Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[F:21][C:22]1[CH:39]=[CH:38][C:25]2[CH:26]=[C:27](B3OC(C)(C)C(C)(C)O3)[O:28][C:24]=2[CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[F:21][C:22]1[CH:39]=[CH:38][C:25]2[CH:26]=[C:27]([C:2]3[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=4)[N:3]=3)[O:28][C:24]=2[CH:23]=1
Reactant: CC1(C)OB(c2cc3ccc(F)cc3o2)OC1(C)C
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cc4ccc(F)cc4o3)c(N(C)C(C)C)nc2c1
Temperature: 95 °C
Reaction time: 0.67 h
Yield: 41.1 %

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (100 mg, 0.34 mmol) in dioxane (2 mL) was added 2-(6-fluoro-1-benzofuran-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (600 mg, crude), Pd(PPh3)4 (20 mg, 0.02 mmol), K3PO4 (140 mg, 0.66 mmol) under nitrogen atmosphere. After stirring 40 min at 95° C., the reaction mixture was dissolved in water (50 mL), extracted with dichloromethane (3×20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 2% ethyl acetate in petroleum ether to afford methyl 2-(6-fluoro-1-benzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate as a light yellow solid (55 mg).
Reaction SMILES: O.[NH2:2][C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=[CH:6][C:5]=2[O:17][CH:18]([CH2:24][CH3:25])[C:19](OCC)=[O:20].CC(C)([O-])C.[K+].[Cl-].[NH4+]>O1CCCC1>[CH2:24]([CH:18]1[C:19](=[O:20])[NH:2][C:3]2=[C:16]3[C:11](=[N:10][C:9]4=[CH:8][CH:7]=[CH:6][C:5](=[C:4]24)[O:17]1)[CH2:12][CH2:13][CH2:14][CH2:15]3)[CH3:25]
Reactant: CCOC(=O)C(CC)Oc1cccc2nc3c(c(N)c12)CCCC3
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCC1Oc2cccc3nc4c(c(c23)NC1=O)CCCC4
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
To a solution of ethyl α-[(9-amino-1,2,3,4-tetrahydroacridin-8-yl)oxy]butyrate hydrate (30.34 g) in dry tetrahydrofuran (370 ml) was added potassium t-butoxide (13 g). The reaction mixture was stirred at room temperature for 1.5 hrs. Saturated ammonium chloride solution (150 ml) was added and stirring was continued for one hr. The mixture was concentrated and the concentrate was cooled. The solid was collected, washed with water, and dried to yield 21.26 g (78%) of product, mp 182°-183° C.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[C:21]([CH2:28][O:29][CH3:30])[N:22]=[CH:23]2>N1C=CC=CC=1>[CH3:30][O:29][CH2:28][C:21]1[N:22]=[CH:23][C:24]2[C:19]([CH:20]=1)=[C:18]([N:17]=[C:4]1[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]1)[CH:27]=[CH:26][CH:25]=2
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Reactant: COCc1cc2c(N)cccc2cn1
Agent: [I-]
Solvent: c1ccncc1
Product: COCc1cc2c(N=C3SC[C@@H]4Cc5ccccc5CN34)cccc2cn1
Reaction time: 18 h
Yield: 84.1 %

Procedure:
(S)-3-Methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (13.0 g) is added to a solution of 5-amino-3-methoxymethylisoquinoline (6.8 g) in pyridine (200 cc). After 18 hours at a temperature of about 20° C., the mixture is concentrated to dryness under reduced pressure (25 mm Hg; 3.3 kPa). The residue is dissolved in a mixture of 4 N sodium hydroxide solution (100 cc) and methylene chloride (200 cc). The organic phase is decanted, washed with water (100 cc), dried over magnesium sulphate and filtered, and the filtrate is then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue is crystallized by trituration with diisopropyl ether (50 cc) and then recrystallised from ethanol (200 cc). (S)-3-[(3-Methoxymethylisoquinol-5-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (11.3 g) is thus obtained in the form of light beige crystals melting at 134° C.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[NH:11][C:10]2[CH2:12][CH2:13][CH2:14][CH2:15][C:9]=2[N:8]=1)(=[O:6])=[O:5].[CH3:16]I.[Cl-].[Cl-].[Ca+2]>CN(C=O)C.CO>[CH3:16][N:11]1[C:10]2[CH2:12][CH2:13][CH2:14][CH2:15][C:9]=2[N:8]=[C:7]1[S:4]([CH3:3])(=[O:5])=[O:6]
Reactant: CI
Reactant: CS(=O)(=O)c1nc2c([nH]1)CCCC2
Agent: [Ca+2]
Agent: [Cl-]
Agent: [H-]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1c(S(C)(=O)=O)nc2c1CCCC2

