Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C([O:25][C:26]([CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:27])C>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:32]4[CH:33]=[CH:34][C:29]([CH2:28][C:26]([OH:27])=[O:25])=[CH:30][CH:31]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Product: CC(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(CC(=O)O)cc4)ccc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidine-1-carboxylic acid isopropyl ester and 4-(ethoxycarbonylmethyl)phenyl boronic acid following a procedure analogous to that described for Intermediate 63. LC (method 5): tR=1.58 min; Mass spectrum (ESI+): m/z=424 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]1[CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:13]1=[C:12]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[OH-].[K+].O>C(O)COCCOCCO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:13]1=[C:12]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCCn2c1c(-c1ccccc1)c1cc(OCc3ccccc3)ccc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: c1ccc(COc2ccc3c(c2)c(-c2ccccc2)c2n3CCCCC2)cc1

Procedure:
An amount of 2.3 g (6 m mole) of 2-benzyloxy-7,8,9,10-tetrahydro-10-oxo-11-phenyl-6H-azepino[1,2-a]indole 4.5 ml of 80% hydrazine hydrate and 1.5 g of potassium hydroxide were heated in 6 ml of triethylene-glycol for two hours to 180° C. and for four hours to 220° C. After cooling, the reaction mixture was mixed with water and extracted with chloroform. After evaporation of the chloroform extracts, the residue was purified by column chromatography on silicagel (solvent: toluene). When the eluates were evaporated, colorless crystals were obtained.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([O:13][CH3:14])=[CH:6][C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)=[CH:18][CH:17]=1.[OH-].[Na+]>C1COCC1>[Cl:34][C:29]1[CH:28]=[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:19]2[CH:20]=[CH:21][C:16]([NH:15][C:5]3[CH:6]=[C:7]([O:13][CH3:14])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=3[C:3]([OH:35])=[O:2])=[CH:17][CH:18]=2)[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1Nc1ccc(CCCCCc2ccc(Cl)c(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(Nc2ccc(CCCCCc3ccc(Cl)c(Cl)c3)cc2)c(C(=O)O)cc1[N+](=O)[O-]
Yield: 42.9 %

