Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][OH:21])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C.O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][S:23]([CH3:22])(=[O:25])=[O:24])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Reaction time: 4 h

Procedure:
[3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol (3.0 g, 10.6 mmol) was dissolved in methylene chloride (50 ml, 0.2 M), to which solution were added dropwise MsCl (1.23 ml, 15.9 mmol) and triethylamine (2.23 ml, 16 mmol-), and a reaction was performed at room temperature for 4 hours. The completion of the reaction was confirmed by liquid chromatography, 5 ml of water was added to the mixture, and the resulting solution was extracted with water and methylene chloride. The organic solvent layer was distilled under reduced pressure to obtain a crude solid compound. This was recrystallized from hexane:ethyl acetate (5:1) to obtain methanesulfonic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester as a white solid compound.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH:5]=1.Br[CH2:29][CH:30]1[O:34][CH2:33][CH2:32][O:31]1>>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:27])=[CH:5][C:6]=1[CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:29][CH:30]3[O:34][CH2:33][CH2:32][O:31]3)[CH:19]=2)[CH2:16][CH2:17]1
Reactant: BrCC1OCCO1
Reactant: COC(=O)c1ccc(Br)c(CN2CCC(c3c[nH]c4ccccc34)CC2)c1
Product: O=C(O)c1ccc(Br)c(CN2CCC(c3cn(CC4OCCO4)c4ccccc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 1 (part E) starting with 0.055 g (0.13 mmol) 4-bromo-3-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid methyl ester and 0.034 mg (0.16 mmol) 2-bromomethyl-[1,3]dioxolane. After the described purification, 0.021 g (32% of yield) of the expected acid was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.Cl[C:12]1[CH:21]=[N:20][C:15]2[N:16]=[CH:17][N:18]=[CH:19][C:14]=2[CH:13]=1>[OH-].[K+]>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][C:19]3[C:14]4[CH:13]=[CH:12][CH:21]=[N:20][C:15]=4[N:16]=[CH:17][N:18]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: Oc1ccc2c(c1)CCC2
Reactant: Clc1cnc2ncncc2c1
Agent: [K+]
Agent: [OH-]
Product: c1cnc2ncnc(Oc3ccc4c(c3)CCC4)c2c1
Yield: 60 %

Procedure:
To a solution of 5-hydroxyindan (1.342 g, 10 mM) in 80 ml of aqueous potassium hydroxide solution containing 1.683 g (30 mM) of solid potassium hydroxide is added 6-chloro-pyrido[2,3-d] pyrimidine (1.656 g, 10 mM). The reaction mixture is stirred for about 0.5 h at room temperature until most of the 6-chloro-pyrido[2,3-d]pyrimidine dissolves and then heated on the steam bath for further 0.5 h. The mixture is cooled, filtered and the residue recrystallized from hot aqueous ethanol to give pure title compound in 60% yield.
Reaction SMILES: C1COCC1.[O:6]([C:13]1[CH:14]=[C:15]([N:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=2)[CH2:20][CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:35]([Mg]Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[NH4+].[Cl-]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:6]([C:13]1[CH:14]=[C:15]([N:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:29]=2)[CH2:20][CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OC(CN(Cc1cccc(Br)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Reactant: Br[Mg]Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(CN(Cc1cccc(Cc2ccccc2)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Yield: 62 %

Procedure:
To a THF (4 mL) solution of 3-[(3-phenoxyphenyl)[[3-bromophenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (0.60 g, 1.3 mmol) from EX-595B was added benzyl-magnesium bromide in THF (2.0 mL, 2.0 M, 4.0 mmol) and Pd(PPh3)4. The resulting yellow solution was refluxed under N2 for 18 h. The cooled solution was poured into saturated aq. NH4Cl, extracted with ethyl acetate, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 15% ethyl acetate in hexane gave an oil which was dissolved in ETOH, stripped and dried in vacuo to give 0.39 g (62%) of the desired 3-[(3-phenoxyphenyl)[[3-(phenylmethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a colorless oil. Anal. calcd. for C29H26NO2F3.0.4 EtOH: C, 72.17; H, 5.77; N, 2.82. Found: C, 72.17; H, 5.42; N, 2.83. HRMS calcd. 478.1994 ([M+H]+, found: 478.1984. 1H NMR (C6D6) δ 1.58 (d, 1H), 3.22 (dd, 1H), 3.46 (dd, 1H), 3.69 (s, 2H), 3.73 (m, 1H), 4.18 (s, 2H), 6.34 (dd, 1H), 6.47 (dd, 1H), 6.53 (t, 1H), 6.8-7.1 (m 15H).
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][CH:8]([P:15]([O:19][CH3:20])([O:17][CH3:18])=[O:16])[P:9]([O:13][CH3:14])([O:11][CH3:12])=[O:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:18][O:17][P:15]([CH:8]([P:9]([O:11][CH3:12])([O:13][CH3:14])=[O:10])[CH2:7][C:6]([OH:21])=[O:5])([O:19][CH3:20])=[O:16]
Reactant: COP(=O)(OC)C(CC(=O)OC(C)(C)C)P(=O)(OC)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COP(=O)(OC)C(CC(=O)O)P(=O)(OC)OC
Temperature: 25 °C
Yield: 105 %