Procedure:
Sodium hydride (55.8 mg) (60% in mineral oil) was added to a solution of 2-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-benzimidazole (233 mg) and MeI (0.080 mL) in DMF (dry) (10 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 1 h. The reaction mixture was diluted with MeOH (2 mL), and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-30% EtOAc in hexane) to give 1-methyl-2-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-benzimidazole (200 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32]([O-:34])=[O:33])[N:27]=[CH:26]4)=[N:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[O:35][CH2:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CO.[Pd]>[NH2:19][C:15]1[CH:14]=[C:13]([C:9]2[N:8]=[C:7]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32]([O:34][C:6]([CH3:11])([CH3:7])[CH3:5])=[O:33])[N:27]=[CH:26]4)[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:35][CH2:36][CH2:37][CH2:38][N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[CH:5]=3)[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)nc(Nc3ccc4c(cnn4C(=O)[O-])c3)c2cc1OCCCN1CCOCC1
Agent: [Pd]
Solvent: CO
Product: COc1cc2nc(-c3cccc(N)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCN1CCOCC1
Reaction time: 0.33 h

Procedure:
To a mixture of 5-(7-methoxy-6-(3-morpholinopropoxy)-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.215 g) in MeOH (60 mL) was added Pd/C (0.21 g) and NH4CO2 (0.21 g). The mixture was heated at 60° C. for 40 mins, upon which an additional portion of NH4CO2 (0.095 g) was added, heating was continued for a further 20 minutes. The mixture was filtered to remove the Pd/C and the filtrate was concentrated under reduced pressure. The residue was taken up in CH2Cl2 (300 mL) wand was washed with water and brine. The mixture was dried (Na2SO4) and the volatiles removed in vacuo. The material was combined with an identical experiment using 0.2 g and the residue was subjected to preparative TLC (SiO2, CH2Cl2:MeOH 9:1) to give the desired product tert-butyl 5-(2-(3-aminophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. HPLC retention time 4.67 mins.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C:10]([O:12]CC)=O)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:15]1([C@@H:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:15]1([C@@H:21]([NH:23][C:10]([C:8]2[O:9][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[N:6][N:7]=2)=[O:12])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CCOC(=O)c1nnc(C(C)(C)C)o1
Solvent: CCO
Product: C[C@H](NC(=O)c1nnc(C(C)(C)C)o1)c1ccccc1
Yield: 92 %

Procedure:
A solution of ethyl 5-tert-butyl-[1,3,4]oxadiazole-2-carboxylate (1.38 g, 7 mmol) and (S)-1-phenylethylamine (1.70 g, 14 mmol) in absolute ethanol (25 ml) is refluxed for 6 hours. The solvent is evaporated in vacuo and the residue is purified by flash column chromatography (silica gel, hexane/ethyl acetate 4:1 v/v) to give (S)-5-tert-butyl-[1,3,4]oxadiazole-2-carboxylic acid (1-phenylethyl)amide (1.76 g, 92%) as colourless crystals, m.p. 123°-125° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[S:14](Cl)(=[O:16])=[O:15])[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[N:9]=[CH:8]2.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH2:32].C(N(CC)CC)C>ClCCl>[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH:32][S:14]([C:13]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:6][C:5]=1[O:4][C:3]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:2]=1[F:1])(=[O:16])=[O:15]
Reactant: CN(C)CCCN
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(S(=O)(=O)Cl)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(S(=O)(=O)NCCCN(C)C)cc21
Reaction time: 4 h
Yield: 39.9 %

Procedure:
To a cooled (0° C.) solution of 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-sulfonyl chloride (0.20 g, 0.50 mmol) in dichloromethane under N2 atmosphere was added 3-(dimethylamino)propylamine (0.05 g, 0.50 mmol) and triethylamine (0.15 g, 1.5 mmol) drop-wise. The reaction mixture was stirred for 4 hours and then diluted with dichloromethane (20 mL), washed with water, saturated NaHCO3 and brine and then dried over MgSO4. The mixture was concentrated under reduced pressure and chromatographed on preparatory TLC plates eluting with dichloromethane/MeOH/Et3N (95:4:1) to afford the 93 mg of final product (40% yield). MS (APCI−) m/z 466 detected; 1H NMR (400 mHz, CDCl3) δ 8.15 (s, 1H), 7.91 (s, 1H), 7.20 (m, 1H), 7.09 (s, 1H), 7.00 (m, 1H), 6.90 (m, 1H), 4.22 (d, 2H), 3.12 (t, 2H), 2.35 (m, 3H), 2.13 (s, 6H), 1.70 (m, 2H), 0.94 (d, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17](O)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=[O:29])[CH2:27][NH2:28])C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([NH:28][CH2:27][C:26]([OH:25])=[O:29])=[O:18])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)O)c2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)NCC(=O)O)c2)CC1