Procedure:
The title compound was prepared from 2-{4-[5-(3,4-dichlorophenyl)-pentyl]phenylamino}-4-methoxy-5-nitrobenzoic acid methyl ester (145 mg, 0.28 mmol) and 1N NaOH (aq.) (0.56 mL) in THF (1.2 mL) using the procedure described in Example 2. Purification by flash chromatography (silica gel, 10% MeOH/CH2Cl2), then recrystallization with MeOH yielded 58 mg (0.12 mmol, 41%) of the desired product. mp 192-193° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[S:20][C:19]2[C:18]([NH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[NH:27][CH:26]=[CH:25]4)=[N:17][CH:16]=[N:15][C:14]=2[CH:13]=1>>[NH:27]1[C:28]2[C:24](=[CH:23][C:22]([NH:21][C:18]3[C:19]4[S:20][C:12]([C:5]5[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=5)=[CH:13][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:30][CH:29]=2)[CH:25]=[CH:26]1
Reactant: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from p-methylbenzeneboronic acid and (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 2. 1H NMR (400 MHz, DMSO) d 11.1 (s, 1H), 9.50 (s, 1H), 8.41 (s, 1H), 7.71 (d, 2H), 7.59 (s, 2H), 7.24 (m, 5H), 6.38 (s, 1H), 2.28 (s, 3H). M.P. 200-220° C.; LC-MS: 357 (MH+); HPLC RT: 4.57 minutes.
Reaction SMILES: C(O[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([NH2:17])[C:11]=2[N:10]=[C:9]1[NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:21]1)=[O:7])(C)(C)C.C(N=C=NC(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.[C:57]([NH:60][CH2:61][CH2:62]C(O)=O)(=[O:59])[CH3:58].O1CCOCC1.Cl>O1CCCC1>[C:57]([NH:60][CH2:61][CH2:62][C:6]([NH:8][C:12]1[C:11]2[N:10]=[C:9]([NH:18][CH2:19][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][C:27]4[C:28]5[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:34]=[CH:35][CH:36]=4)[CH2:24][CH2:25]3)[NH:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)=[O:7])(=[O:59])[CH3:58]
Reactant: CC(C)(C)OC(=O)n1c(NCC2CCN(Cc3cccc4ccccc34)CC2)nc2c(N)cccc21
Reactant: CC(=O)NCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NCCC(=O)Nc1cccc2[nH]c(NCC3CCN(Cc4cccc5ccccc45)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 4-amino-2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-benzimidazole-1-carboxylic acid tert-butyl ester (0.02 mmol) in tetrahydrofuran (1 ml), diisopropylcarbodiimide (0.05 mmol), 1-hydroxybenzotriazole monohydrate (0.05 mmol) and 3-acetylaminopropionic acid (0.05 mmol) were added and the mixture was stirred at room temperature overnight. After adding a 4N hydrogen chloride-1,4-dioxane solution (1 ml) to the reaction mixture, it was stirred at 50° C. for 1 hour, the solvent was removed under reduced pressure, and then dichloromethane and 5N aqueous sodium hydroxide were added to the obtained residue prior to stirring. The organic layer was passed through SCX (Bond Elute SCX500MG), and after washing the SCX with methanol, elution was performed with a 2N ammonia-methanol solution. The solvent was distilled off under reduced pressure to obtain 3-acetylamino-N-{2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazol-4-yl}-propionamide. The compound was identified by LC-MS.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:14]2[CH2:15][CH2:16][NH:17][CH2:18][C:13]2=[N:12][N:11]=1.[C:19]([O:24][C@@H:25]([C:27]1[N:32]=[C:31](Cl)[CH:30]=[CH:29][N:28]=1)[CH3:26])(=[O:23])[CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>C(O)CCC>[C:19]([O:24][C@@H:25]([C:27]1[N:28]=[C:29]([N:17]2[CH2:16][CH2:15][N:14]3[C:10]([C:2]4[S:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)=[N:11][N:12]=[C:13]3[CH2:18]2)[CH:30]=[CH:31][N:32]=1)[CH3:26])(=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Reactant: c1ccc2sc(-c3nnc4n3CCNC4)nc2c1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCn3c(nnc3-c3nc4ccccc4s3)C2)n1
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of 3-benzothiazol-2-yl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine (prepared according to the method of Example 259, Step C, 170 mg, 0.66 mmol), (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 150 mg, 0.66 mmol), and triethylamine (0.28 mL, 1.98 mmol) in n-butanol (2.2 mL) was heated to reflux overnight, cooled to room temperature, evaporated, and purified by flash column chromatography (1% methanol/chloroform) to give 224 mg (76%) of the title compound of Example 259, Step D as a colorless solid. 1H NMR (CDCl3, 300 MHz) δ 8.37 (d, 1H), 8.08 (d, 1H), 7.97 (d, 1H), 7.57-7.43 (c, 2H), 6.53 (d, 1H), 5.71 (q, 1H), 5.09 (s, 2H), 4.82 (t, 2H), 4.33-4.26 (c, 2H), 2.42 (t, 2H), 1.78-1.64 (c, 2H), 1.61 (d, 3H), 0.99 (t, 3H); MS (APCI) 450 (MH+).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:21]1[C:20]2[C:24](=[CH:25][CH:26]=[C:18]([F:17])[CH:19]=2)[NH:23][C:22]1=[O:27])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: O=C1Cc2cc(F)ccc2N1
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ccc(F)cc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-fluoro-2-oxindole to give 0.3 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-5-fluoro-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]([F:38])([F:37])[C:28]([F:36])([F:35])[C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[N:20]=1)[NH2:18]>C(O)(=O)C>[F:38][C:27]([F:37])([C:28]([F:35])([F:36])[C:29]([F:33])([F:34])[CH:30]([F:32])[F:31])[CH2:26][O:25][C:21]1[N:20]=[C:19]([N:17]=[N:18][C:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[OH:16])[CH:24]=[CH:23][CH:22]=1
Reactant: NNc1cccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)n1
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Solvent: CC(=O)O
Product: Oc1c(N=Nc2cccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)n2)c2ccccc2c2ccccc12
Temperature: 110 °C

