Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](Cl)=[N:10][OH:11].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[C:21][C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:23].C(=O)(O)[O-].[Na+].[Cl-]>C(O)(C)C.CCOCC>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[O:11][N:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:21]=1[C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:23]
Reactant: ON=C(Cl)c1ccc(Cl)cc1Cl
Reactant: O=C(C#Cc1ccccc1Cl)c1cccnc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)O
Product: O=C(c1cccnc1)c1c(-c2ccc(Cl)cc2Cl)noc1-c1ccccc1Cl
Temperature: 55 °C
Yield: 84 %

Procedure:
A mixture of 56 mg (0.25 mmol) of 2,4-dichloro-N-hydroxybenzenecarboximidoyl chloride, 60 mg (0.25 mmol) of 3-(2-chlorophenyl)-1-(3-pyridyl)-2-propyn-1-one, and 30 mg (0.36 mmol) of sodium bicarbonate in 2.5 mL of isopropyl alcohol was heated at 55° C. overnight with shaking. An additional 30 mg of carboximidoyl chloride and 15 mg of sodium bicarbonate was then added, and the mixture was heated for another 20 hrs. The reaction mixture was cooled, diluted with ether, and then washed with saturated sodium bicarbonate. The ether fraction was dried over magnesium sulfate. The drying agent was filtered off, and the ether was removed by rotoevaporation. The crude product was purified by prep TLC to give 90 mg (0.21 mmol) of 5-(2-chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)carbonyl]isoxazole. 1H NMR (CDCl3): δ 7.16 (m, 1), 7.60 (m,2), 7.92 (m, 1), 8.53 (br d, 1), and 8.74 ppm (br s, 1). MS m/z: 428.9 (M+H).
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:22][C:23]1[N:24]=[CH:25][N:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:27]=1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=O)(C)(C)C.CC(O)C.Cl>CO>[ClH:21].[NH2:8][CH:9]([CH2:22][C:23]1[N:24]=[CH:25][N:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:27]=1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: CN(C)C(=O)n1cnc(CC(COc2noc3ccc(Cl)cc23)NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: CN(C)C(=O)n1cnc(CC(N)COc2noc3ccc(Cl)cc23)c1

Procedure:
To a solution of 0.2 g of 3-[2-tert-butoxycarbonylamino-3-(1-dimethylcarbamoyl-4-imidazolyl)propoxy]-5-chloro-1,2-benzoisoxazole in 2 ml of methanol is added 1.2 ml of a 2-propanol solution (6.5M) of hydrogen chloride at room temperature and they are subjected to reaction at the same temperature for ten hours, after which the solvent is removed by distillation under reduced pressure. Diisopropyl ether is added to the residue obtained and the crystals precipitated are collected by filtration, to obtain 0.1 g of pale brown, crystalline 3-[2-amino-3-(1-dimethylcarbamoyl-4-imidazolyl)propoxy]-5-chloro-1,2-benzoisoxazole hydrochloride having a melting point of 167.0°-169.5° C. (decomp.).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[N:29])[CH:26]=4)[NH:21][CH:20]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>N1C=CC=CC=1>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[N:29])[CH:26]=4)[NH:21][CH:20]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(CCCCc3c[nH]c4ccc(C#N)cc34)CC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1ccc2[nH]cc(CCCCN3CCN(c4ccc(O)cc4)CC3)c2c1
Reaction time: 3 h

