Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][N:3]=1.I[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)Cc1ccc(I)cc1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
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: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccc(-c2ccnc(C)c2)cc1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a sealed tube were added 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.2 g, 10 mmol), ethyl 2-(4-iodophenyl)acetate 26-1 (2.9 g, 10 mmol), Pd(PPh3)4 (0.231 g, 0.2 mmol), toluene (30 mL), ethanol (10 mL) and 2M Na2CO3 (10 mL). The reaction mixture was flushed with nitrogen and stirred at 90° C. for 10 hours. After cooled down to room temperature, the reaction mixture was diluted into 200 mL ethyl acetate and washed with saturated sodium bicarbonate solution and then brine. The organic phase was dried over Na2SO4 and then taken to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 50% ethyl acetate in hexane to give ethyl 2-(4-(2-methylpyridin-4-yl)phenyl)acetate 26-2 as an oil. MS m/z 256.1 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[Cl:31].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([C:2]2[C:3]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:4][CH:5]=[C:6]([CH:17]=2)[C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[OH:16])=[O:8])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)c1
Temperature: 90 °C

Procedure:
5-Bromo-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide (59.8 g, 151 mmol) was dissolved in toluene (2500 mL) and DMF (200 mL). To this solution was added with stirring [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) CH2Cl2 (6.15 g, 7.5 mmol), 3,4-dichlorophenylboronic acid (30.2 g, 158 mmol) and sodium carbonate solution (2M, 150 mL). This mixture was heated to 90° C. for 2 h, cooled to room temperature and filtered through diatomaceous earth. The filter cake was thoroughly washed with ethyl acetate (3000 mL). The filtrates were combined, washed twice with water (2×2000 mL), and the water phases were extracted with ethyl acetate (2×1500 mL). Organic phases were pooled, dried with MgSO4 and the volatiles removed in vacuo. The residue was purified by filtration through silica (500 g) with ethyl acetate. The solvent was removed and the residue was triturated with diethyl ether to give after drying in vacuo the title compound (45.6 g) as a grayish solid; MS 463.079, 465.077 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:21]=[C:11]3[NH:12][C:13](=[O:20])[C:14]4[C:19]([N:10]3[N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>C(#N)C>[O:20]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]2[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:22](=[O:24])[CH3:23])[CH:7]=[CH:6][CH:5]=3)[CH:21]=[C:11]2[NH:12]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 12 (0.04 g, 0.1 mmol) and acetic anhydride (0.02 mL, 1.5 mmol) in acetonitrile was treated with triethylamine (0.1 mL, 0.8 mmol). The mixture was stirred overnight at ambient temperature and filtered to provide the title compound. 1H NMR (DMSO-d6) δ 12.27 (s, 1H), 10.04 (s, 1H), 8.11-8.20 (m, 3H), 7.87-7.95 (m, 1H), 7.58-7.66 (m, 2H), 7.48-7.56 (m, 1H), 7.38 (t, J=7.8 Hz, 1H), 6.27 (s, 1H), 2.06-2.12 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][O:27][CH2:28][CH2:29][CH2:30][NH:31][CH3:32]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:31]([CH2:30][CH2:29][CH2:28][O:27][CH3:26])[CH3:32])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2]
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: CNCCCOC
Product: COCCCN(C)C(=O)c1ccc(-n2ncc(-c3ccc(C#N)c(F)c3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-methoxy-N-methylpropan-1-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.93 (m, 2H) 2.34 (d, J=2.27 Hz, 3H) 2.98 (s, 3H) 3.07-3.67 (m, 7H) 7.64 (br. s., 1H) 7.70-7.81 (m, 1H) 7.84-8.64 (m, 4H). ESI-MS m/z [M+H]+ 424.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:21])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:10]([F:14])([F:13])[C:11]#[N:12].Cl.[NH2:23][OH:24].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:21])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:10]([F:13])([F:14])[C:11](=[N:23][OH:24])[NH2:12]
Reactant: N#CC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: NC(=NO)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 99.1 %

Procedure:
In 6 ml of chloroform was dissolved 300 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanenitrile. To the resulting solution were added 83 mg of hydroxylamine hydrochloride and 100 mg of triethylamine at 0°-5° C. The resulting mixture was subjected to reaction at 20°-25° C. for 3 hours. The reaction mixture was introduced into a mixed solvent consisting of 10 ml of chloroform and 5 ml of water. The resulting solution was adjusted to pH 9.0 with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 330 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide oxime.