Procedure:
Next, a reaction flask was loaded with acetic acid (54 ml) and 9,10-phenanthrenequinone (3.8 g), and the temperature was raised to 110° C. with stirring to dissolve 9,10-phenanthrenequinone. To this mixture, 2-hydrazino-6-(2,2,3,3,4,4,5,5-octafluoropentyloxy)pyridine (10 g) was added in 30 minutes. After stirring at 110° C. for one hour, the reaction mixture was filtrated. Crystals were stirred in methanol (100 ml) for 30 minutes, filtrated and dried to give intended crystals (5.2 g).
Reaction SMILES: Cl[S:2]([C:5]1[N:13]=[C:12]2[N:7]([C:8]([O:18][CH3:19])=[N:9][C:10]3[N:17]=[CH:16][CH:15]=[CH:14][C:11]=32)[N:6]=1)(=[O:4])=[O:3].[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:22]=1[NH2:23].N1C=CC=CC=1.CS(C)=O>C(#N)C>[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:22]=1[NH:23][S:2]([C:5]1[N:13]=[C:12]2[N:7]([C:8]([O:18][CH3:19])=[N:9][C:10]3[N:17]=[CH:16][CH:15]=[CH:14][C:11]=32)[N:6]=1)(=[O:4])=[O:3]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: COc1nc2ncccc2c2nc(S(=O)(=O)Cl)nn12
Solvent: CS(C)=O
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1nc2ncccc2c2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nn12
Yield: 8.8 %

Procedure:
A mixture of 2.0 g (6.7 mmol) of 2-chlorosulfonyl-5-methoxypyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine, 2.2 g (13.3 mmol) of 2,6-dichloroaniline, 0.50 g (67 mmol) of pyridine, and 30 mL of dry acetonitrile was prepared and to this was added with stirring at ambient temperature 95 microliters (1.3mmol) of dimethyl sulfoxide. The mixture was allowed to react overnight and was then concentrated by evaporation under reduced pressure. The residue was diluted with dichloromethane and water and the resulting mixture was filtered to remove the insoluble solids. The organic phase was recovered and the dichloromethane was removed by evaporation under reduced pressure. The residue was diluted with hexane, recovered by filtration, and redissolved in dichloromethane. The resulting solution was filtered through silica gel and concentrated by evaporation under reduced pressure. The residue was diluted with hexane, recovered by filtration, and dried to obtain 0.25 g of the title compound as a light tan powder melting at 290°-293° C. with decomposition. The proton NMR spectrum of this was compatible with the assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18]([OH:20])[C:17]([F:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].[N+](=[CH2:24])=[N-].C(O)(=O)C>O1CCCC1.C(OCC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18]([O:20][CH3:24])[C:17]([F:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(F)c(O)nc1Nc1ccc(F)cc1F
Reactant: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1cc(F)c(OC)nc1Nc1ccc(F)cc1F
Yield: 71.6 %

