Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([Br:16])=[C:12]([Br:15])[CH:13]=2)[NH:8][C:7](=[O:17])[C:6]1=[O:18])([OH:3])=[O:2].[N+:19]([O-])([O-:21])=[O:20].[K+]>OS(O)(=O)=O>[C:1]([CH2:4][N:5]1[C:14]2[C:9](=[C:10]([N+:19]([O-:21])=[O:20])[C:11]([Br:16])=[C:12]([Br:15])[CH:13]=2)[NH:8][C:7](=[O:17])[C:6]1=[O:18])([OH:3])=[O:2]
Reactant: O=C(O)Cn1c(=O)c(=O)[nH]c2cc(Br)c(Br)cc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)Cn1c(=O)c(=O)[nH]c2c([N+](=O)[O-])c(Br)c(Br)cc21
Temperature: 28 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a stirred solution of 1-carboxymethyl-6,7-dibromo-1,4-dihydroquinoxaline-2,3-dione (100 mg, 0.264 mmol) in concentrated H2SO4 (1.5 mL) at 5°-10° C., KNO3 (28 mg, 0.28 mmol) was added in one portion. The resulting dark green solution was stirred at 5°-10° C. for 30 min and at 28° C. overnight. The yellow colored suspension thus obtained was poured into ice-water (15 g) and the resulting shining yellow solid was filtered and dried under vacuum to obtain 53 mg (47%, pure by 1H NMR) 1-carboxymethyl-6,7-dibromo-5-nitro-1,4-dihydro-2,3-quinoxalinedione as a shining yellow powder; M.p. 260°-264° C. 1H NMR: δ4.91 (s, 1H), 7.98 (s, 1H). IR (KBr, cm-1): 1701, 1543, 1391, 1244. HRMS calcd for C10H5Br2N3O6 (M+) m/z 420.8546, found m/z 420.8559.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([OH:6])=O.[CH3:13][O:14][C:15]1[CH:43]=[CH:42][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([NH2:25])[C:22]([C:26]3[NH:30][C:29]4[CH:31]=[CH:32][C:33]([CH2:35][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[CH:34][C:28]=4[N:27]=3)=[N:21]2)=[CH:17][CH:16]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([NH:25][C:23]1[C:22]([C:26]2[NH:30][C:29]3[CH:31]=[CH:32][C:33]([CH2:35][N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[CH:34][C:28]=3[N:27]=2)=[N:21][N:20]([CH2:19][C:18]2[CH:42]=[CH:43][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH:24]=1)=[O:6]
Reactant: COc1ccc(Cn2cc(N)c(-c3nc4cc(CN5CCOCC5)ccc4[nH]3)n2)cc1
Reactant: COc1cccc(F)c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc(Cn2cc(NC(=O)c3c(F)cccc3OC)c(-c3nc4cc(CN5CCOCC5)ccc4[nH]3)n2)cc1
Yield: 116.8 %

Procedure:
A mixture of 2-fluoro-6-methoxy-benzoic acid (20 mg, 0.12 mmol), 1-(4-methoxy-benzyl)-3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (50 mg, 0.12 mmol), EDC (116 mg, 0.14 mmol) and HOBt (81 mg, 0.14 mmol) was stirred at room temperature in DMF (2 ml) for 20 h. The mixture was reduced in vacuo and the residue partitioned between EtOAc (5 ml) and water (2 ml) and the organic portion washed with saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and reduced in vacuo. The residue was purified by flash column chromatography [SiO2, EtOAc] to give 2-fluoro-6-methoxy-N-[1-(4-methoxy-benzyl)-3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide as a white solid (80 mg, 61%).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C1(NC(C)(C)C)C=CC=CC=1.NC(N)=O.C(NN[CH2:25][C:26]([C:28]1[CH:29]=[CH:30][C:31]([OH:37])=[C:32]([CH2:34][C:35]#[N:36])[CH:33]=1)=[O:27])(C)C>>[OH:37][C:31]1[CH:30]=[CH:29][C:28]([CH:26]([OH:27])[CH2:25][NH:4][CH:1]([CH3:3])[CH3:2])=[CH:33][C:32]=1[CH2:34][C:35]#[N:36]
Reactant: CC(C)NNCC(=O)c1ccc(O)c(CC#N)c1
Reactant: CC(C)N
Agent: CC(C)(C)Nc1ccccc1
Agent: NC(N)=O
Product: CC(C)NCC(O)c1ccc(O)c(CC#N)c1