Reaction SMILES: C([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:16][C@:14]2([C:26]2[CH:27]=[C:28]([NH:32][C:33]([C:35]3[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][N:36]=3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:15]=1)(=O)C1C=CC=CC=1.[ClH:43].CON.N1C=CC=CC=1>C(O)C.ClCCl>[ClH:43].[NH2:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:16][C@:14]2([C:26]2[CH:27]=[C:28]([NH:32][C:33]([C:35]3[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][N:36]=3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:15]=1
Reactant: N#Cc1ccc(C(=O)Nc2cccc([C@]34CN(c5ncc(F)cn5)C[C@H]3CSC(NC(=O)c3ccccc3)=N4)c2)nc1
Agent: CON
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Solvent: c1ccncc1
Product: N#Cc1ccc(C(=O)Nc2cccc([C@]34CN(c5ncc(F)cn5)C[C@H]3CSC(N)=N4)c2)nc1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
N-[3-[(4aR,7aS)-2-Benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-5-cyano-pyridine-2-carboxamide (360 mg, 0.59 mmol) is dissolved in ethanol (10 mL) and dichloromethane (2 mL). O-Methylhydroxylamine hydrochloride (504 mg, 5.91 mmol) and pyridine (478 μL, 5.91 mmol) are added and the reaction is stirred at room temperature over the weekend (70 hrs). The reaction is warmed to 60° C. and stirred for 24 hrs. The reaction is concentrated to give the crude product and purified via silica gel chromatography using a 0-10% gradient of 7 N ammonia methanol in dichloromethane to give the free base of the title compound. This material is dissolved in dichloromethane (5 mL) and 1 M hydrogen chloride in diethyl ether (0.54 mL, 540 μmol) is added. The solvent is removed in vacuo to give the title compound (240 mg, 75%). ES/MS (m/e): 475 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:30]([N:32]([CH2:36][CH2:37][O:38][Si](C(C)(C)C)(C)C)[CH:33]([CH3:35])[CH3:34])=[O:31])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OCCN(C(C)C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N=1)=O>>[CH2:1]([O:8][C:9]1[C:10]([C:30]([N:32]([CH2:36][CH2:37][OH:38])[CH:33]([CH3:35])[CH3:34])=[O:31])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(Cl)c(Cl)c3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccc(Cl)c(Cl)c3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
5-(Benzyloxy)-2-((1-(3,4-dichlorophenyl)cyclopentyl)methyl)-6-hydroxy-N-(2-hydroxyethyl)-N-isopropylpyrimidine-4-carboxamide (490) was synthesized from 5-(benzyloxy)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-((1-(3,4-dichlorophenyl)cyclopentyl)methyl)-6-hydroxy-N-isopropylpyrimidine-4-carboxamide (489) following the procedure described for 5-benzyloxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (246).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].[Br:8][C:9]1[CH:10]=[CH:11][C:12](Cl)=[N:13][CH:14]=1>COCCOC>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:7][CH2:6][CH2:5][O:4][CH3:3])=[N:13][CH:14]=1
Reactant: COCCO
Reactant: Clc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COCCOc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of NaH 55% (133 mg, 3.06 mmol) in DME (3 ml) was cooled to 0° C., then 2-methoxyethanol (Aldrich, Buchs, Switzerland, 0.362 ml, 4.58 mmol) was added. The solution was stirred at rt for 15 min. After that 5-bromo-2-chloropyridine (Aldrich, Buchs, Switzerland, 294 mg, 1.528 mmol) was added and the RM was heated by microwaves at 150° C. for 10 min. Then the RM was quenched with saturated aqueous NaHCO3 (50 ml) and extracted with EtOAc (2×). The combined organic layers were washed with brine (2×), dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by MPLC (hexane/EtOAc 0 to 30%). The fractions containing product were evaporated together to give the title compound as a colorless oil. (LC-MS: tR 1.20 min (Method B); M+H=232, 234 (Br-pattern) MS-ES. 1H-NMR (d6-DMSO, 400 MHz) 8.28.8.21 (m, 1H), 7.91-7.84 (m, 1H), 6.86-6.79 (m, 1H), 4.31 (t, 2H), 3.62 (t, 2H), 3.26 (s, 3H))
