Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]=12.[CH:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[C:18]([OH:23])[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C(O)C>[OH:23][C:18]1[CH:19]=[CH:20][C:21]([NH:22][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]3[CH:13]=[N:14][NH:15][C:3]=23)=[CH:16][CH:17]=1
Reactant: Nc1ccc(O)cc1
Reactant: CCOC(=O)c1cnc2cn[nH]c2c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cn[nH]c2c1Nc1ccc(O)cc1
Yield: 54.5 %

Procedure:
Ethyl 7-chloro-1H pyrazolo[4,3-b]pyridine-6-carboxylate (1.0 g, 0.004 mole) and p-aminophenol (1.0 g, 0.009 mole) were stirred together in ethyl acetate (200 ml) under nitrogen for 48 hours, the temperature being maintained between -10° and -5° C. The ethyl acetate was removed under reduced pressure to give a yellow solid. This solid was dissolved in aqueous ethanol and the pH adjusted to pH8 with 10% sodium carbonate solution. The resulting solid was filtered off washed with water and dried. Recrystallization from methanol/ethyl acetate gave the title compound as a pale yellow solid (650 mg, 50%), m.p. 286°-287° C. (decomposition)
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br/[CH:41]=[CH:42]\[CH2:43][C:44]([CH2:55][CH3:56])([O:47][Si:48]([CH2:53][CH3:54])([CH2:51][CH3:52])[CH2:49][CH3:50])[CH2:45][CH3:46].[H-].[Na+].C1OCCOCCOCCOCCOC1>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24]/[CH:41]=[CH:42]\[CH2:43][C:44]([CH2:55][CH3:56])([O:47][Si:48]([CH2:53][CH3:54])([CH2:49][CH3:50])[CH2:51][CH3:52])[CH2:45][CH3:46])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCC(CC)(C/C=C\Br)O[Si](CC)(CC)CC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(C/C=C\OC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)O[Si](CC)(CC)CC
Yield: 71.7 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene (100 mg, 0.175 mmol), 1-bromo-4-ethyl-4-triethylsilyloxy-(2Z)-hexene (224 mg, 0.697 mmol), sodium hydride (60% in oil, 42 mg, 1.05 mmol), 15-crown-5 (38 mg, 0.173 mmol) and tetrahydrofuran (3 ml) were subjected to reaction using a procedure similar to that of Example 5(1) (reflux under heating for 17 hours), worked up and purified by column chromatography (hexane:toluene=2:1) to give the titled compound (102 mg, 72%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:17]([C:18]([O:20]CC)=[O:19])[CH:16]3[CH2:23][CH:13]2[CH2:14][CH2:15]3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:17]([C:18]([OH:20])=[O:19])[CH:16]3[CH2:23][CH:13]2[CH2:14][CH2:15]3)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1C2CCC(C2)N1S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2C3CCC(C3)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-[(4-methoxyphenyl)sulfonyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate (903 mg, 2.66 mmol) in tetrahydrofuran (25 ml) was added 1N sodium hydroxide (15 ml) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was removed, to give 2-[(4-methoxyphenyl)sulfonyl]-2-azabicyclo[2.2.1]heptane-3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15]C(OCC)=O)[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1.CC[O-].[Na+].[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[CH2:39]/[C:40](=[N:43]/[H])/[NH:41][OH:42]>CCO>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][C:15]3[O:42][N:41]=[C:40]([CH2:39][C:33]4[C:34]([Cl:38])=[CH:35][CH:36]=[CH:37][C:32]=4[Cl:31])[N:43]=3)[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1
Reactant: CCCCCn1c(=O)n(CCCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Reactant: [H]/N=C(/Cc1c(Cl)cccc1Cl)NO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCn1c(=O)n(CCCc2nc(Cc3c(Cl)cccc3Cl)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 140 °C
Yield: 80.1 %

