Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]I.[CH2:3]([C:5]1[CH:14]=[C:13]([O:15]CC2C=CC(B(O)O)=CC=2)[C:12]2CC[CH2:9][CH2:8][C:7]=2[N:6]=1)[CH3:4].[OH-].[Na+]>O>[CH2:8]([C:7]1[NH:6][C:5]([CH2:3][CH3:4])=[CH:14][C:13](=[O:15])[C:12]=1[I:1])[CH3:9]
Reactant: CCc1cc(OCc2ccc(B(O)O)cc2)c2c(n1)CCCC2
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cc(=O)c(I)c(CC)[nH]1
Reaction time: 1 h
Yield: 75.7 %

Procedure:
Iodine (720 mg) was added to a solution of compound C (430 mg) and sodium hydroxide (120 mg) in water (15 ml) and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and purified by flash chromatography, eluting with methanol/dichloromethane (1:19 v/v), to give 2,6-diethyl-3-iodo-4(1H)-pyridone (D) (290 mg), m.p. 225°-227° C.; NMR (d6 -DMSO): 1.15(t,6H), 2.5(q,2H), 2.8(q,2H), 5.9(s,1H), 11.4(br s, 1H).
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[C:9]1[N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)=[O:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:24].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O.C(Cl)(Cl)Cl>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[C:9]1[N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)([OH:24])=[O:2]
Reactant: Cc1c(-n2ccnc2)n(CCCCCC=O)c2ccccc12
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1c(-n2ccnc2)n(CCCCCC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(5-Formylpentyl)-3-methyl-2-(1-imidazolyl)indole (115 mg) is dissolved in dimethylformamide (1.0 ml) and pyridinium dichromate (300 mg) added all at once. The mixture is stirred overnight at room temperature, then diluted with chloroform, and the combined filtrate is extracted with 0.1N aqueous sodium hydroxide (2 ml). The aqueous extract is acidified to about pH 5.5-6.0 and extracted with chloroform. The chloroform extract is dried and concentrated in vacuo. Purification by chromatography on silica gel yields 1-(5-carboxypentyl)-2-(1-imidazolyl)-3-methylindole.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1.O[CH2:42][C:43]1[CH:48]=[CH:47][N:46]=[C:45]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH:44]=1.C(P(CCCC)CCCC)CCC>C(Cl)Cl>[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:42][C:43]4[CH:48]=[CH:47][N:46]=[C:45]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH:44]=4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: CCOC(=O)c1cc(CO)ccn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)c1cc(COc2cc3ncnc(Nc4ccc(Cl)cc4F)c3cc2OC)ccn1
Temperature: 25 °C
Yield: 59 %

Procedure:
1,1'-(azodicarbonyl)dipiperidine (840 mg, 3 mmol) was added in portions to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (315 mg, 1 mmol), ethyl 4-hydroxymethyl-2-pyridinecarboxylate (250 mg, 1.4 mmol), (J. Het. Chem. 1993, 30, 631-635) and tributylphosphine (800 μl, 3 mmol) in methylene chloride (50 ml) at 0° C. The mixture was allowed to warm to ambient temperature over 2 hours, the insolubles were removed by filtration and the filtrate was washed with water and brine, dried (Na2SO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (10:0 increasing to 9:1). The purified product was recrystallised from methylene chloride/hexane to give 4-(4-chloro-2-fluoroanilino)-7-(2-ethoxycarbonylpyrid-4-yl)methoxy-6-methoxyquinazoline (285 mg, 60%). m.p. 212-214° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:3].[CH:21]1([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:23][CH2:22]1>>[CH:14]1([CH2:13][C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:28]3[CH2:29][CH2:30][N:25]([CH2:24][CH:21]4[CH2:23][CH2:22]4)[CH2:26][CH2:27]3)=[O:3])=[CH:6][CH:7]=2)=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(CC1CCCCC1)Nc1ccc(OC(=O)Cl)cc1
Reactant: C1CN(CC2CC2)CCN1
Product: O=C(CC1CCCCC1)Nc1ccc(OC(=O)N2CCN(CC3CC3)CC2)cc1

Procedure:
The title compound was prepared from 4-(2-cyclohexyl-acetylamino)-phenyl chloroformate and 1-cyclopropylmethyl-piperazine, preparative HPLC (methode C (60%, off-white crystals). HPLC-MS m/z=400.3 (M+1), Rt: 2.42 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.Br[CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)([CH3:16])[CH3:15]
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OC(C)C)cc1
Yield: 79.8 %