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:16])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Br:17]Br>C(Cl)(Cl)(Cl)Cl>[Br:17][C:7]1[CH:6]=[CH:5][C:4]([C:8]([CH3:16])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:9])=[CH:3][C:2]=1[OH:1]
Reactant: CCCCCCC(C)(C)c1cccc(O)c1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCC(C)(C)c1ccc(Br)c(O)c1
Reaction time: 0.25 h

Procedure:
To a 0° C. solution of 110 g. (0.50 mole) of 2-(3-hydroxyphenyl)-2-methyloctane in 200 ml. of carbon tetrachloride was added dropwise a solution of 80 g. (0.50 mole) of bromine in 90 ml. of carbon tetrachloride (reaction temperature ≤30° C. with cooling). The reaction mixture was stirred an additional 15 minutes and was then evaporated to yield 150 g. (100%) of product as an oil.
Reaction SMILES: C[O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])[CH2:12][CH2:13][C:7]=2[C:6]([O:23]C)=[C:5]([O:25][CH3:26])[C:4]=1[O:27][CH3:28].N1C(C(O)=O)=CC=CC=1C(O)=O.C1COCC1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(=O)(O)[O-].[Na+].O>[CH3:28][O:27][C:4]1[C:3](=[O:2])[C:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])[CH2:12][CH2:13][C:7]=2[C:6](=[O:23])[C:5]=1[O:25][CH3:26]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCn1ccccc1=O)CC2
Agent: O=C(O)c1cccc(C(=O)O)n1
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC1=C(OC)C(=O)C2=C(CCC(CCn3ccccc3=O)CC2)C1=O
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
To a mixture of 1-[2-(1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-yl)ethyl]-1,2-dihydro-2-pyridinone (334 mg), pyridine-2,6-dicarboxylic acid (433 mg), THF (8 ml), and water (4 ml) was added an water (4 ml) solution of CAN (1.89 g) with cooling with ice. After being stirred for 15 min, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was recrystallized from diisopropylether to obtain the entitled compound (195 mg).
Reaction SMILES: [C:1]1(=[O:32])[N:5]([C@H:6]2[C@@H:9](/[CH:10]=[CH:11]/[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8](C3C=CC(OC)=CC=3)[C:7]2=[O:26])[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>O1CCCC1.O>[C:4]1(=[O:27])[N:5]([C@H:6]2[C@@H:9](/[CH:10]=[CH:11]/[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:8][C:7]2=[O:26])[C:1](=[O:32])[C:2]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:3]12
Reactant: COc1ccc(N2C(=O)[C@@H](N3C(=O)c4ccccc4C3=O)[C@H]2/C=C/c2ccccc2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1N[C@H](/C=C/c2ccccc2)[C@@H]1N1C(=O)c2ccccc2C1=O

Procedure:
In 25 ml of tetrahydrofuran is dissolved 1 g of cis-3-phthalimido-4-(E)-styryl-1-(p-methoxyphenyl)-2-oxoazetidine and under stirring at -5° C. to -10° C., solution of ammonium cerium (IV) nitrate (3 g) in 10 ml of water is added dropwise over a period of 5 minutes. Then, the mixture is stirred at -5° C. to 0° C. for 20 minutes. The tetrahydrofuran is distilled off under reduced pressure and the residue is shaken with ethyl acetate and water. The ethyl acetate layer is taken, washed with aqueous sodium sulfite and aqueous sodium chloride in this order and dried over anhydrous sodium sulfate. The solvent is then distilled off and the residue is purified by silica gel column chromatography [eluent: chloroform-ethyl acetate (7:3)] and crystallized from ethyl acetate-ether to give cis-3-phthalimido-4-(E)-styryl-2-oxoazetidine, melting at 168°-170° C.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH2:6]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH2:22][CH2:23][O:24][C:25]1[C:34]2[C:29](=[CH:30][C:31]([Cl:38])=[C:32]([N+:35]([O-])=O)[CH:33]=2)[NH:28][C:27](=[O:39])[C:26]=1[C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[CH:41]=1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH2:22][CH2:23][O:24][C:25]1[C:34]2[C:29](=[CH:30][C:31]([Cl:38])=[C:32]([NH2:35])[CH:33]=2)[NH:28][C:27](=[O:39])[C:26]=1[C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[CH:41]=1)=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCc3ccccc3)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Agent: Cl[Sn]Cl
