Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:16]#[N:17])[CH3:2].[S:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[S:20].C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:24]3/[C:22](=[O:23])[NH:21][C:19](=[S:20])[S:18]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:16]#[N:17])[CH3:2]
Reactant: CCOc1c(C#N)cnc2ccc(C=O)cc12
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(=S)NC3=O)cc12
Temperature: 25 °C
Yield: 100 %

Procedure:
The suspension of 4-ethoxy-6-formyl-quinoline-3-carbonitrile (example 14e, 1.13 g, 5 mmol) and rodahnine (2-thioxo-thiazolin-4-one) (1.0 g, 7.5 mmol) in anhydrous toluene (50 mL) was added ammonium acetate (0.77 g, 10 mmol). The mixture was stirred under reflux for 6 h. After cooling to room temperature, the solid was collected by filtration, washed with water, toluene and dried to obtain 4-ethoxy-6-[4-oxo-2-thioxo-thiazolidin-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (1.7 g, 100%) as a grey solid. LC-MS m/e 342 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>>[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15]([NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])=[O:16]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Product: O=C(NS(=O)(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1Cl

Procedure:
A mixture of 4-chlorophenylsulfonamide (0.1 mol; 19.0 g) and 2,4-dichlorobenzoyl chloride (0.12 mol; 16.8 mL); the title compound was prepared essentially as described in Example 110.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH3:18])[CH:25]=1)[CH:9]=2)=[O:4]
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Product: COC(=O)c1c(O)c2ccc(-c3cccc(OC)c3)cc2sc1=O

Procedure:
4-Hydroxy-7-(3-methoxy-phenyl)-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) and 3-methoxyphenylboronic acid under conditions analogous to Example 7(a). MS ESI(−) m/e: 341.10 (M−1).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[C:11]2=[N:12][CH:13]=[CH:14][C:15](O)=[C:10]2[S:9][CH:8]=1>ClCCCl>[Cl:3][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[C:7]([CH3:6])=[CH:8][S:9][C:10]=12
Reactant: Cc1csc2c(O)ccnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: Cc1csc2c(Cl)ccnc12
Reaction time: 8 h
Yield: 55.8 %

Procedure:
Phosphorous oxychloride (2.2 mL, 24 mmol) in 1,2-dichloroethane (12 mL) was charged with 3-methylthieno[3,2-b]pyridin-7-ol (2.0 g, 12 mmol). The reaction stirred overnight at reflux under nitrogen. The mixture was the cooled and concentrated. Saturated NaHCO3 solution was carefully added to neutralize the residue. The biphasic mixture was extracted with dichloromethane, dried, and concentrated. Flash chromatography (15% EtOAc/hexanes) of the crude material gave the title compound (1.23 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[C:4]([F:13])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:21](I)([CH3:23])[CH3:22]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]([O:14][CH:21]([CH3:23])[CH3:22])=[C:4]([F:13])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2
Reactant: CC(C)I
Reactant: O=C1NCCc2cc(F)c(O)c(Cl)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1c(F)cc2c(c1Cl)C(=O)NCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 39.6 %

Procedure:
To a solution of 8-chloro-6-fluoro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (Cpd O, 131 mg, 0.607 mmol) in DMF (3.0 mL) was added cesium carbonate (0.210 g, 0.645 mmol) and iso-propyl iodide (0.0850 mL, 0.850 mmol). The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with EtOAc and washed with water (2×) and brine. The organic layer was concentrated under vacuum and the residue was purified by column chromatography (40-100% EtOAc/heptane) to give the title compound (Cpd P, 62 mg, 40%) as a white solid. MS 258 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][CH:30]=[C:29]([Cl:36])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[O:17]CC1C=CC(OC)=C(OC)C=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.O>[Cl:1][C:2]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][CH:30]=[C:29]([Cl:36])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[OH:17]
Reactant: COc1ccc(COc2cc(C)nc3c(OCc4c(Cl)ccc([N+](=O)[O-])c4Cl)cccc23)cc1OC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: Cc1cc(O)c2cccc(OCc3c(Cl)ccc([N+](=O)[O-])c3Cl)c2n1
Yield: 34.2 %

