Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].OS(O)(=O)=O.[CH3:18]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:18])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)cc(OC)c1
Temperature: 25 °C

Procedure:
To a stirred solution of methyl 3,5-dihydroxybenzoate (80 g, 0.52 mol) in CH3OH (600 ml), was added concentrated H2SO4 (40 ml) in portions at room temperature. The reaction mixture was heated to reflux temperature for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. This solution was washed with a saturated aqueous Na2CO3 solution, brine, dried over Na2SO4 and concentrated under reduced pressure to give methyl 3-hydroxy-5-methoxybenzoate (73 g) as a white solid. The crude product was used in the next step without further purification.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44]O)=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=O)C.[NH2:46][C:47]([CH3:52])([CH2:50][OH:51])[CH2:48][OH:49].NCCO>>[C@@H:6]1([O:24][C:25]2[C:30]3[C:31]([CH2:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH2:43][CH2:44][NH:46][C:47]([CH2:50][OH:51])([CH3:52])[CH2:48][OH:49])=[CH:40][CH:41]=4)=[CH:32][O:33][C:29]=3[CH:28]=[CH:27][CH:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(N)(CO)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccc(OCCO)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: NCCO
Product: CC(CO)(CO)NCCOc1ccc(CCc2coc3cccc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c23)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 21 using 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-(2-[4-(2-hydroxyethoxy)phenyl]ethyl)benzofuran and 2-amino-2-methyl-1,3-propanediol instead of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-{2-[4-(3-hydroxypropoxy)phenyl]ethyl}benzofuran and 2-aminoethanol, respectively.
Reaction SMILES: O=[O+][O-].[O:4]=O.[Cl:6][C:7]1[C:8]([CH:22]=C)=[C:9]2[C:14](=[CH:15][C:16]=1[Cl:17])[N:13]=[C:12]([O:18][CH3:19])[C:11]([O:20][CH3:21])=[N:10]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:6][C:7]1[C:8]([CH:22]=[O:4])=[C:9]2[C:14](=[CH:15][C:16]=1[Cl:17])[N:13]=[C:12]([O:18][CH3:19])[C:11]([O:20][CH3:21])=[N:10]2
Reactant: O=O
Reactant: C=Cc1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Agent: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: COc1nc2cc(Cl)c(Cl)c(C=O)c2nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
A mixture of ozone and oxygen was bubbled gently through a stirred solution of 6,7-dichloro-2,3-dimethoxy-5-ethenylquinoxaline (1.76 g, 6.2 mmol) in chloroform (200 mL) at -60° C. until a blue colour persisted. The solution was purged with nitrogen, and then triphenylphosphine (3.23 g, 12.3 mmol) was added. The mixture was allowed to warm to room temperature and stirred for a further 16 hours. The chloroform was removed under reduced pressure and the residue purified by flash chromatography (eluting with toluene) to give 6,7-dichloro-2,3-dimethoxy-5-formylquinoxaline (1.60 g, 90%) as a fluffy white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)[C:9]([C:19]3[C:20]([NH2:24])=[N:21][O:22][N:23]=3)=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1.B(Br)(Br)Br>ClCCl>[NH2:24][C:20]1[C:19]([C:9]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]3[C:2]([Br:1])=[CH:7][N:6]=[CH:5][C:4]=3[N:8]=2)=[N:23][O:22][N:21]=1
Reactant: COc1ccc(-n2c(-c3nonc3N)nc3cncc(Br)c32)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1nonc1-c1nc2cncc(Br)c2n1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.2 %

