Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH2:1].[CH3:2][C:3]1[N+:8]([O-])=[CH:7][C:6]2[CH:10]=[CH:11][O:12][C:5]=2[CH:4]=1.[OH-].[Na+]>C(OC(=O)C)(=O)C.Cl>[OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[CH:10]=[CH:11][O:12][C:5]=2[CH:4]=1
Reactant: O
Reactant: Cc1cc2occc2c[n+]1[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: OCc1cc2occc2cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A mixture of 6-methylfuro[3,2-c]pyridine-N-oxide monohydrate (19.85 g, 0.119 mol) in acetic anhydride (30 mL) was heated at 100° C. for one half hour. Then the reaction mixture was diluted with 20% hydrochloric acid (100 mL) and heating was continued for one hour. The solution was cooled and made basic with sodium hydroxide solution. The product was extracted into chloroform, dried over anhydrous sodium sulfate, filtered through a pad of charcoal and evaporated. The residue was triturated with cool benzene and the crystalline product collected by filtration to give 11.36 g (64% yield), mp: 72°-74° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][CH2:14][C:15](OCC)=[O:16])[N:9]=[CH:8][CH:7]=[C:6]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2.[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][CH2:14][CH2:15][OH:16])[N:9]=[CH:8][CH:7]=[C:6]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: CCOC(=O)CCc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1CCCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.5 %

Procedure:
Ethyl 3-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yl]-propionate (80 mg) was dissolved in tetrahydrofuran (5 ml) to prepare a solution. A diisobutylaluminum hydride/0.93 M hexane solution (1 ml) was added to the solution under ice cooling, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (50 mg, yield 69%).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)[O:9][N:8]=1)(=O)=O.[N:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]3[CH2:31][CH2:32][CH2:33][NH:34][C:29]3=[N:28][N:27]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[N:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]3[CH2:31][CH2:32][CH2:33][N:34]([CH2:6][C:7]4[N:11]=[C:10]([C:12]5[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=5)[C:18]#[N:19])[O:9][N:8]=4)[C:29]3=[N:28][N:27]=2)=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)OCc1noc(-c2cccc(C#N)c2)n1
Reactant: c1cc(-c2nnc3n2CCCN3)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#Cc1cccc(-c2nc(CN3CCCn4c(-c5ccncc5)nnc43)no2)c1
Temperature: 25 °C
Yield: 1.4 %

Procedure:
[5-(3-cyanophenyl)-1,2,4-oxadiazol-3-yl]methyl methanesulfonate (0.278 g; 0.99 mmol) and 3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine (0.220 g; 1.09 mmol) were dissolved in butanone (20 ml) and potassium carbonate (0.275 g; 1.99 mmol) was added portionwise. The mixture was heated at reflux for 18 h before cooling to r.t. This mixture was concentrated in vacuo and DCM (20 ml) was added. The mixture was washed with water, dried (Na2SO4), evaporated and purified using prep. HPLC chromatography to give the title compound (5.4 mg). 1H NMR: 8.77 (m, 2H), 8.41 (s, 1H), 8.34 (d, 1H), 7.87 (d, 1H), 7.68 (t, 1H), 7.56 (m, 2H) 5.51 (s, 2H), 4.09 (m, 2H), 3.62 (m, 2H), 2.19 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.[B:16](OC)([O:19]C)[O:17]C.[Cl-].[NH4+]>O1CCCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([B:16]([OH:19])[OH:17])[CH:7]=1
Reactant: COc1ccc(F)cc1Br
Reactant: COB(OC)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1B(O)O
Reaction time: 1 h
Yield: 382.5 %

