Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([CH3:11])[N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1B(O)O>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.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>[CH3:9][O:8][C:6]1[C:5]([OH:10])=[C:4]([CH3:11])[N:3]=[C:2]([C:15]2[C:14]([O:13][CH3:12])=[CH:19][C:18]([CH3:20])=[CH:17][C:16]=2[CH3:21])[N:7]=1
Reactant: COc1nc(Cl)nc(C)c1O
Reactant: COc1cc(C)cc(C)c1B(O)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+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(C)cc(C)c1-c1nc(C)c(O)c(OC)n1
Temperature: 95 °C

Procedure:
A mixture of 2-chloro-4-methoxy-6-methylpyrimidin-5-ol (348 mg, 2.0 mmol), 2-methoxy-4,6-dimethylphenylboronic acid (540 mg, 3.0 mmol), tetrakis(triphenylphosphine)palladium (0) (115 mg, 5 mol %) in toluene (12 mL) and sodium carbonate (1M in water, 4 mL) is heated at 95° C. (oil bath temperature) in a pressure tube for 14 hours. The reaction is cooled to room temperature, diluted with ethyl acetate, washed with NaOH (2M) and then brine (2×50 mL). The solvents are dried (sodium sulfate) and removed under reduced pressure. Flash chromatography of the crude product (50% ethyl acetate in hexanes) yields 4-methoxy-2-(6-methoxy-2,4-dimethylphenyl)-6-methylpyrimidin-5-ol as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:10](=O)([O-])[O-].[K+].[K+].IC>COCCOC>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=c1[nH]cc(Cl)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: COCCOC
Product: Cn1cc(Cl)cc(Br)c1=O
Yield: 74.6 %

Procedure:
A mixture of 3-bromo-5-chloro-1H-2-pyridone (930 mg, 4.46 mmol), potassium carbonate (1.25 g, 9.1 mmol) and iodomethane (2.8 mL, 45 mmol) in 10 mL of DME was heated to reflux for 18 hr. The mixture was filtered hot and concentrated. The residue was recrystallized from ethyl acetate to give 3-bromo-5-chloro-1-methyl-2-pyridone (740 mg, 74%), mp 162-163° C. HRMS (C6H5BrClNO): Obs. Mass 220.9249. Calcd. Mass 220.9243 (M+H).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[N:11]=[N:10][C:9]([CH:12]([OH:14])[CH3:13])=[N:8]2)[CH:2]=1.[H-].[Na+].[CH:18]1([N:21]2[C:25](S(C)(=O)=O)=[N:24][N:23]=[C:22]2[C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH2:20][CH2:19]1>>[CH:18]1([N:21]2[C:25]([O:14][CH:12]([C:9]3[N:10]=[N:11][N:7]([C:3]4[CH:2]=[C:1]([CH3:15])[CH:6]=[CH:5][CH:4]=4)[N:8]=3)[CH3:13])=[N:24][N:23]=[C:22]2[C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)[CH2:20][CH2:19]1
Reactant: CS(=O)(=O)c1nnc(-c2ccncc2)n1C1CC1
Reactant: Cc1cccc(-n2nnc(C(C)O)n2)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1cccc(-n2nnc(C(C)Oc3nnc(-c4ccncc4)n3C3CC3)n2)c1
Yield: 2 %