Procedure:
Methyl 2-(4-hydroxyphenyl)acetate (10 g, 60.2 mmol), 2-bromopropane (6.49 mL, 69.2 mmol), and potassium carbonate (8.32 g, 60.2 mmol) were heated to 50° C. in DMF (100 mL) for overnight. The reaction was filtered and the organic layer was concentrated under vacuum. The crude material was purified by silica gel chromatography using a gradient of 0-20% EtOAc/hexanes. The product fractions were collected and the solvent removed under vacuum to give methyl 2-(4-isopropoxyphenyl)acetate (10 g, 80% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22-7.14 (m, 2H), 6.88-6.82 (m, 2H), 4.53 (spt, J=6.1 Hz, 1H), 3.70 (s, 3H), 3.57 (s, 2H), 1.34 (d, J=6.0 Hz, 6H).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[O:9]([C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](=O)[CH3:23])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O.C(O)C>[O:9]([C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](=[N:2][OH:3])[CH3:23])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NO
Reactant: CC(=O)COc1ccc(Oc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(COc1ccc(Oc2ccccc2)cc1)=NO
Reaction time: 1 h

Procedure:
Over about 1 hour, a solution of 22 g of hydroxylamine hydrochloride and 26 g of anhydrous sodium acetate in 110 ml of water is added dropwise at room temperature to a solution of 64 g of 4-phenoxyphenoxyacetone in 260 ml of ethanol. After the slightly exothermic reaction has subsided, the mixture is stirred for a further 3.5 hours at reflux temperature. Subsequently, the ethanol is distilled off from the reaction mixture by rotary evaporation, the aqueous residue is extracted three times with a 2:1 mixture of ether and hexane, the combined organic phases are washed with water and with 10% sodium bicarbonate solution and then dried over sodium sulfate. The solvent is then distilled off. Recrystallisation from a mixture of diethyl ether and pentane affords 4-phenoxyphenoxyacetone oxime with a melting point of 59°-61° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[CH3:17][C:7]1[C:6]2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=[C:2]([C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]=12
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Reactant: OB(O)c1cccnc1
Product: Cc1c2n(c3c(-c4cccnc4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, off-white solid (42 mg, 53%), MS (ISP) m/z=317.6 [(M+H)+], mp 260° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available pyridin-3-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Cl)=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:24])[C:12]1(C#N)[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH2:14][CH2:13]1.[Cl-].[NH4+]>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:18]2[CH2:17][O:16][C:15]3([CH2:20][CH2:21][CH:12]([N:11]([CH3:24])[CH3:10])[CH2:13][CH2:14]3)[O:19]2)=[CH:4][CH:3]=1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reactant: Cl[Mg]c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C1CCC2(CC1)OCC(c1ccc(Cl)cc1)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Starting with 38 ml 1.0 molar 4-chlorophenyl magnesium chloride solution in diethylether, 4.00 g 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile, dissolved in 60 ml diethylether, were added dropwise and stirred overnight at ambient temperature. To work up the mixture, 30 ml ammonium chloride solution (20% by weight) were added with ice cooling, the phases were separated, the ethereal phase was washed in succession with 30 ml water and saturated sodium chloride solution, dried over sodium sulfate, filtered, concentrated and substantially freed of solvent residues under vacuum. The crude [-(4-chlorophenyl)-1,4-dioxaspiro[4.5]dec-8-yl]dimethylamine (4.18 g) obtained was initially stirred for 24 hours with a mixture of 10 ml concentrated hydrochloric acid (32% by weight) and 6.0 ml water at ambient temperature without further purification and then heated for 3 hours to reflux. Subsequently, the reaction mixture was first washed three times with 50 ml diethylether in each case, then made basic by addition of concentrated ammonia solution (25% by weight) with ice cooling, extracted three times with 100 ml diethylether in each case, the combined diethylether extracts were dried over sodium sulfate, filtered, concentrated and substantially freed of solvent residues under vacuum. 3.84 g 4-(4-chlorophenyl)-4-dimethylaminocyclohexanone were obtained as a brown oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][CH2:5][C:6]([OH:27])([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[N:8]=1.CCN(CC)CC.[N:35]([CH2:38][C:39](Cl)=[O:40])=[N+:36]=[N-:37]>C(Cl)Cl>[N:35]([CH:38]1[C:39](=[O:40])[N:8]2[CH:7]([C:9]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)=[O:10])[C:6]([OH:27])([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH2:5][S:4][C@:3]12[S:2][CH3:1])=[N+:36]=[N-:37]
Reactant: CSC1=NC(C(=O)OCc2ccc([N+](=O)[O-])cc2)C(O)(COC(C)=O)CS1
Reactant: [N-]=[N+]=NCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS[C@]12SCC(O)(COC(C)=O)C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2N=[N+]=[N-]
Temperature: 25 °C
Yield: 54.1 %