Procedure:
A cold solution (−78° C.) of 2-bromo-4-fluoro-anisole (20 g, 10 mmol, 1 equiv) in anhydrous tetrahydrofuran (200 mL) was treated dropwise, over 20 min, with 2.5M n-butyllithium solution in hexanes (44 mL, 110 mmol, 1.1 equiv). The reaction was stirred for 1 hour, then trimethyl borate (16.75 mL, 150 mmol, 1.5 equiv) was added in one portion. After stirring overnight at room temperature, the reaction was poured into saturated ammonium chloride (200 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The solid residue was triturated with methyl tert-butyl ether (100 mL) to give (5-fluoro-2-methoxyphenyl)boronic acid (1) (6.5 g, 39% yield) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-])=O)[C:5]([C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH:13]=2)=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5]([C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1C1=CCOCC1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(Br)cnc1C1=CCOCC1
Temperature: 65 °C
Reaction time: 19 h

Procedure:
To a stirred mixture of as 5-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-3-nitropyridine (0.19 g, 0.69 mmol) in EtOAc (10 mL) was added tin(II) chloride dihydrate (0.78 g, 3.48 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 65° C. After 19 h, the reaction was cooled to rt and diluted with EtOAc, then washed with 1M NaOH (20 mL), water (20 mL), and brine (20 mL). After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was identified as mostly 5-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-3-pyridinamine.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Cl.Cl[CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(C(C)=O)C.C(OCC)(=O)C.[I-].[K+]>[OH:1][C:2]1[CH:15]=[C:14]([O:16][CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:13]=[CH:12][C:3]=1[C:4](=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClCc1cccnc1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: O=C(c1ccccc1)c1ccc(OCc2cccnc2)cc1O
Reaction time: 18 h
Yield: 69.5 %

Procedure:
A mixture of 2,4-dihydroxybenzophenone (21.4 g), 3-chloromethylpyridine hydrochloride (25 g), potassium carbonate (80 g), potassium iodide (0.5 g) and tetrabutylammonium bromide (0.2 g) in methyl ethyl ketone is heated at reflux with mechanical stirring for 18 hours. The reaction mixture is filtered through hyflo and the solids washed with several portions of methyl ethyl ketone. The filtrate and the washings are combined and concentrated under reduced pressure to leave a brown oil which is dissolved in ethyl acetate (250 mL) and washed four times with water (200 mL). The organic layer is dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a residue which is crystallised from cyclohexane containing a little decolourizing charcoal to give 2′-hydroxy-4′-(pyridin-3-ylmethoxy)benzophenone (21.2 g) as a pale yellow solid, m.p. 88-90° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([C:10]([OH:12])=[O:11])[CH:3]=1>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:6]=[C:4]([C:10]([OH:12])=[O:11])[O:12][C:10]2=[O:11])=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(Br)cc1C(=O)O
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2ccc(Br)cc2c(=O)o1

