Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:8]=2)[N:6]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[C:18]([O:17][C:16](=[O:22])[NH:15][CH2:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:23](=[O:25])[CH3:24])[S:3][CH:4]=2)=[CH:12][CH:11]=1)([CH3:19])([CH3:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2csc(N)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(-c2ccc(CCNC(=O)OC(C)(C)C)cc2)cs1
Reaction time: 8 h
Yield: 85.3 %

Procedure:
tert-Butyl {2-[4-(2-amino-1,3-thiazol-4-yl)phenyl]ethyl}carbamate (290 mg) was dissolved in dichloromethane (5 mL), then acetic anhydride (0.103 mL), 4-dimethylaminopyridine (10 mg) and pyridine (0.147 mL) were added. The mixture was stirred overnight. The mixture was extracted with chloroform, washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The solid was washed with ethyl ether, and dried in vacuo to give tert-butyl(2-{4-[2-(acetylamino)-1,3-thiazol-4-yl]phenyl}ethyl)carbamate as a white solid (280 mg, 85.3%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][N:20]3[C:26](=[O:27])[CH2:25][C:24]4[CH:28]=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:23]=4[CH2:22][CH2:21]3)[CH2:14]2)[CH:7]=[CH:8][C:9]=1[OH:10].[CH3:36][S:37]([Cl:40])(=[O:39])=[O:38]>>[ClH:40].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][N:20]3[C:26](=[O:27])[CH2:25][C:24]4[CH:28]=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:23]=4[CH2:22][CH2:21]3)[CH2:14]2)[CH:7]=[CH:8][C:9]=1[O:10][S:37]([CH3:36])(=[O:39])=[O:38]
Reactant: COc1cc(CCN2CCCC(CN3CCc4cc(OC)c(OC)cc4CC3=O)C2)ccc1O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: COc1cc2c(cc1OC)CC(=O)N(CC1CCCN(CCc3ccc(OS(C)(=O)=O)c(OC)c3)C1)CC2

Procedure:
Prepared from 3-[(N-(2-(3-methoxy-4-hydroxy-phenyl)-ethyl)-piperidin-3-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-hydrochloride and methanesulphonic acid chloride analogously to Example 9.
Reaction SMILES: [NH2:1][C:2](C(Cl)(Cl)Cl)=[C:3]([C:15]#[N:16])[C:4]([NH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[O:13][CH3:14])=O.[OH2:21].[NH2:22][NH2:23]>CN1CCCC1=O>[NH2:1][C:2]1[C:3]([C:4]([NH:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:12]=2[O:13][CH3:14])=[O:21])=[C:15]([NH2:16])[NH:23][N:22]=1
Reactant: NN
Reactant: O
Reactant: COc1ccncc1NC(=O)C(C#N)=C(N)C(Cl)(Cl)Cl
Solvent: CN1CCCC1=O
Product: COc1ccncc1NC(=O)c1c(N)n[nH]c1N
Temperature: 80 °C
Yield: 97.7 %

