Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH2:16]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:15])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: c1ccc(CC2CCNCC2)cc1
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(Cc3ccccc3)CC2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 4-benzylpiperidine (10.5 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (11.5 mg). Calcd for C23H24N2O2: 360.1838, found 360.1842.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[NH2:20][NH2:21]>>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([NH:20][NH2:21])[CH:11]=1
Reactant: NN
Reactant: Clc1cc(-c2ccccc2Cl)c2ccccc2n1
Solvent: O
Product: NNc1cc(-c2ccccc2Cl)c2ccccc2n1

Procedure:
In the manner given in Example 1, 2-chloro-4-(o-chlorophenyl)quinoline is reacted at reflux with hydrazine hydrate to give 4-(o-chlorophenyl)-2-hydrazinoquinoline.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:23][CH2:24][CH:25](OC)OC)[NH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]2[CH2:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[O:14]2)[CH2:8][CH2:7]1)#[N:2].Cl.C([O-])([O-])=[O:32].[Na+].[Na+]>C1COCC1>[O:14]1[C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH2:17][CH2:18][CH:13]1[CH2:12][N:9]1[CH2:10][CH2:11][CH:6]([N:5]2[CH:25]=[CH:24][N:23]=[C:4]2[NH:3][C:1]#[N:2])[CH2:7][CH2:8]1.[O:14]1[C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH2:17][CH2:18][CH:13]1[CH2:12][N:9]1[CH2:8][CH2:7][CH:6]([N:5]2[CH:25]=[CH:24][N:23]=[C:4]2[NH:3][C:1]([NH2:2])=[O:32])[CH2:11][CH2:10]1
Reactant: COC(CNC(=NC#N)NC1CCN(CC2CCc3ccccc3O2)CC1)OC
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CNc1nccn1C1CCN(CC2CCc3ccccc3O2)CC1
Product: NC(=O)Nc1nccn1C1CCN(CC2CCc3ccccc3O2)CC1
Temperature: 0 °C

Procedure:
A mixture of N″-cyano-N-[1-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]4-piperidinyl]-N′-(2,2-dimethoxyethyl)guanidine (0.0153 mol) and HCl (0.5 N, 46 ml) in THF (160 ml) was stirred and refluxed for 100 minutes. Ice-water was added. Na2CO3 was added portionwise to obtain a clear separation. The organic layer was separated, DCM was added, the whole was washed with water, dried, filtered and the solvent was evaporated. The residue was separated and purified by column chromatography over silica gel (separation first compound: eluent: CH2Cl2/CH3OH 95/5: separation second compound: CH2Cl2/(CH3OH/NH3) 90/10). The two pure fraction groups were collected and their solvent was evaporated. Each residue was crystallized from ACN. Each precipitate was filtered off and dried, yielding 1.75 g [1-[1-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-4-piperidinyl]-1H-imidazol-2-yl]cyanamide (compound 59) and 0.48 g (±)-[1-[1-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-4-piperidinyl]-1H-imidazol-2-yl]urea (compound 66).
Reaction SMILES: CN1CCOCC1.[OH:8][C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][C:10]1=[O:19].[CH3:20][Si:21]([CH3:24])([CH3:23])Cl>O1CCCC1>[CH3:20][Si:21]([CH3:24])([CH3:23])[O:8][C@@H:9]1[C@@H:14]([O:15][Si:21]([CH3:24])([CH3:23])[CH3:20])[C@H:13]([O:16][Si:21]([CH3:24])([CH3:23])[CH3:20])[C@@H:12]([CH2:17][O:18][Si:21]([CH3:24])([CH3:23])[CH3:20])[O:11][C:10]1=[O:19]
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of N-methylmorpholine (246.8 mL, 2.24 mol) and (3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-one 1a (50 g, 0.28 mol, bought from Aladdin) in anhydrous tetrahydrofuran (500 mL) was added dropwise trimethylchlorosilane (213 mL, 1.68 mol) over a period of 2 hours. The mixture was stirred at room temperature (rt) for 8 hours and quenched with 1 L of water. The resulting mixture was partitioned. The organic layer was washed with saturated aqueous dipotassium hydrogen phosphate (100 mL×8.3) and saturated aqueous sodium chloride (100 mL×8.3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=40/1 to give the title compound 1b as colorless oil (125.2 g, 100%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 4.17 (m, 1H), 3.99 (d, 1H), 3.89 (t, 1H), 3.81 (m, 3H), 0.18 (s, 9H), 0.17 (s, 9H), 0.15 (s, 9H), 0.11 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=2)[CH:9]=[C:10]([C:12](OC(C)C)=[O:13])[CH:11]=1.[CH2:28]([CH2:30][NH2:31])[OH:29]>C1COCC1>[CH3:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:2]([CH3:1])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=2)[CH:9]=[C:10]([C:12]([NH:31][CH2:30][CH2:28][OH:29])=[O:13])[CH:11]=1
Reactant: NCCO
Reactant: Cc1cccc(C)c1CNc1cc(C(=O)OC(C)C)cn2c(C)c(C)nc12
Solvent: C1CCOC1
Product: Cc1cccc(C)c1CNc1cc(C(=O)NCCO)cn2c(C)c(C)nc12
Temperature: 100 °C