Procedure:
The title compound (7.8 mg, 19%, clear oil) was prepared from 1-(2-m-tolyl-2H-tetrazol-5-yl)-ethanol (1 mmol), sodium hydride (1.5 mmol) and 4-(4-cyclopropyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)-pyridine (1.25 mmol). 1H NMR (CDCl3) δ (ppm): 8.73 (d, 2H), 7.93 (m, 2H), 7.78 (d, 2H), 7.45 (t, 1H), 7.33 (d, 1H), 6.62 (q, 1H), 3.22 (m, 1H), 2.49 (s, 3H), 2.05 (d, 3H), 1.14 (m, 2H), 1.00 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:23][C:13]4=[N:14][CH:15]=[C:16]([C:18]([O:20]CC)=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:24])[NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[Li+].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:23][C:13]4=[N:14][CH:15]=[C:16]([C:18]([OH:20])=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:24])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncc(F)cc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncc(F)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl (6S)-5′-fluoro-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate (200 mg, 0.611 mmol) in THF (4 mL) and water (1 mL) was added 1 N lithium hydroxide (0.733 mL, 0.733 mmol) and the resulting mixture was stirred at ambient temperature for 18 h. The reaction mixture was acidified to pH 4 by addition of 1 N hydrochloric acid and concentrated to dryness in vacuo to give the title compound. MS: m/z=300.2 (M+1). 1H NMR (500 MHz, CD3OD) δ 9.21 (s, 1H), 8.90 (s, 1H), 8.07 (m, 1H), 7.78 (dd, 1H, J=7.8, 2.7 Hz), 3.87-3.78 (m, 2H), 3.72 (d, 1H, J=17.3 Hz), 3.61 (d, 1H, J=17.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21](OCC)=[O:22])=[CH:6][N:5]2[C:26]=1[CH3:27].[CH2:28]([NH2:31])[CH2:29][CH3:30].[C-]#N.[Na+]>CO>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21]([NH:31][CH2:28][CH2:29][CH3:30])=[O:22])=[CH:6][N:5]2[C:26]=1[CH3:27]
Reactant: CCOC(=O)c1cc(NCc2c(C)cccc2CC)c2nc(C)c(C)n2c1
Reactant: CCCN
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: CCCNC(=O)c1cc(NCc2c(C)cccc2CC)c2nc(C)c(C)n2c1
Yield: 42.4 %

Procedure:
Ethyl 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylate (0.12 g, 0.33 mmol), propylamine (1.0 g, 17 mmol) and a cat. amount of sodium cyanide were refluxed in methanol (20 ml) for 24 h. An additional amount of propylamine (1.0 g, 17 mmol) was added and the reaction mixture was refluxed for 24 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dietyl ether as eluent. Crystallization from diethyl ether gave 0.053 g (42%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:6][CH:7]=1.[F:14][C:15]([F:30])([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2)[C:16]([NH:18][NH2:19])=O.CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>C(O)CCC>[F:30][C:15]([F:14])([C:16]1[N:3]2[N:4]=[C:5]([C:8]3[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=3)[CH:6]=[CH:7][C:2]2=[N:19][N:18]=1)[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Reactant: NNC(=O)C(F)(F)c1ccc2ncccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cn1cc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)cn1
Temperature: 130 °C
Yield: 61.8 %

Procedure:
A mixture of 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-pyridazine (step d) (4.57 g, 23.6 mmol) and difluoro-quinolin-6-yl-acetic acid hydrazide (step c) (5.60 g, 23.6 mmol) in n-butanol (125 mL) was heated to 130° C. overnight. The mixture was cooled to room temperature, followed by aqueous work up using AcOEt and a solution of K2CO3. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography (first chromatography: CH2Cl2 100% and CH2Cl2/MeOH: 88/12 followed by another column with toluene/iPrOH/NH4OH: 85/15/2) to give the title compound (5.5 g, 62%). M.p=199.7° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[F:25][C:26]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:28][C:29]([O:40][CH3:41])=[C:30]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:27]3[C:26]([F:25])=[CH:31][C:30]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[C:29]([O:40][CH3:41])[CH:28]=3)[C:10]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(F)cc1NC(=O)OC(C)(C)C
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)c(F)cc1NC(=O)OC(C)(C)C

Procedure:
trans-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.60 g, 1.36 mmol), tert-butyl N-[5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (1.0 g, 2.72 mmol), palladium tetrakistriphenyphosphine(0.094 g, 0.082 mmol) and sodium carbonate (0.35 g, 3.27 mmol) were mixed with ethylene glycol dimethyl ether (14 mL) and water (7 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5 to 70:30) as mobile phase to give trans-tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-5-fluoro-2-methoxyphenyl)carbamate (0.264 g, 35%). 1H NMR (DMSO-d6) δ 1.49 (s, 9H), 1.97 (m, 6H), 2.16 (s, 3H), 2.33 (m, 5H), 2.53 (m, 4H), 3.84 (s, 3H), 4.64 (m, 1H), 7.60 (d, J=6.78 Hz, 1H), 7.83 (d, J=11.96 Hz, 1H), 8.20 (s, 1H), 8.24 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=555.3, Rt=2.00 min.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[NH2:13][C@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1>>[C@H:14]1([NH:13][C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[I:1])[N:7]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: Clc1ccc2c(I)cccc2n1
Product: Ic1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12