Procedure:
To a solution of the product from Example 187 (0.1 g, 0.26 mmol) in anhydrous dichloromethane (10 ml) stirred at 0° C., was added dropwise boron tribromide (1.0 M solution in dichloromethane, 2.3 ml, 2.3 mmol) and the mixture stirred at room temperature for 16 hours. The reaction was quenched with water (20 ml), basified to pH 14 with 50% sodium hydroxide solution. The aqueous phase was washed with dichloromethane 3×, neutralised with 6 N hydrochloric acid, and the resulting precipitate collected, washed with water 3×, diethyl ether and dried in vacuo to yield the title product (40 mg, 40%); MS (ES+) m/e 374 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH2:9]2)[CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:30])=[C:4]([CH:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH2:9]2)[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CC(c2cc(Cl)ccn2)c2cc(C#N)ccc2O1
Solvent: ClCCl
Product: CC1(C)CC(c2cc(Cl)cc[n+]2[O-])c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 24 %

Procedure:
79 mg of 4-(4-chloro-2-pyridyl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile were dissolved in 10 ml of dichloromethane and 70 mg of m-chloroperbenzoic acid were added. The mixture was stirred at room temperature for 3 days, then washed in succession with sodium bisulphite solution, sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 1% (v/v) methanol/ethyl acetate for the elution to give, after trituration with diethyl ether, a solid which was recrystallized from ethyl acetate/petroleum ether. There being obtained 20 mg of 4-chloro-2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 173°-174° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH2:14][CH2:13][NH:12][C:11](=[O:15])[CH:10]=2)=[CH:4][CH:3]=1.CO>CN(C=O)C.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[CH2:14][CH2:13][NH:12][C:11](=[O:15])[C:10]=3[C:4]=2[CH:3]=1
Reactant: O=C1C=C(Nc2ccc(F)cc2)CCN1
Agent: [Cu+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: O=C1NCCc2[nH]c3ccc(F)cc3c21
Temperature: 130 °C
Yield: 44.4 %

Procedure:
Cu(OAc)2 (9.69 g, 53.39 mmol) was added to a stirred solution of 4-(4-fluorophenylamino)-5,6-dihydropyridin-2(1H)-one (I-59e: 5 g, 24.27 mmol) and Pd(OAc)2 (490 mg, 2.18 mmol) in DMF (96 mL) under argon atmosphere and the resulting reaction mass was heated at 130° C. for 2 hours. The reaction was monitored by TLC (5% methanol in DCM). The reaction mass was cooled to room temperature and filtered through a celite bed. The filtrate was partitioned between water and ethyl acetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated to afford the crude product. Purification by column chromatography on silica gel (1% methanol in DCM) afforded 2.2 g of the product (44.7% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:32]=[CH:31][C:20]3[CH:21]=[C:22]([C:24]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:25])[O:23][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:33].[BH4-].[Na+].[CH2:39]1COCC1>>[CH2:15]([C:12]([C:17]1[CH:32]=[CH:31][C:20]2[CH:21]=[C:22]([C:24]([N:26]([CH2:27][C:28]([OH:30])=[O:29])[CH3:39])=[O:25])[O:23][C:19]=2[CH:18]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:34])[C:2]([CH3:1])([CH3:35])[CH3:36])=[C:7]([CH3:33])[CH:8]=1)[CH2:13][CH3:14])[CH3:16]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)NCC(=O)O)oc2c1
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)N(C)CC(=O)O)oc2c1
Reaction time: 2 h
Yield: 59 %

Procedure:
A solution of (6-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-2-carbonyl)-amino]-acetic acid (66 mg, 0.130 mmol) (Example 57) in THF (2 mL) is treated with NaBH4 (11 mg, 0.26 mmol) at room temp. The resulting mixture is stirred for 2 hours. The mixture is concentrated and neutralized to pH 3 and extracted with EtOAc (3×5 mL). The organic layer is dried over sodium sulfate, concentrated to afford the desired compound (39 mg, 59%). MS (ES) m/e: 508.3 (M−1)
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:15][C:16]([CH3:18])=[CH2:17])=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].FC(F)(F)S(O)(=O)=O>ClCCCl>[CH3:17][C:16]1([CH3:18])[CH2:15][C:3]2=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:2]2[O:1]1
Reactant: C=C(C)Cc1c(C(=O)OC)ccc([N+](=O)[O-])c1O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCCl
Product: COC(=O)c1ccc([N+](=O)[O-])c2c1CC(C)(C)O2
Reaction time: 2 h
Yield: 32.1 %

