Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([S:14]([NH:17][C:18]3[CH:19]=[C:20]([CH:33]=[CH:34][CH:35]=3)[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[O:22])(=[O:16])=[O:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.CSC1N=C(C2SC(S(Cl)(=O)=O)=CC=2)[CH:41]=[CH:40]N=1>>[CH2:40]([O:29][C:28](=[O:30])[C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21](=[O:22])[C:20]2[CH:33]=[CH:34][CH:35]=[C:18]([NH:17][S:14]([C:12]3[S:13][C:9]([C:7]4[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=4)=[CH:10][CH:11]=3)(=[O:15])=[O:16])[CH:19]=2)=[CH:32][CH:31]=1)[CH3:41]
Reactant: CSc1nccc(-c2ccc(S(=O)(=O)Nc3cccc(C(=O)Nc4ccc(C(=O)O)cc4)c3)s2)n1
Reactant: CSc1nccc(-c2ccc(S(=O)(=O)Cl)s2)n1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccc(-c4ccnc(SC)n4)s3)c2)cc1

Procedure:
4-{3-[5-(2-Methylsulfanyl-pyrimidin-4-yl)-thiophene-2-sulfonylamino]-benzoylamino}-benzoic acid, MS (ISP): m/e=525.2 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 5-(2-methylsulfanyl-pyrimidin-4-yl)-thiophene-2-sulfonyl chloride and yielded 4-{3-[5-(2-methylsulfanyl-pyrimidin-4-yl)-thiophene-2-sulfonylamino]-benzoylamino}-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][C:4](=[O:8])[C:5]([OH:7])=O.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>ClCCl.CN(C)C=O>[CH3:9][CH:2]([CH3:1])[CH2:3][C:4](=[O:8])[C:5]([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7]
Reactant: C1CCNC1
Reactant: CC(C)CC(=O)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)CC(=O)C(=O)N1CCCC1
Reaction time: 8 h
Yield: 66.7 %