Procedure:
A reactor was charged with isopropyl 8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylate (11.30 kg, 1 equiv., 27.02 mol) and THF (45 L), ethanolamine (18.97 kg, 11 equiv., 309.2 mol) was added at about 20° C. The suspension was heated to about 100° C. Some solvent was distilled off and then THF (35L) was added and the distillation was continued. The procedure of adding THF and distilling it off was repeated until complete conversion. To the suspension ethanol (140L) was added and the suspension was heated to reflux. To obtain a clear solution additional ethanol (13L) was added. The hot solution was filtered and then cooled. The white solid was filtered off, washed with ethanol and dried to yield the product as a white powder. (8271 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1CCCCC1.[H][H].[H][H].C1(O)C=CC=CC=1.C1(=O)CCCCC1>[Pd].C1CCCCC1>[CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [H][H]
Agent: [Pd]
Solvent: O=C1CCCCC1
Solvent: C1CCCCC1
Solvent: Oc1ccccc1
Product: OC1CCCCC1
Yield: 2 %

Procedure:
In the case of hydrogenating phenol through a phenol hydrogenation process of prior art, for example by using an alumina-supported palladium catalyst, and introducing a mixed solution of phenol and cyclohexane with a phenol/cyclohexane molar ratio of ½ at a phenol flow rate of 0.0135 mol/hr into a hydrogen gas stream (hydrogen/phenol molar ratio=5.4) and carrying out reaction at 230° C., at the start of the flow reaction 98% cyclohexanone and 2% cyclohexanol were produced at a phenol conversion ratio of 77%. However, with this method, there is a drawback that a drop in activity and hence a drop in the conversion ratio occurs due to carbonaceous matter accumulating on the catalyst, and hence the conversion ratio became 63% thirty minutes after the start of the reaction, 55% after 1 hour, 44% after 2 hours, and 42% after 8 hours. Moreover, with this method, experimental operation using only phenol was difficult, and hence the phenol had to be used with harmful cyclohexane as a solvent (N. Mahata and V. Vishwanathan, Journal of Catalysis, 196, 262-270 (2000)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[C:27]([OH:34])(=[O:33])[CH2:28][CH2:29][CH2:30][C:31]#[CH:32].C(N(CC)CC)C>COCCOC.[Cu](I)I.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:32]#[C:31][CH2:30][CH2:29][CH2:28][C:27]([OH:34])=[O:33])=[CH:20][CH:19]=1)=[O:26])[CH3:9]
Reactant: C#CCCCC(=O)O
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Cc1noc(-c2ccc(C#CCCCC(=O)O)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(2-chloro-phenyl)-ethyl ester (0.200 g, 0.46 mmol) and 5-hexynoic acid (0.06 mL, 0.55 mmol) in DME (5 mL) was added copper iodide (0.017 g, 0.09 mmol), followed by tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.05 mmol), and the mixture was purged with N2 for 5 minutes. Triethylamine (0.26 mL, 1.83 mmol) was added, and the reaction was purged with N2 for another 10 minutes and then stirred at 80° C. for 2 hours. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])=[CH:10][CH:11]=1.C(N(CC)CC)C>C(OCC)C.C(OCC)(=O)C>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cc(N)ccc1-c1ccccc1Br
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)c1cc(NC(C)=O)ccc1-c1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
Acetyl chloride (70 mg, 63 μl, 0.89 mmol) was added to a solution of methyl 4-amino-2′-bromo-2-biphenylcarboxylate (227 mg, 0.74 mmol) and triethylamine (90 mg, 123 ul, 0.89 mmol) in diethyl ether (3 ml) and stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate(10 ml) and washed with 2M HCl, 5% NaHCO3, water and brine the organic phase was dried and evaporated to leave the title compound as a yellow oil (226 mg, 88%).
Reaction SMILES: O[C:2]1[C:10]([NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(C)=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[N:16]1[CH:15]=[CH:14][C:13]([C:12]2[O:19][C:2]3[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=[CH:9][C:10]=3[N:11]=2)=[CH:18][CH:17]=1
Reactant: O=C(Nc1cccc(C(=O)O)c1O)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C(O)c1cccc2nc(-c3ccncc3)oc12
Yield: 86.4 %

