Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[C@H:7]([N:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8][CH2:9]O)([CH3:4])([CH3:3])[CH3:2].[I:36]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>ClCCl.CO>[C:1]([O:5][C:6](=[O:35])[C@H:7]([N:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8][CH2:9][I:36])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H](CCO)N(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H](CCI)N(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
A solution of the title E compound, (2R)-[t-butoxycarbonyl(4′-chlorobiphenyl-4-sulfonyl)amino]4-hydroxybutyric acid t-butyl ester (2.0 g, 9.58 mmol) in 50 mL dichloromethane is sequentially treated with iodine (2.88 g, 14.37 mmol), triphenylphosphine (3.72 g, 14.37 mmol) and imidazole (0.97 g, 14.37 mmol) at RT. After 2 h, 20 mL of methanol are added and the reaction mixture is stirred at RT for 30 min further. The solvent is evaporated and the product is purified by chomatography on silica gel (eluant; 1/19—EtOAc/hexane) to afford 2.46 g (78%) of (2R)-[t-butyloxycarbonyl(4′-chlorobiphenyl-4-sulfonyl)amino]-4-iodobutyric acid t-butyl ester.
Reaction SMILES: [OH:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C)C=O>[CH3:21][O:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:3]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CCC1OC(=O)C(O)=C1c1ccccc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)CCC1OC(=O)C(OC)=C1c1ccccc1

Procedure:
To a mixture of ethyl 3-(4-hydroxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionate (86 g) and potassium carbonate (51.62 g) in N,N-dimethylformamide (855 ml) was added dropwise methyl iodide (23.25 ml) at ambient temperature with stirring and the mixture was stirred for 2.5 hours at the same temperature. The solvent was evaporated in vacuo to give a residue which was poured into diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and brine successively and dried. Evaporation of the solvent gave ethyl 3-(4-methoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionate which was recrystallized from diisopropyl ether (73.07 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([OH:15])[CH:6]=1)=O.[NH2:16][C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>C(O)C>[N:16]1[C:3]([C:5]2[CH:6]=[C:7]([OH:15])[C:8]([OH:14])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=2)=[CH:2][N:21]2[C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[S:18][C:17]=12
Reactant: O=C(CBr)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: Nc1nc2ccccc2s1
Solvent: CCO
Product: O=[N+]([O-])c1cc(-c2cn3c(n2)sc2ccccc23)cc(O)c1O
Temperature: 25 °C

Procedure:
A mixture of 1.95 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone, 1.06 g of 2-aminobenzothiazole and 50 ml of ethanol is heated to boiling under reflux for 17 hours. The reaction mixture is then cooled to room temperature, whereupon the crystals are removed by filtration under suction. There is obtained 5-(imidazo[2,1-b]benzothiazol-2-yl)-3-nitropyrocatechol of m.p. 303°-305° (from N,N-dimethylformamide/methanol).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:28]=[C:27]([C:29]([NH2:31])=[O:30])[O:26][N:25]=2)=[CH:20][CH:19]=1>CC#N>[N:1]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:28]=[C:27]([C:29]([NH2:31])=[O:30])[O:26][N:25]=3)=[CH:22][CH:23]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cc(-c2ccc(Cn3cnc4ccccc43)cc2)no1
Temperature: 60 °C
Yield: 47.5 %