Procedure:
To a solution of 3,3-bis(dimethoxyphosphoryl)propanoic acid t-butyl ester (2.5 g) in dichloromethane (10 ml) was added trifluoroacetic acid. Stirring at room temperature was followed by evaporation of the volatiles in vacuo. Three cycles of vacuum evaporation of 5 ml portions of toluene gave 2.2 g product.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[CH:9]1[C:21]2[NH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1>O(C1C=CC=CC=1)C1C=CC=CC=1.[Cu-]=O>[CH:18]1[C:19]2[N:20]([C:2]3[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=3)[C:21]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccc(I)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: O=[Cu-]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Nc1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: 190 °C

Procedure:
4-(9H-carbazol-9-yl)benzenamine (A) was prepared through the Ullmann Reaction following the procedures reported in the literature (Macromolecules 2004, 37, 5531-5537). A mixture of 4-iodobenzenamine (2.19 g, 10 mmol), copper (I) oxide (2.18 g, 20 mmol) and carbazole (3.35 g, 20 mmol) in 40 ml 1-phenoxybenzene was heated to 190° C. in an oil bath for 24 h under N2 atmosphere. The reaction mixture was cooled to room temperature and then filtered by fast silica gel column to remove excess copper complex and 1-phenoxybenzene. The filtrate was evaporated to dryness and passed through a silica gel column using hexane and ethyl acetate mixture (6:1) as eluent to give product, yielding 2.37 g (92%). 1H NMR (400 MHz, CDCl3): δ(ppm) 8.164-8.144 (d, J=8.0 Hz, 2H), 7.432-7.395 (t, J=8.0 Hz, 2H), 7.353-7.277 (m, 6H), 6.912-6.891 (d, J=7.6 Hz, 2H), 4.019 (w, 2H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:14][CH:15]=3)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[C:34]([O:38][C:39](=[O:51])[NH:40][CH2:41][CH2:42][CH:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([CH3:37])([CH3:36])[CH3:35].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C([O-])([O-])=O.[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:34]([O:38][C:39](=[O:51])[NH:40][CH2:41][CH2:42][CH:43]([NH:50][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:14][CH:15]=3)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=2)[N:7]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)NCCC(N)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)n2)c2cnc(NCCN3CCOCC3)nc21
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCC(Nc1cccc(-c2nn(COCC[Si](C)(C)C)c3nc(NCCN4CCOCC4)ncc23)n1)c1ccccc1
Temperature: 132 °C
Reaction time: 7.5 h