Procedure:
The procedure of Example 1(c) is repeated with substitution of an equimolar amount of isopropylamine for phenyl-t-butylamine in that example. The resulting aminoketone, 5-[N-(isopropylamino)glycyl]-2-hydroxyphenylacetonitrile, is reduced according to the procedure of Example 1(d) to yield 2-hydroxy-5-[1-hydroxy-2-(isopropylamino)ethyl]benzeneacetonitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C:8]2([CH:17]([F:19])[F:18])[NH:13][C:12](=[O:14])[C:11]([CH3:16])([CH3:15])[O:10][CH2:9]2)[CH:7]=1.C([O-])(=O)C.[Na+].[H][H]>CO.C1COCC1.[Pd]>[F:19][CH:17]([F:18])[C:8]1([C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[F:20])[NH:13][C:12](=[O:14])[C:11]([CH3:16])([CH3:15])[O:10][CH2:9]1
Reactant: CC1(C)OCC(c2cc(Br)ccc2F)(C(F)F)NC1=O
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)OCC(c2ccccc2F)(C(F)F)NC1=O
Yield: 99.3 %

Procedure:
5-(5-Bromo-2-fluoro-phenyl)-5-difluoromethyl-2,2-dimethyl-morpholin-3-one (3.14 g, 8.92 mmol) and sodium acetate (1.46 g, 17.83 mmol) were suspended in 100 mL methanol and 10 mL THF. Eventually, 10% Pd on charcoal (315 mg) was added and the reaction mixture was treated with hydrogen (balloon) at rt. After 60 minutes the reaction mixture was filtered over celite and evaporated. The residue was partitioned between aqueous Na2CO3 solution and EtOAc. The layers were separated, washed with brine and EtOAc. The combined organic layers were dried over MgSO4.H2O and evaporated to give 2.42 g of the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH2:33][CH2:34][CH3:35])=[C:10]([CH2:12][O:13][C:14]3[CH:32]=[CH:31][C:17]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH2:26][C:27]([O:29]C)=[O:28])=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[C:1]1([C:7]2[O:8][C:9]([CH2:33][CH2:34][CH3:35])=[C:10]([CH2:12][O:13][C:14]3[CH:32]=[CH:31][C:17]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH2:26][C:27]([OH:29])=[O:28])=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCc1oc(-c2ccccc2)nc1COc1ccc(COc2ccccc2CC(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCCc1oc(-c2ccccc2)nc1COc1ccc(COc2ccccc2CC(=O)O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a mixture of methyl 2-[2-[4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (0.40 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added a 1N aqueous sodium hydroxide solution (1.7 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.30 g, 77%) of 2-[2-[4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 129-130° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:8]3[CH:21]=[CH:20][NH:19][C:9]=3[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:12]=2)[CH:2]=1.Cl[C:23]1C2C=CNC=2N=C(C2C=CC=CN=2)N=1.ClC1C2C=CNC=2N=C(C2C=CC=C(C)N=2)N=1>>[CH3:23][C:15]1[N:14]=[C:13]([C:11]2[N:12]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[C:8]3[CH:21]=[CH:20][NH:19][C:9]=3[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Clc1nc(-c2ccccn2)nc2[nH]ccc12
Reactant: c1ccc(-c2nc(-c3cccnc3)c3cc[nH]c3n2)nc1
Agent: Cc1cccc(-c2nc(Cl)c3cc[nH]c3n2)n1
Product: Cc1cccc(-c2nc(-c3cccnc3)c3cc[nH]c3n2)n1