Procedure:
Add oxalychloride (5.3 mL, 60.24 mmol, 1.6 eq.) slowly to the solution of 4-methyl-2-oxovaleric acid (4.90 g, 37.65 mmol, 1.0 eq.) in dichloromethane (50 mL) at 0° C. under nitrogen. Add Dimethylforamide (2 drops) last. Stir the reaction mixture overnight. Concentrate in vacuo. Add dichloromethane (100 mL). Add this solution to the solution of pyrrolidine (6.90 g, 97.02 mmol, 2.6 eq.) in dichloromethane (50 mL) at 0° C. slowly under nitrogen. Stir the reaction mixture for 1 hour at room temperature after addition. Wash with HCl (1 N) until the aqueous layer is acidic, then with aqueous saturated sodium chloride (2×20 mL) and water (2×30 mL). Dry the organic phase over MgSO4 and filter the drying reagent off. Concentrate in vacuo. Purify by column chromatography (0%→5% ethyl acetae in dichloromethane) to afford product (4.60 g, 66%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(CC)CC)C.[Cl:22][CH2:23][CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[Cl:22][CH2:23][CH2:24][CH2:25][S:26]([NH:2][C@@H:3]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NS(=O)(=O)CCCCl)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-tert-Butyl 2-amino-4-methylpentanoate hydrochloride (0.516 g, 2.306 mmol) were dissolved in dichloromethane (15 mL) and triethylamine (1.061 mL, 7.61 mmol) was added. 3-Chloropropane-1-sulfonyl chloride (0.337 mL, 2.77 mmol) was added dropwise, and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and the crude material was taken up in ether, filtered, and concentrated to give (S)-tert-butyl 2-(3-chloropropylsulfonamido)-4-methylpentanoate: 1H NMR (300 MHz, CDCl3) δ ppm 4.70 (d, J=9.7, 1H), 4.02-3.91 (m, 1H), 3.77-3.60 (m, 2H), 3.25-2.96 (m, 3H), 2.31 (tdd, J=2.2, 6.6, 9.2, 2H), 1.83 (dq, J=6.5, 13.0, 1H), 1.58-1.53 (m, 8H), 1.38 (t, J=7.3, 1H), 0.96 (dd, J=2.1, 6.6, 6H); MS (ESI+) m/z 345 (M+NH4)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([N:14]([CH:24]([CH3:26])[CH3:25])[NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])=[CH:2]1.C([O-])([O-])=O.[K+].[K+].[C:33](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])=[O:34]>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[CH:24]([N:14]([C:12](=[O:13])/[CH:11]=[CH:10]/[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([C:33](=[O:34])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH:2]=1)[NH:15][C:16](=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:26])[CH3:25]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)/C=C/c1c[nH]c2ccccc12
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)/C=C/c1cn(C(=O)C(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a round bottom flask, (E)-N′-(3-(1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide (60 mg, 0.17 mmol, 1.0 equivalent), K2CO3 (71.6 mg, 0.51 mmol, 3.0 equivalent), and DMAP (cat, 0.12 equivalent) were introduced and dissolved in DMF, after which Piv-Cl (0.04 ml, 0.34 mmol, 2.0 equivalent) was introduced. After stirring at room temperature for 24 hr, the reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc:methanol=7:3:1) and dried so that solid form of (E)-N′-(3-(1-acetyl-1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide was obtained. (10.3 mg, 14%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.[Br:18]NC(=O)CCC(N)=O>S(=O)(=O)(O)O>[Br:18][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([NH:8][C:9](=[O:11])[CH3:10])=[C:5]([S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[CH:4]=1
Reactant: CCCS(=O)(=O)c1ccc(C)cc1NC(C)=O
Reactant: NC(=O)CCC(=O)NBr
Agent: O=S(=O)(O)O
Product: CCCS(=O)(=O)c1cc(Br)c(C)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of N-[5-methyl-2-(propylsulfonyl)phenyl]acetamide (Intermediate 229; 5.0 g, 20 mmol) in conc. sulphuric acid (25 ml) was treated in portions with N-bromosuccinamide (3.8 g, 22 mmol). Reaction mixture was stirred at RT for 18 hrs, carefully quenched on ice and extracted to DCM (100 ml). The organic layer was washed with water and brine, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography (silica) eluting with petroleum ether/ethyl acetate to afford the title compound as a white solid.
Reaction SMILES: [H-].[Na+].CN(C)P(N(C)C)(N(C)C)=O.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[OH:24].Cl[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32]>O>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[O:24][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32]
Reactant: OCCCCCCCl
Reactant: Oc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: OCCCCCCOc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a chilled round bottom flask is added, 4.2 g of 57% sodium hydride in oil, 50 ml of hexamethylphosphoramide and 15.8 g. of 2-naphthol. After 1/2 hour the mixture is allowed to warm to room temperature and 13.6 g. of 6-chlorohexan-1-ol is added. The mixture is heated at 110° C. overnight, cooled, diluted with water and extracted with ether. The ether extract is washed with sodium hydroxide solution, then with water, dried (magnesium sulfate) and the solvent removed under vacuum. The solid is dissolved in ether and the solution washed with sodium hydroxide solution. The ether layer is dried (magnesium sulfate) and the solvent removed under vacuum to give 15.9 g. of product, as crystals, mp 53°-56° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[S:30]>O1CCCC1>[CH2:22]([N:19]1[CH2:18][CH2:17][CH:16]([N:15]2[CH:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[NH:1][C:29]2=[S:30])[CH2:21][CH2:20]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccccc1C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: S=C1Nc2ccccc2C(c2ccccc2)N1C1CCN(Cc2ccccc2)CC1
Yield: 96.3 %

Procedure:
To a solution of 503 mg (1.35 mmol) of α-(2-aminophenyl)-N-(1-benzylpiperidin-4-yl)benzylamine in 10 mL of tetrahydrofuran was added 300 mg (1.68 mmol) of 1,1'-thiocarbonyldiimidazole, and the mixture was heated under reflux for 3 hours. After being cooled, the reaction mixture was concentrated in vacuo, and the residue was purified by means of column chromatography (silica gel, 1:4 ethyl acetate:chloroform) to give 540 mg (1.30 mmol) of the title compound.
Reaction SMILES: [C:1](=S)=[S:2].[NH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[N:4]([CH2:5][CH2:6][CH2:7][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[S:15][C:16]2[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:1]=[S:2]
Reactant: NCCCN1c2ccccc2Sc2ccccc21
Reactant: S=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=C=NCCCN1c2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 124.8 %