Procedure:
(R)-Indan-1-yl-(5-iodo-quinolin-2-yl)-amine was prepared from 5-iodo-2-chloroquinoline and (R)-1-aminoindane as described in example 6 step A.
Reaction SMILES: [N:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[C:11]3[N:10]=[C:9]([NH:22][NH2:23])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=O.C(O)(=O)C>C(O)C>[NH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]([CH:24]=[N:23][NH:22][C:9]2[CH:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:12]3[N:13]=[CH:14][C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[C:11]3[N:10]=2)=[CH:27]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: NNc1cc(N2CCOCC2)n2ncc(-c3ccccn3)c2n1
Solvent: CC(=O)O
Solvent: CCO
Product: C(=NNc1cc(N2CCOCC2)n2ncc(-c3ccccn3)c2n1)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
To a solution of (7-morpholin-4-yl-3-pyridin-2-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (25 mg, 0.080 mM) in ethanol (1.5 mL), there were added 3-formyl-indole (18 mg, 0.12 mM) and acetic acid (3 μL) and then the mixture was stirred at room temperature for 3 hours. The precipitated solid was recovered through filtration and then washed with ethanol to thus give the title compound (18 mg, yield: 51%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:25]1[CH2:26][CH2:27][N:22]([CH2:2][CH2:3][CH2:4][O:5][CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:23][CH2:24]1
Reactant: C1COCCN1
Reactant: ClCCCOC(CCCc1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(CCCC(OCCCN2CCOCC2)c2ccccc2)cc1
Temperature: 100 °C

Procedure:
A mixture of 1.5 g of 1-(3-chloropropoxy)-1,4-diphenylbutane, 7 ml of morpholine, 1.5 g of potassium carbonate and 15 ml of dimethylformamide was heated at 100° C. for 1 hour. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure and chromatographed on silica gel to give 1-(3-morpholinopropoxy)-1,4-diphenylbutane. M.P., 138°-139° C. (oxalate).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1.[CH:24]1([NH:30][C:31]2[C:36]([C:37]([O:39]CC)=O)=[CH:35][N:34]=[C:33]([NH:42][C:43]([NH:45][CH2:46][CH3:47])=[O:44])[CH:32]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[NH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[CH:50]=1>CN(C=O)C.O>[CH:24]1([NH:30][C:31]2[C:36]([C:37]([NH:48][C:49]3[CH:50]=[C:51]([CH3:55])[CH:52]=[CH:53][CH:54]=3)=[O:39])=[CH:35][N:34]=[C:33]([NH:42][C:43]([NH:45][CH2:46][CH3:47])=[O:44])[CH:32]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Cc1cccc(N)c1
Reactant: CCNC(=O)Nc1cc(NC2CCCCC2)c(C(=O)OCC)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1cc(NC2CCCCC2)c(C(=O)Nc2cccc(C)c2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.8 %