Procedure:
A mixture of 8-(2,6-dichloro-3-nitrobenzyloxy)-4-(3,4-dimethoxybenzyloxy)-2-methylquinoline (106 mg), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (50 mg) and dichloromethane-water (18:1, V/V, 2.85 ml) was heated under reflux for 19 hours. The reaction mixture was partitioned into dichloromethane and saturated aqueous sodium hydrogen carbonate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a preparative thin-layer chromatography (dichloromethane-methanol) followed by washing with ethanol to give a brownish powder (26 mg) of 8-(2,6-dichloro-3-nitrobenzyloxy)-4-hydroxy-2-methylquinoline.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:20]=2)[NH:15][CH:14]=1)[CH3:12].Br[C:32]1[C:33]([C:38]([F:41])([F:40])[F:39])=[N:34][N:35]([CH3:37])[CH:36]=1.C([O-])([O-])=O.[K+].[K+].O>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.O1CCOCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:32]3[C:33]([C:38]([F:41])([F:40])[F:39])=[N:34][N:35]([CH3:37])[CH:36]=3)[CH:20]=2)[NH:15][CH:14]=1)[CH3:12]
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Cn1cc(Br)c(C(F)(F)F)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cn(C)nc3C(F)(F)F)cc12

Procedure:
A mixture of 3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (9.00 mg, 0.0209 mmol), 4-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazole (9.57 mg, 0.0418 mmol), Pd(PPh3)4 (1.21 mg, 0.00104 mmol), K2CO3 (0.00866 g, 0.0627 mmol) and 4:1 dioxane:H2O (0.8 mL, 8 mmol) was heated in a microwave reactor at 95° C. for 20 min. The solution was used directly for HPLC purification, and the fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.78 (d, J=7.1 Hz, 3H), 3.62 (br. s., 3H), 3.96 (s, 3H), 5.08 (q, J=6.9 Hz, 1H), 6.86 (dd, J=9.1, 4.3 Hz, 1H), 7.01-7.09 (m, 1H), 7.35 (d, J=1.3 Hz, 1H), 7.52 (s, 1H), 7.78 (s, 1H), 8.10 (d, J=2.0 Hz, 1H). MS (ES+): m/z=453.11/455.11 (100/50) [MH+]. HPLC: tR=1.36 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:11]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH:7]1[O:20][CH2:19][CH2:18][O:8]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc(OCc2ccccc2)c(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 5-bromo-2-benzyloxybenzaldehyde, prepared from commercial 5-bromosalicylicaldehyde by benzylation according to the method given in Reference example 22a), (25 g, 74.6 mmol) in toluene (250 ml) was treated with ethylene glycol (5 ml), and p-toluenesulfonic acid (0.24 g). The reaction was heated to reflux with azeotropic removal of water (Dean Stark trap). After 2.5 hrs, no further water was collected. The reaction was cooled to ambient temperature and washed with saturated aqueous NaHCO3, dried (MgSO4 and evaporated to give 2-(2-benzyloxy-5-bromophenyl)-1,3-dioxolane as a pale orange solid (26.8 g). This material was used without purification.
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:9][C:10]([C:13]#[N:14])=[CH:11][N:12]=2)=[CH:6][N:7]=1.[F:15][CH:16]([F:28])[O:17][C:18]1[C:19]([C:24]([NH2:27])([CH3:26])[CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=1>CC#N>[F:28][CH:16]([F:15])[O:17][C:18]1[C:19]([C:24]([NH:27][C:2]2[N:3]=[N:4][C:5]([C:8]3[S:9][C:10]([C:13]#[N:14])=[CH:11][N:12]=3)=[CH:6][N:7]=2)([CH3:25])[CH3:26])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#Cc1cnc(-c2cnc(Br)nn2)s1
Reactant: CC(C)(N)c1ncccc1OC(F)F
Solvent: CC#N
Product: CC(C)(Nc1ncc(-c2ncc(C#N)s2)nn1)c1ncccc1OC(F)F
Temperature: 90 °C
Reaction time: 12 h

Procedure:
To a scintillation vial was added 2-(3-bromo-1,2,4-triazin-6-yl)thiazole-5-carbonitrile (directly from above reaction), 2-(3-(difluoromethoxy)pyridin-2-yl)propan-2-amine (100 mg, 500 μmol), and CH3CN (2 mL). The reaction was heated to 90° C. and stirred for 12 h. The reaction was then concentrated and purified using silica gel chromatography to afford 15 mg of 2-(3-(2-(3-(difluoromethoxy)pyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)thiazole-5-carbonitrile.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH2:27])[CH:4]=[N:3]1.O=C1CCC(=O)N1[O:35][C:36]([CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1)=O>ClCCl>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:5]([NH:27][C:36]([CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)=[O:35])[CH:4]=[N:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)ON2C(=O)CCC2=O)CC1
Reactant: Cn1ncc(N)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: Cn1ncc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 28.3 %