Solvent: O
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCc3ccccc3)c3cc(N)c(Cl)cc3[nH]c2=O)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
To a solution of 2-{2-[6-nitro-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid benzyl ester (1.11 g in 30 mL ethanol) was added 2 mL tin(II)cloride dihydrate and the mixture heated to 70° C. on an oil bath. After 2 hours, the reaction was cooled to room temperature and quenched by the addition of 300 mL ice-water. The acidity of the resulting solution was adjusted to pH 8 by the addition of saturated aqueous sodium bicarbonate and the mixture extracted (2×) with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification of the crude oil by flash chromatography on silica gel (methylene chloride:ethyl acetate, 95:5) gave the title compound (0.50 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)=[N:26][C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:25]=2)=[CH:4][CH:3]=1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: Nc1ccccc1N
Solvent: ClC(Cl)Cl
Product: Brc1ccc(-c2nc3ccccc3nc2-c2ccc(Br)cc2)cc1
Temperature: 80 °C
Yield: 92 %

Procedure:
A chloroform solution (200 mL) of 30.0 g (81.5 mmol) of 4,4′-dibromobenzil and 9.00 g (83.2 mmol) of o-phenylenediamine was heated and refluxed at 80° C. for 3 hours under nitrogen atmosphere. The reaction solution was washed with water after being cooled to room temperature. An aqueous layer was extracted with chloroform. This extracted aqueous layer and an organic layer were put together and washed with a saturated saline solution. The organic layer was dried over magnesium sulfate and filtered. The filtrate was condensed to obtain 33 g (yield: 92%) of objective 2,3-bis(4-bromophenyl)quinoxaline as a white solid. Synthetic scheme of Step 1 is shown in the following (d-1).
Reaction SMILES: C[Si](C)(C)Cl.BrC(Br)C.[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19](I)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[F:22][CH:23]([F:44])[O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:34]2[C:42]3[C:37](=[CH:38][C:39](I)=[CH:40][CH:41]=3)[CH:36]=[CH:35]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1>CC(N(C)C)=O.[Zn].[Cu]I>[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19]([C:39]2[CH:38]=[C:37]3[C:42](=[CH:41][CH:40]=2)[N:34]([S:31]([C:28]2[CH:27]=[CH:26][C:25]([O:24][CH:23]([F:44])[F:22])=[CH:30][CH:29]=2)(=[O:33])=[O:32])[CH:35]=[CH:36]3)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: O=S(=O)(c1ccc(OC(F)F)cc1)n1ccc2cc(I)ccc21
Agent: [Cu]I
Agent: CC(Br)Br
Agent: C[Si](C)(C)Cl
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CC(c2ccc3c(ccn3S(=O)(=O)c3ccc(OC(F)F)cc3)c2)C1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
In an inert atmosphere, zinc dust (300 mg, 4.59 mmol) was vigorously stirred in dimethylacetamide (1.6 ml) and heated to 65° C. Subsequently, trimethylchlorosilane (70 μl, 0.57 mmol) and dibromoethane (50 μl, 0.57 mmol) were added to the reaction mixture, and the reaction mixture was stirred for another 30 minutes at 65° C. 3-Iodo-azetidine-1-carboxylic acid tert-butyl ester (1.0 g, 3.53 mmol) in dimethylacetamide (2 ml) was added dropwise to the above prepared solution at 65° C., and then the reaction mixture was allowed to cool to room temperature. 