Procedure:
A mixture of methyl ester of 2-hydroxy-3-isonicotinoylamino-benzoic acid (500 mg, 1.84 mmol), p-toluenesulfonic acid mono-hydrate (349 mg, 1.84 mmol) and xylene (20 ml) was heated under reflux for 14 hrs. and then p-toluenesulfonic acid mono-hydrate (349 mg, 1.84 mmol) was further added and refluxed under heating for 2 hrs. The reaction mixture was cooled with ice, and ethyl acetate and 10% aqueous potassium carbonate solution were added thereto. The organic phase was separated, washed with water and brine in turn and then dried. The solvent was distilled off under reduced pressure, and the residue was triturated with a mixture of n-hexane/diisopropyl ether (4/1), filtered and dried to give methyl ester of [2-(4-pyridyl)-benzoxazol-7-yl]carboxylic acid (382 mg, 82%) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:15])[N:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[S:4][C:3]=1[C:22]([O:24][CH3:25])=[O:23].P(Cl)(Cl)(Cl)=O.O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:5][N:6]([CH:16]=[N:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:15])[N:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[S:4][C:3]=1[C:22]([O:24][CH3:25])=[O:23])[CH3:7]
Reactant: COC(=O)c1sc2c(c1N)c1ccccc1c(=O)n2-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1sc2c(c1N=CN(C)C)c1ccccc1c(=O)n2-c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution o 1.05 g of methyl 1-amino-4,5-dihydro-5-oxo-4-phenyl-thieno[2,3-c]isoquinoline-2-carboxylate in 20 ml of dimethylformamide was added 0.55 g of phosphorus oxychloride at room temperature, and the mixture was stirred for 30 minutes. The reaction mixture was poured into water, and neutralized with a saturated sodium bicarbonate aqueous solution, and precipitates were collected by a filtration. The precipitates were washed with water, and dried under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.09 g of the desired product as pale yellow crystals (eluent: n-hexane/chloroform=1/1).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[Na+].[CH2:8]([N:15]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:16][C:17]([C:19]1[CH:27]=[C:23]([C:24]([NH-:26])=[O:25])[C:22]([OH:28])=[CH:21][CH:20]=1)=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH2:29]([N:15]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:16][C:17]([C:19]1[CH:20]=[CH:21][C:22]([O:28][CH2:2][CH:3]([OH:6])[CH2:4][OH:5])=[C:23]([CH:27]=1)[C:24]([NH2:26])=[O:25])=[O:18])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: [NH-]C(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1O
Reactant: OCC(O)CCl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCC(O)CO
Reaction time: 6 h