Procedure:
A sealed tube was charged with [3-(6-bromo-pyridin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 32 supra) (500 mg, 0.936 mmol), (3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester (from Example 2 supra) (328 mg, 1.31 mmol), Pd2(dba)3 (54 mg, 0.094 mmol), DavePhos (74 mg, 0.187 mmol), K2CO3 (181 mg, 1.31 mmol) and dioxane (20 mL). The mixture was stirred at 132° C. under an atmosphere of N2 for 7.5 hours. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 14 g, 100-200 mesh, eluting with dichloromethane:MeOH, 80:1) to give crude product which was further purified by prep-HPLC to afford (3-{6-[6-(2-morpholin-4-yl-ethylamino)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-pyridin-2-ylamino}-3-phenyl-propyl)-carbamic acid tert-butyl ester. (Yield 147 mg, 16%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:16]=[CH:15][C:6]([CH:7]([NH2:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([NH:28][CH2:29][C:30](O)=[O:31])=[O:27])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26]([NH:28][CH2:29][C:30](=[O:31])[NH:14][CH:7]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:27])=[CH:22][CH:23]=1
Reactant: O=C(O)CNC(=O)CCc1ccc(Cl)cc1
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CCc1ccc(Cl)cc1)NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.1 from rac-4-chlorobenzhydrylamine hydrochloride and [3-(4-chloro-phenyl)-propionylamino]-acetic acid (Example 2.1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][N:11]([CH3:15])[C:12]([NH2:14])=[O:13].CC(O)=O.O>CCO.CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:10]/[N:11]([CH3:15])[C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CN(N)C(N)=O
Reactant: O=Cc1ccc(Br)cc1
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CN(/N=C/c1ccc(Br)cc1)C(N)=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromobenzaldehyde (4.3 g, 23 mmol) and 1-amino-1-methylurea (2.5 g, 28 mmol) in EtOH (40 mL) was added AcOH (2.5 mL) and water (4.5 mL). The resulting solution was stirred overnight at 80° C. and allowed to cool to rt. A precipitate formed by the addition of Et2O (50 mL). The solids were collected by filtration and compound 51a was obtained as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C9H10BrN3O: 256.0 (M+H). Found 256.1.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[C:20]([O:24][C:25](=[O:32])[CH:26]([NH2:31])[C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])([CH3:22])[CH3:21]>>[CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:31][CH:26]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]([O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:32])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)C(N)C(C)(C)C
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Product: C[C@H](Oc1cc(C(=O)NC(C(=O)OC(C)(C)C)C(C)(C)C)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 68a) and 2-Amino-3,3-dimethyl-butyric acid tert-butyl ester (CAN 99285-38-8) as starting materials and isolated (526 mg, 87%); MS (ESI, m/z): 445.6 (M+H+).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH2:4][C:5]1[N:10]=[C:9](F)[N:8]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[N:6]=1>O1CCCC1>[NH2:4][C:5]1[N:10]=[C:9]([N:2]([CH3:3])[CH3:1])[N:8]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[N:6]=1
Reactant: CNC
Reactant: Nc1nc(F)nc(OC(F)(F)F)n1
Solvent: C1CCOC1
Product: CN(C)c1nc(N)nc(OC(F)(F)F)n1
Reaction time: 8 h

Procedure:
5.0 g (0.111 mol) of gaseous dimethylamine were passed into a solution of 11 g (0.055 mol) of 2-amino-4-fluoro-6-trifluoromethoxy-1,3,5-triazine in 150 ml of tetrahydrofuran in the course of 20 minutes at 0° C. while stirring. Stirring was continued for one hour at 0° C. and overnight at 22° C. Evaporating down, washing with water and drying gave 9.9 g (80.7% of theory) of the title compound of melting point 114°-118° C. (decomposition).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]#[CH:15])(=O)=O)=CC=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>ClCCCl>[CH2:12]([N:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)[CH2:13][C:14]#[CH:15]
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C#CCCN1CCN(C)CC1
Temperature: 70 °C
Reaction time: 4.5 h

Procedure:
A mixture of but-3-ynyl 4-methylbenzenesulfonate (972 mg) and N-methyl piperazine (482 μL) was heated to 80 C. for 4.5 h, diluted with 1,2-dichloroethane (5 mL) and heated to 70° C. for 18 h. Saturated aq. NaHCO3 was added (10 mL) and the mixture was extracted with DCM (3×40 mL), and concentrated to afford 0.70 g of 1-(but-3-ynyl)-4-methylpiperazine as a 3:2 mixture of tosylate salt and free base.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[N:14]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:17]1[CH2:18][CH2:19][CH2:20][N:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][CH2:16]1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 22.7 %

Procedure:
To 1-fluoro-2-methyl-5-(methyloxy)-4-nitrobenzene (1.6 g, 8.64 mmol) (Example 113, Step B) in 25 mL of DMSO was added, 1,1-dimethylethyl hexahydro-1H-1,4-diazepine-1-carboxylate (2.6 g, 13 mmol), and K2CO3 (3.6 g, 26 mmol). The mixture was heated to 130° C. for 24 h. The mixture was then poured into 400 mL of H2O and extracted with EtOAc. The product was isolated by flash chromatography to give the title compound of step A (0.7 g, 1.96 mmol, 22%). 1H NMR (400 MHz, DMSO-d6) δ 7.73 (s, 1H), 6.66 (d, J=4.58 Hz, 1H), 3.87 (s, 3H), 3.40-3.52 (m, 4H), 3.33 (d, J=9.34 Hz, 2H), 3.24 (d, J=4.58 Hz, 2H), 2.19 (s, 3H), 1.80-1.90 (m, 2H), 1.36 (s, 5H), 1.30 (s, 4H).
Reaction SMILES: N1C=CC=CC1=[O:7].[H-].[Na+].N#N.[CH3:12][C:13]1([CH3:26])[N:18]=[C:17](Cl)[C:16]2[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:15]=2[O:14]1.C(C1C=CC(O)=C(C=1)C(N)=O)#N>CN(C=O)C.CC(C)=O>[CH3:12][C:13]1([CH3:26])[NH:18][C:17](=[O:7])[C:16]2[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:15]=2[O:14]1
Reactant: CC1(C)N=C(Cl)c2cc(C#N)ccc2O1
Reactant: O=c1cccc[nH]1
Agent: N#Cc1ccc(O)c(C(N)=O)c1
Agent: N#N
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC1(C)NC(=O)c2cc(C#N)ccc2O1
Reaction time: 0.5 h

