Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C@@H:11]([OH:30])[C@H:12]([N:19](C(C3C=CC=CC=3)CO)[CH3:20])[CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:9]=[CH:10][C:2]1=2>CO.Cl.[Pd]>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C@@H:11]([OH:30])[C@H:12]([NH:19][CH3:20])[CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[CH:9]=[CH:10][C:2]1=2
Reactant: CN(C(CO)c1ccccc1)[C@H](CN1CCCC1)[C@H](O)c1ccc2c(c1)OCCO2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN[C@H](CN1CCCC1)[C@H](O)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of compound 4 (0.22 g, 0.468 mmol) in methanol 20 mL and 1 N HCl (5 mL) was added palladium (10%) on carbon (0.08 g, 0.752 mmol) (Degussa wet catalyst). The flask was attached to a Parr 3911 hydrogenation apparatus, evacuated via a water aspirator, and filled with H2 (40 psi). After shaking for 18 hours at room temperature, the mixture was filtered through celite with MeOH eluent. The celite pad then was washed with methanol (2×) and 2 M NH3 in dioxane (2×). The filtrate was concentrated, diluted with water, and washed with EtOAc (1×). The aq layer was made basic with satd. aq. NaHCO3 and extracted with CH2Cl2(2×) and EtOAc (3×). The combined layers were dried over MgSO4, concentrated to an oil, and used without further purification. HPLC purity 89% (tR=4.88 min). NMR (500 MHz, CDCl3) δ 6.9 (s, 1H), 6.7-6.8 (m, 2H), 4.6 (d, 1H), 4.3 (s, 4H), 2.8-2.9 (m, 1H), 2.4-2.5 (m, 6H), 2.4 (m, 3H), 1.7-1.8 (m, 5H). ESI-MS m/z 293.1 (M+H+).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].CS(O[CH:18]1[CH2:21][N:20]([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19]1)(=O)=O.CCN(C(C)C)C(C)C>CC#N>[CH:22]([N:20]1[CH2:21][CH:18]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C:2]([F:1])([F:11])[F:12])[CH2:6][CH2:7]2)[CH2:19]1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C(N1CCNCC1)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1)C(F)(F)F

Procedure:
To a solution of 2,2,2-trifluoro-1-piperazin-1-yl-ethanone (6 g, 32.94 mmol) and 1-benzhydrylazetidin-3-yl methanesulfonate (12.5 g, 39.38 mmol) in CH3CN (60 mL) was added DIPEA (12 mL, 68.89 mmol) at room temperature. The resulting mixture was refluxed for 2 h. The solvent was removed by evaporation and the residue was partitioned between CH2Cl2 and aq NaHCO3. The organic layer was washed with aq NaHCO3 (2×) and then extracted with 1N HCl (2×). The aqueous layer was cooled and then the pH adjusted with 1N NaOH until basic (pH=10). The resulting mixture was extracted with CH2Cl2 (2×). The organic layer was dried over MgSO4 and concentrated. The title compound was purified by reverse phase chromatography. MS m/z (M+H+) 404.2.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[N:16][C:15]=2Cl)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:29]=[C:28]([CH2:30][NH2:31])[CH:27]=[CH:26][N:25]=1.C(=O)(O)[O-].[Na+].CC(O)C>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[N:16][C:15]=2[NH:31][CH2:30][C:28]2[CH:27]=[CH:26][N:25]=[C:24]([O:23][CH3:22])[CH:29]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(CN)ccn1
Reactant: CC(C)(C)c1ccc(NC(=O)c2cc(Cl)nnc2Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1cc(CNc2nnc(Cl)cc2C(=O)Nc2ccc(C(C)(C)C)cc2)ccn1

Procedure:
3,6-Dichloro-pyridazine-4-carboxylic acid (4-tert-butyl-phenyl)-amide (162 mg, 0.5 mmol), C-(2-Methoxy-pyridin-4-yl)-methylamine (211 mg, 1 mmol), and sodium bicarbonate (840 mg, 20 mmol) were added to IPA (2.5 mL). The reaction was ran in microwave (150° C., 15 min). Water (5 mL) was added to the reaction and the mixture was extracted with DCM (2×5 mL). The organic layer was dried over sodium sulfate and reduced. The crude was subjected to Flash chromatography (2% MeOH/DCM) for further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1
Reactant: Clc1cccc(Cl)c1CBr
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OCc1ccc(OCc2c(Cl)cccc2Cl)cc1
Temperature: 25 °C
Yield: 100710.4 %