Procedure:
To a solution of 1-methyl-N5-trityl-1H-pyrazole-4,5-diamine (4 g) in dichloromethane (100 ml) was added tert-butyl 4-{[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl}-1-piperidinecarboxylate (4.05 g), and the mixture was refluxed for 72 hours. The reaction mixture was washed successively with water 10% aqueous citric acid solution, water and brine. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give tert-butyl 4-({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)-1-piperidinecarboxylate (1.806 g).
Reaction SMILES: [N:1]1([CH2:6][CH:7]=[CH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>CO>[N:1]1([CH2:6]/[CH:7]=[CH:8]/[C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(C=CCn2ccnc2)cc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(/C=C/Cn2ccnc2)cc1-c1ccc(F)cc1
Yield: 89 %

Procedure:
A solution of methyl 4-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate (B and Z isomers) (1.9 g; 5.6 mmol) and 2N aqueous sodium hydroxide solution (8.5 ml; 17 mmol) in methanol (100 ml) was refluxed for 9 hours. After evaporation and acidification with 12N HCl (1.5 ml), the resulting solid was washed with distilled water and ether, taken up in dichloromethane/methanol (99/1) to give 4-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoic acid (E isomer) after evaporation as a foam. Yield: 89%
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:22][C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>>[O:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[CH2:22][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: ClCc1nc2ccccc2o1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2nc3ccccc3o2)c1
Yield: 44.8 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 2-chloromethyl benzoxazole were reacted by the same way with the example 1 to obtain the titled compound (189 mg, yield: 44.8%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:26]3[CH:31]=[CH:30][C:29]([S:32][C:33]4[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:39][C:36]1[CH:35]=[CH:34][C:33]([S:32][C:29]2[CH:30]=[CH:31][C:26]([C:17]([C:14]3[CH:15]=[CH:16][C:11]([S:10][C:7]4[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=4)=[CH:12][CH:13]=3)([C:18]([F:21])([F:19])[F:20])[C:22]([F:23])([F:24])[F:25])=[CH:27][CH:28]=2)=[CH:38][CH:37]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ccc(C(c3ccc(Sc4ccc([N+](=O)[O-])cc4)cc3)(C(F)(F)F)C(F)(F)F)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Sc2ccc(C(c3ccc(Sc4ccc(N)cc4)cc3)(C(F)(F)F)C(F)(F)F)cc2)cc1

Procedure:
Compound 8 was is prepared by hydrogenating 2,2-bis[4-(4-nitrophenylthio)phenyl]hexafluoropropane (Compound 7) in a Parr apparatus under 4 atmospheres of hydrogen over palladium-on-charcoal catalyst in ethyl alcohol solvent.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]=[C:31]=[O:32])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:30][C:31](=[O:32])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: COc1ccc(N=C=O)cc1OC
Product: COc1ccc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4ncccc34)cc2)cc1OC

Procedure:
79 mg of solid beige-coloured 3-{4-[3-(3,4-dimethoxyphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 3,4-dimethoxyphenyl isocyanate.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([O:12][CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[N:5]=[CH:4][N:3]=1.Cl[C:17]1N=CN=C(NC2CC2)[C:18]=1N>C(#N)C>[Cl:1][C:2]1[C:11]2[N:10]=[C:9]([O:12][CH3:13])[C:8](=[O:14])[N:7]([CH:15]3[CH2:18][CH2:17]3)[C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: COc1nc2c(Cl)ncnc2n(C)c1=O
Reactant: Nc1c(Cl)ncnc1NC1CC1
Solvent: CC#N
Product: COc1nc2c(Cl)ncnc2n(C2CC2)c1=O