Procedure:
7-Bromoisocoumarin-3-carboxylic acid, mp. (EtOH-H2O) 320°-4°, (Found: C, 44.72; H, 1.86; Br. 29.41. C10H5BrO4 requires C, 44.64; H, 1.87; Br. 29.70), was prepared from 4-bromo-2-carboxybenzaldehyde by an analogous procedure to that described in Example 1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]1([CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:14][CH2:15][CH2:16][CH2:17]Br)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C.[Na+].[Cl-]>[C:19]1([CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:14][CH2:15][CH2:16][CH2:17][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C1CNCCN1
Reactant: BrCCCOC(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(C(OCCCN2CCNCC2)c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
In 20 mL of ethanol was dissolved 20 g of piperazine with heating. Then, a solution of 3-(diphenylmethoxy)propyl bromide (7.0 g) in ethanol (20 mL) was added dropwise and the mixture was stirred at 70° C. for 1 hour. This reaction mixture was diluted with saturated aqueous NaCl and extracted with chloroform. The extract was washed with saturated aqueous NaCl to remove the starting material piperazine, dried over MgSO4, and concentrated under reduced pressure to provide 7.1 g of the title compound. Yield 99%. This product was not further purified but directly submitted to the next reaction.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.Br[C:40]1[CH:41]=[C:42]([S:46]([NH2:49])(=[O:48])=[O:47])[CH:43]=[N:44][CH:45]=1.CCCCCCC>C1(C)C=CC=CC=1>[F:20][C:17]([F:18])([F:19])[C:15]1[CH:14]=[C:13]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:40]3[CH:41]=[C:42]([S:46]([NH2:49])(=[O:48])=[O:47])[CH:43]=[N:44][CH:45]=3)[N:7]=[CH:8]2)[CH:16]=1
Reactant: NS(=O)(=O)c1cncc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: NS(=O)(=O)c1cncc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (Example G.11) (0.503 g, 0.7 mmol), commercially available 5-bromo-pyridine-3-sulfonic acid amide (0.183 g, 0.77 mmol), tetrakis(triphenyl-phosphine)palladium (0.040 g, 0.030 mmol) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (258 mg, 72%). MS (ISP) 514.2 [(M+H)+]; mp>250° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:19][C@@H:20]1[C:26](=[O:27])[N:25]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:24]2[CH:36]=[CH:37][CH:38]=[CH:39][C:23]=2[S:22][CH2:21]1)[C:14]([O:16]CC)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[Na+].O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:19][C@@H:20]1[C:26](=[O:27])[N:25]([CH2:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[C:24]2[CH:36]=[CH:37][CH:38]=[CH:39][C:23]=2[S:22][CH2:21]1)[C:14]([OH:16])=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O)CSc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
In a mixture of 40 ml of methanol and 25 ml of 1N aqueous sodium hydroxide solution is dissolved 0.6 g of tert-butyl 3(R)-[5-tert-butoxycarbonylamino-1(S)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as obtaiend in Example 37, and 10 ml of water is further added to the solution, followed by stirring at room temperature for 2 hours. The methanol is evaporated off under reduced pressure, and the residual solution is made weakly acidified with phosphoric acid and extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.37 g of tert-butyl 3(R)-[5-tert-butoxycarbonylamino-1(S)-carboxypentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless viscous material. This product is treated with ethyl acetate to yield a colorless crystalline powder, melting at 134°-135° C.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[N:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[N:8]([CH2:11][CH2:12][CH2:13][OH:14])[C:9](=[O:10])[C:4]=2[CH:3]=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[Br:1][C:2]1[CH:18]=[N:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][O:19]3)[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: Cn1c(=O)n(CCCO)c(=O)c2cc(Br)cnc21
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.7 %

Procedure:
To a solution of 6-bromo-3-(3-hydroxypropyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (6.2 g, 19.8 mmol) in DCM (100 mL) at 0° C. was added 3,4-dihydro-2H-pyran (6 mL, 65.7 mmol) and pyridinium p-toluenesulfonate (50 mg, 0.2 mmol). The reaction was stirred at RT for 16 h then diluted with DCM (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography PE/EA (8:1 to 2:1) to give 6-bromo-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.5 g, 31.8% yield) as a white solid. 1H NMR (CDCl3) δ: 8.68 (m, 1H), 8.54-8.53 (m, 1H), 4.57 (s, 1H), 4.26-4.17 (m, 2H), 3.87-3.80 (m, 2H), 3.68 (s, 3H), 3.52-3.47 (m, 2H), 2.04-1.97 (m, 2H), 1.76-1.63 (m, 2H), 1.49-1.46 (m, 2H). LCMS: [MH+-THP] 314 and TR=1.626 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN(c3ccc(C)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)ccn2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-methylphenyl)amino]piperidine (581 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]#[C:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1.[CH3:22][O-:23].[Na+]>CC(N(C)C)=O>[CH3:20][N:19]([CH3:21])[CH2:18][C:17]#[C:16][C@H:13]1[CH2:14][CH2:15][C@H:10]([N:8]([C:5]2[N:6]=[N:7][C:2]([O:23][CH3:22])=[CH:3][CH:4]=2)[CH3:9])[CH2:11][CH2:12]1
Reactant: C[O-]
Reactant: CN(C)CC#C[C@H]1CC[C@H](N(C)c2ccc(Cl)nn2)CC1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(N(C)[C@H]2CC[C@H](C#CCN(C)C)CC2)nn1
Temperature: 80 °C

