Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([N:25](COCC[Si](C)(C)C)[S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17]2)([CH:11]2[CH2:13][CH:12]2[C:14]#[N:15])[CH2:9][CH3:10])=[CH:4][CH:3]=1>Cl.CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17]2)([CH:11]2[CH2:13][CH:12]2[C:14]#[N:15])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CCC(c1ccc(Cl)cc1)(C1CC1C#N)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Agent: Cl
Solvent: CCO
Product: CCC(c1ccc(Cl)cc1)(C1CC1C#N)n1ncc2c(NS(C)(=O)=O)cccc21
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of N-(1-(1-(4-chlorophenyl)-1-(2-cyanocyclopropyl)propyl)-1H-indazol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (14 mg) in 2 N HCl/EtOH (1 mL/1 mL) was stirred at 50° C. for 3 h, cooled to room temperature, concentrated, and extracted with ethyl acetate (10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified using a silica gel column (PE/EA=3/1) to afford the title compound as a brown solid. LC/MS m/z=429.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl.Cl.N1CCNCC1>O>[Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccc1Br
Reactant: C1CNCCN1
Agent: Cl
Solvent: O
Product: Brc1cccnc1N1CCNCC1
Temperature: 190 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
Add 3-bromo-2-chloro-pyridine (10.08 g, 52.4 mmol) to piperazine (45 g) and piperazine dihydrochloride (83.4 g). Heat the mixture to 190° C. with stirring for one hr. Allow the mixture to cool to about 80° C. then pour the material into water and extract 5 times with DCM. Dry the solution (sodium sulfate), filter and concentrate. Purify using silica gel chromatography, eluting with 15:85 methanol (with 2 M ammonia): DCM to give 1-(3-bromo-pyridin-2-yl)-piperazine as a white solid (8.98 g, 71%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[OH:9].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[N:32]1[CH:37]=[C:36]([CH2:38][CH2:39][C:40]2[C:48]([C:49]3[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=3)=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][N:41]=2)[CH:35]=[N:34][CH:33]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[OH:9][C@@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:3]1[NH:2][C:44](=[O:45])[C:43]1[CH:47]=[C:48]([C:49]2[CH:50]=[CH:51][C:52]([C:55]([F:56])([F:57])[F:58])=[CH:53][CH:54]=2)[C:40]([CH2:39][CH2:38][C:36]2[CH:35]=[N:34][CH:33]=[N:32][CH:37]=2)=[N:41][CH:42]=1
Reactant: O=C(O)c1cnc(CCc2cncnc2)c(-c2ccc(C(F)(F)F)cc2)c1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(CCc2cncnc2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 44 %

Procedure:
A solution of (1R,2R)-2-amino-cyclohexanol hydrochloride (41 mg, 0.27 mmol) in N,N-dimethylformamide (1.2 ml) was added to a suspension of TBTU (234 mg, 0.73 mmol), 6-(2-pyrimidin-5-yl-ethyl)-5-(4-trifluoromethyl-phenyl)-nicotinic acid (0.24 mmol) and N-ethyldiisopropylamine (0.21 ml, 1.22 mmol) in N,N-dimethylformamide (1.7 ml). The reaction mixture was shaken at room temperature for 20 hours then concentrated in vacuo. The residue was then dissolved in dichloromethane (2 ml) and washed with water (2 ml). The aqueous layer was separated and extracted with dichloromethane (2 ml), the organics were combined and the whole was dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC to afford N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(2-pyrimidin-5-yl-ethyl)-5-(4-trifluoromethyl-phenyl)-nicotinamide, 49 mg (44% yield over 2 steps). LC at 215 nm; Rt 3.92: 92%, m/z (ES+): 471 (M+H).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[CH3:11])=[O:2].Cl.CN(C)CCCN=C=N.ON1C2C=CC=CC=2N=N1.[CH2:32]([N:34]([CH2:37][CH2:38][NH2:39])[CH2:35][CH3:36])[CH3:33]>CN(C=O)C>[CH2:32]([N:34]([CH2:35][CH3:36])[CH2:37][CH2:38][NH:39][C:8]([C:6]1[NH:7][C:3]([CH:1]=[O:2])=[C:4]([CH3:11])[CH:5]=1)=[O:10])[CH3:33]
Reactant: Cc1cc(C(=O)O)[nH]c1C=O
Reactant: CCN(CC)CCN
Agent: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Reaction time: 12 h
Yield: 78 %

