Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC([N:5]1[CH:14]=[C:13]2[C:7]([CH:8]([O:27][C:28](=O)C)[N:9]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:11]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:12]=32)=[CH:6]1)=O.[OH-].[Na+]>O1CCCC1.CO.O>[Cl:19][C:17]1[CH:16]=[CH:15][C:12]2[C:13]3[C:7](=[CH:6][NH:5][CH:14]=3)[CH:8]([O:27][CH3:28])[N:9]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:11]=2[CH:18]=1
Reactant: COC(=O)n1cc2c(c1)C(OC(C)=O)N=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC1N=C(c2ccccc2Cl)c2cc(Cl)ccc2-c2c[nH]cc21
Reaction time: 0.5 h

Procedure:
A mixture of 1.0 g (2.2 mmol) of 4-(acetyloxy)-8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-carboxylic acid methyl ester and 2.5 ml of 3 N aqueous sodium hydroxide solution in a mixture of 25 ml of tetrahydrofuran and 10 ml of methanol was stirred at 0° for 30 min. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was triturated with a mixture of ether and methylene chloride to give a cream colored solid, mp 215°-218°. Recrystallization from a mixture of tetrahydrofuran and hexane gave tan prisms, mp 221°-224°.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:19][C:20]1[CH:21]=[C:22]([C@@:27]2([CH2:33][CH2:34][OH:35])[O:32][CH2:31][CH2:30][NH:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26]>C(#N)C>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([N:29]2[CH2:30][CH2:31][O:32][C@:27]([CH2:33][CH2:34][OH:35])([C:22]3[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=3)[CH2:28]2)=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OCC[C@@]1(c2ccc(Cl)c(Cl)c2)CNCCO1
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CC#N
Product: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCO[C@](CCO)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To a solution of 3,5-bis(trifluoromethyl)phenylacetic acid (10.0 g, 36.8 mmol) in acetonitrile (100 ml), N,N′-carbonyldiimidazole (9.5 g, 58.8 mmol) was added at room temperature, then (2R)-2-[2-(3,4-dichlorophenyl)morpholin-2-yl]ethanol (17.3 g, 62.5 mol) was further added, and the resulting mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was evaporated to dryness. To the obtained residue, methylene chloride (100 ml), water (100 ml) and concentrated hydrochloric acid (15 ml) were added, and the resulting mixture was partitioned. The separated organic layer was washed with water twice (100 ml each) and evaporated to dryness. The residue obtained was purified by chromatography on a silica gel column to afford the title compound [13.3 g, yield: 68.1%] as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:36]=[CH:35][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26](=[O:34])[N:27]([CH2:31][CH2:32][OH:33])[CH:28]([CH3:30])[CH3:29])[N:19]=4)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:37]>[Pd]>[ClH:37].[OH:33][CH2:32][CH2:31][N:27]([CH:28]([CH3:30])[CH3:29])[C:26]([C:20]1[N:19]=[C:18]2[N:22]([CH2:23][CH2:24][O:25][C:16]3[CH:15]=[C:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:36]=[CH:35][C:17]=32)[CH:21]=1)=[O:34]
Reactant: CC(C)N(CCO)C(=O)c1cn2c(n1)-c1ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Agent: [Pd]
Agent: Cl
Product: CC(C)N(CCO)C(=O)c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Temperature: 50 °C
Reaction time: 4.5 h
Yield: 110 %