Procedure:
A mixture of benzimidazole (24 mg, 0.20 mmol), K2CO3 (0.2 mmol), and 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 25 mg, 0.09 mmol) in CH3CN (1 mL) was heated overnight at 60° C. The mixture was filtered and the solvent was evaporated from the filtrate. The residue was purified by chromatography to give 3-(4-benzoimidazol-1-ylmethyl-phenyl)-isoxazole-5-carboxylic acid amide (13.6 mg, 48%). Based on the NMR, the purity was estimated as 80%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[CH2:22]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH:29]([CH3:33])[CH2:28]1)=[O:26])[CH3:23]>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:30]2[CH2:31][CH2:32][N:27]([C:25]([O:24][CH2:22][CH3:23])=[O:26])[CH2:28][CH:29]2[CH3:33])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CCOC(=O)N1CCNC(C)C1
Solvent: CS(C)=O
Product: CCOC(=O)N1CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C(C)C1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
In the same manner as described in Example 1 (1), a mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-ethoxycarbonyl-3-methyl-piperazine, and dimethyl sulfoxide was stirred at 150° C. for 2 hours to give 5-amino-1-cyclopropyl-6,8-difluoro-7-(4-ethoxycarbonyl-2-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 220°-225° C.
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[C:9]([CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12])#[CH:10].C(NCC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:10]#[C:9][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[OH:12])[CH:4]=1
Reactant: Brc1cccnc1
Reactant: C#CC(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCNCC
Product: OC(C#Cc1cccnc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Place 3-bromopyridine hydrochloride (0.78 g, 4 mmol), α-(ethynyl)-benzenemethanol (661 mg, 5 mmol) and diethylamine (25 mL) under nitrogen atmosphere. Add bis(triphenylphosphine)palladium(II) chloride (140 mg) then copper(I) iodide (20 mg). Stir overnight at room temperature and filter. Evaporate the solvent in vacuo and filter through silica gel (2:1 ethyl acetate/hexane). Evaporate the solvent in vacuo and recrystallize (25% ethyl acetate/hexane) to yield the title compound.
Reaction SMILES: F.[F:2]C1N=C(Cl)N=C(Cl)N=1.[F:11][C:12]1[N:17]=[C:16]([F:18])[N:15]=[C:14](Cl)[N:13]=1.FC1N=C(Cl)N=C(Cl)N=1.N1C(Cl)=NC(Cl)=NC=1Cl>>[N:13]1[C:14]([F:2])=[N:15][C:16]([F:18])=[N:17][C:12]=1[F:11]
Reactant: Fc1nc(F)nc(Cl)n1
Reactant: Fc1nc(Cl)nc(Cl)n1
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: F
Product: Fc1nc(F)nc(F)n1

Procedure:
If 2,4-difluoro-6-chloro-s-triazine or 2-fluoro-4,6-dichloro-s-triazine is used in place of cyanuric chloride as the starting material, very good yields of pure cyanuric fluoride are possible even with molar ratios of hydrogen fluoride/cyanuric halide which are lower than those mentioned above. For example, when 2,4-difluoro-6-chloro-s-triazine is used the reaction is advantageously carried out with a molar ratio of hydrogen fluoride/2,4-difluoro-6-chloro-s-triazine of 1:1 to 4:1, preferably about 2:1; if 2-fluoro-4,6-dichloro-s-triazine is used as the starting material, advantageous results are obtained with a molar ratio of hydrogen fluoride/2-fluoro-4,6-dichloro-s-triazine of 2:1 to 5:1 and preferably the reaction is carried out using a molar ratio of hydrogen fluoride/2-fluoro-4,6-dichloro-s-triazine of 3:1. When 2,4-difluoro-6-chloro-s-triazine or 2-fluoro-4,6-dichloro-s-triazine is used as the starting material, the reaction is also carried out at temperatures betwen 150° C. and 300° C.; preferably the reaction is carried out at between 180° C. and 220° C., as when cyanuric chloride is used as the starting material. Pure cyanuric fluoride is likewise obtaining in high yield when a mixture of 2,4-difluoro-6-chloro-s-triazine and 2-fluoro-4,6-dichloro-s-triazine or a mixture of cyanuric chloride, 2,4-difluoro-6-chloro-s-triazine and 2-fluoro-4,6-dichloro-s-triazine is employed, in place of cyanuric chloride, 2,4-difluoro-6-chloro-s-triazine or 2-fluoro-4,6-dichloro-s-triazine, as the starting material. In this case the most advantageous molar ratio of hydrogen fluoride/cyanuric halide mixture depends on the mixing ratio of the two or the three cyanuric halide components in the starting mixture. The most advantageous temperature range for the reaction when a mixture of cyanuric halides is used is the same as that when pure cyanuric chloride is employed as the starting material.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:21](=O)[CH2:22][CH3:23])[C:5]2[CH2:10][O:9][CH2:8][N:7]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])[C:6]=2[N:20]=1.Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>C(O)C>[CH3:1][C:2]1[N:3]=[C:4](/[C:21](=[N:26]\[OH:27])/[CH2:22][CH3:23])[C:5]2[CH2:10][O:9][CH2:8][N:7]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])[C:6]=2[N:20]=1
Reactant: NO
Reactant: CCC(=O)c1nc(C)nc2c1COCN2c1c(C)cc(C)cc1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC/C(=N/O)c1nc(C)nc2c1COCN2c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
A mixture of 1-[7-methyl-1-(2,4,6-trimethyl-phenyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-5-yl]-propan-1-one (50 mg, 0.154 mmol), hydroxylamine hydrochloride (43 mg, 0.62 mmol), and sodium acetate (57 mg, 0.693 mmol) in ethanol (4 ml) was stirred at room temperature overnight. The mixture was concentrated to dryness, then diluted with water, and extracted with 3 times with ethyl acetate. The organic layer was separated, dried (MgSO4) and concentrated to dryness to give 51 mg of a mixture of the title (E) and (Z)-isomers as a white solid. Both isomers were separated by preparative thin layer chromatography plate with 40% ethyl acetate in hexane as solvent.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[NH2:19])=[CH:12][CH:11]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:17](=[O:22])[C:18]([CH3:20])([CH3:21])[NH:19][C:24]2=[O:26])=[CH:12][CH:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cccc(Oc2ccc(NC(=O)C(C)(C)N)cc2)c1C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cccc(Oc2ccc(N3C(=O)NC(C)(C)C3=O)cc2)c1C
Reaction time: 0.08 h
Yield: 207.4 %