Procedure:
Ethyl 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (70 mg, 0.19 mmol) was dissolved in EtOH. The solution was treated with a 21% solution of NaOEt in EtOH (78 μl, 0.21 mmol) and (1Z)-2-(2,6-dichlorophenyl)-N-hydroxyethanimidamide (46 mg, 0.21 mmol). The reaction was heated in the microwave at 140° C. for 10 min. The mixture was partitioned between EtOH and 2M HCl (aq). The organic layer was decanted off and concentrated by nitrogen blowdown. The crude product was purified on the MDAP. The product fractions were combined and concentrated to give the title compound as a white solid (80 mg, 80%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH:28]1([C:32](O)=[O:33])[CH2:31][CH2:30][CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32]([CH:28]5[CH2:31][CH2:30][CH2:29]5)=[O:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)C1CCC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)C1CCC1

Procedure:
The title compound, white solid (77 mg, 75%), MS (ISP) m/z=413.5 [(M+H)+], mp 202° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and cyclobutanecarboxylic acid.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH2:17][C:18]([O:20]CC)=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[K+]>O>[C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC=Cc1cccc(C(=O)c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CC=Cc1cccc(C(=O)c2ccccc2)c1
Yield: 66.7 %

Procedure:
A mixture of 275 mg of ethyl 4-(m-benzoyl-phenyl)-3-butenoate, 2.75 ml of ethanol, 0.275 ml of ethanol, 0.275 ml of water and 0.08 ml of 12.5N potassium hydroxide was refluxed for 30 minutes and then was evaporated to dryness. The residue was dissolved in 10 ml of water and the solution was treated with activated carbon, and filtered. 3 ml of N hydrochloric acid were added thereto and the mixture was extracted with methylene chloride. The organic phase was washed with water, dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure to obtain 166 mg of 4-(m-benzoyl-phenyl)-3-butenoic acid in the form of a yellow oil soluble in chloroform and ethanol and insoluble in water.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]23[CH2:21][CH:19]([CH2:20]2)[C:18](=[O:22])[N:17]([CH2:23][CH2:24][CH3:25])[C:16]3=[O:26])=[CH:11][CH:10]=1>O1CCCC1.CN(C)C1C=CN=CC=1.C(O)C>[C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]23[CH2:20][CH:19]([CH2:21]2)[C:18](=[O:22])[N:17]([CH2:23][CH2:24][CH3:25])[C:16]3=[O:26])=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCCN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCO
Product: CCCN1C(=O)C2CC(c3ccc(NC(C)=O)cc3)(C2)C1=O
Reaction time: 0.25 h

Procedure:
A solution of 0.11 ml of acetic anhydride in 0.5 ml of tetrahydrofuran is added dropwise to a solution of 260 mg of 1-(4-aminophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione and 6 mg of 4-dimethylaminopyridine in 8 ml of tetrahydrofuran. After stirring at room temperature for 21/2 hours, two drops of ethanol are added to the reaction mixture and stirring is continued for a further 15 minutes. After concentration by evaporation and subsequent recrystallisation from ethyl acetate/petroleum ether, the title compound is obtained in the form of white crystals having a melting point of 138.5°-139.5°. Rf (methylene chloride/methanol/glacial acetic acid 40:5:1)=0.55.
Reaction SMILES: [Cl:1]C1C=C(C=CC=1)C(O[CH:8]1[C:13](=[O:14])[NH:12][C:11]([CH3:15])=[C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[S:9]1)=O.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.Cl>>[ClH:1].[CH3:15][C:11]1[NH:12][C:13](=[O:14])[CH:8]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[S:9][C:10]=1[C:16]1[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=1
Reactant: C1CCNCC1
Reactant: CC1=C(c2ccncc2)SC(OC(=O)c2cccc(Cl)c2)C(=O)N1
Agent: Cl
Product: CC1=C(c2ccncc2)SC(N2CCCCC2)C(=O)N1