Procedure:
2-(6-Methyl-pyridin-2-yl)-4-pyridin-3-yl-7H-pyrrolo[2,3-d]pyrimidine is prepared by an analogous method to 4-pyridin-3-yl-2-pyridin-2-yl-7H-pyrrolo[2,3-d]pyrimidine (Example 1) by replacing 4-chloro-2-pyridin-2-yl-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 1) with 4-chloro-2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[N:12][C:11]([NH:14][CH2:15][C:16]3([C:20]4[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:28][NH2:29].O1CCOCC1>C(OCC)(=O)C>[F:26][C:25]1[C:20]([C:16]2([CH2:15][NH:14][C:11]3[N:12]=[N:13][C:8]([C:7]4[C:2]([NH:28][NH2:29])=[N:3][CH:4]=[CH:5][CH:6]=4)=[CH:9][CH:10]=3)[CH2:19][CH2:18][CH2:17]2)=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: NN
Reactant: Fc1cccnc1C1(CNc2ccc(-c3cccnc3Cl)nn2)CCC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: NNc1ncccc1-c1ccc(NCC2(c3ncccc3F)CCC2)nn1
Temperature: 160 °C

Procedure:
To a 5 mL microwave reaction vessel was added 6-(2-chloropyridin-3-yl)-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine (750 mg, 2.0 mmol), hydrazine hydrate (1 mL), and dioxane (4 mL). The reaction was heated in a microwave reactor to 160° C. for 15 min, then diluted with ethyl acetate (50 mL), and washed with brine (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by reverse phase column chromatography to give 150 mg of N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)-6-(2-hydrazinylpyridin-3-yl)pyridazin-3-amine as an off-white solid. The isolated product was then dissolved in methanol and added to a vial containing ˜1 mL of Raney Nickel suspension in water. The mixture was then stirred under 50 psi of hydrogen for 2 h. The reaction was then filtered, concentrated, and purified by reverse phase column chromatography to give 10 mg (88%) of 6-(2-aminopyridin-3-yl)-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine as an off-white solid, m/z=351.1 [M+H].
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:10]1[S:11][C:12]([S:26][CH3:27])=[C:13]([S:15]([C:18]2[CH:19]=[N:20][C:21](Cl)=[C:22]([Br:24])[CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])(C)(C)C.[NH2:29][CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33].C(Cl)Cl.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C1COCC1>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[Br:24][C:22]1[CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8]([NH2:7])=[NH:9])[S:11][C:12]=2[S:26][CH3:27])(=[O:17])=[O:16])[CH:19]=[N:20][C:21]=1[NH:29][CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33]
Reactant: CC(C)(CN)CO
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cnc(Cl)c(Br)c1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cnc(NCC(C)(C)CO)c(Br)c1

Procedure:
The reaction was conducted following the procedure for Example 164: step c, using {[4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.035 g, 0.066 mmol), 3-amino-2,2-dimethylpropanol (0.013 g, 0.133 mmol), THF [2 mL], followed by DCM/TFA (1:1) and reverse-phase HPLC to yield the title compound. ESI-MS (m/z): Calcd. for C17H22BrN3O3S3: 493.48 (M+H); found 493.1, 495.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9](C=O)[NH:8][C:7]=1[CH2:19][CH2:20][NH:21]C(OC(C)(C)C)=O)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][NH:8][C:7]=1[CH2:19][CH2:20][NH2:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CCNC(=O)OC(C)(C)C)[nH]c(C=O)c1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccccc2)c[nH]c1CCN
Reaction time: 3 h