Procedure:
The acid 16-3 was coupled with glycine ethyl ester followed by hydrolysis of the resulting ester using previously described chemistry to yield 17-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[C:15](=O)[CH2:14][CH2:13][N:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8][C:9]3[CH2:10][CH2:11][N:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:14][C:15]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)N1CCC(=O)C(Sc2ccc(Br)cc2)CC1
Solvent: O
Product: CCOC(=O)N1CCc2sc3ccc(Br)cc3c2CC1

Procedure:
A solution of 44.3 g (119 mmol) ethyl 4-(4-bromo-phenylsulphanyl)-5-oxo-azepan-1-carboxylate in 443 g polyphosphoric acid is heated to 80° C. for 45 min and then diluted with 1000 mL water. The aqueous phase is extracted three times with chloroform. The organic phase is washed with water, dried over Na2SO4 and the solvent is eliminated i.vac. The purification is carried out by repeated column chromatography on silica gel (chloroform/EtOAc 19:1) and by recrystallisation from MeOH/acetone.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[O:3]1.[Br:17]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(#N)C>[Br:17][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[B:4]1[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]1
Reactant: Cc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC#N
Product: CC1(C)OB(c2ccccc2CBr)OC1(C)C
Temperature: 25 °C

Procedure:
A mixture of 32.3 g (148 mmol) of 4,4,5,5-tetramethyl-2-(2-methylphenyl)-1,3,2-dioxaborolane, 25.0 g (141 mmol) of N-bromosuccinimide, and 0.32 g (2.62 mmol) of AIBN was refluxed in 1000 ml of acetonitrile for 2 h. The mixture was then cooled to room temperature and then evaporated to dryness. The residue was dissolved in 500 ml of hexane. The formed precipitate was filtered on glass frit (G3), and the filtrate was evaporated to dryness to give yellowish crystalline powder. Yield 28.9 g (66%). Anal. calc. for C13H18BBrO2: C, 52.57; H, 6.11. Found: C, 52.63; H, 6.29. 1H NMR (CDCl3): 7.81 (m, 1H, 6-H), 7.37-7.42 (m, 2H, 3, 5-H), 7.28 (m, 1H, 4-H), 4.91 (s, 2H, CH2Br), 1.37 (s, 1H, Bpin).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:11]([CH3:23])[CH2:10]2)=[CH:4][CH:3]=1.[C:30]1([C:36]#[CH:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC.CCOC(C)=O>[CH3:23][C@@H:11]1[CH2:10][N:9]([C@@H:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]2[CH:6]=[CH:7][C:2]([C:37]#[C:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:3][CH:4]=2)[CH2:14][CH2:13][N:12]1[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: C[C@@H]1CN([C@@H](c2ccccc2)c2ccc(Br)cc2)CCN1CC(=O)OC(C)(C)C
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@@H]1CN([C@@H](c2ccccc2)c2ccc(C#Cc3ccccc3)cc2)CCN1CC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of tert-butyl 2-((R)-4-((S)-(4-bromophenyl)(phenyl)methyl)-2-methyl-piperazin-1-yl)acetate (459 mg, 0.1 mmol, its preparation follows the general procedures of Reference G), 1-phenylethyne (0.137 ml, 1.249 mmol), tetrabutylammonium fluoride trihydrate (946 mg, 2.997 mmol) and dichlorobis(triphenylphosphine)palladium(ii) (21.0 mg, 0.030 mmol) was heated at 80° C. under N2 atmosphere for 1 h. The residue was subjected to flash chromatography (SiO2, hexane to hexane/EtOAc=100:10 to 100:15 to 100:20) to give tert-butyl 2-((R)-2-methyl-4-((S)-phenyl(4-(2-phenylethynyl)phenyl)methyl)-piperazin-1-yl)acetate (460 mg) as a yellow oil.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH2:29][CH3:30])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.C(N(CC)CC)C.[CH3:38][C@H:39]1[CH2:41][O:40]1>C(O)(C)C.C(#N)C>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:28][CH2:29][CH3:30])=[C:7]([CH:5]4[CH2:4][N:3]([CH2:38][C@@H:39]([OH:40])[CH3:41])[CH2:6]4)[C:12]([F:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH3:27])[C:20]=12
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CC(C)O
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C[C@H](C)O)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 23.6 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (46 mg, 0.11 mmol) (from isomer 1) and triethylamine (50 μL, 0.4 mmol) in isopropyl alcohol (0.3 mL) was added (S)-(−)-methyloxirane (16 μL, 0.23 mmol). The resulting mixture was stirred at 90° C. for 3 h. After cooling, the mixture was diluted with acetonitrile and purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (12 mg, 23%). The product was isolated as a single diastereomer. 1H NMR (400 MHz, DMSO-d6): δ 8.05 (s, 1H), 7.38 (d, 1H), 6.15 (m, 1H), 4.26 (d, 1H), 3.76-3.60 (m, 6H), 2.99 (m, 2H), 2.48 (s, 3H), 2.22 (m, 2H), 1.62 (d, 3H), 1.25 (t, 3H), 0.93 (d, 3H) ppm; LCMS calculated for C22H29ClFN6O2 (M+H)+: m/z=463.2; Found: 463.2.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[C:7](=[CH:20][NH:21][CH:22]=3)[CH:8]([O:18][CH3:19])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[CH3:25]C(C)([O-])C.[K+].CI>CN(C)C=O.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[C:7](=[CH:20][N:21]([CH3:25])[CH:22]=3)[CH:8]([O:18][CH3:19])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: COC1N=C(c2ccccc2Cl)c2cc(Cl)ccc2-c2c[nH]cc21
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC1N=C(c2ccccc2Cl)c2cc(Cl)ccc2-c2cn(C)cc21
Reaction time: 0.25 h