Procedure:
2-(3-Chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one and piperidine were reacted. The resultant compound was added with hydrochloric acid and was recrystallized from ethanol to give the titled compound as yellowish brown crystals.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:6][N:7]([CH3:18])[C:8]([C:10]1[C:15](Br)=[CH:14][N:13]=[C:12]([CH3:17])[N:11]=1)=[O:9].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:6][N:7]([CH3:18])[C:8]([C:10]1[C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:14][N:13]=[C:12]([CH3:17])[N:11]=1)=[O:9]
Reactant: Cc1ncc(Br)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ncc(-c2ccccc2)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Yield: 56.9 %

Procedure:
To a suspension of 0.456 g (1 mmol) 5-bromo-2-methyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, 0.034 g (0.2 mmol) tetrakis-(triphenylphosphin)palladium and 0.121 g (1 mmol) phenylboronic acid in 20 ml 1,2-dimethoxyethane a solution of 0.105 g (1 mmol) Na2CO3 in 8 ml H2O was added. The resulting reaction mixture was heated at reflux for 16 hrs. After evaporation of the 1,2-dimethoxyethan, the aqueous phase was extracted twice with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 40:1) and crystallised (Ethanol) to give 0.258 g (57%) 2-methyl-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as off-white crystalls, m.p. 149-152°.
Reaction SMILES: I[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)=[CH:5][N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=1.[CH3:21][C:22]1[C:23]([NH2:37])=[N:24][CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[NH2:37][C:23]1[N:24]=[CH:25][C:26]([C:2]2[C:6]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=3)=[CH:5][N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=2)=[CH:27][C:22]=1[CH3:21]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
Reactant: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(I)n1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(-c2nn(C(C)C)cc2-c2ccnc(NC[C@H](C)O)n2)cnc1N
Temperature: 85 °C
Reaction time: 8 h
Yield: 11.6 %

Procedure:
To a solution of (2S)-1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-1-3) (0.52 g, 1.34 mmol) in toluene (21 mL) and EtOH (7 mL) were added 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (B-3-2) (1 g, 2.68 mmol in theory) and 2 N aq. Na2CO3 (2 mL). The resulting mixture was degassed under N2 for 2 minutes. Then Pd(PPh3)4 (0.15 g, 0.134 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90° C. and stirred overnight. The mixture was cooled. The organic layer was separated and concentrated. The residue was purified by prep. HPLC to afford (2S)-1-(4-(3-(6-amino-5-methylpyridin-3-yl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-3) (0.057 g, 11.6%) as a light yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10](Cl)=[O:11].[NH2:13][CH2:14][C:15]1[N:19]([C:20]2[S:21][C:22]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:23][C:24]=2[C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[C:18]([CH3:39])=[N:17][N:16]=1>>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]([C:24]1[CH:23]=[C:22]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[S:21][C:20]=1[N:19]1[C:18]([CH3:39])=[N:17][N:16]=[C:15]1[CH2:14][NH:13][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:11])=[O:33]
Reactant: COC(=O)Cc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Product: COC(=O)Cc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2cc3ccccc3[nH]2)s1

Procedure:
Indole-2-carbonyl chloride and methyl (2-(3-aminomethyl-5-methyl[1,2,4]triazol-4-yl)-3-(2-chlorobenzoyl)thiophen-5-yl)acetate are reacted to give methyl (3-(2-chlorobenzoyl)-2-(3-(2-indolecarbonylaminomethyl)-5-methyl[1,2,4]triazol-4-yl)thiophen-5-yl)acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][C:13]2[C:18]([O:19][CH3:20])=[N:17][CH:16]=[CH:15][N:14]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[Cl:41]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Cl:41][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:10]
Reactant: COc1cccc(S(=O)(=O)Nc2nccnc2OC)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)Nc2nccnc2OC)c1Cl
Yield: 46.1 %

Procedure:
Prepared as for Example 130, 3-methoxy-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide (Example 132a) (0.295 g), lithium di-iso-propylamide (prepared from di-iso-propylamine (0.30 g) and n-butyl lithium (0.96 mL of a 2.5M solution in hexanes)) and hexachloroethane (0.994 g) in anhydrous tetrahydrofuran (20 mL) afforded the titled compound (0.152 g) as a white solid after re-crystallisation from tert-butyl methylether.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])[CH2:5]Br.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[C:4](=[N:3][O:2][CH3:1])[CH2:5][N:19]1[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]2[C:15]1=[O:25]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CON=C(CBr)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CON=C(CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.1 %

