minutes and adjusted to pH 4 with a saturated aqueous solution of sodium hydrogencarbonate to give 1.1 g of (±)-4-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)butyric acid as white powdery crystals, melting point 185°-187° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[CH2:11][CH2:12][N:13]([C:16]([C@@H:18]3[C@@H:23]([C:24]([O:26][CH3:27])=[O:25])[CH2:22][C@@H:21]([OH:28])[CH2:20][N:19]3[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:17])[CH2:14][CH:15]=2)=[CH:5][C:4]=1[CH3:36])#[N:2].O1CCCC1.[Cl:42][C:43]1[CH:44]=[C:45](O)[CH:46]=[N:47][CH:48]=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>>[Cl:42][C:43]1[CH:44]=[C:45]([O:28][C@@H:21]2[CH2:20][N:19]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[C@H:18]([C:16]([N:13]3[CH2:12][CH:11]=[C:10]([C:6]4[CH:7]=[C:8]([CH3:9])[C:3]([C:1]#[N:2])=[C:4]([CH3:36])[CH:5]=4)[CH2:15][CH2:14]3)=[O:17])[C@@H:23]([C:24]([O:26][CH3:27])=[O:25])[CH2:22]2)[CH:46]=[N:47][CH:48]=1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN(C(=O)OC(C)(C)C)[C@@H]1C(=O)N1CC=C(c2cc(C)c(C#N)c(C)c2)CC1
Reactant: Oc1cncc(Cl)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](Oc2cncc(Cl)c2)CN(C(=O)OC(C)(C)C)[C@@H]1C(=O)N1CC=C(c2cc(C)c(C#N)c(C)c2)CC1
Temperature: 70 °C
Yield: 36.9 %

Procedure:
To a solution of 1-tert-butyl 3-methyl(2S,3S,5R)-2-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-5-hydroxypiperidine-1,3-dicarboxylate (100 mg, 0.0002 mol) in tetrahydrofuran (0.912 mL, 0.0112 mol) was added 5-chloropyridin-3-ol (35.0 mg, 0.000270 mol), triphenylphosphine (70.8 mg, 0.000270 mol), followed by diisopropyl azodicarboxylate (0.0532 mL, 0.000270 mol). The mixture was heated at 70 Celsius overnight. After concentrated to dry, the mixture was purified on silica gel, elution with 0 to 40% EtOAc in hexane, to yield the desired product (45 mg, 32.84%). MS (ESI) (M+H) 609.1.