Procedure:
To a solution of 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2.50 g, 16.32 mmol) in DMF (54 mL) was added 1-ethyl-3-(3-dimethylamino-propylcarbodiimide hydrochloride (EDC, 3.76 g, 19.59 mmol), 1-hydroxybenzotriazole (HOBt, 2.65 g, 19.59 mmol) followed by diethylaminoethyl amine (2.75 mL, 19.59 mmol). The reaction solution was stirred for 12 h, and then DMF solvent was removed. The residue was purified on a silica gel column eluting with 1-5% methanol in dichloromethane to provide 3.2 g (78%) of 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[N:7][O:8][C:9]=1[CH3:10])=[O:4].[OH-].[Na+]>CO>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:6]1[C:5]([C:3]([OH:4])=[O:2])=[C:9]([CH3:10])[O:8][N:7]=1
Reactant: COC(=O)c1c(-c2ccccc2Cl)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)O
Yield: 89.9 %

Procedure:
In a similar manner as described in Preparation Example 25, by using methanol (60 mL), methyl-3-(2-chlorophenyl)-5-methylisoxazol-4-carboxylate (6.0 g, 23.84 mmol) and 3% sodium hydroxide aqueous solution (60 mL), a white solid required compound (5.10 g, 21.44 mmol, 90%) was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]([NH:12][NH:13][C:14]([NH2:16])=[S:15])=O.S(=O)(=O)(O)O>>[NH2:16][C:14]1[S:15][C:10]([C:3]2[N:2]([CH3:1])[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=2)=[N:12][N:13]=1
Reactant: Cn1c([N+](=O)[O-])cnc1C(=O)NNC(N)=S
Agent: O=S(=O)(O)O
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc(N)s1

Procedure:
To 0.05 g. of 1-(1-methyl-5-nitro-2-imidazolecarbonyl)-3-thiosemicarbazide is added 0.5 ml. of conc. sulfuric acid and the mixture is heated on a steam bath for 30 minutes. Ice is added to the reaction mixture and the solid is filtered. The filtrate is made basic with sodium hydroxide and cooled in an ice bath. The solid is filtered, washed with water and dried affording 17 mg. (37%) of 2-(2-amino-1,3,4-thiaziazol-5-yl)-1-methyl-5-nitroimidazole.
Reaction SMILES: [Cl-].[CH2:2]([O:4][N:5]=[C:6]([C:45]1[N:49]=[C:48]([NH2:50])[S:47][N:46]=1)[C:7]([NH:9][CH:10]1[C:43](=[O:44])[N:12]2[C:13]([C:27]([O:29]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:28])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH3:3].C1(OC)C=CC=CC=1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[CH2:2]([O:4][N:5]=[C:6]([C:45]1[N:49]=[C:48]([NH2:50])[S:47][N:46]=1)[C:7]([NH:9][CH:10]1[C:43](=[O:44])[N:12]2[C:13]([C:27]([O-:29])=[O:28])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH3:3]
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[n+]3cccc(N(C)C)c3)CS[C@H]12)c1nsc(N)n1
Agent: [Cl-]
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3cccc(N(C)C)c3)CS[C@H]12)c1nsc(N)n1
Reaction time: 0.25 h
Yield: 39.4 %