Procedure:
In one portion 1.0 g (2.8 mmol) of 8-chloro-6-(2-chlorophenyl)-4-methoxy-2H,4H-pyrrolo[3,4-d][2]benzazepine was added to a solution of 0.35 g (3.0 mmol) of potassium t-butoxide in 20 ml of dimethylformamide which was cooled to 0°. After stirring for 15 min, 0.3 ml (4.8 mmol) of methyl iodide was added. The mixture was stirred for 5 min, diluted with water and extracted with ether. The ether solution was washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give a pale yellow oil. Purification by column chromatography (silica gel, 25 g; 5% ether in methylene chloride, eluent) gave an off-white solid, mp 128°-130°. Recrystallization from a mixture of ether and petroleum ether gave off-white prisms, mp 128°-130°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][CH:5]=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[C:11]([C:3]1[C:2]([N:1]=[CH:15][N:16]([CH3:18])[CH3:17])=[N:7][C:6]([CH2:8][CH2:9][CH3:10])=[CH:5][N:4]=1)#[N:12]
Reactant: COC(OC)N(C)C
Reactant: CCCc1cnc(C#N)c(N)n1
Solvent: Cc1ccccc1
Product: CCCc1cnc(C#N)c(N=CN(C)C)n1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
A mixture of 3-amino-5-propylpyrazine-2-carbonitrile (0.140 g, 0.863 mmol) (prepared according to the method of Taylor and LaMattina, JOC 1977, 47, 1523) and dimethylformamide dimethylacetal (0.123 g, 1.04 mmol, 1.2 eq) in toluene (10 mL) was heated under reflux for 2 h. The mixture was cooled to room temperature and the solvent evaporated under reduced pressure to provide the title compound (0.188 mg, 100%) as a thick oil.
Reaction SMILES: [C:1]1([C:7]#[C:8]/[CH:9]=[CH:10]/[CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.[CH2:26]([O:28][C:29](=[O:42])[C@@H:30]([O:39][CH2:40][CH3:41])[CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[CH3:27].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH2:26]([O:28][C:29](=[O:42])[C@@H:30]([O:39][CH2:40][CH3:41])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:12][CH2:11]/[CH:10]=[CH:9]/[C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:34][CH:33]=1)[CH3:27]
Reactant: OC/C=C/C#Cc1ccccc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C/C#Cc2ccccc2)cc1)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
(E)-5-Phenyl-pent-2-en-4-yn-1-ol (328 mg, 2.07 mmol), tributylphosphine (606 mg, 3.0 mmol) and (S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (Tetrahedron Letters, Vol. 35, No. 19, 3139–3142, 1994) (495 mg, 2.07 mmol) were successively dissolved in dry benzene (30 mL) under a nitrogen atmosphere and the solution cooled to 0° C. Solid 1,1′-(azodicarbonyl) dipiperidine (756 mg, 3.0 mmol) was added, the mixture stirred for 10 min., then warmed to room temperature and stirred for 16 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The product was purified by flash column chromatography eluting with toluene graduated to toluene/ethyl acetate (19:1) to give 450 mg (57%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:12])[C:9]=1[O:10][CH3:11])[CH:5]=O.C1C(/C=N/O)=CC=[N+:17](C[N+]2C=CC(/C=N/O)=CC=2)C=1.[Br-].[Br-].B.O.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:12])[C:9]=1[O:10][CH3:11])[CH2:5][NH2:17]
Reactant: O/N=C/c1cc[n+](C[n+]2ccc(/C=N/O)cc2)cc1
Reactant: COc1c(Cl)cc(C=O)cc1Cl
Agent: B
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(Cl)cc(CN)cc1Cl
Yield: 64.5 %