Procedure:
3-Amino-4,4,4-trichloro-2-cyano-N-(4-methoxy-3-pyridyl)but-2-enamide (37.2 g, 110.9 mmol) was dissolved in N-methylpyrrolidinone (200 mL). Hydrazine hydrate (14.43 g, 14.02 mL, 288.3 mmol) was added portionwise, then the mixture heated to 80° C. for 20 hr. The mixture was cooled to ambient and concentrated in vacuo. The viscous red oil was stirred as TBME (180 ml)/DCM (20 ml) was added. The yellow solid that precipitated was filtered, washed with TBME and dried to afford the title compound (26.9 g, 98%). LC-MS (M+H)+ 249.0; 1H NMR (500 MHz, DMSO-d6) δ 11.90 (br s, 1H), 9.32 (s, 1H), 9.14 (s, 1H), 8.15 (d, 1H), 7.10 (d, 1H), 3.92 (s, 3H).
Reaction SMILES: Cl[C:2]1[NH:7][C:6]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]([CH3:28])=[C:24]([Cl:27])[C:25]=3[Cl:26])=[O:20])[CH2:14][CH2:13]2)(C(OC)=O)[CH:5]=[CH:4][N:3]=1.[SH:29][CH2:30][CH2:31][OH:32].[C:33](=O)([O-:35])[O-:34].[K+].[K+]>CN(C=O)C.CCOC(C)=O.Cl>[Cl:26][C:25]1[C:24]([Cl:27])=[C:23]([CH3:28])[NH:22][C:21]=1[C:19]([NH:18][CH:15]1[CH2:14][CH2:13][N:12]([C:6]2[N:7]=[C:2]([S:29][CH2:30][CH2:31][OH:32])[N:3]=[C:4]([C:33]([OH:35])=[O:34])[CH:5]=2)[CH2:17][CH2:16]1)=[O:20]
Reactant: COC(=O)C1(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)C=CN=C(Cl)N1
Reactant: OCCS
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(SCCO)n3)CC2)c(Cl)c1Cl
Temperature: 65 °C
Reaction time: 3 h
Yield: 24.2 %

Procedure:
A suspension of methyl 2-chloro-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)pyrimidine-4-carboxylate (Example 6, 150 mg, 0.34 mmol), 2-mercaptoethanol (31 mg, 0.40 mmol) and potassium carbonate (139 mg, 1.01 mmol) in DMF (3 ml) were stirred at 65° C. under nitrogen for 3 hours. The mixture was cooled to room temperature and diluted with EtOAc (75 ml) and 1 N HCl (3 ml). The organic layer was separated, dried over Na2SO4, filtered and concentrated under vacuum. Purification of the residue by reversed-phase HPLC (water/acetonitrile gradient, 10-95%) gave 39 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1.[F:31][C:32]([F:43])([F:42])[C:33]1C=CC(B(O)O)=C[CH:34]=1.C([O-])(O)=O.[Na+].[CH2:49]1[CH2:53]O[CH2:51][CH2:50]1>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>[CH2:28]([N:3]1[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=[C:2]1[C:49]1[CH:50]=[CH:51][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:53]=1)[CH2:29][CH3:30]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: C1CCOC1
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
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+]
Product: CCCn1c(-c2ccc(C(F)(F)F)cc2)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 25 °C
Yield: 36 %

Procedure:
A mixture of 2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (0.1 g, 0.239 mmol) and 4-Trifluoromethylphenyl boronic acid (0.038 g, 0.239 mmol) in THF (5 ml) were stirred at room temperature under argon and added 1M aqueous NaHCO3 (0.04 g, 0.478 mmol) and Pd(PPh3)4 (0.013 g, 0.0119 mmol). The reaction mixture was heated at 80° C. for overnight and the solvent was removed under reduced pressure. The residue was purified by column chromatography to obtain 1-Propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-2-(4-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one (0.05 g, 36%) as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17]I.O>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:17])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ccc(I)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Under an argon atmosphere, a solution of N-(4-iodophenyl)pyrimidin-2-amine (1.47 g) in anhydrous DMF (10 ml) was added dropwise to a suspension of sodium hydride (218 mg) in anhydrous DMF (8 ml), and the resulting mixture was stirred at room temperature for 75 minutes. Methyl iodide (0.37 ml) was added dropwise to the reaction solution and the resulting mixture was stirred at room temperature for another 1 hour. Water was added thereto and the resulting mixture was extracted with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from hexane to obtain N-(4-iodophenyl)-N-methylpyrimidin-2-amine (1.38 g). NMR (H1, CDCl3): δ 3.49 (3H, s), 6.58 (1H, t, J=4.6 Hz), 7.07-7.09 (2H, m), 7.67-7.69 (2H, m), 8.32 (2H, d, J=4.6 Hz)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])[NH2:6].[Cl:14]C1C=C(C=CC=1S(C)(=O)=O)[NH2:18]>>[ClH:14].[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:6][NH2:18])[CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)c1ccc(N)cc1CO
Reactant: CS(=O)(=O)c1ccc(N)cc1Cl
Product: CS(=O)(=O)c1ccc(NN)cc1CO
Product: Cl