Procedure:
A mixture of 4.05 g of 3-[4-(4-p-methoxyphenylpiperazino)butyl]-5-cyanoindole, 3.5 g of pyridine hydrochloride and 80 ml of pyridine is boiled for 3 hours. It is cooled, evaporated and worked up in a conventional manner, and 3-[4-(4-p-hydroxyphenylpiperazino)butyl]-5-cyanoindole is obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:24]=[CH:23][C:13]2[NH:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[CH2:17][CH2:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[CH2:26][C:27]1[N:31]([C:32]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]=[N:29][N:28]=1.[I-].[Na+].[H-].[Na+]>CN(C=O)C>[Si:1]([O:8][CH2:9][C:10]1[CH:24]=[CH:23][C:13]2[N:14]([CH2:26][C:27]3[N:31]([C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:30]=[N:29][N:28]=3)[C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[CH2:17][CH2:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: ClCc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc2c(c1)CCc1ccccc1N2
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc2c(c1)CCc1ccccc1N2Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A mixture of 1.3 g of Compound 31-2b, 2.0 g of 5-chloromethyl-N-triphenylmethyltetrazole, 0.6 g of sodium iodide, 0.2 g of sodium hydride (60% oily) and 50 ml of DMF was stirred at 80° C. for 15 hours. The solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (10/1)] to give 1.05 g of an oily substance containing the desired compound.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:17][C:18]([C:20]2[C:29]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[O:19])[C@H:14]([CH3:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@@H:7]1[CH3:16])=[O:5])C.[OH-].[K+].O>CCO>[CH3:16][C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:14]([CH3:15])[C:6]1([NH:17][C:18]([C:20]1[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[CH:23]=[CH:22][CH:21]=1)=[O:19])[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)[C@H](C)c2ccccc2[C@@H]1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@@H]1c2ccccc2[C@H](C)C1(NC(=O)c1cccc2c1CCCC2)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.1 %

Procedure:
The mixture of (cis)-1,3-dimethyl-2-[(5,6,7,8-tetrahydro-naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (76) (62 mg, 1.2 mmol) and KOH (300 mg, 5.4 mmol) is dissolved in EtOH (3 mL) and water (0.3 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until pH˜4. The precipitate is filtered to give a pure product (77) as white solid (44 mg, 75%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([Cl:14])([F:13])[F:12])=[N:9][N:10]=2)[CH:7]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:14][C:11]([F:13])([F:12])[C:8]1[N:6]2[CH:7]=[C:2]([C:21]3[CH:20]=[CH:19][C:18]([O:17][C:16]([F:15])([F:27])[F:28])=[CH:23][CH:22]=3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: FC(F)(Cl)c1nnc2ccc(Br)cn12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(-c2ccc3nnc(C(F)(F)Cl)n3c2)cc1
Temperature: 70 °C

Procedure:
6-Bromo-3-(chloro-difluoro-methyl)-[1,2,4]triazolo[4,3-a]pyridine (2.76 g, 9.8 mmol), 4-trifluoromethoxyphenyl boronic acid (2.5 g, 12.1 mmol), dppfPdCl2 (1,1′-bis(diphenylphosphino)ferrocene palladium dichloride)(350 mg, 0.5 mmol), and potassium carbonate (2.76 g, 20 mmol) were suspended in degassed toluene (20 mL), degassed isopropanol (10 mL) and degassed water (10 mL) under an atmosphere of nitrogen. The reaction mixture was heated at 70° C. for 1 hour before being cooled to room temperature. The aqueous phase was discarded and the organic phase was concentrated and purified by flash chromatography (rf=0.5 in 1:1 hexanes/ethyl acetate) to give 3-(chloro-difluoro-methyl)-6-(4-trifluoromethoxy-phenyl)-[1,2,4]triazolo[4,3-a]pyridine as a pale orange powder.
Reaction SMILES: [CH2:1]([N:8]([CH:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:13]#[N:14])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=[O:24]>>[CH2:1]([N:8]([CH:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:13]([NH2:14])=[O:24])[CH2:9][CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC(c1ccc(F)cc1)N(CCO)Cc1ccccc1
Reactant: CS(C)=O
Product: NC(=O)C(c1ccc(F)cc1)N(CCO)Cc1ccccc1
Reaction time: 0.33 h