Procedure:
In 6 ml of tetrahydrofuran was dissolved 200 mg of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinate, and a solution of about 40 mg of diazomethane in diethyl ether was added to the resulting solution with ice-cooling, after which the resulting mixture was subjected to reaction at room temperature for 30 minutes. Subsequently, acetic acid was added until foaming was not caused in the reaction mixture, after which the solvent was removed by distillation under reduced pressure. The crystals thus obtained were washed with 6 ml of isopropyl alcohol to obtain 150 mg (yield 71.6%) of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinate having a melting point of 160°-161° C.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C@H:15]([NH:18][C:19]([N:21]2[C:27](=[O:28])[C@@H:26]([CH2:29][C:30]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=3[O:37][CH3:38])[CH2:25][N:24]3[CH:39]=[CH:40][N:41]=[C:23]3[CH2:22]2)=[O:20])[CH2:16][CH3:17])[CH:12]=[CH:11][C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5]>Cl.C(O)(=O)C>[ClH:36].[NH2:1][C:2]1[CH:14]=[C:13]([C@H:15]([NH:18][C:19]([N:21]2[C:27](=[O:28])[C@@H:26]([CH2:29][C:30]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=3[O:37][CH3:38])[CH2:25][N:24]3[CH:39]=[CH:40][N:41]=[C:23]3[CH2:22]2)=[O:20])[CH2:16][CH3:17])[CH:12]=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC[C@@H](NC(=O)N1Cc2nccn2C[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)OC(C)(C)C)c(N)c1
Agent: Cl
Solvent: CC(=O)O
Product: CC[C@@H](NC(=O)N1Cc2nccn2C[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)O)c(N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound 89b obtained at Step (2) (27.2 mg) was dissolved in a 1M hydrochloric acid in acetic acid solution, then the mixture was stirred at room temperature for 3 hours. The precipitated solid was collected by filtration to obtain the title compound (17.8 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH2:18]C3C=CC=CC=3)=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[N+:25]([C:28]1[CH:33]=[CH:32][C:31](S)=[CH:30][CH:29]=1)([O-:27])=[O:26]>>[CH3:18][C:13]1=[N:14][NH:15][C:16](=[O:17])/[C:12]/1=[C:4]1\[NH:5][C:6]2[C:11]([C:2]([C:31]3[CH:32]=[CH:33][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=3)=[CH:3]\1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C1NN=C(Cc2ccccc2)/C1=C1\C=C(Cl)c2ccccc2N1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Product: CC1=NNC(=O)/C1=C1/C=C(c2ccc([N+](=O)[O-])cc2)c2ccccc2N1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-benzyl-1H-pyrazol-5(4H)-one and 4-nitrobenzenethiol using a procedure analogous to the one described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.99 (s, 3H) 6.65 (s, 1H) 7.03-7.10 (m, 2H) 7.44 (d, J=8.34 Hz, 2H) 7.64 (t, J=7.45 Hz, 1H) 7.88 (t, J=7.83 Hz, 1H) 7.96 (d, J=8.59 Hz, 1H) 8.08 (d, J=8.08 Hz, 2H) 13.12 (bs, 1H); ESI-MS: m/z calc'd for C19H14N4O3S 378.08. found 379.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9](Cl)[C:4]=2[CH:3]=1.[C:12]1([CH:19]=[CH:18][CH:17]=[C:15]([OH:16])[CH:14]=1)[OH:13].C(N(C(C)C)CC)(C)C>O1CCOCC1>[Br:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([O:13][C:12]3[CH:19]=[CH:18][CH:17]=[C:15]([OH:16])[CH:14]=3)[C:4]=2[CH:3]=1
Reactant: Oc1cccc(O)c1
Reactant: Clc1ncnc2[nH]c(Br)cc12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Oc1cccc(Oc2ncnc3[nH]c(Br)cc23)c1
Temperature: 150 °C
Yield: 32.7 %

Procedure:
6-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.41 mmol), prepared as in reference 1, is mixed with resorcinol (451 mg, 4.1 mmol) and diisopropylethylamine (714 μL, 4.1 mmol) in dioxane (1.3 mL). The mixture is heated to 150° C. for 3 days, with stirring. The reaction is then cooled to ambient temperature and the solvent is removed. The resultant crude product is purified by flash column chromatography using a gradient of 3-5% MeOH in DCM to yield 5-(6-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yloxyl)-phenol (41 mg; 32%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[CH3:30][NH:31][CH3:32]>>[CH3:30][N:31]([CH3:32])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1
Reactant: CNC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Product: Cc1ccccc1-c1cc2c(N(C)C)nc(-n3cc(C(=O)O)cn3)nc2cc1F