Procedure:
The title compound was prepared according to the procedure of step1 of Example 155 using 3-hydroxymethyl-4-(methylsulfonyl)aniline from step3 instead of 3-chloro-4-(methylsulfonyl)aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:10]([C:11](=O)[C:12]#[C:13]C)=[C:4]2[CH:3]=1.Cl.[CH:24]1([NH:29][C:30]([NH2:32])=[NH:31])[CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:10]([C:11]3[CH:12]=[CH:13][N:32]=[C:30]([NH:29][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[N:31]=3)=[C:4]2[CH:3]=1
Reactant: CC#CC(=O)c1c(-c2ccc(F)cc2)nn2ccc(Cl)cc12
Reactant: N=C(N)NC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 80 °C

Procedure:
To a solution of 1-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-butyn-1-one (0.61 g. 2.0 mmol) in N,N-dimethylformamide was added cyclopentyl guanidine hydrochloride (0.67 g, 4.1 mmol) followed by anhydrous potassium carbonate (0.57 g, 4.1 mmol). The resulting mixture was heated at 80° C. for 12 hours. Upon cooling to room temperature, water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (1:1 ethyl acetate-hexane) to give, after recrystallization from acetonitrile, 4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (0.6 g, 74%) as a white solid. 1H-NMR (CDCl3): δ8.54 (broad s, 1H), 8.40 (d, 1H), 8.04 (d, 1H), 7.60 (q, 2H), 7.16 (t, 2H), 6.88 (dd, 1H), 6.28 (d, 1H), 5.22 (d, 1H), 4.40 (m, 1H), 1.4–2.2 (m, 8H); 19F-NMR (CDCl3): δ −112.5; MS m/z 408 (M+1).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[C:7](=O)[CH:6]([C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:5]1)(=[O:3])[CH3:2].Cl.[O:26]1[C:30]2[CH:31]=[CH:32][C:33]([NH:35][NH2:36])=[CH:34][C:29]=2[O:28][CH2:27]1>C(O)(=O)C>[C:1]([N:4]1[C:13]2[CH:12]=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=2[C:7]2[N:35]([C:33]3[CH:32]=[CH:31][C:30]4[O:26][CH2:27][O:28][C:29]=4[CH:34]=3)[N:36]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)C1CN(C(C)=O)c2ccc([N+](=O)[O-])cc2C1=O
Reactant: NNc1ccc2c(c1)OCO2
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CN(C(C)=O)c1ccc([N+](=O)[O-])cc1-2
Temperature: 60 °C
Yield: 78 %

Procedure:
The material of Step 3 (1.1 g, 0.00331 mol) and 1-(1,3-benzodioxol-5-yl)hydrazine hydrochloride (500 mg, 0.00265 mol) were combined in acetic acid (10 mL) and heated to 60° C. for 5 hours. The suspension was then cooled and filtered to give the product as a brown solid. 930 mg (MW=450.4 g/mol, 78% yield). LC/MS m/z=451.5 (m+1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH2:20][C:19]4[C:25]([C:29]([NH2:31])=[O:30])=[N:26][N:27]([CH3:28])[C:18]=4[C:17]=3[N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)=O>C(O)C.[Pd]>[CH3:28][N:27]1[C:18]2[C:17]3[N:16]=[C:15]([NH:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[N:24]=[CH:23][C:22]=3[CH2:21][CH2:20][C:19]=2[C:25]([C:29]([NH2:31])=[O:30])=[N:26]1
Reactant: Cn1nc(C(N)=O)c2c1-c1nc(NC3CCN(Cc4ccccc4)CC3)ncc1CC2
Agent: [Pd]
Solvent: CCO
Solvent: O=CO
Product: Cn1nc(C(N)=O)c2c1-c1nc(NC3CCNCC3)ncc1CC2
Temperature: 60 °C
Reaction time: 12 h
Yield: 44.5 %