Procedure:
N1-{4-[(2,3-dimethylphenyl)oxy]phenyl}-2-methylalaninamide (Intermediate 76, 68 mg) was solved in 2 mL of ethyl acetate under nitrogen atmosphere. TEA (0.070 mL, 0.50 mmol) was added followed by a solution of triphosgene (33.8 mg, 0.11 mmol) in 1.0 mL of ethyl acetate. After stirring for 5 minutes, DMAP (13.9 mg, 0.11 mmol) was added and the reaction mixture was stirred at room temperature for 10 minutes. After quenching with a saturated solution of NaHCO3, the mixture was extracted two times with ethyl acetate, and the collected organic were dried over sodium sulphate, filtered and evaporated. The residue obtained was purified by silica gel chromatography eluting with a gradient cHex/EtOAc from 100/0 to 0/100. This afforded the title compound (74 mg).
Reaction SMILES: ClC(OCC)=O.[C:7]([C@@H:10]1[N:13]([C:14](=[O:16])[CH3:15])[C:12](=[O:17])[C@H:11]1[CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])=[N:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])(O)=[O:8].C(N(CC)CC)C.Cl.[CH2:53]([O:60][C:61](=[O:67])[C@@H:62]1[CH2:66][CH2:65][CH2:64][NH:63]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C(Cl)Cl>[C:54]1([CH2:53][O:60][C:61]([CH:62]2[CH2:66][CH2:65][CH2:64][N:63]2[C:7]([C@@H:10]2[N:13]([C:14](=[O:16])[CH3:15])[C:12](=[O:17])[C@H:11]2[CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:34][C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])=[N:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:8])=[O:67])[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C(=O)N1CCCC1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 14 %