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI): predicted mass calcd. for C21H18FN5O2, 391.1
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[CH2:33]([O:35][C:36]([C:38]1[C:42]([CH:43]=O)=[CH:41][S:40][C:39]=1[NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[O:37])[CH3:34]>C1COCC1>[CH2:33]([O:35][C:36]([C:38]1[C:42]([CH:43]=[CH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:41][S:40][C:39]=1[NH:45][C:46]([O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[O:47])=[O:37])[CH3:34]
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1c(C=O)csc1NC(=O)OC(C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C=Cc2ccccc2)csc1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 91.9 %

Procedure:
Benzyltriphenylphosphonium bromide (1.30 g, 3.01 mmol) was suspended in anhydrous THF (6 mL) and cooled to 0° C. This was treated with n-butyllithium (1.20 mL, 3.01 mmol, 2.5M in hexanes) by slow addition. It was then stirred at 0° C. for 1.5 hr. Next it was treated with a solution of 2-t-butoxycarbonylamino-4-formyl-thiophene-3-carboxylic acid ethyl ester (0.300 g, 1.00 mmol) dissolved in anhydrous THF (6 mL) by slow addition. The reaction was allowed to stir at room temperature for 1 hr. It was then quenched with sat. NH4Cl (12 mL). This was extracted with CH2Cl2 (3×25 mL). The combined extracts were washed with H2O (1×25 mL) and brine (1×25 mL). The extracts were dried (Na2SO4), filtered, and the solvent removed in vacuo. The crude product was purified by flash chromatography (SiO2, 1 EtOAc/3 hexanes) to afford the title compound (0.3432 g, 92%). MS m/e (CI) 374.1 (M+H)+; 1H NMR (300 MHz, CDCl3): δ ppm 1.26 (m, 1H), 1.36 (t, 1H), 1.44 (m, 1H), 1.54 (s, 9H), 4.35 (m, 1H), 6.34 (s, 1H), 6.59 (m, 1H), 6.93 (d, 1H), 6.89 (s, 1H), 7.17 (s, 1H), 7.35 (t, 1H), 7.47 (d, 1H), 7.59 (d, 1H), 10.40 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15](OP(C(=[N+]=[N-])C(=O)C)(=O)OCC)C.C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]#[CH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)C1
Reactant: CCOP(=O)(OCC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h

Procedure:
To 1.23 g (6.17 mmol) 3-Formyl-pyrrolidine-1-carboxylic acid tert-butyl ester in 30 mL dry MeOH was added at room temperature 1.42 g (7.41 mmol) (1-Diazo-2-oxo-propyl)-phosphonic acid diethyl ester and 1.71 g (12.4 mmol) K2CO3 and stirring was continued for 2 h. 10 g of silica gel was added to the reaction mixture, stirring continued for 20 min and then filtered. After evaporation of the solvent the residue was purified by column chromatography (silica, cyclohexane/EtOAc 1:1).
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]([C:11]#[N:12])=[C:4]([F:13])[C:3]=1[F:14].[F-].[K+].[CH2:17]([SH:21])[CH2:18][CH2:19][CH3:20].O>C(#N)C>[F:10][C:6]1[C:5]([C:11]#[N:12])=[C:4]([F:13])[C:3]([F:14])=[C:2]([S:21][CH2:17][CH2:18][CH2:19][CH3:20])[C:7]=1[C:8]#[N:9]
Reactant: CCCCS
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCSc1c(F)c(F)c(C#N)c(F)c1C#N
Yield: 77 %