Procedure:
A solution of crude p-nitrobenzyl 2-methylthio-5-hydroxy-5-acetoxymethyl-5,6-dihydro-4H-1,3-thiazine-4-carboxylate (6.31 g., 15.23 mMol) in andydrous CH2Cl2 (75 ml.) is cooled to -78° C. under a N2 atmosphere. Et3N (2.97 ml., 21.3 mMol) is added to the stirring solution followed by dropwise addition of a solution of azidoacetyl chloride (1.85 ml., 21.2 mMol) in CH2Cl2 (20 ml.). The resulting solution is allowed to warm slowly to room temperature. The solution is washed with H2O (3x) and brine, dried with MgSO4, filtered, and concentrated in vacuo to a dark, reddish-brown, viscous oil (7.3 g.). This material is purified by chromatography on silica gel (140 g.). Elution of the column with 10% EtOAc/Oh provides p-nitrobenzyl 7-azido-6-methylthio-3-hydroxy-3-acetoxymethyl-cepham-4-carboxylate (4.10 g.) as a dark oil: ir (CHCl3) 2.91, 4.72, 5.58, 5.73, 6.20, 6.55, and 7.39μ; nmr (CDCl3)δ 2.13 (s, 3, COCH3), 2.23 (s, 3, SCH3), 2.83, 3.63 (ABq, 2, J=14Hz, SCH2), 4.17 (s, 1, OH), 4.30, 4.57 (ABq, 2, J=12Hz, CH2OAc), 4.87 (s, 2, H4 and H7), 5.37 (s, 2, CH2Ar), and 7.60, 8.25 (ABq, 4, J=9Hz, ArH); mass spectrum m/e 497 (M+), 469, 454, 422, 414, 368, 354, 341, 311, 299, 278, 261, and 136.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][NH2:26]>>[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][NH:26][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NCc1nccs1
Product: CCc1cc(-c2cncc(C(=O)NCc3nccs3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and (thiazol-2-ylmethyl)-amine to afford the title compound. MS: m/e=355 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@:13]([CH2:15][CH2:16]3)([CH3:14])[CH:12]=[CH:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.C12BC(CCC1)CCC2.[OH-:30].[Na+].OO>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@:13]([CH2:15][CH2:16]3)([CH3:14])[CH2:12][C@H:11]([OH:30])[CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@@]2(C)C=CC[C@@H]12
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@@]2(C)C[C@H](O)C[C@@H]12
Temperature: 25 °C