Procedure:
5 g of [Benzyl-(2-hydroxyethyl)-amino]-(4-fluorophenyl)-acetonitrile of Formula XI and 15 ml of dimethylsulfoxide (DMSO) were charged in a clean and dry 4 neck round bottom flask followed by stirring for about 20 minutes. 3.8 g. of potassium carbonate was charged to the above reaction solution followed by addition of 7 ml of 50% hydrogen peroxide over about 30 minutes. The resultant reaction solution was stirred for about 2 hours, after completion of the reaction, reaction was quenched by adding 50 ml of water over about 30 minutes. The reaction suspension was stirred for about 1 hour. Separated solid was filtered and the solid was washed with 10 ml of water. Wet cake obtained and 50 ml of petroleum ether were charged in a clean and dry 4neck round bottom flask followed by stirring for about 15 minutes. The solid was filtered and the solid was dried at about 30° C. for about 5 hours to yield 3.8 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:23]=1)=[O:5].N[C:30]1C=CC2C(=O)C(C)CCCC=2C=1.NC1C=CC2C(=O)CCCCC=2C=1>>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]([CH3:30])[CH2:14][CH2:13][CH2:12][C:11]=2[CH:23]=1)=[O:5]
Reactant: O=C(Nc1ccc2c(c1)CCCC=C2c1ccccc1)c1c(F)cccc1F
Reactant: CC1CCCc2cc(N)ccc2C1=O
Agent: Nc1ccc2c(c1)CCCCC2=O
Product: CC1=C(c2ccccc2)c2ccc(NC(=O)c3c(F)cccc3F)cc2CCC1

Procedure:
Compound 7 was prepared by a method analogous to the method used to prepare Compound 6 except that 2-amino-6-methyl-6,7,8,9-tetrahydro-benzocyclohepten-5-one (see Allinger, J. Org. Chem. 1962, 27, 70-6) was used as the starting material instead of 2-amino-6,7,8,9-tetrahydro-benzocyclohepten-5-one (g).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([CH3:3])[CH3:2].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:20])[C@@H:11]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Reactant: CC(C)(C)OC(=O)CBr
Product: CCCCCCCC[C@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)OC[C@@H]1C(C)C

Procedure:
Following the procedure described in Referential Example 4, but using 4-(S)-isopropyl-3-(1-oxodecyl)-2-oxazolidinone (9.85 g), prepared in Referential Example 49, and tert-butyl bromoacetate (25.4 ml) as starting materials, the desired compound (9.17 g) having a m.p. of 58°-59° C. was obtained.
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.[CH:29](N(CC)C(C)C)(C)C.IC>C(#N)C.ClCCl>[CH3:29][N:13]1[CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:17][CH:16]=2)[CH2:9][CH:8]1[C:1]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: Cc1ccc(Cl)c(-c2ccc(CN3CCNC(Cc4ccccc4)C3)cc2)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CI
Solvent: ClCCl
Product: Cc1ccc(Cl)c(-c2ccc(CN3CCN(C)C(c4ccccc4)C3)cc2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
This compound could be made the following manner: 100 mg of 3-benzyl-1-(2′-chloro-5′-methyl-biphenyl-4-ylmethyl)-piperazine would be dissolved in acetonitrile, 3 equiv. of N,N-diisopropylethylamine would be added followed by 1.1 equiv. of iodomethane. The reaction would be stirred at 80° C. overnight. The reaction would be diluted with dichloromethane and washed with 1N aqueous NaOH solution. The organic layer would be dried over Na2SO4, filtered and concentrated in vacuo. The crude residue would be purified by column chromatography to afford 1-methyl-2-phenyl-4-(2′-chloro-5′-methyl-biphenyl-4-ylmethyl)-piperazine.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]3[CH2:20][O:19]3)=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:35][NH:36][CH3:37]>C1COCC1>[CH2:1]([C:5]1[N:6]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@H:18]([OH:19])[CH2:20][N:36]([CH3:37])[CH3:35])=[CH:14][CH:15]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CNC
Reactant: CCCCc1nc(-c2ccc(OC[C@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: C1CCOC1
Product: CCCCc1nc(-c2ccc(OC[C@H](O)CN(C)C)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A solution of 2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((R)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (100 mg, 2.1 mmol, from intermediate A2) in 3 mL of dimethylamine in THF (2M) was stirred at 76° C. for 1 h in a microwave reactor. Upon completion (determined by LC/MS), the reaction was evaporated in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 96% EtOAc/(2M NH3/MeOH) as an eluent to afford (R)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-dimethylamino-propan-2-ol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]3[N:24]=[N:25][N:26]=[C:16]3[C:15]=2[NH2:27])[CH:2]=1.[C:28](OCC)(OCC)(OCC)[CH3:29].C(Cl)(Cl)Cl.CO>ClCCCl>[CH3:28][C:29]1[N:13]([CH2:12][CH2:11][O:10][CH2:9][CH2:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]3[N:24]=[N:25][N:26]=[C:16]3[C:15]=2[N:27]=1
Reactant: Nc1c(NCCOCCCc2cccnc2)c2ccccc2n2nnnc12
Reactant: CCOC(C)(OCC)OCC
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCCl
Product: Cc1nc2c(c3ccccc3n3nnnc23)n1CCOCCCc1cccnc1
Yield: 98.1 %