Procedure:
EDCI.HCl (1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, 0.092 g, 0.480 mmol) and 1-hydroxybenzotriazole monohydrate (0.073 g, 0.480 mmol) were added to a stirred solution of ethyl 4-(cyclohexylamino)-6-(3-ethylureido)nicotinate iii (0.100 g, 0.320 mmol) in DMF (3 mL) at room temperature. After 15 min, m-toluidine (0.052 g, 0.480 mmol) was added and the reaction mixture stirred at room temperature for 24 h. The mixture was treated with water (5 mL) and the resulting colourless precipitate filtered, washed with water, air-dried and recrystallized from EtOH to afford Compound 3 (0.030 g, 0.076 mmol, 29%) as colourless microcrystals. 1H NMR (300 MHz, DMSO-d6): δ 10.00 (1H, s), 9.01 (1H, s), 8.44 (1H, s), 8.28 (1H, br), 8.10 (1H, d, J 9.0), 7.52 (1H, s), 7.42 (1H, d, J 9.0), 7.20 (1H, t, J 6.0), 6.90 (1H, d, J 6.0), 6.66 (1H, s), 3.25-3.13 (3H, m), 2.29 (3H, s), 1.94-1.91 (2H, m), 1.67-1.57 (3H, m), 1.42-1.23 (5H, m), 1.08 (3H, t, J 7.2); [M+H]+ m/z=396.2.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5](N)=[C:4]([N+:15]([O-:17])=[O:16])[C:3]=1[F:18].[I:19]I>C(Cl)(Cl)Cl.S(=O)(O)[O-].[Na+]>[Br:1][C:2]1[C:3]([F:18])=[C:4]([N+:15]([O-:17])=[O:16])[C:5]([I:19])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:8]=1
Reactant: II
Reactant: Nc1c(-c2ccccn2)cc(Br)c(F)c1[N+](=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1c(F)c(Br)cc(-c2ccccn2)c1I
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-cold solution of 4-bromo-3-fluoro-2-nitro-6-(pyridin-2-yl)aniline (4.0 g, 12.81 mmol) in chloroform (50 mL) was added iodine (18.21 g, 71.77 mmol) and the resulting mixture was stirred at 0° C. for 10 min followed by addition of isoamyl nitrile (3.44 mL, 25.63 mmol). The mixture was then heated up to 65° C. for 5 h. After completion of reaction (by TLC), the reaction was diluted with 10% sodium bisulfite and extracted with DCM (3×100 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 20% EtOAc:hexane to obtain the desired product as an off white solid (2.0 g, 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH:64]1[CH2:69][CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH:64]1[CH2:69][CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCOC(=O)CCC1CCCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)CCC1CCCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and ethyl 3-piperidin-2-yl-propionate in DMSO at ambient temperature.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:3]=1.[CH2:20]([Mg]Cl)[CH3:21]>C1COCC1>[CH3:1][C:2]1[C:7]([CH:8]([OH:9])[CH2:20][CH3:21])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:19])[F:18])[CH:11]=2)[N:3]=1
Reactant: CC[Mg]Cl
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1C=O
Solvent: C1CCOC1
Product: CCC(O)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C

Procedure:
0.600 g (2.26 mmol) of the above prepared 2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine-3-carbaldehyde was dissolved in 11 ml of abs. THF and treated at −15° C. with 1.08 ml of 2.5 M ethyl magnesium chloride solution (in THF). After 30 Min., the reaction mixture was carefully poured onto crashed ice/NH4Cl, extracted twice with AcOEt, washed with water and brine, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=8/2) produced finally 0.473 g of pure title compound as white crystals of mp. 97-99° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].[NH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:17](=[O:19])[CH3:18].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:17]([C:10]1[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=1[NH:8][C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[O:7])(=[O:19])[CH3:18]
Reactant: COc1ccc(C(C)=O)c(N)c1
Reactant: O=Cc1nccs1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nccs2)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution of 2-thiazolecarboxaldehyde (500 mg, 3.87 mmol) in 35 mL of pyridine, 1-(2-amino-4-methoxyphenyl)ethanone (640 mg, 3.87 mmol) was added and the solution was cooled to −30° C. before POCl3 (750 μl, 8.13 mmol) was added drop wise. The reaction mixture was stirred at −10° C. for 1 hour and then at room temperature for 2 hours. The mixture was concentrated under vacuum and the residue was triturated with NaHCO3 to pH 7. The precipitate was filtrated, washed with water and dried. The amide was pure enough for the next step without purification (972 mg, 91%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:13](=[O:14])[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[O:9]2)[CH:5]=[CH:6][CH:7]=1.O.[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:20]([C:2]1[CH:3]=[C:4]([CH:8]2[C:13](=[O:14])[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[O:9]2)[CH:5]=[CH:6][CH:7]=1)#[N:21]
Reactant: CN(C)C=O
Reactant: O=C1Nc2ccccc2OC1c1cccc(Br)c1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1cccc(C2Oc3ccccc3NC2=O)c1
Temperature: 100 °C
Yield: 76 %