Procedure:
A mixture of diphenylmethyl 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-dimethylamino-1-pyridiniomethyl)-3-cephem-4-carboxylate chloride (syn isomer) (0.42 g) and anisole (1 ml) in trifluoroacetic acid (3.5 ml) was stirred for 15 minutes under cooling in an ice bath. The mixture was poured into diisopropyl ether (10 ml) and a resulting precipitate was filtered. The powder was dissolved in water and subjected to column chromatography on a non ionic adsorption resin "Diaion HP 20" (10 ml). After the column was washed with water, the elution was carried out with 30% aqueous methanol. The eluates containing an object compound were collected, evaporated to remove methanol under reduced pressure and lyophilized to give 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-dimethylamino-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (0.12 g), mp 129° to 138° C. (dec.).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17](C(OCC)=O)[CH2:16][CH2:15]2)=[CH:8][CH:7]=1.[OH-].[K+]>CC(O)C>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)N1CCC(CNc2ccc(C3=NCCO3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: c1cc(C2=NCCO2)ccc1NCC1CCNCC1
Reaction time: 6 h
Yield: 49.1 %

Procedure:
A mixture of 13.3 parts of ethyl 4-[[[4-(4,5-dihydro-2-oxazolyl)phenyl]amino]methyl]-1-piperidinecarboxylate, 22.4 parts of potassium hydroxide and 240 parts of 2-propanol was stirred for 6 hours at reflux temperature. The reaction mixture was evaporated. The residue was taken up in water and the whole was evaporated again till all traces of 2-propanol were removed. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 5.1 parts (49.1%) of N-[4-(4,5-dihydro-2-oxazolyl)phenyl]-4-piperidinemethanamine as a residue (int. 77).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:21])[CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][C:18]([OH:20])=O)[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][NH:23][CH2:24][CH2:25][OH:26].C(N1CCOCC1)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CCOCC.Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([CH2:17][C:18](=[O:20])[N:23]([CH2:24][CH2:25][OH:26])[CH3:22])[CH2:15][CH2:16]1)[CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(CC[C@H]1CC[C@H](CC(=O)O)CC1)C(=O)OC(C)(C)C
Reactant: CNCCO
Agent: CCN1CCOCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Solvent: CCOCC
Product: CN(CCO)C(=O)C[C@H]1CC[C@H](CCN(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 200 mg (0.67 mmol) of trans-{4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexyl}-acetic acid and 0.065 mL (0.8 mmol, 1.2 eq) of 2-(methylamino)-ethanol were added 0.4 mL (3.3 mmol, 5 eq) of 4-ethylmorpholine and 0.31 g (0.7 mmol, 1.05 eq) of BOP at RT. The solution was stirred at RT for 3 h, diluted with ether and 1M HCl was added. The phases were separated and the organic phases were washed with water and brine and dried over magnesium sulfate. Evaporation yielded 234 mg (quantitative) of crude trans [2-(4-{[(2-hydroxy-ethyl)-methyl-carbamoyl]-methyl}-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester as colorless oil, MS: 357 (MH+).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:17]=[CH:18]/[C:19]([NH:21][NH2:22])=[O:20])[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=O)=[CH:26][CH:25]=1.O>CN(C=O)C>[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]2[O:20][C:19](/[CH:18]=[CH:17]/[C:7]3[CH:8]=[CH:9][C:10]([N:11]4[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]4)=[C:5]([O:4][CH3:3])[CH:6]=3)=[N:21][N:22]=2)=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1cc(/C=C/C(=O)NN)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(/C=C/c2nnc(Nc3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
TEA (1.25 mL) was added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid hydrazide dihydrochloride (771 mg) in DMF (15 mL) at room temperature, and the reaction solution was stirred at room temperature for 10 minutes. 4-Fluorophenyl isocyanate (0.26 mL) was added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for one hour. The reaction solution was added to cold water. The generated solid was separated by filtration, washed with water and diethyl ether and then dried at 60° C. for three hours. Phosphorus oxychloride (15 mL) was added to the resulting solid at room temperature, and the reaction solution was heated under reflux for three hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the residue. The generated solid was separated by filtration, washed with diethyl ether and then dried at 60° C. for one hour to obtain 820 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:27][CH3:28])=[O:4].[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39]Br>>[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39][O:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:17]2[CH2:16][O:15][C:11]3=[CH:12][C:13]4[CH2:14][C@@H:5]([C:3]([OH:2])=[O:4])[N:6]([C@H:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:27][CH3:28])[CH2:7][C:8]=4[CH:9]=[C:10]3[O:18]2)=[CH:20][CH:21]=1
Reactant: Clc1cccc(CBr)c1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(O)cc1)O3
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2cccc(Cl)c2)cc1)O3