Procedure:
A solution of 92.1 mg (0.3 mmol) of trans-(6-Chloro-pyridazin-3-yl)-[4-(3-dimethylamino-prop-1-ynyl)-cyclohexyl]-methyl-amine in 0.6 ml DMA was treated with 0.56 ml (3 mmol) of sodium methylate (5.4 M in MeOH) and heated at 80° C. for 54 h. The reaction was extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried (Na2SO4), filtered and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 99:1 to 97:3) yielded 67 mg (74%) of pure trans-[4-(3-Dimethylamino-prop-1-ynyl)-cyclohexyl]-(6-methoxy-pyridazin-3-yl)-methyl-amine, MS: 303 (MH+).
Reaction SMILES: [CH2:1]([N:5]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)[C:6](=[O:15])[CH:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH:3][CH3:4].C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[CH2:3]([CH:2]1[CH2:1][N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:6](=[O:15])[CH:7]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:4]
Reactant: CC=CCN(C(=O)C(Cl)c1ccccc1)c1cccc(C(F)(F)F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CCC1CN(c2cccc(C(F)(F)F)c2)C(=O)C1c1ccccc1
Reaction time: 1.17 h

Procedure:
N-(2-Butenyl)-N-(3-trifluoromethylphenyl)-2-chloro-2-phenylacetamide (1.5 g) was added to 15 ml of benzene, followed by the addition of 1.2 g of tributyltin hydride and an extremely small amount of α,α-azobisisobutyronitrile (AIBN) under stirring at the refluxing temperature. After the reaction mixture was continuously stirred for 70 minutes, 40 ml of saturated saline were added, followed by extraction with toluene. After the extract was dried over anhydrous magnesium sulfate, the extract was concentrated in an evaporator and then subjected to chromatography on a silica gel column. The 3,4-trans isomer (0.67 g) and the 3,4-cis isomer (0.27 g) were obtained.
Reaction SMILES: C1C=CC=CC=1.[C:7]([Cl:10])(Cl)=[O:8].C([N:18]1[CH2:22][CH2:21][CH:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[CH2:19]1)C1C=CC=CC=1>O1CCCC1>[Cl:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[O:23][CH:20]1[CH2:21][CH2:22][N:18]([C:7]([Cl:10])=[O:8])[CH2:19]1
Reactant: Clc1cccc(OC2CCN(Cc3ccccc3)C2)c1
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: O=C(Cl)N1CCC(Oc2cccc(Cl)c2)C1
Yield: 8.1 %

Procedure:
A benzene solution of 450 ml of 2M phosgene (0.9 mole) was cooled to 10° C. and while stirring, 210 g (0.81 mole) of 1-benzyl-3-(3-chlorophenoxy)pyrrolidine in 210 ml of tetrahydrofuran was added over a 31/2 hr period. The reaction mixture was allowed to stir overnight and then filtered to remove the hydrochloric acid salt of unreacted starting material. The filtrate was evaporated to give a dark colored oil which was triturated with three 500 ml portions of 30/60 petroleum ether decanting off the petroleum ether each time from the oil residue. The petroleum ether layers were cooled and the oils which separated were combined to give 17 g of pure title product as an oil. After washing with more petroleum ether, the oil (203 g) residue contained about 17% benzyl chloride by NMR analysis. Yield of contained product in both portions was 88%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28](OCC)=[O:29])=[C:26]([CH:33]=O)[N:25]=[C:24]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:41].Cl.[NH2:43][NH2:44]>C(O)C>[ClH:41].[O:38]1[CH2:37][CH2:36][N:35]([C:24]2[N:23]=[C:22]([NH:21][C:18]3[CH:19]=[CH:20][C:15]([CH2:14][N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:16][CH:17]=3)[C:27]3[C:28](=[O:29])[NH:44][N:43]=[CH:33][C:26]=3[N:25]=2)[CH2:40][CH2:39]1
Reactant: NN
Reactant: CCOC(=O)c1c(C=O)nc(N2CCOCC2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: CCO
Product: O=c1[nH]ncc2nc(N3CCOCC3)nc(Nc3ccc(CN4CCNCC4)cc3)c12
Yield: 59.3 %