Procedure:
Under an atmosphere of nitrogen, N5-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,5-a]quinoline-4,5-diamine (0.70 g, 1.92 mmol) was dissolved in 1,2-dichloroethane (15 ml). Triethyl orthoacetate (0.53 ml, 2.88 mmol) was added via syringe and the reaction was heated to reflux for 3 hours. Analysis by thin layer chromatography (95/5 chloroform/methanol) showed complete consumption of the diamine. The reaction was quenched by the addition of water (15 ml). The phases were separated and the aqueous fraction was extracted with dichioromethane (3×10 ml). The combined organic fractions were washed with brine (15 ml), dried (Na2SO4), filtered and concentrated in vacuo to yield 0.73 g of 5-methyl-6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline as a red oil. This material was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH2:23][CH3:24])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[C:27]([C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=2)=[O:34])=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH2:23][CH3:24])[CH:19]=[CH:18][C:14]=1[C:15]([NH:25][C:26]1[C:27]([C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=2)=[O:34])=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1)=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCSc1ccc(C(=O)O)c(OCCCNC(=O)OC(C)(C)C)c1
Reactant: Cc1ccc(N)c(C(=O)Nc2ccc(Cl)cn2)n1
Product: CCSc1ccc(C(=O)Nc2ccc(C)nc2C(=O)Nc2ccc(Cl)cn2)c(OCCCNC(=O)OC(C)(C)C)c1
Yield: 67 %

Procedure:
Using a procedure analogous to Example 1-G, 2-(3-t-butoxycarbonylaminopropoxy)-4-(ethylthio)benzoic acid and 3-amino-N-(5-chloropyridin-2-yl)-6-methylpyridine-2-carboxamide gave the title compound as a solid (2.2 g, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([NH2:9])=[N:7][CH:8]=1.[CH3:10][C:11]1([CH3:19])[CH2:17][C:16](=O)[O:15][C:13](=[O:14])[CH2:12]1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([N:9]2[C:13](=[O:14])[CH2:12][C:11]([CH3:19])([CH3:10])[CH2:17][C:16]2=[O:15])=[N:7][CH:8]=1
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: COc1cnc(N)nc1
Solvent: ClCCl
Product: COc1cnc(N2C(=O)CC(C)(C)CC2=O)nc1
Temperature: 180 °C
Yield: 39.7 %

Procedure:
A mixture of 5-methoxy-pyrimidin-2-ylamine (1.00 g, 7.99 mmol) and 3,3-dimethylglutaric anhydride (1.14 g, 7.99 mmol) was heated at 180° C. for 9 hours. After cooling to room temperature the reaction mixture was dissolved in a small amount of dichloromethane and purified by flash column chromatography (SiO2, ethyl acetate:heptane 70:30), yielding the title compound (0.79 g, 40% yield) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:29])[CH:27]=[CH2:28])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:30]I>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][N:13]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([N:25]([C:26](=[O:29])[CH:27]=[CH2:28])[CH3:30])=[CH:23][CH:24]=2)(=[O:17])=[O:18])[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CI
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC(=O)N(C)c1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 1 h
Yield: 6.4 %