Procedure:
To a solution of 4-{2-[(2-hydroxy-ethyl)-isopropyl-carbamoyl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (112 mg, 0.23 mmol) in IMS (3 mL) was added hydrochloric acid (2 mL, 2M, 4.0 mmol) and palladium on carbon (20 mg, 10% by wt) added. The reaction mixture was stirred under an atmosphere of hydrogen at 50° C. for 4.5 h. The reaction mixture was filtered and the solids washed with IMS (10 mL). The filtrate was concentrated in vacuo and azeotroped with acetonitrile to yield 8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide hydrochloride as a thick oil (110 mg). LCMS: RT=0.32 min, [M+H]+=399
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=1)=[O:9].B(Br)(Br)Br>C(Cl)(Cl)Cl.ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)=[O:9]
Reactant: COc1ccc(C(=O)c2ccccc2C)cc1
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1ccccc1C(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
4-Methoxyphenyl 2-methylphenyl ketone (1.660 g) obtained in Example 125 was dissolved in chloroform (10 ml), a solution of 1.0 M boron tribromide in dichloromethane (29 ml) was added while cooled in ice, and the admixture was stirred at room temperature overnight. A solution of 1.0 M boron tribromide in dichloromethane (15 ml) was further added, and the admixture was stirred at room temperature for 2 days. The reaction mixture was then treated in the same manner as described in Example 121 to obtain 1.501 g of the title compound (yield: 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:21][CH:22]3[CH2:39][CH:38]4[N:24]([C:25](=[O:45])[N:26]([CH3:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]5[C:35]([C:41](O)=[O:42])([NH:36][C:37]4=[O:40])[CH2:34]5)[CH2:23]3)=[N:8][C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=3)=[N:10]2)=[CH:5][CH:4]=1.[CH:46]1([S:49]([NH2:52])(=[O:51])=[O:50])[CH2:48][CH2:47]1>>[CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:21][CH:22]3[CH2:39][CH:38]4[N:24]([C:25](=[O:45])[N:26]([CH3:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]5[C:35]([C:41]([NH:52][S:49]([CH:46]6[CH2:48][CH2:47]6)(=[O:51])=[O:50])=[O:42])([NH:36][C:37]4=[O:40])[CH2:34]5)[CH2:23]3)=[N:8][C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3cccc(C)n3)nc2c1C
Reactant: NS(=O)(=O)C1CC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3cccc(C)n3)nc2c1C
Yield: 22.6 %

Procedure:
Compound 118 (50 mg, 0.08 mmol) was reacted with cyclopropanesulfonic acid amide (44 mg, 0.36 mmol) according to the procedure described in Example 53 which gave the title compound (13 mg, 22%). MS (M−H)+ 718.2
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:12]([O:11][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Temperature: 90 °C

Procedure:
157 g (1.00 mol) of 3-fluoro-6-nitrophenol are initially taken in 500 ml of acetonitrile in a three-necked flask (KPG stirrer, reflux condenser, inert gas connection), and 174 g (1.02 mol) of benzyl bromide and 345 g (2.50 mol) of potassium carbonate are added in this sequence under inert gas. The mixture is refluxed for 3 hours at 90° C. After cooling to room temperature, the mixture is filtered with suction and the remaining solid is rinsed twice with 100 ml of acetonitrile each time. The solution is evaporated down until it crystallizes, and the crude product is filtered off with suction. The crude product is dissolved at room temperature in ethyl acetate (1 ml/g of crude product) and precipitated with hexane (3.6 ml/g of crude product). The mixture is stored overnight at T<−10° C. for complete crystallization.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]([O:12][C:13]([CH3:15])=[CH2:14])=[O:11].C([O-])(O)=O.[Na+]>CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:11])[O:12][C:13]([CH3:15])=[CH2:14])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: C=C(C)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)OC(=O)Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.5 %

Procedure:
To a biphasic solution of 3-fluoroaniline (0.3 mL, 3.12 mmol) in 1:1 EtOAc/water (10 mL) was added isopropenyl chloroformate (0.564 g, 4.68 mmol) and NaHCO3 (1.31 g, 15.6 mmol) and the mixture stirred at RT overnight. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were concentrated to dryness and purified by silica gel chromatography (EtOAc/Hex) to furnish prop-1-en-2-yl 3-fluorophenylcarbamate (125 mg, 21% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.14 (s, 1H), 7.35 (m, 1H), 7.31 (m, 1H), 7.21 (m, 1H), 6.83 (m, 1H), 4.74 (m, 2H), 1.92 (s, 3H).
Reaction SMILES: C[O:2][C:3](F)([F:10])[C:4]([F:9])([F:8])[C:5]([F:7])=[O:6].S(=O)(=O)=O>>[F:8][C:4]([F:9])([C:5]([F:7])=[O:6])[C:3]([F:10])=[O:2]
Reactant: COC(F)(F)C(F)(F)C(=O)F
Agent: O=S(=O)=O
Product: O=C(F)C(F)(F)C(=O)F