Procedure:
4.2 g of carbon disulfide was added dropwise to a solution of 12.8 g of 10-(3-aminopropyl)phenothiazine and 7.7 ml of triethylamine in 100 ml of tetrahydrofuran. After stirring the solution at room temperature for 2 hours, a solution of 11.3 g of dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran was added dropwise thereto, and the reaction was conducted at room temperature for 5 hours. After removing solvents in vacuo, 50 ml of ethyl acetate was added to the residue, and the crystals precipitated were collected by filtration, and the filtrate was concentrated to obtain 18.6 g of the desired compound (oily).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-])=O>O>[CH:6]1[C:7]2[C:2](=[N:1][C:12]3[C:11]([N:8]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:3]=[CH:4][CH:5]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1
Solvent: O
Product: c1ccc2nc3ccccc3nc2c1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
195.4 gms of calcined and protonated ZSM-5 was added to a mixture of 156.3 gms of 25% aqueous TMA(OH) and 195 ml of deionized water. The solution was ion exchanged for three hours at 40° C. using a hot water bath. The slurry was filtered and the filtrate was set aside for future loadings and ion exchange. The filter cake was subjected to further drying in a vacuum desiccator that was equipped with a nitrogen purge. The drying in the vacuum desiccator was at 35° C. and maintained at that temperature for several hours (48 hours or less) for complete removal of the moisture. The dried material was treated with 216.3 gms of 25% aqueous TMA(OH) for a 20% target loading of TMA(OH). The resulting slurry was dried in a rotary evaporator set-up for several hours until it was moist dry. The rotary evaporator was run at 35° C. and 4 to 35 mm Hg. The dried material was transferred to a flat dish and placed in a vacuum desiccator with an inert gas purge. The vacuum desiccator is maintained at 40° C. and drying was allowed for several hours (48 hours or less). The resulting dried material was not hard, and easy to grind and consisted of what appears to be one phase when ground. A coupling reaction test based on reacting aniline and nitrobenzene failed to produce phenazine.
Reaction SMILES: CN(C=O)C.[NH:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH2:11]([O:13][N:14]=[C:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH3:12]>CCOCC>[CH2:11]([O:13][N:14]=[C:15]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[CH3:12]
Reactant: c1c[nH]cn1
Reactant: CCON=C(Cl)c1ccccc1SCc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCON=C(c1ccccc1SCc1ccc(Cl)cc1)n1ccnc1
Temperature: 170 °C
Reaction time: 21 h
Yield: 14.8 %

Procedure:
DMF (3 ml) and imidazole (0.41 g) were added to α-chloro-2-(4-chlorobenzylthio)benzaldehyde O-ethyloxime (0.68 g), and the mixture was stirred at 170° C. for 21 hours. After completion of the reaction, ether (100 ml) was added, and the mixture was washed with brine (80 ml) twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography and recrystallized from ethyl acetate/n-hexane to give 2-(4-chlorobenzylthio)-α-(1-imidazolyl)benzaldehyde O-ethyloxime (0.11 g) as colorless crystals. mp. 96.5°-97.5° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[CH:20][CH:19]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:3].C(O)(=O)C.C(O)C>[Pd].[H][H]>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][CH:8]([C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:3]
Reactant: [H][H]
Reactant: CN(C)CCCOC(CCCc1ccccc1)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C)CCCOC(CCCc1ccccc1)c1ccc(O)cc1

Procedure:
A mixture of 1.5 g of 1-[3-(N,N-dimethylamino)propoxy]-1-(p-benzyloxyphenyl)-4-phenylbutane obtained in Example 6, 0.5 g of 10% palladium on charcoal (50% wet reagent), 1 g of acetic acid and 50 ml of ethanol was vigorously stirred in hydrogen atmosphere at room temperature until the theoretical amount of hydrogen was consumed. The reaction mixture was poured into water, made alkaline with aqueous ammonium hydroxide and extracted. After the catalyst was filtered off, the organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-[3-(N,N-dimethylamino)propoxy]-1-(p-hydroxyphenyl)-4-phenylbutane. M.P., 91.5°-94.5° C. (oxalate).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][CH:8]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)[CH2:9][CH3:10].Br[C:21]1[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=1>COCCOC.O.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>[CH3:7][CH:8]([C:11]1[CH:16]=[CH:15][C:14]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCC(C)c1ccc(B(O)O)cc1
Reactant: Nc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCC(C)c1ccc(-c2cccnc2N)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A mixture of sodium carbonate (412 mg), tetrakis(triphenylphosphine)palladium(0) (112 mg), 4-(1-methylpropyl)phenylboronic acid (450 mg) and 3-bromopyridin-2-amine (336 mg) in 1,2-dimethoxyethane (15 mL) and water (3 mL) was stirred under a nitrogen atmosphere at 80° C. overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (392 mg) as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([Li])CCC.C[O:16][B:17](OC)[O:18]C.Cl>C1COCC1.C(Cl)Cl>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([B:17]([OH:18])[OH:16])=[CH:3][CH:4]=1)#[N:7]
Reactant: COB(OC)OC
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1ccc(B(O)O)cc1
Temperature: -100 °C
Reaction time: 0.08 h
Yield: 59.9 %