Procedure:
A solution of 4-(hydroxymethyl)phenol (38.0 g, 0.31 mmol) and 2,6-dichlorobenzyl bromide (73.4 g, 0.31 mmol) in DMF (500 ml) was treated with caesium carbonate (100 g, 0.31 mmol) and heated to 60° for 16 h. The mixture was cooled to room temperature and the solvent evaporated in vacuo. The residue was partitioned between EtOAc (250 ml) and water (250 ml), the aqueous layer was separated and extracted with EtOAc (250 ml) and the combined organic layers washed with 10% hydrochloric acid (100 ml), NaHCO3 solution (100 ml) and brine (200 ml), dried (MgSO4) and the solvent evaporated in vacuo to give the title compound as a brown oil (88.4 g) which was used without further purification. δH (CDCl3) 7.38-7.21 (5H, m, ArH), 7.02 (2H, d, J 8.7 Hz, ArH), 5.28 (2H, s, CH2OAr) and 4.63 (2H, s, CH2OH).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([NH:22][CH2:23][CH3:24])=[O:21])[C:3]1=[O:25].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>O1CCCC1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH2:19][C:20]([NH:22][CH2:23][CH3:24])=[O:21])[C:3]2=[O:25])=[O:35])=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCNC(=O)CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CCNC(=O)CN1C(=O)C(NC(=O)Nc2ccc(Cl)cc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-ethylaminocarbonylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 293° C. (d).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16]>>[CH2:13]([NH:17][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCCCN
Product: CCCCCCC/C=C/C(=O)NCCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and butylamine as starting materials to give the aimed compound.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][C@H:27]1[C@@H:31]([OH:32])[CH2:30][N:29](C(OCC2C=CC=CC=2)=O)[CH2:28]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][C@H:27]3[CH2:28][NH:29][CH2:30][C@H:31]3[OH:32])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Br)c2c1
Reactant: N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N[C@H]3CNC[C@H]3O)c2c1

Procedure:
The title compound was prepared in analogy to Example 28-1 in Scheme 8 by using 4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and benzyl cis-3-amino-4-hydroxypyrrolidine-1-carboxylate. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.12-8.07 (m, 2 H), 7.98-7.90 (d, J=7.6 Hz, 1 H), 7.78-7.70 (m, 2 H), 7.63-7.58 (m, 2 H), 6.16 (s, 1 H), 5.41-5.28 (m, 2 H), 4.61-4.50 (m, 2 H), 4.48 (s, 2 H), 4.02-3.93 (q, J=6 Hz, 1 H), 3.78-3.68 (m, 3 H), 3.60-3.50 (dd, J=2.8, 12.8 Hz, 1 H), 3.48-3.40 (d, J=3.6 Hz, 1 H), 2.46 (s, 3 H).
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][C:8](=[O:17])[C:4]([C:5]([OH:7])=[O:6])=[C:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+].[Br:26]Br>CO.O>[Br:26][C:9]1[C:8](=[O:17])[C:4]([C:5]([OH:7])=[O:6])=[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:2]([CH3:1])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cn1c(-c2ccccc2)cc(=O)c(C(=O)O)c1-c1ccccc1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(-c2ccccc2)c(Br)c(=O)c(C(=O)O)c1-c1ccccc1
Yield: 63.6 %

Procedure:
3.75 gms of 1-methyl-2,6-diphenyl-4-oxonicotinic acid was dissolved in 40 mls of methanol. The pH was adjusted to 12 with the addition of aqueous NaOH. A methanolic solution of bromine (2.95 gms Br2 in 50 mls methanol) was added. Additional NaOH was added as required to maintain a basic medium. Removal of the solvent yielded a semisolid that was taken up in 100 mls of water. Water insoluble material was removed by filtration. Acidification of the aqueous solution provided 3.0 gms of 5-bromo-1-methyl-2,6-diphenyl-4-oxonicotinic acid (mp 242°-243°, with decomposition) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:17][C:18]([NH2:20])=[S:19].N.CO>CO.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([C:4]1[N:17]=[C:18]([NH2:20])[S:19][C:5]=1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16]
Reactant: NC(N)=S
Reactant: COC(=O)C(=O)C(Cl)CCc1ccccc1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1nc(N)sc1CCc1ccccc1
Yield: 91 %