Procedure:
0.81 g (3 mmol) of 3-methoxy-13α-estra-1,3,5(10),16-tetraene is dissolved under a cover gas in 10 ml of anhydrous tetrahydrofuran and mixed with 0.73 g of 9-bora-bicyclo[3.3.1]nonane. It is stirred at room temperature until the reaction is completed. Then, it is mixed with 15 ml of water. After gas generation is completed, 7.8 ml of 3 M sodium hydroxide solution is added. 7.8 ml of hydrogen peroxide solution (30%) is then slowly added in drops to the reaction mixture while being cooled. It is stirred for 1 hour at room temperature and extracted with ethyl acetate. The chromatography of the crude product on silica gel (eluant: cyclohexane/ethyl acetate 4+1) yields 604 mg of 3-methoxy-13α-estra-1,3,5(10)-trien-16α-ol in the form of a colorless oil.
Reaction SMILES: [Br:1]Br.[CH2:3]([NH:5][C:6]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)[CH:9]=[C:8]([Cl:16])[N:7]=1)[CH3:4].O.N>C(Cl)Cl>[CH2:3]([NH:5][C:6]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:14][CH2:15]2)[C:9]([Br:1])=[C:8]([Cl:16])[N:7]=1)[CH3:4]
Reactant: CCNc1nc(Cl)cc(NC2CC2)n1
Reactant: BrBr
Agent: N
Solvent: ClCCl
Solvent: O
Product: CCNc1nc(Cl)c(Br)c(NC2CC2)n1
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A solution of 6.4 g of bromine (0.04 mol) in 30 ml of methylene chloride is added dropwise over the course of one hour to a solution of 8.5 g (0.04 mol) of 2-ethylamino-4-cyclopropylamino-6-chloropyrimidine in 300 ml of methylene chloride, whilst cooling with ice. The solution is left to stand overnight at room temperature, 150 ml of water are then added and the mixture is brought to pH 9-10 with dilute ammonia solution. The organic phase is separated off, rinsed with water, dried over magnesium sulphate, filtered and evaporated. The evaporation residue (12 g), when recrystallised from methanol-water (1:1), gives 10.4 g of colourless crystals of melting point 100°-101°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[NH:21][S:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)(=[O:24])=[O:23])[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+].O1CCCC1>CO>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[NH:21][S:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)(=[O:24])=[O:23])[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)sc1C(=O)O
Temperature: 60 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
A mixture of ethyl 4-methyl-2-{7-[(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazole-5-carboxylate (0.42 g), 8N aqueous sodium hydroxide solution (0.4 mL), tetrahydrofuran (6 mL) and methanol (6 mL) was stirred at 60° C. for 1 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were dissolved in tetrahydrofuran, treated with activated carbon, and concentrated to give the title compound (0.17 g, yield 44%) as yellow crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point>253° C. (decomposition).
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][S:13][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[Cl:14][CH2:15][C:16](Cl)=[O:17].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[C:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[C:12]([C:16](=[O:17])[CH2:15][Cl:14])[S:13][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCc2ccsc2C1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCCc2cc(C(=O)CCl)sc2C1
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of 2 g of 7-acetyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine and 1.7 g of chloroacetyl chloride in 25 ml of dichloromethane was added 4.8 g of aluminum chloride under ice-cooling. The mixture was stirred for 30 minutes and refluxed under heating for an hour. The mixture was poured into water and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated to give 2.2 g of 7-acetyl-2-chloroacetyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine as an oil.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[C:9]1=[O:18].[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[S:19]1[CH:23]=[CH:22][C:21]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[C:9]2=[O:18])=[CH:20]1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: OB(O)c1ccsc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C(=O)N(c2ccsc2)c2ccccc21
Reaction time: 8 h
Yield: 4.7 %

Procedure:
Triethylamine (56.9 mL, 0.408 mol), was added to a mixture of 1H-indole-2,3-dione (15.0 g, 0.102 mol), copper (II) acetate (46.0 g, 0.255 mol), and 3-thienylboronic acid (19.6 g, 0.153 mol) in CH2Cl2 (500 mL). The reaction mixture was stirred overnight, filtered through Celite®, rinsed with EtOAc/hexane (1:1, 300 mL), and concentrated in vacuo. The crude product was purified by column chromatography on silica using Hexane/EtOAc (1:1), giving the desired product (1.1 g, 50%).
Reaction SMILES: N([O-])=O.[Na+].S(=O)(=O)(O)O.[I:10][C:11]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([I:21])[C:12]=1N>C(O)(=O)C.C(O)C>[I:10][C:11]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([I:21])[CH:12]=1
Reactant: Nc1c(I)cc([N+](=O)[O-])cc1I
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=[N+]([O-])c1cc(I)cc(I)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
13.8 G (0.2M) of solid sodium nitrite were slowly added to stirred concentrated sulfuric acid at 0° C. The resulting thick mixture was stirred at 0° C. for 10 mins. A suspension of 68.28 G (0.175M) of finely powdered 2,6-diiodo-4-nitroaniline in 175 mL of glacial acetic acid was added portionwise cautiously to the above mixture at 0° C. over a period of 25 minutes. This mixture was then stirred 30 mins, and then added to a vigorously stirred suspension of 4 G of cuprous oxide in 420 mL of absolute ethanol over a period of 25 minutes. Vigorous effervescence was observed during this addition. The resulting mixture was stirred 20 mins. at room temperature and then heated to reflux for 30 mins. After cooling, this reaction mixture was poured into large amount of ice. Solid separated was filtered, and washed with water. This solid was dissolved in minimum amount of chloroform, and dried over anhydrous magnesium sulfate. Solvent removal gave 62 G of 3,5-diiodo-nitrobenzene as light yellow solid.
Reaction SMILES: [N:1]1([C:5]2[C:10]3=[C:11]([C:15]4[CH:16]=[N:17][N:18]([CH3:21])[C:19]=4Br)[N:12]=[C:13]([CH3:14])[N:9]3[N:8]=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([CH3:33])[CH:25]=1.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=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.O>[N:1]1([C:5]2[C:10]3=[C:11]([C:15]4[CH:16]=[N:17][N:18]([CH3:21])[C:19]=4[C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][C:26]=4[CH3:33])[N:12]=[C:13]([CH3:14])[N:9]3[N:8]=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(B(O)O)c(C)c1
Reactant: Cc1nc(-c2cnn(C)c2Br)c2c(N3CCC3)ncnn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(-c3nc(C)n4ncnc(N5CCC5)c34)cnn2C)c(C)c1
Temperature: 150 °C