Procedure:
4-chloro-8-cyclopropyl-6-methoxypteridin-7(8H)-one was prepared in the same manner as 4-chloro-8-methyl-6-methoxypteridin-7(8H)-one. The reaction of 6-Chloro-N4-cyclopropyl-pyrimidine-4,5-diamine (3.00 g, 16.2 mmol), methyl 2,2,2-trimethocyacetate (3.73 g, 22.7 mmol), 1-camphorsulfonic acid (0.754 g, 3.25 mmol) in acetonitrile (30 mL) at 80° C. for 16 hours gave 3.045 g of 4-chloro-8-cyclopropyl-6-methoxypteridin-7(8H)-one as a tan colored solid. 1H NMR (400 MHz, DMSO-d6): δ 8.75 (s, 1H), 4.01 (s, 3H), 2.95 (m, 1H), 1.16 (m, 2H), 0.86 (m, 2H). MS (EI) C10H9ClN4O2: 253 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([F:30])=[C:16]([C@:18]2([CH3:29])[CH2:23][S:22](=[O:25])(=[O:24])[C:21]([CH3:27])([CH3:26])[C:20]([NH2:28])=[N:19]2)[CH:17]=1>>[NH2:28][C:20]1[C:21]([CH3:26])([CH3:27])[S:22](=[O:24])(=[O:25])[CH2:23][C@:18]([C:16]2[CH:17]=[C:12]([NH:11][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:10])[CH:13]=[CH:14][C:15]=2[F:30])([CH3:29])[N:19]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC1(C)C(N)=N[C@](C)(c2cc(N)ccc2F)CS1(=O)=O
Product: CC1(C)C(N)=N[C@](C)(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)CS1(=O)=O
Yield: 97.4 %

Procedure:
Prepared from 5-chloropicolinic acid (60.8 mg, 386 μmol, Eq: 1.1) and (R)-5-(5-amino-2-fluoro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (105 mg, 351 μmol, Eq: 1.00) as described for example 2 (method b) to give the title compound (150 mg, 342 μmol, 97.4% yield) as a white foam. MS (ISP): m/z=439.3 [(M+H)+] and 441.2 [(M+2+H)+].
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][C:32]=2[Si:38]([CH3:41])([CH3:40])[CH3:39])[CH2:26][CH2:25]1.CCN=C=NCCCN(C)C>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([NH:35][C:34]2[CH:36]=[CH:37][C:31]([CH2:30][N:27]3[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]3)=[C:32]([Si:38]([CH3:39])([CH3:41])[CH3:40])[CH:33]=2)=[O:18])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C#Cc2cc(C(=O)O)ccc2C)cn1
Reactant: CN1CCN(Cc2ccc(N)cc2[Si](C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C#Cc2cc(C(=O)Nc3ccc(CN4CCN(C)CC4)c([Si](C)(C)C)c3)ccc2C)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{[6-(acetylamino)pyridin-3-yl]ethynyl}-4-methylbenzoic acid (0.22 mmol) in dry pyridine (5 mL) is added 4-(4-methylpiperazin-1-ylmethyl)-3-trimethylsilylaniline (60 mg, 0.22 mmol) and EDCI (62 mg, 0.325 mmol). The resulting mixture is stirred at r.t. overnight. The solvent is removed on rotavap and the residue is partitioned between DCM and aq. NaHCO3. The combined organic layers from extraction are dried (Na2SO4), filtered, concentrated, and the resulting residue is purified by silica gel flash chromatography [eluted with 5% MeOH (pre-saturated with NH3) in DCM] to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[C:11]1[C:15]([CH3:16])=[N:14][NH:13][C:12]=1[NH2:17].[C:18](OC)(=O)[CH2:19][C:20](C)=[O:21]>C(O)(=O)C.C(OCC)C>[Cl:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[C:11]1[C:15]([CH3:16])=[N:14][N:13]2[C:20](=[O:21])[CH:19]=[CH:18][NH:17][C:12]=12
Reactant: COc1cc(Cl)c(-c2c(C)n[nH]c2N)c(Cl)c1
Reactant: COC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1cc(Cl)c(-c2c(C)nn3c(=O)cc[nH]c23)c(Cl)c1
Yield: 77 %

Procedure:
To a solution of 4-(2,6-dichloro-4-methoxy-phenyl)-5-methyl-2H-pyrazol-3-ylamine (10.1 g, 39 mmol) in acetic acid (17 mL) was added methyl acetoacetate. After the mixture was heated at reflux for 3 hours it was cooled and then diluted with diethyl ether (50 mL) to generate a colorless precipitate. The solid was collected by vacuum filtration and washed with additional ether to afford the title compound as a colorless solid (10.3 g, 77%): +APcI MS (M+1)+338; 1H NMR (methanol-d4) δ: 7.14 (s, 2H), 5.68 (s, 1H), 3.86 (s, 3H), 2.30 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[CH3:12])C.[OH:16][CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23]CC(N(OC)C)=O>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]2[C:6]=1[CH:12]=[C:14]([CH2:15][CH2:23][N:19]1[CH2:20][CH2:21][CH2:22][C@@H:18]1[CH2:17][OH:16])[NH:3][C:4]2=[O:13]
Reactant: CCN(CC)C(=O)c1cccc(Cl)c1C
Reactant: CON(C)C(=O)CCN1CCC[C@@H]1CO
Product: O=c1[nH]c(CCN2CCC[C@@H]2CO)cc2c(Cl)cccc12
Yield: 14.2 %