Procedure:
A stirred solution of 2-(2-tert-butoxycarbonylamino-ethyl)-5-formyl-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (1.120 g, 3 mmol) in dichloromethane (32 ml) was added dropwise slowly with trifluoroacetic acid (3.2 ml) at room temperature. Upon completion of the addition, the mixture was stirred for 3 hours, and concentrated to give 2-(2-amino-ethyl)-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester which Was used as such.
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[O:6][C:7]1[CH:8]=[C:9]([CH3:23])[C:10]2[C@@H:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][B:12]([OH:21])[C:11]=2[CH:22]=1.C1COCC1.[Li+].[OH-].Cl>O.CO>[S:1]1[CH:5]=[N:4][N:3]=[C:2]1[O:6][C:7]1[CH:8]=[C:9]([CH3:23])[C:10]2[C@H:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][B:12]([OH:21])[C:11]=2[CH:22]=1
Reactant: CCOC(=O)C[C@H]1OB(O)c2cc(Oc3nncs3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOC(=O)C[C@@H]1OB(O)c2cc(Oc3nncs3)cc(C)c21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)-ethyl 2-(6-(1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (0.9 g, 2.69 mmol) in a mixed solution of THF (30 mL) and methanol (4 mL) was added a solution of LiOH. H2O (0.57 g, 13.5 mmol) in water (30 mL) at 0° C. The resulting mixture was stirred at room temperature for 1.5 hrs and then acidified to pH=2 with diluted hydrochloric acid at 0° C. After removal of the volatile organics, the residue was dissolved in EtOAc. The aqueous phase was dried and concentrated in vacuo to give the products.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH:14]1([CH2:19][NH2:20])[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl.CN(C)CCCN=C=NCC.C(Cl)Cl>CN(C)C1C=CN=CC=1.C(OCC)(=O)C.CN(C)C=O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=[O:13])[NH:20][CH2:19][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: O=C(O)c1ccc2c(Br)n[nH]c2c1
Reactant: NCC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCC1CCCC1)c1ccc2c(Br)n[nH]c2c1
Reaction time: 48 h
Yield: 72 %

Procedure:
To a mixture of 3-bromo-6-carboxyindazole (5.84 g), cyclopentylmethylamine (3.48 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.25 g), methylene chloride (120 ml) and dimethylformamide (40 ml) was added 4-dimethylaminopyridine (5.10 g). After stirring for 48 hours, the reaction mixture was added to 450 ml ethyl acetate; washed with 1N hydrochloric acid, 0.5M sodium carbonate and brine: dried (MgSO4); and evaporated. The residue was flash chromatographed over 175 g silica gel, eluting sequentially with methylene chloride (350 ml), 15:85 ethyl acetate:methylene chloride (350 ml), and 1:3 ethyl acetate:methylene chloride to afford 3-bromo-6-(N-cyclopentylmethylcarbamoyl)indazole as a light red solid (5.6 g, 72%), mp 119°-125°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccc(Cl)cc3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 4-chloro-phenylboronic acid (51 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][SH:18].C(=O)([O-])[O-].CS(O[CH:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]1)(=O)=O>CN(C)C=O>[C:37]([O:36][C:35]([NH:34][CH:31]1[CH2:32][CH2:33][CH:28]([S:18][CH2:17][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=3)[O:6][C:2]=2[CH3:1])[CH2:29][CH2:30]1)=[O:41])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)NC1CCC(OS(C)(=O)=O)CC1
Reactant: COC(=O)c1ccc(-c2nc(CS)c(C)o2)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CSC3CCC(NC(=O)OC(C)(C)C)CC3)c(C)o2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed A mixture of methyl 4-[5-methyl-4-(sulfanylmethyl)-1,3-oxazol-2-yl]benzoate (3 g, 11.39 mmol, 1.00 equiv), cescium carbonate (5.13 g, 15.70 mmol, 1.39 equiv) and tert-butyl N-[4-(methanesulfonyloxy)cyclohexyl]carbamate (3.22 g, 10.98 mmol, 1.20 equiv) in N,N-dimethylformamide (30 mL) was stirred at 50° C. for 3 h. The reaction was quenched by the addition of 50 mL of water and the resulting solution was extracted with 3×60 mL of ethyl acetate. The organic combined layers was washed with 2×200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on\ a silica gel column eluted with ethyl acetate/petroleum ether (1:15-1:5). The collected fractions were combined and concentrated under vacuum to give 760 mg (14%) of methyl 4-(4-[[(4-[[(tert-butoxy)carbonyl]amino]cyclohexyl)sulfanyl]methyl]-5-methyl-1,3-oxazol-2-yl)benzoate as a yellow solid. LC-MS: (ES, m/z): 461 [M+H]+, 405, 361, 271, 230, 115.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][C:4]#[C:5][CH2:6][N:7]1[CH2:11][CH2:10][C@@H:9]([OH:12])[C:8]1=[O:13].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:14][N:2]([CH3:1])[CH2:3][C:4]#[C:5][CH2:6][N:7]1[CH2:11][CH2:10][C@@H:9]([O:12][S:23]([CH3:22])(=[O:25])=[O:24])[C:8]1=[O:13]
Reactant: CN(C)CC#CCN1CC[C@@H](O)C1=O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CC#CCN1CC[C@@H](OS(C)(=O)=O)C1=O