Procedure:
1.9 g of 1H-2-pyridone are added to a stirred slurry of 741 mg of NaH (80%) in 40 ml of dry DMF while passing N2 into the flask. After the mixture has been stirred for 0.5 hour, 2.2 g of 2,2-dimethyl-4-chloro-6-cyano-2H-1,3-benzoxazine ("IIa"; m.p. 127°-129°; obtainable by condensing 5-cyano-2-hydroxybenzamide with acetone to form 2,2-dimethyl-6-cyano-3,4-dihydro-2H-1,3-benzoxazin-4-one (m.p. 213°-216°) and subsequently reacting the product with POCl3 /PCl5) are added, and the mixture is stirred at 50° for a further 72 hours. Saturated NaCl solution is subsequently added, the mixture is extracted with ethyl acetate, the organic phase is washed with NaCl solution, dried over sodium sulfate and evaporated, and the residue is chromatographed on silica gel (ethyl acetate/petroleum ether). 2,2-Dimethyl-4-(2-pyridyl-oxy)-6-cyano-2H-1,3-benzoxazine ("A"; m.p. 115°- 116°) is obtained as the first fraction, and 2,2-dimethyl-4-(2-oxo-1,2-dihydropyridyl)-6-cyano-2H-1,3-benzoxazine ("B"; m.p. 158°-159°) as the second fraction.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[S:15][CH:14]=[C:13]([CH2:16][NH:17][CH3:18])[CH:12]=1.C(N(CC)CC)C>O1CCCC1>[Br:10][C:11]1[S:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:18])[C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNCc1csc(Br)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1csc(Br)c1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
1.6 ml (13 mmol) of benzoyl chloride are added dropwise to a solution of 2.3 g (11 mmol) of (5-bromothiophen-3-ylmethyl)methylamine and 3 ml (22 mmol) of triethylamine in 30 ml of tetrahydrofuran. The reaction medium is stirred at room temperature for 1 hour, filtered, diluted with ethyl acetate and washed with water. The organic phase obtained is dried over sodium sulfate, filtered and evaporated to dryness. The residue obtained is purified by chromatography on a column of silica eluted with an 8/2 heptane/ethyl acetate mixture. 3.1 g (80%) of N-(5-bromothiophen-3-ylmethyl)-N-methylbenzamide are obtained.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)[CH2:19][CH2:20][CH3:21]>ClCCl.O>[CH2:18]([O:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[S:1][CH:2]=[CH:3][C:4]2=3)=[O:28])=[CH:30][CH:31]=1)[CH2:19][CH2:20][CH3:21]
Reactant: c1cc2c(s1)CCCCN2
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCOc1ccc(C(=O)N2CCCCc3sccc32)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a chilled (0° C.) solution of 0.306 g of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine and 417 μl of triethylamine is added 474 μl of 4-(n-butoxy)benzoyl chloride. The mixture is stirred for 3 days at room temperature, diluted with 50 ml of dichloromethane and 20 ml of water. The organic layer is separated and washed with 20 ml each of 2N citric acid, 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate, the pad washed with CH2Cl2 and the filtrate evaporated. The residue is crystallized from hexane containing a small amount of ethyl acetate. The crystals (0.585 g) are purified by chromatography on silica gel plates with hexane-ethyl acetate (2:1) as solvent to give 0.40 g of crystals (from ethyl acetate-hexane), m.p. 87° C. to 90° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:13](=[O:14])[N:12]([C:15](=[P:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([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)[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[C@@H:11]1[CH2:41][C:42]([C:44]1[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=1)[C:47]([OH:49])=O)=[O:43])[CH3:9])=[O:6])[CH:2]=[CH2:3].[NH3:53]>>[CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:13](=[O:14])[N:12]([C:15](=[P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[C@@H:11]1[CH2:41][C:42]([C:44]1[CH:52]=[CH:51][CH:50]=[C:46]([C:47]([NH2:53])=[O:49])[CH:45]=1)=[O:43])[CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1CC(=O)c1cccc(C(=O)O)c1
Reactant: N
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1CC(=O)c1cccc(C(N)=O)c1