Procedure:
In the same manner as in Example 16b and using N,N-diethyl-3-chloro-2-methylbenzamide (3.35 g) and (R)-3-(2-hydroxymethylpyrrolidin-1-yl)-N-methoxy-N-methylpropanamide (3.22 g), (R)-5-chloro-3-[2-(2-hydroxymethylpyrrolidin-1-yl)ethyl]-2H-isoquinolin-1-one (645 mg) was obtained.
Reaction SMILES: Br.Br.[NH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[O:15])[CH2:7][CH2:6]1.[NH2:23][C:24]1[C:32]([Cl:33])=[CH:31][C:27]([C:28](O)=[O:29])=[C:26]([O:34][CH3:35])[CH:25]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C>[NH2:23][C:24]1[C:32]([Cl:33])=[CH:31][C:27]([C:28]([NH:3][CH2:4][CH:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)=[O:15])[CH2:7][CH2:6]2)=[O:29])=[C:26]([O:34][CH3:35])[CH:25]=1
Reactant: NCC1CCN(CCCC(=O)c2ccc(O)cc2)CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCC(=O)c2ccc(O)cc2)CC1
Yield: 78.7 %

Procedure:
4-Aminomethyl-1-(4-(4-hydroxyphenyl)-4-oxobutyl)piperidine dihydrobromide (3.67 g) as a starting compound, 4-amino-5-chloro-2-methoxybenzoic acid (1.69 g), triethylamine (4.65 ml), 1-hydroxybenzotriazole (1.20 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.69 g) were reacted and purified in the same manner as in Example 270 to give 3.03 g of 4-amino-5-chloro-2-methoxy-N-((1-(4-(4-hydroxyphenyl)-4-oxobutyl)piperidin-4-yl)methyl)benzamide, m.p. 199°-201° C.
Reaction SMILES: C(O[C:4](=[O:24])[CH2:5][N:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[CH3:17])=[S:8])C.C(N(CC)CC)C>C(O)C>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([CH3:17])=[C:10]([N:9]2[C:4](=[O:24])[CH2:5][N:6]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:7]2=[S:8])[CH:15]=1
Reactant: CCOC(=O)CN(C(=S)Nc1cc(Cl)ccc1C)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(Cl)cc1N1C(=O)CN(c2ccccc2)C1=S
Temperature: 25 °C
Yield: 73.5 %

Procedure:
A mixture of 2-[3-(5-chloro-2-methylphenyl)-1-phenyl-thioureido]-acetic acid ethyl ester (9.5 g), triethyl amine (1 mL), and ethanol (150 mL) was heated at reflux for 2 hours. The mixture was concentrated to one-half volume and cooled to ambient temperature. The solid was collected and air dried to give the title compound (6.1 g) as an off-white solid, m.p. 168°-170° C. Anal. Calcd. for. C16H13Cl N2 O S: C, 60.66; H, 4.14; N, 8.84. Found: C, 60.81; H, 4.16; N, 8.81. Mass spectrum (EI, M.+) m/z 316/318.
Reaction SMILES: Br[CH2:2][C:3]1[S:17][C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10](=[O:11])[N:5]2[CH:4]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CN(C=O)C.C(Cl)Cl>[N:18]1([CH2:2][C:3]2[S:17][C:6]3=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10](=[O:11])[N:5]3[CH:4]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cnc2sc(CBr)cn2c1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2sc(CN3CCOCC3)cn2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A mixture of ethyl 2-(bromomethyl)-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylate (Preparation 9, 159 mg) and morpholine (0.5 mL) in DMF (10 mL) is stirred for 4 h at rt. The mixture is diluted with CH2Cl2 (100 mL) and is washed with water. The organic layer is dried (MgSO4) and concentrated to afford 130 mg (80%) of the title compound as a white solid. Physical characteristics: MS (ESI+) m/z 324 (M+H)+. 1H NMR (DMSO) δ 8.62, 8.22,4.25, 3.75, 3.59, 2.49, 1.28.