Procedure:
A solution of 0.4 g of (R)-1-[4-(dimethylamino)-2-butynyl]-3-hydroxy-2-pyrrolidinone, 0.6 ml of triethylamine and 0.3 ml of methane sulfonyl chloride in 10 ml of dichloromethane was stirred at 0° C. for 1 hour. Saturated aqueous sodium carbonate was added and the mixture separated. The aqueous portion was washed with dichloromethane. The organic layer and wash were combined, washed with sodium chloride solution, dried and evaporated. The residue was evaporated from 10 ml of toluene. The residual oil was purified by chromatography (silica gel), giving 0.4 g of (R)-1-[4-(dimethylamino)-2-butynyl]-3-[(methane sulfonyl)oxy]-2-pyrrolidinone as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6].[C:12]1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C(O)c1ccc(I)c(O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(I)c(O)c1
Temperature: 70 °C
Yield: 377.8 %

Procedure:
Overall, 61.31 g of 3-hydroxy-4-iodobenzoic acid are obtained in the form of a white solid. 47 g (150 mmol) of this 3-hydroxy-4-iodobenzoic acid are placed in 300 mL of methanol and 6.13 g (35.6 mmol) of para-toluenesulfonic acid are added. The reaction mixture is heated at 70° C. for 48 hours.— The reaction is stopped by addition of 11 of water. The precipitated product is filtered off and rinsed with water to neutral pH. 37.4 g (76%) of methyl 3-hydroxy-4-iodobenzoate are obtained in the form of a beige-colored powder.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]#[N:11])=[C:4](Cl)[N:3]=1.[CH:13]([O:16][CH2:17][CH2:18][OH:19])([CH3:15])[CH3:14].[B:20]1([OH:30])[C:24]2[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:23]=2[CH2:22][O:21]1>>[OH:30][B:20]1[C:24]2[CH:25]=[CH:26][C:27]([O:29][C:2]3[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]#[N:11])=[C:4]([O:19][CH2:18][CH2:17][O:16][CH:13]([CH3:15])[CH3:14])[N:3]=3)=[CH:28][C:23]=2[CH2:22][O:21]1
Reactant: N#Cc1cc(C#N)c(Cl)nc1Cl
Reactant: CC(C)OCCO
Reactant: OB1OCc2cc(O)ccc21
Product: CC(C)OCCOc1nc(Oc2ccc3c(c2)COB3O)c(C#N)cc1C#N

Procedure:
This compound was prepared from 2,6-dichloropyridine-3,5-dicarbonitrile (obtained from Aces Pharma), 2-isopropoxyethanol, and benzo[c][1,2]oxaborole-1,5(3H)-diol in a similar manner to that of D230. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 1.0 (d, J=4.5 Hz, 6H), 3.42-3.45 (m, 1H), 3.49-3.51 (m, 2H), 4.14-4.16 (m, 2H), 5.01 (s, 2H), 7.3 (d, J=6.3 Hz, 1H), 7.39 (s, 1H), 7.81 (d, J=6.6 Hz, 1H), 8.94 (s, 1H), 9.28 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].[I:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[OH:24]>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:14].[I:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[O:24][CH3:2]
Reactant: Oc1ccc2ccccc2c1I
Reactant: Oc1ccc2ccccc2c1Br
Product: COc1ccc2ccccc2c1Br
Product: COc1ccc2ccccc2c1I

Procedure:
Repeating this procedure with 1-bromo-2-hydroxynaphthalene or 1-iodo-2-hydroxynaphthalene yields 1-bromo-2-methoxynaphthalene or 1-iodo-2-methoxynaphthalene, respectively.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[C:10]([C:12](=[C:18](OCC)[CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]>C(O)C>[NH2:11][C:10]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[C:18]([CH3:19])[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(C#N)=C(C)OCC
Reactant: NNc1ccc(F)cc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2ccc(F)cc2)c1N
Yield: 23.3 %