Procedure:
Reflux equimolar 3-chloro-2-oxo-5-phenyl-pentanoic acid methyl ester and thiourea in MeOH (1.0 M) for 4 h. Basify with ammonia-MeOH and add brine. Extract with ethyl acetate (4×). Wash combined organic layers with brine, dry (MgSO4), and concentrate under reduced pressure to give (91%) of title compound. HPLC (GRAD80-100M) t=2.193 (95%). MS (APCI): 263 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][C:10](=[O:13])[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].[CH3:16]S(C)=O>O>[CH3:16][N:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=2[O:11][C:10]1=[O:13]
Reactant: CS(C)=O
Reactant: O=c1[nH]c2cccc([N+](=O)[O-])c2o1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cn1c(=O)oc2c([N+](=O)[O-])cccc21
Reaction time: 16 h
Yield: 85 %

Procedure:
3.94 g (21.9 mmol) of 7-nitro-2-benzoxazolidinone (for preparation of the latter compound, see EP 0189612 and references cited therein), were dissolved in 40 ml of DMSO after which 1.72 g of 85% powdered KOH (26.2 mmol) were added. While stirring and cooling (water) 3.72 g (26.2 mmol) of Mel dissolved in 6 ml of DMSO, were added dropwise over a period of 10 minutes. Stirring was continued at room temperature for 16 hrs, during the latter period an extra amount of Mel (0.5 g) was added. After the reaction was completed, the reaction mixture was diluted with water after which extraction took place with CH2Cl2. The combined organic fractions were washed with water and brine respectively, after which the organic fraction was dried on MgSO4. After removal of the drying agent and evaporation of the solvent in vacuo, 4.1 g of a solid residue was left. Flash column chromatography (SiO2, eluent: CH2Cl2) of the latter yielded 3.6 g (85%) of pure 3-methyl-7-nitro-2-benzoxazolidinone.
Reaction SMILES: [C:1]([Si:5]([O:18][CH2:19][CH2:20][C:21]1([CH2:27][CH2:28]I)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH:30]([C:42]([O:44][CH2:45][CH3:46])=[O:43])([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[O:18]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][C:30]([C:37]([O:39][CH2:40][CH3:41])=[O:38])([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)[Si](OCCC1(CCI)CCCCC1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)CC(CCC1(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCCCC1)(C(=O)OCC)C(=O)OCC
Yield: 65.8 %

Procedure:
Using tert-butyl-[2-[1-(2-iodoethyl]cyclohexyl]ethoxy]diphenylsilane (1.77 g) and triethyl 1,1,2-ethanetricarboxylate (2.51 g), the title compound (1.43 g) was obtained in the same manner as in Preparation Example 3B-1. This product was subjected to the subsequent step without further purification.
Reaction SMILES: [CH3:1][S:2]([C:4]([S:19][CH3:20])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)=O.N1C=CC=CC=1.S(Cl)([Cl:29])=O>C(Cl)Cl>[CH3:1][S:2][C:4]([S:19][CH3:20])=[C:5]([Cl:29])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CSC(=Cc1cccc(Oc2ccccc2)c1)S(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSC(SC)=C(Cl)c1cccc(Oc2ccccc2)c1
Yield: 70.4 %