Procedure:
Methyl 3-hydroxy-2-(2-methylallyl)-4-nitro-benzoate 4b (2.58 g, 10.30 mmol) was dissolved in 50 mL 1,2-dichloroethane followed by the addition of trifluoromethanesulfonic acid (77 mg, 0.50 mmol). The reaction solution was stirred for 2 hours and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl 2,2-dimethyl-7-nitro-3H-benzofuran-4-carboxylate 4c (0.83 g, yield: 32.1%) as a yellow solid.
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH2:21]>CCO>[C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[N:21][CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cccc(C=O)c1
Solvent: CCO
Product: CN=Cc1cccc(OCCO[Si](C)(C)C(C)(C)C)c1
Temperature: 40 °C
Yield: 87.89 %

Procedure:
3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzaldehyde (2.375 g, 8.47 mmol) was dissolved in 10 mL EtOH. MeNH2 (1.2 mL, 40% in H2O) was added and the mixture was heated to 40° C. for 30 min. The mixture was then concentrated in vacuo. The aqueous residue was diluted with isopropanol and then concentrated in vacuo. This was repeated twice more giving 2.184 g (87.89%) of a dry white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[CH:4][CH:3]=1.I[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:14]([N:11]1[N:10]=[N:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[N:12]1)[CH3:15]
Reactant: CCI
Reactant: Cc1ccc(-c2nnn[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCn1nnc(-c2ccc(C)cc2)n1
Reaction time: 2 h
Yield: 79.9 %

Procedure:
A solution of 20.0 grams (0.125 mole) of 5-(4-methylphenyl)-1,2,3,4-tetraazole in 230 mL of acetonitrile was stirred and 48.7 grams (0.312 mole) of iodoethane, followed by 17.3 grams (0.125 mole) of potassium carbonate were added. Upon completion of addition, the reaction mixture was warmed to reflux, where it stirred for two hours. After this time, the reaction mixture was concentrated under reduced pressure to a residue. The residue was taken up in ethyl acetate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:4 ethyl acetate:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 18.8 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([O-])(O)=O.[Na+]>C1COCC1>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH:7]([OH:6])[CH2:8][CH2:9][CH:10]2[CH2:14][CH2:13][C:12](=[O:15])[N:11]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])=[CH:26][CH:27]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1CCCCCCC#N)Cc1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: N#CCCCCCCN1C(=O)CCC1CCC(O)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
To a solution of 7-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-(4-fluoro-phenyl)-butyl]-5-oxo-pyrrolidin-1-yl}-heptanenitrile (158 mg, 0.333 mmol) in THF (20 mL) at 0° C. was added TBAF (1M in THF, 0.50 mL, 0.50 mmol). The reaction mixture was stirred at room temperature for 3 h and saturated aqueous NaHCO3 was added. The volatiles were removed in vacuo. The remaining aqueous solution was washed with CHCl3 (4×5 mL) and the combined organic solutions were dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography (1:1 hexanes:EtOAc to EtOAc) provided 7-{2-[4-(4-fluoro-phenyl)-3-hydroxy-butyl]-5-oxo-pyrrolidin-1-yl}-heptanenitrile (82 mg). 1H NMR (CDCl3) δ7.15 (m, 2H), 7.00 (m, 2H), 3.77 (m, 1H), 3.58 (m, 2H), 2.89 (m, 1H), 2.79 (m, 1H), 2.64 (m, 1H), 2.34 (m, 4H), 2.12 (m, 1H), 1.68-1.24 (m, 14H); MS 361.2 (M+1).
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33](=[N:40][O:41][CH3:42])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][C:27]=3[S:26][C:25]2=[O:43])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33](=[N:40][O:41][CH3:42])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][C:27]=3[S:26][C:25]2=[O:43])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(NC(=O)OC(C)(C)C)C(=O)OC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(N)C(=O)OC)cc1
Reaction time: 5 h