Procedure:
Sodium hydride (0.050 g, 26 mmol) was added in one portion to a stirred solution of 4-(4-acryloylamino-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (0.1 g, 0.25 mmol) in THF (1 ml). The reaction was stirred at room temperature for 5 minutes before methyl iodide (0.05 g, 0.25 mmol) was added in one portion and stirring continued for 1 hour. After this time, the reaction mixture was concentrated under vacuum and the resulting residue purified by prep HPLC to give the title compound (6.6 mg, 7% yield) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)([CH3:17])[C:10](OC(C)(C)C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)([CH3:17])[CH:10]=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(C(=O)OC(C)(C)C)c1cc(F)cc(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C)(C=O)c1cc(F)cc(F)c1
Temperature: -78 °C
Reaction time: 6 h

Procedure:
To a stirred solution of tert-butyl 2-[(tert-butoxycarbonyl)amino]-2-(3,5-difluorophenyl)propanoate from Step B (2.00 g, 5.60 mmol) in THF (20 mL) at −78° C. was added LiAlH4 (5.60 mL of a 1 M solution in THF, 5.60 mmol), dropwise. The reaction mixture was stirred at −78° C. for 6 h, then quenched with EtOAc (5.6 mL), then H2O (15.6 mL), then 1 N aqueous NaOH (5.6 mL), then EtOAc (17 mL). The reaction mixture was warmed to ambient temperature, stirred for 1 h, filtered, and extracted with EtOAc (2×40 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound in sufficient purity for use in the next step. MS: m/z=186 (M−CO2C4H7).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1I.C(=O)([O-])[O-].[Cs+].[Cs+].[C:16]([NH:24][C:25]1[CH:37]=[C:36]([CH:38]=[CH2:39])[CH:35]=[CH:34][C:26]=1[C:27]([O:29]C(C)(C)C)=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:16]([NH:24][C:25]1[CH:37]=[C:36](/[CH:38]=[CH:39]/[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:35]=[CH:34][C:26]=1[C:27]([OH:29])=[O:28])(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2ccccc2)c1
Reactant: Fc1ccc(I)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(/C=C/c2ccc(F)cc2F)ccc1C(=O)O)c1ccccc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
0.030 mL of 2,4-difluoroiodobenzene, 81 mg of cesium carbonate, 12 mg of tetrabutylammonium bromide and 19 mg of polymer supported bis(acetato)triphenylphosphine palladium(II) were added to 1.0 mL of toluene solution containing 40 mg of tert-butyl 2-(benzamido)-4-vinylbenzoate at room temperature and stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, 19 mg of polymer supported bis(acetato)triphenylphosphine palladium(II) was added and stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. 10 mL of trifluoroacetic acid was added to the obtained residue and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and methanol was added to the obtained residue and a solid substance was separated by filtration to obtain 15 mg of 2-(benzamido)-4-((E)-2-(2,4-difluorophenyl)vinyl)benzoic acid as brown solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][N:7]([CH3:30])[N:6]=1)=[O:4].[OH-].[Na+]>CO>[CH3:30][N:7]1[CH:8]=[C:9]([NH:10][C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([C:3]([OH:4])=[O:2])=[N:6]1
Reactant: COC(=O)c1nn(C)cc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(C(=O)O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.9 %

Procedure:
A solution of 1-methyl-4-(trityl-amino)-1H-pyrazole-3-carboxylic acid methyl ester (70 mg, 0.18 mmol) in methanol (2.0 mL) cooled to 0° C. was treated with a 1N aqueous sodium hydroxide solution (0.7 mL, 0.70 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was treated with another portion of a 1N aqueous sodium hydroxide solution (0.7 mL, 0.70 mmol). The reaction was stirred for 24 h. At this time, the reaction was warmed to 50° C. for 5 days. At this time, the reaction was concentrated in vacuo. The residue was dissolved into dichloromethane and methanol and then brought to pH=4 by the addition of a 1N aqueous hydrochloric acid solution. The resulting mixture was concentrated in vacuo. The solids were slurried in cold water, collected by filtration, washed with water, and dried in vacuo to afford 1-methyl-4-(trityl-amino)-1H-pyrazole-3-carboxylic acid (60 mg, 88.9%) as an off-white solid: EI-HRMS m/e calcd for C24H21N3O2 (M+Na)+ 406.1526, found 406.1526.