Procedure:
4-(Azetidin-1-yl)-5-(5-bromo-1-methyl-1H-pyrazol-4-yl)-7-methylimidazo[5,1-f][1,2,4]triazine (200 mg, 0.574 mmol) was combined with (4-methoxy-2-methylphenyl)boronic acid (180 mg, 1.08 mmol), potassium phosphate dihydrate (98%, 571 mg, 2.25 mmol), tetrakis(triphenylphosphine)palladium(0) (99.9%, 65.9 mg, 0.057 mmol) and N,N-dimethylformamide (12 mL) and heated in a microwave reactor at 150° C. for 60 minutes. This reaction mixture was combined with crude reaction products from three other identical reactions, and poured into water. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with water, then with saturated aqueous sodium chloride solution. After drying over sodium sulfate, the organic extracts were filtered and concentrated in vacuo. Purification via silica gel chromatography (Eluants: heptane/ethyl acetate/methanol mixtures, 90:15:10 followed by 60:30:10, 45:55:10, 30:70:10 ratios) provided the product as a solid. Combined yield: 508 mg, 1.30 mmol, 56%. LCMS m/z 390.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.08 (s, 3H), 2.26-2.35 (m, 2H), 2.60 (s, 3H), 3.69 (s, 3H), 3.79 (s, 3H), 3.8-4.2 (v br m, 4H), 6.72-6.76 (m, 2H), 7.17-7.24 (br m, 1H), 7.67 (s, 1H), 7.78 (s, 1H).
Reaction SMILES: [CH:1]12[CH2:7][CH:6]1[CH2:5][CH2:4][CH:3]([CH:8]=O)[CH2:2]2.[NH2:10][OH:11]>>[CH:1]12[CH2:7][CH:6]1[CH2:5][CH2:4][CH:3]([CH:8]=[N:10][OH:11])[CH2:2]2
Reactant: O=CC1CCC2CC2C1
Reactant: NO
Product: ON=CC1CCC2CC2C1

Procedure:
Bicyclo[4.1.0]heptane-3-carbaldehyde oxime (I-12D) was prepared by reaction of bicyclo[4.1.0]heptane-3-carbaldehyde and hydroxylamine following the same procol as described for I-6c. MS m/z 140.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([O:24][CH2:25][CH3:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]=[C:37]=[O:38].C(N(CC)C(C)C)(C)C.Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:27])[CH:4]([O:24][CH2:25][CH3:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:37]([NH:36][C:30]3[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=3[F:28])=[O:38])[CH2:13][CH2:14]2)=[CH:8][CH:7]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCCCCCCNCC1(c2ccc(CC(OCC)C(=O)OC)cc2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCCCCCCN(CC1(c2ccc(CC(OCC)C(=O)OC)cc2)CC1)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-ethoxy-3-[4-(1-heptylaminomethyl-cyclopropyl)-phenyl]-propionic acid methyl ester (54 mg, 0.13 mmol), and 2,4-difluorophenylisocyanate (0.156 mmol, 0.0185 mL) in toluene (2.5 mL) was added N,N-diisopropylethylamine (0.29 mmol, 0.050 mL). The mixture was allowed to stir at room temperature for 18 hours, then was poured over 1 M HCl (5 mL). The aqueous layer was isolated and extracted with diethyl ether (2×). The organic layers were combined, washed with 2 M HCl (1×), brine (1×), dried over anhydrous sodium sulfate, and concentrated to give a clear film. The crude product was chromatographed on silica (Merck silica gel 60, art#9385-3) eluting with 20% ethyl acetate/hexanes to give 3-(4-{1-[3-(2,4-difluoro-phenyl)-1-heptyl-ureidomethyl]-cyclopropyl}-phenyl)-2-ethoxy-propionic acid methyl ester as a clear film (50 mg, 73%).