Procedure:
A solution of 4-bromobenzonitrile (91 g, 0.50 mole) in THF (1.1 L) was dried in the presence of activated 3 Å molecular sieves at room temp. This solution was filtered and cooled to −100° C. A 1.6 M solution of n-butyllithium in hexanes (355 mL. 0.567 mol) was added to the cold solution over 15 min while maintaining the internal temperature between −105 and −93° C. To the resulting orange reaction mixture was added trimethylborate (81 g, 0.78 mol) over 3 min, briefly increasing the reaction temperature to −72° C. The reaction mixture was recooled to −100° C. over 5 minutes and then was allowed to warm slowly to room temperature over 2.3 h. The reaction mixture was acidified with 4N HCl to pH 2.2, and was diluted with CH2Cl2 (200 mL). The aqueous layer was separated and the organic layer was washed with brine (2×200 mL), dried over anhydrous MgSO4, filtered, and the solvent removed under reduced pressure to a pale yellow solid. This solid was additionally purified by dissolution in 1N NaOH and extraction into CH2Cl2/THF (1:1, 2×200 mL). The aqueous phase was acidified with 4N HCl to pH 2.2 and was extracted into CH2Cl2/THF (1:1, 500 mL). The combined organic extracts were concentrated to a crude solid (64.6 g) that was triturated with diethyl ether (160 mL) and dried under vacuum to afford the intermediate title compound (44.0 g, 59.9%) as a white powder. 1H NMR (d6-acetone, 300 MHz): δ 8.03 (d, 2H, J=8.1), 7.75 (d, 2H, J=8.4), 7.54 (s, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([O:13][CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Oc1ccc(Cl)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(OC2CCNC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
3-Hydroxy-pyrrolidine-1-carboxylic acid tert butyl ester (2.1 g, 9.9 mmol) and triphenyl phosphine (2.59 g, 9.9 mmol) were dissolved in dry THF (35 ml) under nitrogen. The solution was cooled to 0° C. and 4-chlorophenol (1.28 g, 9.9 mmol) dissolved in dry THF (10 ml) was added followed by diethyl azodicarboxylate (DEAD) (1.55 ml, 9.9 mmol). After 15 minutes the ice bath was removed and the reaction was stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue was stirred with ether. The solid triphenyl phosphine oxide was filtered off. The solution was washed three times with sodium hydroxide (1M) and concentrated. The BOC-protected product was purified by flash chromatography on silica using EtOAc/heptane as eluant. It was dissolved in dichloromethane (35 ml) and trifluoroacetic acid (17 ml). The reaction mixture was stirred at room temperature overnight, concentrated and purified by flash chromatography on silica (MeOH:CHCl3:NH3, 100:100:1) to give the subtitle compound (1.72 g, 88%).
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH3:12])=[CH:5][CH:4]=1.Br[C:16]1[CH:17]=[CH:18][C:19]2[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:23][C:22]([C:33]([O:35][CH3:36])=[O:34])=[CH:21][C:20]=2[CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.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>[C:29]([O:28][C:26]([N:25]1[C:19]2[CH:18]=[CH:17][C:16]([C:3]3[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH3:12])=[CH:5][CH:4]=3)=[CH:37][C:20]=2[CH:21]=[C:22]([C:33]([O:35][CH3:36])=[O:34])[CH2:23][CH2:24]1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C(=O)OC(C)(C)C)CC1
Reactant: CCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a mixture of water:ethanol toluene (1:1:10, v/v. 42.0 ml) were dissolved 4-propoxyphenyl borate (746 mg) and methyl 7-bromo-1-(t-butoxycarbonyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1320 mg). To the solution was added potassium carbonate (1145 mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (160 mg), and the mixture was heated to reflux under argon atmosphere for 14.5 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (75 g, hexane:ethyl acetate=3:1) to give methyl 1-(t-butoxycarbonyl)-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate as yellow amorphous. The obtained methyl 1-(t-butoxycarbonyl)-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate was dissolved in ethyl acetate (80 ml). To the solution was added 6N hydrochloric acid (20 ml) at room temperature, and the mixture was stirred at 100° C. for 30 minutes and neutralized with 1N sodium hydroxide and saturated sodium hydrogen carbonate solution. The separated organic layer was washed with saturated sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give methyl 7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (947 mg) as yellow crystals. The mother liquor was concentrated, and the residue was purified with silica gel column chromatography (15 g, hexane:ethyl acetate=4:1) to give desired product (147 mg).
Reaction SMILES: [CH:1]1([CH2:5][NH:6][C:7]#[N:8])[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].O>COCCOC>[C:18]([C:17]1[O:22][C:7](=[NH:8])[N:6]([CH2:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[CH:16]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)CBr
Reactant: N#CNCC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)c1cn(CC2CCC2)c(=N)o1
Temperature: 80 °C
Yield: 80 %

Procedure:
A mixture of N-(cyclobutylmethyl)cyanamide (0.40 g, 3.6 mmol), cesium carbonate (2.4 g, 7.3 mmol) and 1-bromo-3,3-dimethylbutan-2-one (0.50 mL, 3.6 mmol, Aldrich) in 1,2-dimethoxyethane (20 mL) was heated to 80° C. overnight. The mixture was poured into water, and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure to provide the title compound (0.6 g). LCMS (APCI+) m/z 209 (M+H)+.