Procedure:
3-Methoxytetrafluoropropionyl fluoride (F. S. Fawcett, C. W. Tullock and D. D. Coffman, J. Amer. Chem. Soc., 84, 4275 (1962)) (81 g, 0.45 mol) was slowly added to sulfur trioxide (80 g, 1.0 mol) at 40° C., and the product difluoromalonyl difluoride, bp-9° C., was continuously removed by distillation through a low temperature still, yield 58 g (0.40 mol, 90%). The product structure was confirmed by: λmax 1860 cm-1 (COF), 19F NMR (no solvent), +17.1 ppm (t J=10 Hz) 2F, COF and -114.2 ppm (t J=10 Hz) 2F, CF2.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][S:8]([C:11]1[N:12]=[C:13]([O:27][CH2:28][CH2:29][CH3:30])[C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[O:17][C:15]=2[N:16]=1)(=O)=O.SC1[S:33][CH:34]=[CH:35][N:36]=1>CN(C=O)C>[CH2:28]([O:27][C:13]1[C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[O:17][C:15]=2[N:16]=[C:11]([S:8][C:7]2[S:33][CH:34]=[CH:35][N:36]=2)[N:12]=1)[CH2:29][CH3:30]
Reactant: CCCOc1nc(S(C)(=O)=O)nc2oc(-c3cccc(C)c3)nc12
Reactant: Sc1nccs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCOc1nc(Sc2nccs2)nc2oc(-c3cccc(C)c3)nc12
Temperature: 100 °C
Yield: 12.6 %

Procedure:
113 mg of cesium carbonate and 100 mg of 5-methanesulfonyl-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine were added to a solution of 34 mg of 2-mercaptothiazole in 3 ml of DMF. The mixture was heated to 100° C. in a microwave reactor for 15 min. After cooling and filtration, the solvent was distilled off in vacuo, and the product was isolated via preparative HPLC to yield 14 mg of the title compound.
Reaction SMILES: [OH-].[Na+].[N:3]1[CH:8]=[C:7]([C:9]([NH:11][C:12]2([C:15]([O:17]CC)=[O:16])[CH2:14][CH2:13]2)=[O:10])[CH:6]=[N:5][CH:4]=1.C(O)(=O)C>CO>[N:3]1[CH:8]=[C:7]([C:9]([NH:11][C:12]2([C:15]([OH:17])=[O:16])[CH2:13][CH2:14]2)=[O:10])[CH:6]=[N:5][CH:4]=1
Reactant: CCOC(=O)C1(NC(=O)c2cncnc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NC1(C(=O)O)CC1)c1cncnc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
65 mL of a 2N sodium hydroxide solution were added to a solution of 11.0 g (46.76 mmol) of ethyl 1-[(pyrimidine-5-carbonyl)amino]-cyclopropanecarboxylate in 200 mL methanol and the mixture was stirred for one hour at 50° C. Then it was neutralised with concentrated acetic acid and evaporated to dryness in vacuo. The crude product thus obtained was purified by chromatography.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][NH:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][N:35]([CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[C:1](=[O:5])[CH2:2][OH:3])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: O=C(O)CO
Reactant: Clc1cc(Nc2ncnc3cccc(OCCNC4CCOCC4)c23)ccc1OCc1ccccn1
Product: O=C(CO)N(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C1CCOCC1
Yield: 12 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(tetrahydro-2H-pyran-4-ylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 20, preparation of starting materials) to give the title compound in 12% yield; NMR spectrum (DMSO-d6) 1.53-1.69 (m, 2H), 1.77-2.07 (m, 2H), 3.34-3.42 (m, 2H), 3.73-3.92 (m, 5H), 4.14-4.25 (m, 2H), 4.31-4.54 (m, 3H), 5.31 (s, 2H), 7.21-7.29 (m, 2H), 7.32-7.40 (m, 2H), 7.57-7.63 (m, 2H), 7.70-7.76 (m, 1H), 7.86-7.91 (m, 1H), 8.03 (s, 1H), 8.47 (s, 1H), 8.61 (d, 1H), 9.99 (s, 1H); Mass spectrum MH+ 564.
Reaction SMILES: [Cl:1][C:2](=[N:7][OH:8])[C:3]([Cl:6])=[N:4][OH:5].[C:9](Cl)(=[O:11])[CH3:10].C(N(CC)CC)C>ClC(Cl)C>[C:9]([OH:11])(=[O:5])[CH3:10].[C:9]([OH:11])(=[O:5])[CH3:10].[Cl:1][C:2](=[N:7][OH:8])[C:3]([Cl:6])=[N:4][OH:5]
Reactant: CC(=O)Cl
Agent: ON=C(Cl)C(Cl)=NO
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)O

Procedure:
The mixture of 2.0 g (0.0127 mol) of dichloroglyoxime (Compound No.6), 20 ml of dichloroethane and 2.4 g (0.0306 mol) of acetyl chloride was stirred in an ice bath. To the mixture, triethylamine (3.1 g, 0.0307 mol) was added dropwise, followed by stirring for 30 minutes. The reaction mixture was washed twice with 15 ml of water. The dichloroethane solution was concentrated under reduced pressure, to obtain white crystals of dichloroglyoxime diacetate (Compound No.2, yield: 30%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1OS(C(F)(F)F)(=O)=O)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:4][C:1]([C:5]1[CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:12]=[CH:13][C:14]=1[C:30]1[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:29]=1[F:28])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C(C)(C)C)c1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C(C)(C)C)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 926.5 %