Procedure:
To a solution of 1 g (2.4 mmol) of 8-[(1-benzylpiperidin-4-yl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide in 90 mL of absolute ethanol 1 g of palladium on charcoal 10% w and 30 mL of 98% formic acid were added. The resulting mixture was stirred at 60° C. for 12 hours. The catalyst was then filtered on celite and the filtrate evaporated. The crude was purified by chromatography on a silica gel column eluted with a mixture CH2Cl2-MeOH-Et3N, giving 350 mg (45% yield) of the title compound.
Reaction SMILES: [CH:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[CH2:2].[CH2:8]([Br:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].CO>C(OCC)C>[Br-:26].[CH:1]([N+:3]1[CH:7]=[CH:6][N:5]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])[CH:4]=1)=[CH2:2]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: C=Cn1ccnc1
Solvent: CO
Solvent: CCOCC
Product: C=C[n+]1ccn(CCCCCCCCCCCCCCCCCC)c1
Product: [Br-]
Temperature: 60 °C
Reaction time: 15 h

Procedure:
(From Yuan & Antonietti, DOI: 10.1021/ma102858b.) A solution/suspension comprising 0.1 mol of 1-vinylimidazole, 0.1 mol of n-octadecyl bromide and 30 mL of methanol were loaded into a 100 mL reactor. The mixture was stirred at 60° C. for 15 h. After cooling the reaction mixture was added dropwise into 1 L of diethyl ether. The white precipitate was filtered off and dried at room temperature to yield a powder.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:7])[CH2:5][Cl:6].C(N(CC)CC)C.[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18]>C1C=CC=CC=1>[Cl:6][CH2:5][C:4]([O:7][C:17](=[O:18])[N:16]([CH3:20])[CH3:15])=[N:3][O:2][CH3:1]
Reactant: CN(C)C(=O)Cl
Reactant: CONC(=O)CCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CON=C(CCl)OC(=O)N(C)C
Temperature: 25 °C

Procedure:
N-Methoxychloroacetamide (12.3 grams; 0.1 mole), benzene (75 ml) and triethylamine (12 grams; 1.2 mole) are charged into a glass reaction flask equipped with a mechanical stirrer, therometer and reflux condenser. N,N-Dimethylcarbamoyl chloride (11 grams; 0.1 mole) dissolved in benzene (25 ml) is incrementally added to the reaction mixture, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 3 hours. After this time the reaction mixture is distilled to remove benzene and unreacted starting material thereby yielding the desired product 1-chloro-2-(N,N-dimethylcarbamoyloxy)-2-methoxyiminoethane.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].Cl[CH2:9][C:10]1[N:11]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:13][CH:14]=1.O>CN1C(=O)N(C)CCC1.C1COCC1>[C:15]1([C:12]2[O:13][CH:14]=[C:10]([CH2:9][O:4][CH2:3][CH2:2][CH2:1][OH:5])[N:11]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCCCO
Reactant: ClCc1coc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: OCCCOCc1coc(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1,3-Propanediol (3.6 mL, 50 mmol) is dissolved in 10% DMPU in THF and cooled to 0° C. Sodium hydride is added portionwise (60%, 400 mg, 10 mmol). The contents are stirred for 10 min at 0° C., warmed to r.t. and stirred for another 10 min. 4-Chloromethyl-2-phenyl-oxazole (2.0 g, 10 mmol, EXAMPLE 21) is added, and the contents heated to 60° C. for 4 days. The reaction is cooled to r.t., poured into water (200 mL) and extracted with ethyl acetate (2×200 mL). The organic fractions were pooled and washed with brine (2×200 mL), dried over MgSO4, filtered and reduced under vacuum to an oil. The crude material was purified by flash chromatography (silica, 2% methanol in dichloromethane) to give the title compound. MS (ESI) 234 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]1(=[O:10])[O:9][CH2:8][CH2:7]1>>[Br:1][CH2:2][CH2:3][CH2:4][O:5][CH2:8][CH2:7][C:6]([OH:10])=[O:9]
Reactant: O=C1CCO1
Reactant: OCCCBr
Product: O=C(O)CCOCCCBr
Temperature: 80 °C
Yield: 63.6 %