Procedure:
A solution of 3,5-dichloro-4-methoxybenzaldehyde methoxime (10.7 g, 46 mmol) in freshly distilled tetrahydrofuran (THF) (60 ml) was cooled to 0° and stirred while 47 ml of 0.98M borane in THF was added. The resulting mixture was heated under reflux for 2 hours, cooled, and water (20 ml) added followed by 20% aqueous sodium hydroxide (20 ml). The mixture was heated under reflux for 2 hours, cooled and extracted twice with diethyl ether. The organic layer was extracted with 3N HCl, the aqueous layer made basic with 50% aqueous sodium hydroxide and the product was extracted into diethyl ether. The organic extracts were dried (Na2SO4) and concentrated to give 6.11 g (65%) of the title compound as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][OH:16])=[CH:6][C:5]=1[CH3:17])([O-])=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:30].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:30].[ClH:30].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][OH:16])=[CH:6][C:5]=1[CH3:17]
Reactant: Cc1cc(NCCOCCO)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1cc(NCCOCCO)ccc1N

Procedure:
The 2-[2-(4-nitro-2-methylphenylamino)ethoxy]ethanol (15) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[N:18][C:19]([Cl:25])=[CH:20][CH:21]=2)[N:16]=1>>[Cl:25][C:19]1[N:18]=[C:17]2[C:22]([CH:23]=[CH:24][C:15]([NH:14][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:16]2)=[CH:21][CH:20]=1
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: Nc1ccc2ccc(Cl)nc2n1
Product: COc1ccc(C(=O)Nc2ccc3ccc(Cl)nc3n2)cc1OC
Yield: 49.9 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 3,4-dimethoxybenzoic acid (14.6 g), N,N'-carbonyldiimidazole (12.9 g) and 2-amino-7-chloro-1,8-naphthyridine (8.9 g), and heating for 17 hours under reflux. The product obtained, after precipitation of the reaction mixture in water (1000 cc) and drying, is purified by recrystallization in acetonitrile (250 cc). N-(7-Chloro-1,8-naphthyridin-2-yl)-3,4-dimethoxybenzamide (8.5 g), m.p. 196° C., is thereby obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][CH:10]=[C:5]2[C:4]([N:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][C:20]2=[O:32])=[CH:3]1.[ClH:33]>C(Cl)Cl.CCOC(C)=O>[ClH:33].[CH3:1][N:2]1[C:6]2=[N:7][C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][CH:10]=[C:5]2[C:4]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][C:20]2=[O:32])=[CH:3]1
Reactant: Cn1cc(N2CCN(C(=O)OC(C)(C)C)CC2=O)c2ccc(OCc3ccccn3)nc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1cc(N2CCNCC2=O)c2ccc(OCc3ccccn3)nc21
Temperature: 25 °C
Reaction time: 67 h

Procedure:
To a solution of tert-butyl 4-[1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-oxopiperazine-1-carboxylate (0.278 g, 0.653 mmol) in DCM (10 mL) is added a saturated solution of hydrogen chloride in EtOAc (6 mL) at room temperature, and the reaction mixture stirred at room temperature for 67 h. The solvent is carefully decanted off and the residue triturated with Et2O/MeOH. The solvent is again decanted off and the residue further triturated with Et2O/MeOH. The resultant residue is dried in vacuo for 3 h. to give the title compound (0.217 g, 0.580 mmol) as a pale yellow solid. MS (m/z): 338 (M+1).