Procedure:
To a stirred solution of 8.7 (0.100 g, 0.29 mmol) in DMF (2.00 mL, 26 mmol) at 23° C., was added 2-fluoro-5-methoxyphenylboronic acid (available from Aldrich) (0.100 g, 0.59 mmol), potassium carbonate (0.12 g, 0.88 mmol), followed by tetrakis(triphenylphosphine)palladium (0.034 g, 0.029 mmol). The mixture was heated to 100° C. After 2 hours, the reaction was cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (3×50 mL) and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-15% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to provide 8.8 as a colorless oil (0.85 g, 71%). MS ESI (pos.) m/e: 317.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:8]=[CH:9][C:10]2[NH:16][C:15]3[N:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:14]=3[CH2:13][N:12]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:11]=2[CH:39]=1)([CH3:6])[C:3]([OH:5])=O.[CH3:40][NH:41][CH3:42]>>[CH3:40][N:41]([CH3:42])[C:3](=[O:5])[C:2]([CH3:6])([C:7]1[CH:8]=[CH:9][C:10]2[NH:16][C:15]3[N:17]=[C:18]([C:21]([F:23])([F:22])[F:24])[CH:19]=[CH:20][C:14]=3[CH2:13][N:12]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]([F:36])([F:37])[F:38])=[CH:32][CH:33]=3)(=[O:27])=[O:26])[C:11]=2[CH:39]=1)[CH3:1]
Reactant: CC(C)(C(=O)O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2
Reactant: CNC
Product: CN(C)C(=O)C(C)(C)c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2

Procedure:
The title compound was prepared from 2-methyl-2-[6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]propanoic acid (Example 382) and dimethylamine using the procedure described in Example 516 to afford the title compound; Mass Spectrum: m/e=603 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][N:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[N+:18]([O-])=O.S.[Na]>C(O)(=O)C.O>[CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][N:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[NH2:18]
Reactant: CC(C)CNc1c([N+](=O)[O-])c2nnnn2c2cnccc12
Agent: S
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)CNc1c(N)c2nnnn2c2cnccc12
Yield: 90.8 %

Procedure:
N5-(2-Methylpropyl)-4-nitrotetrazolo[1,5-a][1,7]naphthyridin-5-amine (1.5 g, 5.22 mmol) was suspended in acetic acid (75 mL). An excess of sodium hydrogen sulfide was dissolved in a minimum of water and added to the suspension. The reaction mixture turned red and all of the material went into solution. The reaction mixture was extracted twice with dichloromethane (150 mL). The extracts were combined, washed with water, dried over magnesium sulfate, filtered and concentrated under vacuum to provide 1.22 g of N5-(2-methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-4,5-diamine as a light yellow solid, m.p. 203-204.5° C. Analysis: Calculated for: C12H15N7: %C, 56.02; %H, 5.88; ON, 38.11; Found: %C, 55.68; %H, 5.81; %N, 37.74.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@@H:4]([N:12]1[CH2:16][C:15]2=[CH:17][C:18]3[C:19]([O:25][CH3:26])=[CH:20][CH:21]=[CH:22][C:23]=3[O:24][CH:14]2[C:13]1=[O:27])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.O.[OH-].[Li+]>O1CCCC1.O>[CH3:26][O:25][C:19]1[C:18]2[CH2:17][C:15]3[CH2:16][N:12]([C@@H:4]([CH2:5][CH:6]4[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]4)[C:3]([OH:28])=[O:2])[C:13](=[O:27])[C:14]=3[O:24][C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC2=Cc3c(OC)cccc3OC2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Yield: 94.6 %

Procedure:
A solution of (S)-2-(8-methoxy-3-oxo-3,3a-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid methyl ester (1.2 g, 3.13 mmol) and lithium hydroxide monohydrate (0.17 g, 4.04 mmol) was stirred at 25° C. for 2 hours in tetrahydrofuran-water (3:1) mixture (20 mL). The reaction mixture was concentrated in vacuo to remove tetrahydrofuran, and the residue was acidified with 2N hydrochloric acid, and diluted with water. The resulting solution was extracted with ethyl acetate (3×). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford (S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (1.1 g, 95.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)=[CH:12][N:11]=[C:10]([Cl:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:23](Cl)(=[O:26])[CH:24]=[CH2:25].C(N(CC)CC)C>>[Cl:22][C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:23](=[O:26])[CH:24]=[CH2:25])[CH:7]=[CH:6][CH:5]=2)[C:13]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[CH:12][N:11]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1cccc(-c2nc(Cl)ncc2Nc2cccc(F)c2)c1
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1cccc(-c2nc(Cl)ncc2Nc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 18.4 %