Procedure:
3-Chloropropane-1,2-diol (2.65 g) was added to a refluxing suspension of 5-(N,N-dibenzylglycyl)salicylamide sodium salt (10.0 g) in toluene (100 ml) and heating was continued for 6 hours. The mixture was cooled and filtered and the filtrate was evaporated. The residue was crystallised twice from ethanol to give the required product m.p. 169°-173°.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[S:13][CH:12]=[C:11]([CH3:14])[C:9]=2[N:10]=1>CCO>[Cl:4][C:5]1[N:6]=[C:7]([NH:2][NH2:3])[C:8]2[S:13][CH:12]=[C:11]([CH3:14])[C:9]=2[N:10]=1
Reactant: NN
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: O
Solvent: CCO
Product: Cc1csc2c(NN)nc(Cl)nc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
Hydrazine monohydrate (2.21 mL; 45.6 mmol; 2.0 equiv) was added to a suspension of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine (5 g; 22.8 mmol; 1.0 equiv) in 40 mL of EtOH. The reaction was stirred at ambient temperature for 2 days. The solid was filtered, washed with H2O and dried to give 2-chloro-4-hydrazino-7-methylthieno[3,2-d]pyrimidine as an off-white solid (4.4 g; 90% yield); MS (ES) 214.97 (M+H), 212.99 (M−H).
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[I:13].[CH3:15]C([O-])(C)C.[K+].CI>C1COCC1>[F:14][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:15])[N:8]=[C:7]2[I:13]
Reactant: FC(F)Oc1ccc2[nH]nc(I)c2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(I)c2cc(OC(F)F)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of 5-(difluoromethoxy)-3-iodo-1H-indazole (562 mg, 1.81 mmol) in THF (10.00 mL) at 0° C. was added KOtBu (1M in THF, 2.54 mL, 2.54 mmol) and the mixture stirred at 0° C. for 30 min then MeI (360 mg, 159 μL, 2.54 mmol) added. The reaction mixture was stirred at 0° C. for 30 min then warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride in water and extracted with dichloromethane (3×30 mL), organics dried over MgSO4 and concentrated to a clear oil. Purification by chromatography (80 g column, 50 μm from Analogix, 0-20% EtOAc in hexanes over 20 min) gave 5-(difluoromethoxy)-3-iodo-1-methyl-1H-indazole (465 mg, 1.43 mmol, 79.2%) as a waxy off-white solid. MS (M+H)+=324.9; 1H NMR (CDCl3) δ: 7.32-7.40 (m, 1H), 7.24-7.30 (m, 1H), 7.21 (d, J=2.3 Hz, 1H), 6.55 (t, J=73.7 Hz, 1H), 4.10 (s, 3H). The regioisomeric product, 5-(difluoromethoxy)-3-iodo-2-methyl-2H-indazole, (108 mg, 333 μmol, 18%) was also obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=2[O:37][CH3:38])=[CH:22][CH:21]=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:38][O:37][C:29]1[CH:30]=[C:31]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=4)=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:32]=[CH:33][C:28]=1[O:27][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=1
Reactant: Oc1ccc(-c2c[nH]c3ncc(Br)cc23)cn1
Reactant: COc1ccc(COc2ccc(B(O)O)cc2OC)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(COc2ccc(-c3cnc4[nH]cc(-c5ccc(O)nc5)c4c3)cc2OC)cc1
Reaction time: 0.33 h
Yield: 46 %

Procedure:
To the 5-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridin-2-ol, 4-(4-methoxyphenylmethoxy)-3-methoxyphenylboronic acid (1.3 equiv.), and 6 mol % of dichlorobis(triiphenylphosphino)palladium (II) in a Smith process vial was added a 3:2:1 mixture of acetonitrile, water and a 2 M aqueous solution of sodium carbonate (0.10 M). The reaction was run in a Personal Chemistry® microwave reactor at 165° C. for 1200 s. Water was added and the mixture was extracted three times with ethyl acetate Purification on silica gel with a gradient or methanol/dichloromethane by flash chromatography afforded 5-{5-[3-methoxy-4-(4-methoxy-benzyloxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-pyridin-2-ol as a tan solid (46% yield). 1H NMR (DMSO-d6): δ 11.86 (broad s, 1H), 11.67 (broad s, 1H), 8.51 (d, J=2.5 Hz, 1H), 8.22 (s, 1H), 7.89 (dd, J=2.5, 9;5 Hz, 1H), 7.75 (d, J=2.5 Hz, 1H), 7.72 (s, 1H), 7.38 (d, J=8.5 Hz, 2H), 7.30 (d, J=2.0 Hz, 1H), 7.20 (dd, J=2.0, 8.5 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.94 (d, J=8.5 Hz, 2H), 6.44 (d, J=9.5 Hz, 1H), 5.03 (s, 2H), 3.85 (s, 3H), 3.75 (s, 3H); HPLC/MS m/z: 454.1 [MH]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8]C2C=CC=C(O)C=2)[C:5](F)=[CH:4][N:3]=1.[CH2:17]([NH:20][C:21]([C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])=[O:22])[CH2:18][CH3:19]>>[CH2:17]([NH:20][C:21]([C:23]1[CH:24]=[C:25]([NH:26][C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=2)[CH:27]=[CH:28][CH:29]=1)=[O:22])[CH2:18][CH3:19]
Reactant: CCCNC(=O)c1cccc(N)c1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: CCCNC(=O)c1cccc(Nc2nccc(N)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 3-[(N-propylamino)carbonyl]aniline were reacted to provide 5-fluoro-N4-3-hydroxyphenyl)-N2-[3-[(N-propylamino)carbonyl]phenyl]-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.00 (d, 1H, J=5.4 Hz), 7.84 (t, 1H, J=1.8 Hz), 7.69–7.59 (m, 2H), 7.44 (t, 1H, J=7.5 Hz), 7.16–7.05 (m, 3H), 6.67 (td, 1H, J=2.4 and 7.2 Hz), 3.34–3.29 (m, 2H), 1.65–1.56 (m, 2H), 0.96 (t, 3H, J=7.5 Hz); 19F NMR (282 MHz, CD3OD): −46049; LCMS: purity: 94%; MS (m/e): 382(MH+).
Reaction SMILES: [NH2:1][CH:2]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[N:15][C:16]=3[NH2:18])[N:11]([C@H:19]3[CH2:24][CH2:23][C@@H:22]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[N:10]=2)=[CH:5][CH:4]=1.[C:38]1(=[O:43])[O:42][CH:40]([CH3:41])[CH2:39]1>O1CCOCC1>[C:38]([OH:43])(=[O:42])[CH3:39].[NH2:18][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:11]([C@H:19]3[CH2:24][CH2:23][C@@H:22]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)[CH2:21][CH2:20]3)[N:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH:2]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[NH:1][C:38](=[O:43])[CH2:39][CH:40]([OH:42])[CH3:41])=[CH:8][CH:7]=3)[C:17]=12
Reactant: CC1CC(=O)O1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(C(N)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Solvent: C1COCCO1
Product: CC(=O)O
Product: CC(O)CC(=O)NC(c1ccccc1)c1ccc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)cc1