Procedure:
To a flask was added 3-bromopropanol (25 mL, 0.28 mol) and β-propiolactone (5.0 mL, 0.07 mol) and the resulting mixture was heated to 80° C. for 14 h. The reaction mixture was then cooled to room temperature and the excess 3-bromopropanol was removed under reduced pressure. The crude product was dissolved in dichloromethane (300 mL) and extracted with 1 N sodium hydroxide (300 mL). The aqueous layer was then acidified to pH 2 and extracted with dichloromethane (300 mL). The organic layer was then washed with water (200 mL), brine (200 mL), dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure to give 9.4 g of the title intermediate, which was used without further purification (64% yield).
Reaction SMILES: O/[C:2](=[C:4]1\[C:5](=[O:17])[NH:6][C:7](=[O:16])[CH2:8][CH:9]\1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)/[CH3:3].[NH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:27][CH3:28])=[C:24]([OH:26])[CH:25]=1.C([O-])(=O)C.[Na+]>C(O)C>[OH:26][C:24]1[CH:25]=[C:20]([CH:21]=[CH:22][C:23]=1[O:27][CH3:28])[CH2:19][NH:18]/[C:2](=[C:4]1\[C:5](=[O:17])[NH:6][C:7](=[O:16])[CH2:8][CH:9]\1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)/[CH3:3]
Reactant: C/C(O)=C1/C(=O)NC(=O)CC1c1ccccc1
Reactant: COc1ccc(CN)cc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(CN/C(C)=C2\C(=O)NC(=O)CC2c2ccccc2)cc1O
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To a suspension of (3Z)-3-(1-hydroxyethylidene)-4-phenylpiperidine-2,6-dione (0.12 g, 0.52 mmol) and 5-(aminomethyl)-2-methoxyphenol (98 mg, 0.52 mmol) in absolute ethanol (5 mL) is added sodium acetate (0.75 mmol). The mixture is heated at reflux overnight and then allowed to cool to room temperature. The solvent is evaporated under reduced pressure and the residue is triturated with diethyl ether. The solid is collected, washed with diethyl ether, water, and methanol, and dried under vacuum to give (3Z)-3-{1-[(3-hydroxy-4-methoxybenzyl)amino]ethylidene}-4-phenylpiperidine-2,6-dione as a white powder (0.17 g, 88%).
Reaction SMILES: [CH3:1][C:2]1([C:6]([OH:8])=O)[CH2:5][O:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:33][C:34]1[N:39]=[C:38]([N:40]2[C:48]3[C:43](=[CH:44][CH:45]=[C:46]([C:49]#[N:50])[CH:47]=3)[CH:42]=[N:41]2)[C:37]([NH2:51])=[CH:36][N:35]=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[NH2:33][C:34]1[N:39]=[C:38]([N:40]2[C:48]3[C:43](=[CH:44][CH:45]=[C:46]([C:49]#[N:50])[CH:47]=3)[CH:42]=[N:41]2)[C:37]([NH:51][C:6]([C:2]2([CH3:1])[CH2:5][O:4][CH2:3]2)=[O:8])=[CH:36][N:35]=1
Reactant: CC1(C(=O)O)COC1
Reactant: N#Cc1ccc2cnn(-c3nc(N)ncc3N)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C(=O)Nc2cnc(N)nc2-n2ncc3ccc(C#N)cc32)COC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 3-methyloxetane-3-carboxylic acid (17 mg, 0.143 mmol) and HATU (54.5 mg, 0.143 mmol) was added a solution of 1-(2,5-diaminopyrimidin-4-yl)-1H-indazole-6-carbonitrile (30 mg, 0.072 mmol) in DMF (0.5 mL) followed by triethylamine (0.030 mL, 0.215 mmol). The mixture was stirred at RT for 10 min, then diluted with EtOAc (10 mL) and washed with water (2×3 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the crude compound. The crude product was purified by flash chromatography (Isolute column, 90% EtOAc in heptane to 100% EtOAc and then 0.5% MeOH/EtOAc) to afford the title compound as a pale yellow solid: 1H NMR (250 MHz, DMSO) δ 1.61 (3H, s), 4.31 (2H, d, J=5.94 Hz), 4.83 (2H, d, J=5.94 Hz), 7.20 (2H, br. s.), 7.65-7.92 (1H, m), 8.12 (1H, dd, J=8.22, 0.76 Hz), 8.49 (1H, s), 8.64 (1H, d, J=0.91 Hz), 9.14 (1H, s), 9.70 (1H, s); LC-MS: m/z=+350.1 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[C:24]([CH2:28][CH3:29])=[CH:25][CH2:26][CH3:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH2:28]([C:24]([C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:30])=[CH:25][CH2:26][CH3:27])[CH3:29]
Reactant: CCC=C(CC)c1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC=C(CC)c1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
The mixture of 2-[2-(-1-ethyl-but-1-enyl)-3-methyl-benzoylamino]-indan-2-carboxylic acid ethyl ester (128) (503 mg, 1.24 mmol) and KOH (1 g, 17.9 mmol) is dissolved in EtOH (10 mL) and water (1 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 (40 mL) and acidified with conc. HCl until pH˜3. The precipitate is filtered to give a pure product (129) as a brown solid (452 mg, 97%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].OO.S(S([O-])=O)([O-])(=O)=[O:18].[Na+].[Na+]>C(O)(=O)C>[CH3:1][S:2]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])=[O:18]
Reactant: CSc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CS(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 89 %