Procedure:
To 2.17 g of 2-bromo-1-(2,4-dichlorophenyl)ethanone-O-methyloxime in 20 ml of N,N-dimethylformamide, 3.03 g of potassium phthalimide and 1.61 g of potassium carbonate were added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 40 ml of water and extracted with ethyl acetate (50 ml×1), the resulting organic layer was washed with water (20 ml×1) and then dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 2.10 g of the desired product as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH3:27])[CH:20]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH3:27])[CH:20]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)=[CH:3][C:2]=1[C:34]1[C:29]([F:28])=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: OB(O)c1cccnc1F
Reactant: COc1ccc(C2(c3ccc(F)c(Br)c3)N=C(N)c3ccccc32)cc1C
Product: COc1ccc(C2(c3ccc(F)c(-c4cccnc4F)c3)N=C(N)c3ccccc32)cc1C
Yield: 5 %

Procedure:
The title compound was synthesized from 1-(3-bromo-4-fluorophenyl)-1-(4-methoxy-3-methylphenyl)-1H-isoindol-3-amine (Example 126) as described in Example 67 Scheme #10, D in 5% yield using 2-fluoropyridine-3-boronic acid. 1H NMR (DMSO-d6) δ 8.54-8.46 (m, 1 H), 8.22-8.15 (m, 1 H), 8.05-7.84 (m, 2 H), 7.76-7.55 (m, 5 H), 7.53-7.41 (m, 1 H), 7.32-7.23 (m, 2 H), 7.08-6.78 (m, 3 H), 3.93 (s, 3 H), 2.27 (s, 3 H); MS (ESI) m/z 442 [M+1]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.Cl.[O:12]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3[S:27][C:26]([NH:28][C:29](=[O:31])[CH3:30])=[N:25][CH:24]=3)=[CH:22][C:17]=2[CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].CO>CN(C)C=O>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:15]2[CH2:16][C:17]3[CH:22]=[C:21]([C:23]4[S:27][C:26]([NH:28][C:29](=[O:31])[CH3:30])=[N:25][CH:24]=4)[CH:20]=[CH:19][C:18]=3[O:12][CH2:13][CH2:14]2)=[O:9])[CH2:4][CH2:3]1
Reactant: CC1CCN(C(=O)Cl)CC1
Reactant: CC(=O)Nc1ncc(-c2ccc3c(c2)CNCCO3)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)Nc1ncc(-c2ccc3c(c2)CN(C(=O)N2CCC(C)CC2)CCO3)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64150.9 %

Procedure:
4-Methylpiperidine-1-carbonyl chloride (reagent preparation 37) (103 mg, 0.64 mmol) was added to a mixture of N-[5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1,3-thiazol-2-yl]acetamide hydrochloride, (173 mg, 0.53 mmol) and potassium carbonate (374 mg, 2.7 mmol) in N,N-dimethylformamide (2 mL). The resulting mixture was stirred at room temperature for 18 hours, then methanol (2 mL) was added and concentrated. The residue was diluted with ethyl ether (40 mL), a solid was collected by filtration, and washed with ether and water to give N-(5-{4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1,3-thiazol-2-yl)acetamide (140 mg, 0.34 mol, 63% yield), 1H NMR (400 MHz, DMSO-d6): 7.58 (s, 1H), 7.35 to 7.32 (m, 2H), 6.91 (d, 1H), 4.36 (s, 2H), 4.12 (br, 2H), 3.54 to 3.47 (m, 4H), 2.71 to 2.65 (m, 2H), 2.00 (s, 3H), 1.60 to 1.43 (m, 3H), 1.16 to 1.067 (m, 2H), 0.92 (d, 3H); MS (EI) for C21H26N4O3S: 415 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:17]([NH:27][CH2:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([O-:34])=[O:33])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].[Cs+]>>[C:17]([NH:27][CH2:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([O:34][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:33])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: O=C([O-])CCC(=O)CNC(=O)OCc1ccccc1
Reactant: O=C(CCCCCBr)OCc1ccccc1
Agent: [Cs+]
Product: O=C(CCC(=O)OCCCCCC(=O)OCc1ccccc1)CNC(=O)OCc1ccccc1
Reaction time: 48 h