Procedure:
(3S,8S)-3-(4-Hydroxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (20 mg) was reacted with 3-chloro-benzyl bromide according to General Procedure J and the resulting ester was hydrolyzed according to General Procedure AB to provide (3S,8S)-3-[4-(3-chloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (20 mg). The title compound (18 mg) was prepared from (3S,8S)-3-[4-(3-chloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (20 mg) and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride according to General Procedures L and B. LCMS (m/z): 823.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[O:6][CH2:7][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9][C:10]3([O:14][N:13]([CH3:15])[C:12]([NH2:16])=[N:11]3)[C:4]=2[CH:3]=1.[C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)#[N:26]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:16][C:12]1[N:13]([CH3:15])[O:14][C:10]2([CH2:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7][O:6][C:5]3[CH:23]=[CH:24][C:2]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[C:25]#[N:26])=[CH:3][C:4]2=3)[N:11]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN1OC2(CC(c3ccccc3)COc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1OC2(CC(c3ccccc3)COc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Yield: 24.4 %

Procedure:
Pd(PPh3)2Cl2 (3 mg, 0.003 mmol) in a 10 mL of flask under Ar2 was treated sequentially with 7-bromo-2′-methyl-3-phenyl-3,4-dihydro-2H,2′H-spiro[benzo[b]oxepine-5,5′-[1,2,4]oxadiazol]-3′-amine (77.4 mg, 0.2 mmol) in [1,4]dioxane (2.0 mL), Cs2CO3 (2 N, 1 mL) and 3-cyanophenylboronic acid (58.8 mg, 0.4 mmol) The mixture was heated under 120 at Ar2 under microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC and HPLC to give 3-(3′-amino-2′-methyl-3-phenyl-3,4-dihydro-2H,2′H-spiro[benzo[b]oxepine-5,5′-[1,2,4]oxadiazole]-7-yl)benzonitrile (20 mg, 24%). 1H-NMR (MeOD): 2.67 (m, 2H), 3.48 (m, 3H), 3.65 (m, 1H), 3.88 (m, 0.3H), 4.19 (m, 0.7H), 4.50 (d, 1H), 7.23 (m, 6H), 7.66 (m, 3H), 7.81 (m, 1H), 8.02 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][CH:30]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:24][CH:23]=[C:22]([C:25]([OH:27])=[O:26])[CH:21]=2)[CH:15]=1)=[O:8].[CH2:31](O)[CH2:32][OH:33].Cl.C(N=C=NCCCN(C)C)C.C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.CN(C=O)C.O>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][CH:30]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:24][CH:23]=[C:22]([C:25]([O:27][CH2:31][CH2:32][OH:33])=[O:26])[CH:21]=2)[CH:15]=1)=[O:8]
Reactant: OCCO
Reactant: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc(-c3cc(C(=O)O)c[nH]3)c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc(-c3cc(C(=O)OCCO)c[nH]3)c2)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid (70 mg, 0.17 mmol), ethylene glycol (1 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl, 40 mg, 0.21 mmol) and 4-dimethylaminopyridine (DMAP, 10 mg, 0.08 mmol) in anhydrous DMF (10 ml) was stirred at 70° C. for 3 hours then room temperature for 16 hours. The mixture was poured into 100 ml of water. Saturated NaHCO3 solution was added until pH=9. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with a gradient of 3˜4% MeOH/CHCl3 to give 2-hydroxyethyl 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate as white solid. Yield: 40 mg, 51%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29](=[O:35])[CH2:30][CH2:31][N:32](C)[CH3:33])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.CN>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29](=[O:35])[CH2:30][CH2:31][NH:32][CH3:33])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CN(C)CCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Agent: CN
Product: CNCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Yield: 96 %

Procedure:
The procedure of (141-2) of Example 141 was repeated except for using methylamine instead of dimethylamine to obtain the title compound (0.41 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19])([CH3:15])([CH3:14])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CC(C)(C)c1cccc(N)c1
Product: CC(C)(C)c1cccc(NC(=O)c2cc(Cl)ccc2O)c1