Procedure:
To a solution of 2-(3-bromophenyl)-3,4-dihydro-2H-1,4-benzoxazin-3-one (I7) (3.00 g, 9.87 mmol) in DMF (20 mL) was added Zinc cyanide (0.68 g, 5.79 mmol) and then tetrakistriphenylphosphine palladium (0) (0.96 g, 8 mol %). The degassed solution was heated at 100° C. for 5 hours, cooled to room temperature, and then treated with water (50 mL). The product was extracted into ethyl acetate (2×100 mL), washed with brine (50 mL), dried over MgSO4, and then purified by silica gel chromatography, eluant 50% ethyl acetate in hexane. This process affords the title compound (1.866 g, 76%) that was recrystallized from ethanol/water.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:14])[N:3]=1.[CH:15]([NH2:18])([CH3:17])[CH3:16]>O1CCOCC1>[Cl:14][C:4]1[N:3]=[C:2]([NH:18][CH:15]([CH3:17])[CH3:16])[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=1
Reactant: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Reactant: CC(C)N
Solvent: C1COCCO1
Product: CC(C)Nc1nc(Cl)cc2ncn(C)c(=O)c12
Temperature: 80 °C

Procedure:
A mixture of 5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (920.2 mg, 4.0 mmol) and isopropylamine (1.7 mL, 1.182 g, 20.0 mmol) in dioxane (10 mL) was heated at 80° C. for 26 hours and evaporated to result in a residue which was partitioned between saturated NH4Cl solution (200 mL) and EtOAc (100 mL). The aqueous phase was extracted with EtOAc (2×50 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, and evaporated to afford crude title product. 1H NMR (DMSO-d6) 1.22 (d, J=6.4 Hz, 6H, 2CH3), 3.42 (s, 3H, NCH3), 4.19 (m, 1H), 6.59 (s, 1H), 8.45 (s, 1H), 8.90 (d, J=7.6 Hz, 1H, NH); ESI-MS m/z 253.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([CH2:14]O)[S:11][N:10]=2)=[CH:5][CH:4]=1.P(Br)(Br)[Br:17].O>C1(C)C=CC=CC=1>[Br:17][CH2:14][C:12]1[S:11][N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:13]=1
Reactant: COc1ccc(-c2nsc(CO)n2)cc1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2nsc(CBr)n2)cc1
Temperature: 120 °C
Yield: 58 %

Procedure:
To a solution of [3-(4-methoxyphenyl)-[1,2,4]thiadiazol-5-yl]-methanol (0.07 g, 0.29 mmol) in toluene (10 ml) was added PBr3 (0.041 ml, 0.43 mmol) and the resulting reaction mixture was refluxed at 120° C. for 15 min. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0° C., added water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organics was washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated under vacuum to get the desired product (0.048 g, 53%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][C:14]3([OH:27])[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH:12]=2)=[CH:4][C:3]=1[O:28][CH:29]([C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=1[Cl:39])[CH3:30].Cl.O1CCOCC1>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][C:14]3([OH:27])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:12]=2)=[CH:4][C:3]=1[O:28][CH:29]([C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=1[Cl:39])[CH3:30]
Reactant: CC(Oc1cc(-c2cnn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(Oc1cc(-c2cnn(CC3(O)CCNCC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
A reaction mixture of compound (3-6) (145 mg; 0.25 mmol) with 4.0 M HCl in dioxane (2.0 mL; 8.1 mmol) in 5 mL of CH2Cl2 was stirred at room temperature for 2.0 hours. The reaction mixture was concentrated by vacuum. The residue was purified by Dionex system (5% to 95% MeCN:H2O w 0.1% HOAc buffer) to collect the desired fraction to afford 76 mg of (3-7) as a yellow grease (63% yield). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.41-1.55 (m, 2H) 1.59-1.71 (m, 2H) 1.81 (d, J=6.57 Hz, 3H) 2.88-3.00 (m, 2H) 3.02-3.14 (m, 2H) 4.08 (s, 2H) 5.17 (s, 2H) 6.14-6.27 (m, J=6.57 Hz, 1H) 7.05 (s, 1H) 7.40-7.49 (m, J=8.72, 8.72 Hz, 1H) 7.51-7.60 (m, J=9.09, 4.80 Hz, 1H) 7.63 (s, 1H) 7.76 (s, 1H) 7.91 (s, 1H) 8.51 (s, 1H) 8.81 (s, 1H). LCMS calcd for C22H24Cl2FN5O2 (M+H) 481, found 481. HPLC purity 98%. Anal. (C22H24Cl2FN5O2×2.2HOAc×2.3H2O)C, H, N.