Procedure:
1-Methylsulfinyl-1-methylthio-2-(m-phenoxyphenyl)ethylene (4.56 g) was dissolved in 40 ml of methylene chloride, and 2 ml of pyridine was added. With stirring under ice cooling, 10 ml of a methylene chloride solution of 2.15 g of thionyl chloride was added dropwise over the course of 5 minutes. The mixture was further stirred for 1 hour under ice cooling, and methylene chloride was added in an amount sufficient to adjust the total amount of the mixture to 80 ml. The mixture was then washed three times with 20 ml of water. The product was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a Florisil column using hexane/benzene as an eluant to afford 3.403 g of 1,1-bis(methylthio)-2-chloro-2-(m-phenoxyphenyl)ethylene as an oil in a yield of 70%. Samples for analysis were obtained by short-path distillation of this product [160°-180° C. (bath temperature)/0.01 mmHg].
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:30])([F:29])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:28])[CH2:13][C@@H:14](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:15][CH3:16])=[CH:7][CH:6]=1.O>O1CCCC1>[CH2:15]([C@H:14]1[N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([F:30])([F:29])[F:3])=[CH:6][CH:7]=2)[C:12](=[O:28])[CH2:13]1)[CH3:16]
Reactant: CC[C@@H](CC(=O)Nc1ccc(C(F)(F)F)cc1)OS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@@H]1CC(=O)N1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 109.4 %

Procedure:
26.5 mg of sodium hydride (60 wt %; 0.662 mmol) was suspended in tetrahydrofuran (1.5 mL) and to the solution, a tetrahydrofuran solution (1.5 mL) containing 274.9 mg (0.662 mmol) of (S)-N-[4-(trifluoromethyl)phenyl]-3-(4-methylphenyl)sulfonyloxypentanoic acid amide produced in Example 4 was added dropwise at room temperature for 5 minutes. After stirring at room temperature for further 3.5 hours, water (5 mL) was added and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine and the product was dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain (R)-4-ethyl-1-[4-(trifluoromethyl)phenyl]-2-azetidinone as a brown solid (176.1 mg). The reaction yield of the product was determined by the method described in Example 7 to be 83%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])[CH2:16][CH2:15][CH:14]([O:17][S:18](=[O:21])(=[O:20])[NH2:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])[CH2:12][CH2:13][CH:14]([O:17][S:18](=[O:20])(=[O:21])[NH:19][C:30](=[O:32])[CH3:31])[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: NS(=O)(=O)OC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Solvent: c1ccncc1
Product: CC(=O)NS(=O)(=O)OC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reaction time: 2.5 h

Procedure:
A solution of the product from Example 119 (69 mg, 0.15 mmol) in pyridine (2 mL) was treated with acetic anhydride (2 μL) at room temperature. After stirring for 2.5 hours, ice was added to the mixture until a white precipitate formed. The mixture was extracted with ethyl acetate, washed with water and brine, dried (MgSO4) and evaporated. The product was purified by flash chromatography on silica eluting with 50% ethyl acetate/iso-hexane to obtain the title compound as a white solid (14 mg). MS (ES+) 530 ([MNa]+).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9].[OH-:12].[Na+]>C(O)CCC>[NH:2]1[C:3]2[CH:7]=[CH:6][S:5][C:4]=2[C:8](=[O:9])[O:10][C:11]1=[O:12]
Reactant: [OH-]
Reactant: COC(=O)c1sccc1N
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: O=c1[nH]c2ccsc2c(=O)o1
Reaction time: 2.5 h

Procedure:
A mixture of 175 g (0.93 mol) of methyl 3-amino-2-thiophenecarboxylate hydrochloride, 1.8 liters of n-butanol and 77 g of sodium hydroxide is heated to boiling under reflux for 30 minutes. After concentration of the resulting suspension on a rotary evaporator, the mixture of sodium 3-amino-2-thiophenecarboxylate and sodium chloride is used directly in the next step. For this purpose, the mixture is treated with 800 ml of water, 280 ml of concentrated hydrochloric acid and 230 ml of tetrahydrofuran. Phosgene is conducted through this mixture at 15°-25° C. for 2.5 hours and then air conducted through for 15 minutes. The separated solid material is filtered off under suction, washed with water and dried. There is obtained 2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione of melting point 220°-221° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10](=[O:11])[C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)[C@@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=1
Reactant: N#Cc1cnc(Cl)nc1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C#N)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2-chloropyrimidine-5-carbonitrile. ESI-MS (m/z): 418 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:17])([CH3:16])[C:12]([NH:14][NH2:15])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:17])([CH3:16])[C:12]([NH:14][NH:15][C:26](=[S:27])[NH:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(C)(C)C(=O)NN)cc1OC
Reactant: Fc1ccc(N=C=S)cc1
Solvent: CCO
Product: COc1ccc(C(C)(C)C(=O)NNC(=S)Nc2ccc(F)cc2)cc1OC
Yield: 71.9 %