Procedure:
This material was prepared according to the method of Example 1 using 5-chlorosalicylic acid and 3-tert-butylaniline with reagents and solvents employed in similar molar ratios. 1HNMR (500 MHz, DMSO-d6): δ 1.28 (s, 9H), 7.00 (d, 1H), 7.18 (m, 1H), 7.24 (m, 1H), 7.46 (dd, 1H), 7.56 (m, 1H), 7.68 (m, 1H), 7.95 (d, 1H), 10.38 (s, 1H), 11.90 (br s, 1H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]#[N:8])=[O:6])[CH3:3]>>[CH2:2]([O:4][C:5]([C:7]1[N:8]=[C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[N:8]=[C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[N:8]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C#N
Agent: Cl
Product: CCOC(=O)c1nc(C(=O)OCC)nc(C(=O)OCC)n1

Procedure:
Hydrogen chloride gas was bubbled through neat ethylcyanoformate (0.997 ml, 10.1 mmol) until the solution became a white solid, approximately 2 hours. The solid was partitioned between CH2Cl2 and water. The CH2Cl2 layer was collected dried (MgSO4) and concentrated to a white solid. The product was crystallized from hot absolute ethanol to give the title compound (m. p. 169-170° C.). 1H NMR (CDCl3)δ 1.42 (t, 9H, 3x CH3), 4.50 (q, 6H, 3x CH2). 13C NMR (DMSO) δ 14.06 (CH3), 64.02 (CH2), 161.27 (CO), 166.86 (Triazine Ar).
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)(O)=[O:2].C(Cl)(=O)C(Cl)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>C(OCC)(=O)C.CN(C)C=O.C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:25]([C:1]([C:4]1[S:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)=[O:2])=[N+:26]=[N-:27]
Reactant: CC(C)(C)c1ccc(-c2ccc(C(=O)O)s2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(Cl)C(=O)Cl
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2ccc(C(=O)N=[N+]=[N-])s2)cc1
Temperature: 25 °C
Yield: 29.1 %

Procedure:
To a solution of 2-carboxy-5-(4'-(1,1-dimethylethyl)phenyl)thiophene (11.42 g, 0.0439 mol), which was prepared according to this method described in European Patent Application 0 259 972, in ethyl acetate (125 mL) was added three drops of dimethylformamide and then stirred at room temperature. To this reaction mixture 1.2 equivalents of oxalyl chloride (20 mL) was added over a period of 15 minutes. The reaction mixture was then stirred at room temperature for 11/2 hours. The ethyl acetate was then removed under reduced pressure to afford a yellow solid, a compound of formula (H). The yellow solid was dissolved in methylene chloride (70 mL) and the resulting solution was cooled. To this solution tetrabutylammonium bromide (200 mg) was added and then an aqueous solution of sodium azide (4.0 g in 15 mL H2O) was added. The reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was then washed twice with water (150 mL) and then dried over magnesium sulfate. The product was then purified by chromatography on silica gel (400 g, elute with ethyl acetate/hexane (20/80)) and then recrystallized from t-butyl methyl ether and hexane to yield 3.64 g of 2-azidocarbonyl-5-(4'-(1,1-dimethylethyl)phenyl)thiophene, m.p. 162°-164.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4](Cl)[N:3]=1.C(O)CCC.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4]([NH:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCSC3)c2n1
Reactant: NCc1ccccc1
Solvent: CC(C)O
Solvent: CCCCO
Product: Clc1nc(NCc2ccccc2)c2ncn(C3CCSC3)c2n1
Temperature: 97.5 °C

Procedure:
120 mg of the product obtained in Stage 1 above, 2 ml of butanol and 0,105 ml of benzylamine are mixed together and the reaction medium is heated to a temperature of approximately 95 to 100° C. for 10 hours. It is then left to return to ambient temperature and diluted with 5 ml of isopropanol, followed by separating, washing with 5 ml of isopropanol and drying under vacuum at approximately 30° C. In this way 132 mg of expected product is obtained in the form of white crystals.