Procedure:
Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-formyl-2-morpholinopyrimidine-5-carboxylate (100 mg, 0.18 mmol) was dissolved in ethanol, hydrazine dihydrochloride (28 mg, 26 mmol) was added and the mixture was refluxed for 3 hours. The solid precipitated was filtered and dried in vacuum to give the desired product (49 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:3]=1[C:19]#[N:20].[OH-].[NH4+:22]>>[NH2:22][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:3]=1[C:19]#[N:20]
Reactant: [NH4+]
Reactant: CSc1nc(Cl)c(C#N)c(-c2cccc([N+](=O)[O-])c2)n1
Agent: [OH-]
Product: CSc1nc(N)c(C#N)c(-c2cccc([N+](=O)[O-])c2)n1
Reaction time: 8 h

Procedure:
A solution of 6-chloro-5-cyano-4-(3-nitrophenyl)-2-methylthio-pyrimidine (example 9b, 10.0 g) was treated with ammonium hydroxide (28% NH3 in water, 15 ml) and the mixture was stirred overnight. The formed crystals were collected by filtration and washed with water. The product was dried at 50° C. under vacuum yielding the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([N:8]([CH2:10][CH2:11]Cl)[CH3:9])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([CH3:9])[CH2:10][CH2:11][NH:13]2
Reactant: CN(CCCl)c1ccc(Br)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCNc2cc(Br)ccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
4-bromo-N1-(2-chloroethyl)-N1-methylbenzene-1,2-diamine 1 (3.1 g, 0.012 mol) was dissolved in DMF (6 ml), Potassium carbonate (3.3 g, 0.024 mol) was added. The reaction was stirred at 100° C. for 2 h. The mixture was partitioned between water and EtOAc (2×30 mL) The combined organic layers was concentrated and purified by flash chromatography eluted with EtOAc to give 1.9 g, (69.6%) of 6-bromo-1-methyl-1,2,3,4-tetrahydroquinoxaline. 1H NMR (300 MHz, DMSO-d6) δ 6.50-6.45 (m, 2H), 6.31 (d, J=8.2 Hz, 1H), 5.79 (s, 1H), 3.29 (s, 4H). 3.07 (t, J=2.4 Hz, 2H), 2.71 (s, 3H), LCMS-ESI+ (m/z): [M+H]+ calcd for C9H11BrN2:226.01; found 226.96.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](O)=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:14])=O.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([Cl:14])=[N:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In DMF (40 mL) was stirred 5-bromo-3-nitro-2-pyridinol (8.76 g, 40 mmol) and the solution treated dropwise with phosphorus oxychloride (28 mL). The solution warmed to 80° for 5 hours. The mixture was cooled to room temperature and carefully poured into a mixture of ice and water (400 mL). This mixture was stirred overnight to precipitate. The solid was collected by filtration, washed with water (2×100 mL) and dried at 65° C. on the high vacuum line for 3 hours to give the title compound. MS: M+−1=237.9 Da.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.Cl.[OH:23][C:24]1[C:33]([N:34]([CH3:36])[CH3:35])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:18]=[C:17]([C:19]([N:28]2[CH2:27][CH2:26][C:25]3[C:30](=[CH:31][CH:32]=[C:33]([N:34]([CH3:36])[CH3:35])[C:24]=3[OH:23])[CH2:29]2)=[O:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=C(O)c1nc(-c2ccc(F)cc2F)nc2ccccc12
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Agent: Cl
Product: CN(C)c1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(F)cc3F)nc3ccccc13)C2
Yield: 8 %

Procedure:
Reaction of 2-(2,4-difluorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 60 (8% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 2.64 and 2.70 (2s, 6H), 2.85 and 3.08 (2t, 2H), 3.62 and 4.19 (2t, 2H), 4.53 and 5.07 (2s, 2H), 6.38 and 6.81 (2d, 1H), 6.96-7.15 (m, 3H), 7.63-7.70 (m, 1H), 7.96-8.09 (m, 2H), 8.14-8.26 (m, 2H); MS (ESI) m/z 461 ([M+H]+).