1-(4-Difluoromethoxy-benzenesulfonyl)-5-iodo-1H-indole (961 mg, 2.12 mmol) in dimethylacetamide (4 ml) was added to the reaction mixture. Subsequently, [1,1-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)-dichlormethane (52.4 mg, 0.06 mmol) and copper(I)iodide (24.4 mg, 0.13 mmol) were added. The reaction mixture was heated to 80° C. for 1 hour, before it was cooled to room temperature and quenched with water (150 ml). Ammonium chloride (2 g) was added and the reaction mixture was extracted twice with diethylether (150 ml). The organic layer was dried over magnesium sulphate, filtered, and the solvent was evaporated under reduced pressure to give an oil (950 mg). The crude product was purified by silica gel chromatography with dichloromethane as eluent, yielding the purified product (553 mg, 52%). ESI-MS [m/z]: 423.05 [M-(C4H9)+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=[O:6].Cl.[CH3:30][O:31][C:32](=[O:35])[CH2:33][NH2:34]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:22]1)[N:14]=2)[C:5]([NH:34][CH2:33][C:32]([O:31][CH3:30])=[O:35])=[O:6]
Reactant: COC(=O)CN
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Product: COC(=O)CNC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzoic acid (0.050 g, 0.13 mmol) and glycine methyl ester hydrochloride (0.019 g, 0.15 mmol), according to Reference S and the general procedure for amide formation afforded methyl 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzamido)acetate. MS (ESI) m/z: Calculated: 461.1; Observed: 462.0 (M++1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:20]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)C1Cc2ccccc2N1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C1Cc2ccccc2N1C(=O)c1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of indoline-2-carboxilic acid (6.52 g, 40 mmol) and triethyl amine (11 mL, 78 mmol) in anhydrous CH2Cl2 (100 mL) was added dropwise a solution of benzoyl chloride (5.62 g, 40 mmol) in CH2Cl2 (25 mL) at 0° C. The reaction mixture was stirred at this temperature for 15 min and then at room temperature for additional 2.5 hours. The reaction mixture was washed successively with 5% aqueous KHSO4 solution (2×20 mL), brine (25 mL), dried over Na2SO4, and evaporated under reduced pressure to dryness. The residue was chromatographed on a silica gel column (3×35 cm) using CHCl3/MeOH (100:1) as the eluent. The main fractions containing the desired product was combined, evaporated under reduced pressure to dryness and the solid residue was recrystallized from MeOH to give the known 1-benzoyl-2,3-dihydro-1H-indole-2-carboxylic acid, 10.66 g (81%): mp 209-210° C. (191-193° C.)19; 1H NMR (DMSO-d6) δ 3.09 (1H, d, J=16.3 Hz, CH), 3.61-3.63 (1H, m, N—CH), 4.97 (1H, brs, CH), 7.06 (1H, m, ArH), 7.25-7.26 (2H, m, 2×ArH), 7.49 (5H, m, 5×ArH), 8.14-8.17 (1H, m, ArH), 13.01 (1H, brs, exchangeable, OH). MS: m/z 268.0 (M+H)+.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16](Cl)([Cl:18])=[O:17]>>[Cl:18][C:16]([N:6]1[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH:9]=[CH:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)=[O:17]
Reactant: O=C(Cl)Cl
Reactant: C1=Cc2ccccc2Nc2ccccc21
Product: O=C(Cl)N1c2ccccc2C=Cc2ccccc21

Procedure:
There is known from the German Patent Specification No. 1,136,707 a process for producing 5H-dibenz[b,f]azepine-5-carboxamide by reaction of 5H-dibenz[b,f]azepine with phosgene to give 5-chlorocarbonyl-5H-dibenz[b,f]azepine and the subsequent reaction thereof with ammonia to obtain the stated compound. The reaction of 5H-dibenz[b,f]azepine with phosgene is performed in toluene firstly at 70° C., and then under reflux. The subsequent reaction of this compound with ammonia is carried out in ethanol at boiling temperature.