Procedure:
To a -5° C. methylene chloride (1 mL) solution of ethyl chloroformate (0.12 g, 1.1 mmol) was added a methylene chloride solution of compound 29 (0.35 g, 0.7 mmol), followed by the addition of triethylamine (0.112 g, 1.1 mmol). The resultant reaction mixture was stirred for 1 h between -5° C. and 5° C. Triethylamine (0.11 g, 1.1 mmol) and proline benzylester hydrochloride (260 mg, 1.1 mmol) was added, and the solution was stirred between -5° C. to 5° C. for an additional 15 min and for 16 h at room temperature. The solution was washed with saturated aqueous NaHCO3 solution, dried (MgSO4), and concentrated. The residue was purified by silica gel chromatography (Et2O:EtOAc/8:2) to afford 70 mg (14%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH2:4]O.C(N(CC)CC)C.CS([Cl:23])(=O)=O>ClCCl>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH2:4][Cl:23]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CO)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To a solution of 2-chloro-4-methoxybenzyl alcohol (1.5 g, 8.7 mmol) in dichloromethane (10 mL) were added under ice-cooling triethylamine (2.4 mL, 17.4 mmol) and methanesulfonyl chloride (0.74 mL, 9.5 mmol) and the mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an almost pure title compound (1.01 g, 61%).
Reaction SMILES: Cl.C(O[C:5]([CH:7]1[C:11](=O)[CH2:10][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8]1)=[O:6])C.Cl.[C:21]([NH2:26])(=[NH:25])[CH:22]([CH3:24])[CH3:23].CC([O-])(C)C.[K+]>C(O)(C)(C)C>[CH2:13]([N:9]1[CH2:8][C:7]2[C:5]([OH:6])=[N:26][C:21]([CH:22]([CH3:24])[CH3:23])=[N:25][C:11]=2[CH2:10]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)C(=N)N
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)c1nc(O)c2c(n1)CN(Cc1ccccc1)C2
Temperature: 100 °C
Yield: 23 %

Procedure:
To a solution of 1-benzyl-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester hydrochloride (U.S. Pat. No. 3,312,716; 0.568 g, 2.30 mmol) in tert-BuOH was added isobutyramidine hydrochloride (0.282 g, 2.30 mmol) and KOtBu (0.516 g, 4.6 mmol). After heating for 6 h at 100° C., the reaction was cooled to rt, concentrated, diluted with water and washed with Et2O. The organic layer discarded. The aqueous layer was adjusted to pH 7 and extracted with Et2O. The organic layers were then dried and concentrated to give 0.145 g (23%) of the title compound of yellow solid that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:33]=[CH:32][C:17]4[O:18][CH2:19][C:20]5[CH:31]=[CH:30][CH:29]=[CH:28][C:21]=5[CH:22]([O:23][CH2:24][CH2:25][C:26]#[N:27])[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.C[Sn]([N:38]=[N+:39]=[N-:40])(C)C>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:33]=[CH:32][C:17]4[O:18][CH2:19][C:20]5[CH:31]=[CH:30][CH:29]=[CH:28][C:21]=5[CH:22]([O:23][CH2:24][CH2:25][C:26]5[NH:40][N:39]=[N:38][N:27]=5)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: N#CCCOC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Product: Clc1ccc2ccc(COc3ccc4c(c3)C(OCCc3nnn[nH]3)c3ccccc3CO4)nc2c1

Procedure:
2-(7-Chloroquinolin-2-yl)methoxy-11-(2-cyanoethoxy)-6,11-dihydrodibenz[b,e]oxepine and trimethyltin azide were used and reacted in the same manner as in Example 30 to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:15]I.O>CN(C=O)C>[CH3:15][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:10]=2)[C:6]([CH:11]=[O:12])=[CH:7]1
Reactant: CI
Reactant: Cc1ccc2c(C=O)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(C=O)cn(C)c2c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
A solution of the known 6-methyl-1H-indole-3-carboxaldehyde (5 g, 31 mm) in DMF (100 mL) was cooled to 0° C. and treated with NaH (38 mm), and stirred at 0° C. for 3 hours. After treatment with CH3I (2.35 mL, 38 mm), the mixture was allowed to warm to room temperature overnight. The mixture was poured into H2O(500 mL) and extracted with ethylacetate (EtOAc) (200 mL×3). The combined organic layers were dried over MgSO4, filtered and evaporated. Purification by flash column chromatography afforded 1,6-dimethyl-1H-indole-3-carboxaldehyde (5.2 g, 97%).
Reaction SMILES: [C:1]([N:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1)(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H-].[Na+].[CH3:21]I.O>C1COCC1>[C:1]([N:12]1[CH2:13][CH2:14][CH:15]([O:18][CH3:21])[CH2:16][CH2:17]1)(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CI
Reactant: CCCCCCC/C=C/C(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCC/C=C/C(=O)N1CCC(OC)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.4 %