Procedure:
4-Fluorophenylhydrazine (25 g) and ethyl 2-cyano-3-ethoxy-3-methylacrylate (32 g) were stirred in ethanol (130 ml) at a refluxing temperature for 3 h. The solvent was evaporated and diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (10.7 g), melting point: 129–131° C.
Reaction SMILES: CC1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=O)O1.C(=O)[C:12]1[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[C:14]([O:15][CH3:16])[CH:13]=1.C(O)=O.Cl>C(N(CC)CC)C>[CH3:16][O:15][C:14]1[CH:13]=[C:12]([CH2:4][CH2:6][C:7]([OH:9])=[O:8])[CH:21]=[CH:20][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COc1ccc(CCC(=O)O)cc1OC
Temperature: 90 °C

Procedure:
After weighing 14.4 g (0.1 mol) of Meldrum's acid and 16.6 g (0.1 mol) of veratraldehyde to 50 ml of the mixture of formic acid and triethylamine prepared according to Example 1, the reaction mixture was heated to 90° C. during 1 hour and maintained at 90° C. for 2 hours. After cooling down to room temperature 200 ml of ice-water were added to the reaction mixture, the pH value was adjusted to 1 by adding concentrated hydrochloric acid and the mixture was let stand at 5° C. for 16 hours. After filtration the precipitate was washed 3 times on the filter and dried at 40° C. under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:24])OCC2C=CC=CC=2)[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C1(N)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)CCC1.[CH2:36]([N:39]([CH2:53][CH2:54][CH3:55])[C:40]([C:42]1[CH:43]=[C:44]([CH:48]=[C:49]([CH2:51]C)[CH:50]=1)C(O)=O)=[O:41])[CH2:37][CH3:38]>>[F:8][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([F:1])[CH:7]=1)[CH2:9][C@H:10]([NH:14][C:15](=[O:24])[C:44]1[CH:48]=[C:49]([CH3:51])[CH:50]=[C:42]([C:40]([N:39]([CH2:36][CH2:37][CH3:38])[CH2:53][CH2:54][CH3:55])=[O:41])[CH:43]=1)[C@H:11]([OH:12])[CH2:13][NH:14][CH2:10][CH2:11][O:12][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NC1CCCc2ccccc21
Reactant: O=C(N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1)OCc1ccccc1
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCCOc2ccccc2)c1

Procedure:
Following the general procedure of EXAMPLEs 4, 5 and 6 and making non-critical variations but using tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V), H2N—CH2—CH2—O-phenyl (VI) and “5-Me-PHTH” (IX), the title compound is obtained, MH+=582.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:16][CH:17]=[N:18][C:19]=2[NH2:20])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](Cl)[N:31]=1>>[Cl:29][C:30]1[N:31]=[C:32]([N:26]2[CH2:27][CH2:28][CH:23]([CH2:22][NH:21][C:15]3[C:14]([C:11]4[CH:12]=[CH:13][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:9][CH:10]=4)=[C:19]([NH2:20])[N:18]=[CH:17][N:16]=3)[CH2:24][CH2:25]2)[CH:33]=[CH:34][CH:35]=1
Reactant: Clc1cccc(Cl)n1
Reactant: Nc1ncnc(NCC2CCNCC2)c1-c1ccc(Oc2ccccc2)cc1
Product: Nc1ncnc(NCC2CCN(c3cccc(Cl)n3)CC2)c1-c1ccc(Oc2ccccc2)cc1
Yield: 25 %

Procedure:
N4-((1-(6-chloropyridin-2-yl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine was prepared from 5-(4-phenoxyphenyl)-N4-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine and 2,6-dichloropyridine using Method B (25% yield). HPLC: 99%, RT: 5.214 min. MS: m/z=487 [M+H]+, RT=2.11 min. 1H-NMR (DMSO-d6) □(s, 1H), 7.44-7.36 (m, 3H), 7.20 (d, 2H), 7.15-6.95 (m, 8H), 6.69 (d, 1H), 6.52 (d, 1H), 4.14 (d, 2H), 3.18 (m, 2H), 2.71 (t, 2H), 1.77 (m, 1H), 1.56 (d, 2H), 0.98 (m, 2H).