Procedure:
This compound was prepared from the product of 9a (0.77 g; 2.7 mmol) and 8b (1.0 g; 2.5 mmol) according to Procedure C. The reaction time was 2 days. The crude product was purified on a 75×45 mm silica gel 60 column eluted with ethyl acetate-hexane (1:1) (1000 mL) collecting 14×50 mL fractions. Fractions containing the product (5-7) were collected, and after evaporation 0.52 g (44%) product was obtained (amber oil that solidified to a waxy solid on standing in the freezer).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH:11]([NH:14][C:15]([C:17]2[C:18]3[CH:25]=[N:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]=3[CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:12][CH3:13])[O:8][C:9]=1[CH3:10])=O.[CH3:33][NH2:34].C(O)C>>[CH3:10][C:9]1[O:8][C:7]([CH:11]([NH:14][C:15]([C:17]2[C:18]3[CH:25]=[N:24][N:23]([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[C:19]=3[CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:12][CH3:13])=[N:6][C:5]=1[C:3](=[O:2])[NH:34][CH3:33]
Reactant: CN
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1nc(C(=O)OC)c(C)o1
Solvent: CCO
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1nc(C(=O)NC)c(C)o1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(1-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-propyl)-5-methyl-oxazole-4-carboxylic acid methyl ester (40 mg, 0.091 mmol) in a solution of methyl amine in ethanol (455 μL, 33% solution, 3.66 mmol) was stirred at 100° C. in a sealed tube. After 16 hours, the reaction was cooled to room temperature, vented, opened and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-8% methanol in methylene chloride to afford the title compound as white solid. MS m/z 437.63 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][C:9]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C:10]2=1
Reactant: O=C1C=C(Nc2ccccc2F)CCC1
Agent: [Cu+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C1CCCc2[nH]c3c(F)cccc3c21
Yield: 68.9 %

Procedure:
3-[(2-Fluorophenyl)amino]-2-cylcohexen-1-one (14.8 g), palladium (II) acetate (1 g), and copper (II) acetate (29.5 g) were heated together in DMF (10 ml) under nitrogen at 140° for 2 h. The solvent was removed in vacuo, and the residue was purified by FCC eluting with ether to give the title compound (10.1 g), m.p. 222°-224°.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[CH3:31][C:32]1([NH2:36])[CH2:35][CH2:34][CH2:33]1>C(O)C>[CH3:31][C:32]1([NH:36][C:2]2[N:6]=[C:5]([CH:7]3[CH2:12][CH:11]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=4)[CH2:10][N:9]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])[CH2:8]3)[O:4][N:3]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Reactant: CC1(N)CCC1
Solvent: CCO
Product: CC1(Nc2noc(C3CC(c4ccc(C(F)(F)F)cc4)CN(C(=O)N4CCOCC4)C3)n2)CCC1
Reaction time: 2 h

Procedure:
To a solution of 100 mg (0.225 mmol) of the oxadiazole from Example 23A in 1.5 ml of ethanol were added 383 mg (4.50 mmol) of 1-methylcyclobutanamine, and then the reaction mixture was stirred in the microwave at 80 for 2 h and then at 90° C. for 2 h. Another 383 mg (4.50 mmol) of 1-methylcyclobutanamine were added and the mixture was stirred in the microwave at 90° C. for a further 6 h and then at 100° C. for 6 h. Subsequently, another 383 mg (4.50 mmol) of 1-methylcyclobutanamine were added and the mixture was stirred in the microwave at 100 for a further 20 h. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 27.2 mg (24% of theory)