Procedure:
Compound 8 (0.62 g, 2.4 mmol) was dissolved in THF (10 mL), and sodium hydride (60% in mineral oil) (0.10 g, 2.6 mmol) was added thereto under ice-cooling. After mixing for 15 minutes under ice-cooling, methyl iodide (0.16 mL, 2.6 mmol) was added thereto, and stirred at room temperature for 20 hours. Water was added to the liquid reaction mixture, the mixture was extracted with ethyl acetate, an organic layer was washed with water and saturated sodium chloride solution, and the washed extract was then dried over anhydrous sodium sulfate. The residue was purified with silica gel column chromatography (developing solvent: hexane:ethyl acetate=3:2), to give an intended compound (0.42 g, 65%) in the form of a pale yellow oily substance.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].C([O:17][C:18]1[CH2:23][CH2:22][CH2:21][C:20](=O)[CH:19]=1)C.Cl>CCCCCC.C(OCC)C>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][C:11]([C:20]2[CH2:21][CH2:22][CH2:23][C:18](=[O:17])[CH:19]=2)=[CH:12][CH:7]=1
Reactant: CCOC1=CC(=O)CCC1
Reactant: COc1ccccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc(C2=CC(=O)CCC2)cc1
Reaction time: 2 h

Procedure:
100 ml of n-butyllithium 1.6M in hexane are added dropwise at 0° C. to a solution of 20 ml of bromoanisole in 600 ml of diethyl ether. After 2 hours, 20.2 ml of 3-ethoxy-2-cyclohexenone in 80 ml of diethyl ether are added dropwise. After 3 hours, 100 ml of 3N hydrochloric acid are added dropwise. The organic phase is separated off and concentrated, and the residue is purified over silica gel. 3-(4-Methoxyphenyl)-2-cyclohexen-1-one is obtained in the form of colourless crystals, m.p.: 83-85° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:21])([CH3:20])[C:18]#[N:19])=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([CH3:21])([CH3:20])[C:18]#[N:19])=[CH:15][CH:16]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C#N)c1ccc(N)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C#N)c1ccc(Nc2nc(Cl)ncc2Br)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Bromo-2,4-dichloropyrimidine (1.37 gm, 6 mmol), 2-(4-aminophenyl)-2-methylpropanenitrile (0.96 gm, 6 mmol) and diisopropyl ethylamine (1.6 mL, 9 mmol) were combined in 30 ml acetonitrile and stirred for 16 hr at RT. LC/MS at 16 hr indicated reaction was complete. Organics were washed sequentially with 1M citric acid solution, water, then brine. Organics were dried over sodium sulfate then decanted and evaporated to yield a crude material which was carried on as-is in the next step. (1.45 gm, 69%). MS m/z 353.3 (M+H)
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH2:20][NH2:21])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH2:20][NH:21][S:26]([CH3:25])(=[O:28])=[O:27])[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Product: CS(=O)(=O)NCc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Yield: 45.6 %

Procedure:
Following procedures essentially as described in Example 90, reaction of the benzylamine (70 mg, 0.225 mmol) prepared in Example 144 and methanesulfonyl chloride (52□L, 0.68 mmol) affords 40 mg of the title compound in 46% yield as a colorless oil after purification using column chromatography (30% ethyl acetate/hexane). MS (ES) 388 (M−1). HPLC shows 97% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=1)[C:18]([NH2:20])=[O:19].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=1)[C:18]([NH2:20])=[O:19])=[O:8]
Reactant: NC(=O)c1ccnc(N)c1
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1ccnc(NC(=O)COc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
To solution of (2,4-dichloro-phenoxy)-acetic acid (51 mg, 0.23 mmol), 2-amino isonicotinamide (47.66 mg, 0.34 mmol) and DMAP (56.6 mg, 0.46 mmol) in DMF 4 ml was added PyBOP (236 mg, 0.46 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by PLC (EtoAC:Hexane:MeOH=3:6:1-2:4:1) to afford 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-isonicotinamide as a colorless solid (0.06 g, 77% yield).