Procedure:
A mixture of 2-(3,4-dimethoxyphenyl)-2-methylpropanehydrazide (1.04 g, 4.37 mmol) and 4-fluorophenyl isothiocyanate (1.34 g, 8.73 mmol) in EtOH (30 mL) was heated at reflux 2 h. The reaction mixture was cooled and filtered. The filtrate was concentrated in vacuo and the residue was triturated with Et2O. The solids were collected by filtration and dried in vacuo to give 2-(2-(3,4-dimethoxyphenyl)-2-methylpropanoyl)-N-(4-fluorophenyl)hydrazinecarbothioamide (1.23 g, 72%). 1H NMR (400 MHz, DMSO-d6) δ 9.70 (br s, 1H), 9.65 (br s, 1H), 7.38 (b, 1H), 7.17 (t, 3H), 6.94-6.82 (m, 4H), 3.73 (s, 3H), 3.71 (s, 3H), 1.52 (s, 6H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CC(C)([O-])C.[K+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](F)=[CH:17][C:16]=1[Cl:22]>C1COCC1.C(OCC)(=O)C>[Cl:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][C:16]=1[Cl:22])[O:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: Fc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1ccc(OC2CCNCC2)cc1Cl
Temperature: 25 °C

Procedure:
4-Hydroxypiperidine (50 g) was added portionwise to a stirred suspension of potassium tert-butoxide (110.9 g) in THF (900 mL) at room temperature and under nitrogen. The mixture was heated at reflux and 1,2-dichloro-4-fluorobenzene (98 g) added dropwise over 30 min. The mixture was stirred at reflux for another 1 h then cooled down to room temperature, diluted with ethyl acetate (500 mL) and washed with water (500 mL). The organic phase was diluted further with ethyl acetate (500 mL) and extracted with 1M hydrochloric acid (200 mL). The aqueous extract was adjusted to over pH 10 by addition of a solution of sodium hydroxide and extracted twice with tert-butylmethyl ether (750 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to yield the sub-title compound as a dark oil which was used as such in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[CH:12]1[CH2:16][CH:10]([CH2:11]1)[N:9]1[C:5]2=[N:6][C:7](I)=[CH:8]1.C[Si](N[Si](C)(C)C)(C)C.C[N:28](C)[CH:29]=[O:30]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[CH:12]1[CH2:16][CH:10]([CH2:11]1)[N:9]1[C:5]2=[N:6][C:7]([C:29]([NH2:28])=[O:30])=[CH:8]1
Reactant: CN(C)C=O
Reactant: Brc1ccc2c(c1)-c1nc(I)cn1C1CC2C1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1C1CC2C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Into a 2-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 9-bromo-4-iodo-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene (65 g, 162.08 mmol, 1.00 equiv), N,N-dimethylformamide (1.2 L), HMDS (208 g, 1.29 mol, 8.00 equiv), and Pd(PPh3)2C1 (9.1 g, 0.08 equiv). To the above CO (2 atm) was introduced in. The resulting solution was stirred at 60° C. for 2 h. This reaction was repeated for 3 more times. The reaction mixture was cooled to 40° C. and quenched by the addition of 1500 mL of water. The solids were collected by filtration and washed with 3×500 mL of water. The solids were diluted with 2 L of EA and stirred at room temperature for 1 h. The solids were collected by filtration. The filter cake was diluted with 2 L of EA and stirred at 50° C. for 1 h. The solids were collected by filtration and dried to afford 172 g (83%) of 9-bromo-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-4-carboxamide as a brown solid. LC-MS: 318 [M+1]+1H-NMR (DMSO, 300 MHz, ppm): □ 18.75 (s, 1H), 7.85 (s, 1H), 7.58 (s, 1H), 7.44-4.44 (dd, 1H), 7.23-7.25 (dd, 1H), 7.14 (s, 1H), 4.89-4.95 (m, 1H), 3.67-3.73 (m, 1H), 3.04-3.12 (m, 2H), 1.64-1.68 (m, 2H).