Procedure:
Dissolve the compound obtained in Example 10 (1 eq.) in 250 ml of anhydrous DCM and add TFA (20 eq.) dropwise. Stir for 5 hours and evaporate. Take up in water and render alkaline using 10% K2CO3. Extract with ethyl acetate. Wash the organic phases with water, dry over MgSO4, filter and evaporate. Take up in a minimum of methanol and bubble HCl gas through the mixture for 30 minutes. Evaporate to dryness and take up in diisopropyl ether. Filter off the precipitate and recrystallise from diethyl ether.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(O[CH:22]=[C:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])C>C(O)C(C)C>[CH3:18][N:15]1[CH2:14][CH2:13][N:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[CH:4][N:3]=[C:2]3[NH:1][CH:22]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:17][CH2:16]1
Reactant: CN1CCN(c2ccc3ncnc(N)c3c2)CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CC(C)CO
Product: CCOC(=O)C(=CNc1ncnc2ccc(N3CCN(C)CC3)cc12)C(=O)OCC
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 42.5 %

Procedure:
A mixture of 4-amino-6-(4-methylpiperazinyl)quinazoline (2.19 g) and diethyl ethoxymethylenepropanedioate (2.13 g) in isobutylalcohol (9 ml) was stirred for 2 hours and 25 minutes at 100° C. and then cooled to ambient temperature. The resultant mixture was concentrated under reduced pressure to give a residue, which was recrystallized from ethanol to give crystalline diethyl [{6-(4-methylpiperazinyl)-4-quinazolinylamino}methylene]propanedioate (1.58 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([CH:11]3[CH2:14][CH2:13][CH2:12]3)[NH:8][C:5]2=[CH:6][N:7]=1.[NH3:15].O>CCO>[CH:11]1([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([NH2:15])[CH:3]=[C:4]3[CH:10]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: N
Reactant: Clc1cc2cc(C3CCC3)[nH]c2cn1
Solvent: O
Solvent: CCO
Product: Nc1cc2cc(C3CCC3)[nH]c2cn1
Temperature: 180 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To the solution of 5-chloro-2-cyclobutyl-1H-pyrrolo[2,3-c]pyridine (200 mg, 0.97 mmol) in EtOH (10 mL) and NH3.H2O (30 mL) was added CuSO4.5H2O (30 mg, 0.12 mmol). The reaction mixture was stirred under 3 MPa at 180° C. for 16 h. The mixture was extracted with ethyl acetate (3×30 mL). The extract was dried, concentrated in vacuo and purified by chromatography on silica gel (5-10% MeOH in ethyl acetate as eluant) to afford the pure 2-cyclobutyl-1H-pyrrolo[2,3-c]pyridin-5-amine (40 mg, 22% yield). 1H NMR (300 MHz, MeOH) δ: 8.02 (s, 1H), 6.72 (s, 1H), 6.11 (s 1H), 3.72-3.60 (m, 1H), 2.47-1.90 (m, 6H). MS (ESI): m/z [M+H+] 188.1.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][OH:33]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:33][CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([O:28][CH3:27])[CH:30]=2)[CH:7]=1
Reactant: COc1cccc(CO)c1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: COc1cccc(COc2cc(F)ccc2-c2ncnc(Nc3cccc(CS(C)(=O)=O)c3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.197 mmol), intermediate 42.1, and 3-methoxybenzyl alcohol (111 mg; 0.789 mmol), example 70 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[N:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:24][C:25](=[O:28])[CH2:26]Br)(C)(C)C.[OH-].[Na+]>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:8][C:9]([N:10]([CH3:11])[C@H:12]1[CH2:17][CH2:16][C@H:15]([O:18][CH2:26][C:25]([OH:28])=[O:24])[CH2:14][CH2:13]1)=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN(C(=O)OCc1ccccc1)[C@H]1CC[C@H](O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C(=O)OCc1ccccc1)[C@H]1CC[C@H](OCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 15.0 g (57 mmol) of trans-(4-hydroxy-cyclohexyl)-methyl-carbamic acid benzyl ester in 230 mL of toluene were added 16.8 mL (114 mmol, 2 eq) of bromo-acetic acid tert-butyl ester and 1.93 g (5.7 mmol, 0.1 eq) of tetra-n-butylammonium hydrogensulfate and 400 mL of 50% aqueous NaOH. The mixture was stirred at RT for 4 h, additional 1.93 g (5.7 mmol, 0.1 eq) of tetra-n-butylammonium hydrogensulfate and 4.2 mL of bromo-acetic acid tert-butyl ester were added and stirring was continued over night. The solution was concentrated and acidified by addition of 400 mL of 37% HCl. The solution was extracted with EtOAc, the organic phase was washed with brine and dried over Na2SO4. The solvent was removed to yield 18.2 g (quantitative) of trans-[4-(benzyloxycarbonyl-methyl-amino)-cyclohexyloxy]-acetic acid as white solid, MS: 320 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29](Br)[C:28](=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:44]([O:46][CH2:47][CH3:48])=[CH2:45])CCC>C1(C)C=CC=CC=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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([C:44]([O:46][CH2:47][CH3:48])=[CH2:45])[C:28](=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Yield: 78.2 %