Procedure:
A 2.0 g amount of tetrafluoroisophthalonitrile and 0.87 g of potassium fluoride were dissolved in 10 ml of acetonitrile. After cooling to a temperature of 0° C., 0.90 g (1.04 ml) of n-butylmercaptan was gradually dropwise added to the mixture and the resultant mixture was stirred at a temperature of 0° C. or less for 12 hours. After 50 ml of water was added to the reaction mixture, the reaction mixture was extracted with chloroform and the extract was then washed with a saturated aqueous sodium bicarbonate solution, followed by drying with anhydrous magnesium sulfate. After distilling off the chloroform, the resultant crude product was distilled in vacuo. Thus, 2.08 g (77% yield) of the desired compound No. 52 was obtained.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[N:13][C:12]=1[CH2:23][CH2:24][CH3:25])=[O:10].[N:26]1([C:32]2[N:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([C:32]2[N:37]=[CH:36][C:35]([NH:38][C:9]([C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:22])=[N:13][C:12]=3[CH2:23][CH2:24][CH3:25])=[O:10])=[CH:34][CH:33]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: CCCc1nc(-c2ccccc2C)oc1C(=O)ON1C(=O)CCC1=O
Product: CCCc1nc(-c2ccccc2C)oc1C(=O)Nc1ccc(N2CCOCC2)nc1

Procedure:
With a procedure similar to example 50 above, 4-propyl-2-o-tolyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 4-propyl-2-o-tolyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C23H26N4O3 (m/e) 406, obsd 407 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH2:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([O:13][CH:14]([O:19][CH2:20][CH3:21])[C:15](=[NH:18])OC)[CH3:12]>CO>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][NH:9][C:15](=[NH:18])[CH:14]([O:19][CH2:20][CH3:21])[O:13][CH2:11][CH3:12]
Reactant: CCOC(OCC)C(=N)OC
Reactant: NCc1cccc(Cl)c1F
Solvent: CO
Product: CCOC(OCC)C(=N)NCc1cccc(Cl)c1F
Yield: 71.8 %

Procedure:
(3-Chloro-2-fluorophenyl)methanamine (1.0 g, 6.27 mmol) was added to a solution of methyl 2,2-diethoxyacetimidate (1.12 g, 6.96 mmol) in methanol (10 ml). The mixture was heated at 70 C for 1 h. The mixture was purified by chromatography (Biotage: 100% ethyl acetate) to yield N-(3-chloro-2-fluorobenzyl)-2,2-diethoxyacetimidamide (1.3 g, 4.5 mmol, 65% yield) as a colorless viscous oil. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.23-7.40 (m, 2H), 7.07 (t, J=7.9 Hz, 1H), 4.93 (s, 1H), 4.54 (s, 2H), 3.50-3.74 (m, 4H), 1.18-1.35 (m, 6H). MS (LC/MS) R.T.=1.78; [M+H]+=289.17.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:11]=[C:10]([O:12][CH:13]([F:15])[F:14])[N:9]([CH3:16])[N:8]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[Br:19]Br>C(O)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:11]([Br:19])=[C:10]([O:12][CH:13]([F:14])[F:15])[N:9]([CH3:16])[N:8]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18]
Reactant: BrBr
Reactant: Cn1nc(-n2ncc(C#N)c2N)cc1OC(F)F
Solvent: CC(=O)O
Product: Cn1nc(-n2ncc(C#N)c2N)c(Br)c1OC(F)F
Reaction time: 0.25 h

Procedure:
5.0 g (20 mmol) 5-Amino-1-(5-difluoromethoxy-1-methyl-3-pyrazolyl)-4-pyrazolecarbonitrile was dissolved in 80 ml acetic acid. At room temperature, 1.2 ml (23 mmol) bromine was added, dropwise. After stirring for 15 minutes, the mixture was concentrated and stirred with diisopropyl ether/propanol. The solid material was suction filtered and dried.