Procedure:
4-(3-Aminophenyl)-2-chloro-N-(3-fluorophenyl)pyrimidin-5-amine (15 mg, 0.048 mmol) was added to a solution of acryloyl chloride (4.24 μL, 0.052 mmol) in the presence of triethylamine (0.013 mL, 0.095 mmol) at 0° C., and the reaction mixture was stirred for 12 h at rt. The reaction was monitored by TLC. After completion of the reaction, the compound was purified by column chromatography to give the title compound (3.26 mg, 16% yield). ESI-MS: m/z 369.09 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:24])=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]3=[N:10][C:9]=2[CH3:23])[S:5][C:6]=1Br.[Li]CCCC>C1COCC1>[Br:1][C:2]1[C:3]([Cl:24])=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]3=[N:10][C:9]=2[CH3:23])[S:5][CH:6]=1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)c(Br)c3Cl)c(C)nc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3scc(Br)c3Cl)c(C)nc12
Yield: 68.3 %

Procedure:
Using a procedure similar to Example 76, 3-(4,5-dibromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (1.83 g, 3.72 mmol), 1.6 M n-BuLi (2.56 mL, 4.09 mmol), and THF (30 mL) furnish the title compound (1.05 g, 2.54 mmol, 68%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.73-1.92 (m, 4H), 2.48 (s, 3H), 2.51 (s, 3H), 3.27-3.36 (m, 1H), 6.71 (s, 1H), 7.55 (s, 1H). LC/MS (m/z): calcd. for C17H19BrClN3S (M+H)+: 412.0; found: 412.1.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=2)[CH2:5][CH2:4]1.C(O)(=O)C.C(N(CC)CC)C.[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([O:43][CH2:44][CH3:45])[C:41]=1[F:42])[CH:37]=O)[CH3:32].C([BH3-])#N.[Na+]>C(O)C>[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([O:43][CH2:44][CH3:45])[C:41]=1[F:42])[CH2:37][N:3]1[CH2:4][CH2:5][CH:6]([NH:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=2)[CH2:7][CH2:8]1)[CH3:32]
Reactant: CC(=O)Nc1cccc(NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(Nc3cccc(NC(C)=O)c3)CC2)cc(OCC)c1F
Temperature: 50 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
To a solution of N-[3-(piperidin-4-ylamino)-phenyl]-acetamide dihydrochloride (61.2 mg, 0.2 mmol, 1.0 equiv; intermediate B1), acetic acid (60.1 mg, 1.0 mmol, 5.0 equiv) and triethylamine (40.5 mg, 0.4 mmol, 2.0 equiv) in ethanol (1 mL) was added 3,5-diethoxy-4-fluoro-benzaldehyde (53.1 mg, 0.25 mmol, 1.25 equiv; intermediate E5, vide infra) and the mixture stirred at 50° C. After 1 h, sodium cyanoborohydride (15.1 mg, 0.24 mmol, 1.2 equiv), dissolved in ethanol (1 mL), was added and the mixture stirred at 50° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 19.9 mg (23%) of the title compound. MS (ISP): 430.4 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:12])=[C:5]([C:8]([F:11])=[CH:9][CH:10]=1)[C:6]#[N:7])=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[F:11][C:8]1[C:5]([C:6]#[N:7])=[C:4]([CH3:12])[C:3]([CH:1]2[CH2:2][O:21]2)=[CH:10][CH:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc(F)c(C#N)c1C
Solvent: ClCCl
Product: Cc1c(C2CO2)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3-Ethenyl-6-fluoro-2-methylbenzonitrile (14.9 g, 92.0 mmol) was added to DCM (400 mL) at 0° C. then mCPBA (47.85 g, 277.5 mmol) was added and the mixture was stirred at RT for 72 h. The reaction mixture was washed with saturated aqueous Na2S2O3, then with 1N NaOH, and brine. The organic layer was separated, dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by chromatography through a 330 g Redi-sep column, eluting with 0-100% hexane/DCM solvent system to afford 6-fluoro-2-methyl-3-(oxiran-2-yl)benzonitrile. LC-MS: M+1=178.