Procedure:
Cis-3-{4-[amino(phenyl)methyl]phenyl}-1-[4-(4-methylpiperazino) cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.05 g, 0.0001 mol) and β-butyrolactone (0.009 g, 0.0001 mol) were heated in dioxane at reflux for three hours. The solvent was removed under reduced pressure and the resulting residue purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile—0.1M ammonium acetate over 25 min, 21 mL/min) to yield cis-N1-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)methyl]-3-hydroxybutanamide acetate (0.027 g, 0.000042 mol) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17](=S)[CH2:18][C:19](=O)[CH3:20])=[O:4].[CH:23]1([NH:27][NH2:28])[CH2:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17]1[N:27]([CH:23]2[CH2:26][CH2:25][CH2:24]2)[N:28]=[C:19]([CH3:20])[CH:18]=1)=[O:4]
Reactant: NNC1CCC1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1c1cc(C)nn1C1CCC1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-cyclopropylmethanesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 445c) was reacted with cyclobutylhydrazine (CAS Reg. No. 742673-64-9) to give the title compound as brown solid. MS (ESI): m/z=382.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:6]=[C:7]([C:11]([F:16])([CH3:15])[C:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)=[S:3].Br[CH2:18][C:19](=O)[C:20]([F:23])([F:22])[F:21].[C:25]([O-])(O)=O.[Na+]>O1CCOCC1.O>[F:16][C:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([NH:4][C:2]2[S:3][CH:18]=[C:19]([C:20]([F:23])([F:22])[F:21])[N:1]=2)[CH:6]=1)([CH3:15])[C:12]([O:14][CH3:25])=[O:13]
Reactant: O=C([O-])O
Reactant: O=C(CBr)C(F)(F)F
Reactant: CC(F)(C(=O)[O-])c1cccc(NC(N)=S)c1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C(C)(F)c1cccc(Nc2nc(C(F)(F)F)cs2)c1
Temperature: 25 °C
Yield: 77 %

Procedure:
To a solution of 2-{3-[(aminocarbonothioyl)amino]phenyl}-2-fluoropropanoate (0.84 g, 3.3 mmol) in a 1:1 dioxane/water mixture (10 mL), 3-bromo-1,1,1-trifluoroacetone (0.42 mL, 4.0 mmol) was added dropwise and the mixture refluxed for 18 h. After cooling at room temperature, a saturated solution of NaHCO3 (20 mL) was added and the mixture trasferred into a separator funnel; the aqueous phase was extracted with EtOAc (3×20 mL) and the collected organic extracts dried over Na2SO4 and evaporated under vacuum to give a crude that, after purification by flash chromatography, afforded pure methyl 2-fluoro-2-(3-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate as yellow solid (0.89 g, yield 77%). 1H-NMR (CDCl3) δ 7.95 (bs, 1H, NH), 7.53 (s, 1H), 7.42 (m, 2H), 7.28 (s, 1H), 7.10 (s, 1H), 3.80 (s, 3H), 1.95 (d, 3H, J=23 Hz).