Procedure:
4-Methylthio-3-nitrobenzoic acid (4.36 g, 20 mM) was dissolved in acetic acid (200 ml), and treated at ambient temperature with H2O2 (2.5 ml, 30%, 22 mM). After stirring at ambient temperature for 4 days, excess peroxide was decomposed with sodium metabisulfite, and solvent evaporated. The residue was purified by chromatography on silica, eluting with methanol, to give 4-methanesulphinyl-3-nitrobenzoic acid (4.1 g, 89%), mp 238-239°. Nmr (DMSO-d6): δ 2.90 (s, 3H); 8.29 (d, 1H); 8.56 (dd, 1H); 8.68 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[S:12])[NH2:11])[CH:5]=1.ClC[C:16](=[O:19])[CH2:17]Cl.[C:20]([O-])(O)=O.[Na+].C[O-].[Na+]>O1CCOCC1.CO>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:12][CH:20]=[C:17]([CH2:16][OH:19])[N:11]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(C(N)=S)c1
Reactant: O=C([O-])O
Reactant: O=C(CCl)CCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2nc(CO)cs2)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
A mixture of 3-thiocarbamoyl-benzoic acid methyl ester (7.8 g), 1,3-dichloro-2-propanone (8.4 g) and NaHCO3 (8.4 g) in 1,4-dioxane (180 mL) was heated to 60° C. for 24 h. The reaction mixture was cooled to 20° C. and added to a stirred solution of NaOMe (5.4 g) in MeOH (200 mL). Stirring was continued for 0.5 h. The mixture was poured into ice-cold 2N HCl (200 mL) and the product was extracted with AcOEt. The organic layer was washed with brine, dried and evaporated in vacuum. The residue was crystallized from CH2Cl2/hexane to give 3-(4-hydroxymethyl-thiazol-2-yl)-benzoic acid methyl ester (7.5 g) as light-brown crystals.