Procedure:
Allyl ((2R,3S)-3-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-2-{2-[3-(aminocarbonyl)phenyl]-2-oxoethyl}-4-oxo-1-azetidinyl)(triphenylphosphoranylidene)acetate (324 mg) was obtained from a half amount of 3-({(2R,3S)-3-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-1-[2-(allyloxy)-2-oxo-1-(triphenylphosphoranylidene)ethyl]-4-oxo-2-azetidinyl}acetyl)benzoic acid obtained in Step e) and a 28% aqueous ammonia solution in a similar manner to Reference Example 2-c).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][C:12]1=[O:17]>>[CH3:7][N:6]1[C:2]([N:14]2[CH2:15][CH2:16][NH:11][C:12](=[O:17])[CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: O=C1CNCCN1
Product: Cn1ncc([N+](=O)[O-])c1N1CCNC(=O)C1
Yield: 100 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and piperazin-2-one gave 4-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperazin-2-one as a white solid (166 mg, 100%). 1H NMR (400 MHz, d6-DMSO) δ 8.21 (s, 1H), 8.09 (s, 1H), 3.78 (s, 3H), 3.44-3.30 (m, 6H)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:9])[CH2:7][CH3:8].C(O[CH:15]([N:19]([CH3:21])[CH3:20])N(C)C)(C)(C)C>>[CH3:21][N:19]([CH3:20])[CH:15]=[C:7]([CH3:8])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:9]
Reactant: CCC(=O)c1cccs1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CC(=CN(C)C)C(=O)c1cccs1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
1-(Thiophen-2-yl)propan-1-one (0.15 g, 1.069 mmol) was treated with tert-butoxybis-(dimethylamino)methane (0.5 mL) and the mixture stirred at 55° C. overnight. The volatiles were removed in vacuo and the residual liquid was azeotroped with toluene. The resulting residue was dissolved in ethyl acetate and passed through a plug of silica gel. The filtrate was concentrated and placed under vacuum to afford a thick yellow oil. Yield=0.2 g. MS (M+H)+ 196.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([CH2:10][C:11]2[CH:19]=[C:18]3[C:14]([C:15]([CH:36]=[CH:37][C:38]([O:40][CH3:41])=[O:39])=[CH:16][N:17]3[CH2:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][C:22]=3[O:34][CH3:35])=[CH:13][CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([CH2:6][NH:7][C:8]([CH2:10][C:11]2[CH:19]=[C:18]3[C:14]([C:15]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:16][N:17]3[CH2:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][C:22]=3[O:34][CH3:35])=[CH:13][CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C=Cc1cn(Cc2ccc(C(=O)OC(C)(C)C)cc2OC)c2cc(CC(=O)NCC3CCCC3)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1cn(Cc2ccc(C(=O)OC(C)(C)C)cc2OC)c2cc(CC(=O)NCC3CCCC3)ccc12
Yield: 83 %

Procedure:
A solution of t-butyl 4-[6-(cyclopentylmethylcarbamoyl)methyl-3-(2-methoxycarbonylvinyl)indol-1-ylmethyl]-3-methoxybenzoate (0.54 g) in methanol (20 ml) was treated with 10% palladium on carbon (0.13 g) and shaken under 3.45 bars of hydrogen for 18 hours. The catalyst was removed by filtration through diatomaceous earth, and the filtrate was evaporated to give t-butyl 4-[6-(cyclopentylmethylcarbamoyl)methyl-3-(2-methoxycarbonylethyl)indol-1-ylmethyl]-3-methoxybenzoate (0.45 g, 84%) as a white foam; partial NMR (80 MHz, CDCl3): 1.54(s, 9H, C(CH3)3), 2.69(t, 2H, COCH2), 3.62(s, 2H, COCH2Ar), 3.65(s, 3H, CO2CH3), 3.93(s, 3H, OCH3), 5.25(s, 2H, NCH2Ar).