Procedure:
A suspension of 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (5.93 g, 0.010 mol, prepared as in Example 1A), tetrakis(triphenylphosphine)palladium(0) (1.40 g, 0.00121 mol), and tributyl(1-ethoxyvinyl)tin (5.32 mL, 0.0157 mol) in toluene (30 mL) was heated under reflux for 3.5 hours. The mixture was cooled and filtered to give a solid. Purification of the solid by silica gel chromatography using a gradient of 5%-66% ethyl acetate/hexane over 15 minutes gave 4-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester as a yellow foam (4.50 g, 78%). MS (APCI) M++1: calc'd 576.2, found, 576.3.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([NH:17][NH:18][CH:19]=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[C:21](OC)=[O:22])=N[CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)(=O)C>[CH2:1]([NH:8][C:9](=[O:10])[C:11]1[CH:16]=[CH:31][C:14]([N:17]2[C:21]([OH:22])=[C:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:19]=[N:18]2)=[CH:13][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(=CNNc1ccc(C(=O)NCc2ccccc2)cn1)c1ccccn1
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccc1)c1ccc(-n2ncc(-c3ccccn3)c2O)cc1

Procedure:
Combined methyl 3-(2-(5-(benzylcarbamoyl)pyridin-2-yl)hydrazinyl)-2-(pyridin-2-yl)acrylate (110 mg, 0.273 mmol) and potassium carbonate (56.5 mg, 0.409 mmol) in ethanol (10 mL) and heated at 60° C. for 1 hour. The precipitate was filtered and washed with ethanol to give an off-white solid. This solid was then dissolved in ethyl acetate. The organic layer was washed with water, dried and concentrated to give the title compound as a yellow solid. (60 mg, 59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.50 (d, J=6.06 Hz, 2 H), 6.69 (ddd, J=7.07, 4.80, 1.26 Hz, 1 H), 7.19-7.30 (m, 1 H), 7.34 (d, J=4.55 Hz, 4 H), 7.44 (ddd, J=8.21, 7.20, 2.02 Hz, 1 H), 7.85 (s, 1 H), 8.10-8.19 (m, 2 H), 8.19-8.25 (m, 1 H), 8.64 (dd, J=8.84, 0.76 Hz, 1 H), 8.84 (dd, J=2.53, 0.76 Hz, 1 H), 9.04 (t, J=5.81 Hz, 1 H). MS m/z [M+H]+ 372.4