Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)(=[O:23])=[O:22])[CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CN)N1CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.3 %

Procedure:
A solution containing 1 g (2.3 mmol) of methyl (S)-3-tert-butoxycarbonylamino-2-[4-(toluene-4-sulphonyl)piperazin-1-yl]propanoate in 10 ml of dichloromethane and 2.6 ml (3.4 mmol) of trifluoroacetic acid is stirred at ambient temperature for 18 h. After addition of a saturated aqueous solution of sodium hydrogen carbonate up to a pH of 8, the reaction medium is extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and evaporated. 780 mg (100%) of methyl (S)-3-amino-2-[4-(toluene-4-sulphonyl)piperazin-1-yl]propanoate are obtained in the form of an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[Cl:9][C:4]1[CH:3]=[C:2]([C:12]2[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: Clc1cc(Cl)cc(Br)c1
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
Solvent: O
Product: Clc1cc(Cl)cc(-c2cccnc2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 114.2 %

Procedure:
Synthesized according to General Procedure 36. A mixture of 1-bromo-3,5-dichloro-benzene (424 mg, 1.88 mmol), 3-pyridineboronic acid pinacol ester (500 mg, 2.44 mmol), aqueous 2M Na2CO3 (1.96 mL, 3.93 mmol) and Pd(PPh3)4 (89 mg, 4 mol %) in anhydrous toluene (18 mL) was stirred overnight at 80° C. under nitrogen. The reaction was cooled down to room temperature, diluted with water (5 ml) and ethyl acetate (10 ml). The organic phase was separated, dried (Na2SO4), filtered and concentrated under reduced pressure to give a pale yellow oil, which was purified by silica-gel column chromatography to give 3-(3,5-dichlorophenyl)pyridine (481 mg, 74%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.81 (d, J=2.1 Hz, 1H), 8.65 (dd, J=1.4, 4.8 Hz, 1H), 7.85-7.82 (m, 1H), 7.46 (d, J=1.8 Hz, 2H), 7.41-7.38 (m, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=224.3; tR=1.21 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6](=O)[CH2:5][CH2:4][N:3]1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].C([O-])(=O)C.[Na+].Cl.[CH3:23][O:24][NH2:25]>CO>[CH3:23][O:24]/[N:25]=[C:6]1/[C:2]([CH3:16])([CH3:1])[N:3]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:5]/1
Reactant: CC1(C)C(=O)CCN1C(=O)c1ccccc1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CO/N=C1\CCN(C(=O)c2ccccc2)C1(C)C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a solution of 2,2-dimethyl-1-(phenylcarbonyl)-3-pyrrolidinone (2.0602 g, 9.482 mmol) in MeOH (50 mL) was added sodium acetate (0.956 g, 11.38 mmol) and methoxyamine hydrochloride (0.950 g, 11.37 mmol). The mixture was stirred overnight and then concentrated in vacuo. The residue was dissolved in DCM (200 mL) and washed with sat. aq. NaHCO3 (50 mL), water (50 mL), and brine (50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford (3E)-2,2-dimethyl-1-(phenylcarbonyl)-3-pyrrolidinone O-methyloxime (1.9567 g, 84% yield) as a light yellow oil that solidified under high vacuum. LCMS: (M+H)+: 247.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH2:15][CH:7]3[C:6]=2[N:24]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:24]=1
Reactant: CCOC(=O)C1Oc2ccc(Cl)nc2C2Cc3c(F)cccc3N12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Yield: 84.9 %

Procedure:
To a solution of ethyl 2-chloro-11-fluoro-12,12a-dihydro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxylate (10.22 g, 29.36 mmol) and DDQ (8.67 g, 38.17 mmol) in toluene (80 mL) was stirred at 80° C. for 2 hours. The mixture was then diluted with water (50 mL) and extracted with EtOAc (30 mL*3). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether:EtOAc=20:1) to provide ethyl 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxylate (8.64 g, yield: 85%), which was also prepared from 6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-ol and methyl 2,2-dibromoacetate in the presence of base, such as DBU etc. 1H-NMR (CDCl3, 400 MHz) δ 7.33 (d, J=8.4 Hz, 1H), 7.30 (s, 1H), 7.09˜7.18 (m, 3H), 6.78˜6.83 (m, 1H), 6.52 (s, 1H), 3.96˜4.09 (m, 2H), 1.02 (t, J=7.2 Hz, 3H). MS (M+H)+: 347.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(Cl)CCl.C(N(C(C)C)C(C)C)C.[CH2:28]([N:30]1[N:34]=[N:33][C:32]([C:35]2[S:39][C:38]([NH2:40])=[N:37][C:36]=2[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N:31]1)[CH3:29]>CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([NH:40][C:38]2[S:39][C:35]([C:32]3[N:33]=[N:34][N:30]([CH2:28][CH3:29])[N:31]=3)=[C:36]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:37]=2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: CCn1nnc(-c2sc(N)nc2-c2ccccc2)n1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCn1nnc(-c2sc(NC(=O)Cc3ccc(OC)c(OC)c3)nc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
200 μL of a 0.6M stock solution of (3,4-dimethoxy-phenyl)-acetic acid was mixed with 200 μL of a 0.3M stock solution of EDC containing 1 eq. of ethyl-diisopropyl-amine. Then 100 μL of a 0.3M stock solution of 5-(2-ethyl-2H-tetrazol-5-yl)-4-phenyl-thiazol-2-ylamine containing 1 eq. of DMAP was added. The reaction mixture was shaken overnight at ambient temperature. Purification was performed by preparative LC-MS. Yield: 13%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([OH:39])[CH:34]=[C:35]([CH2:37][OH:38])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CC(C)=O.O.Cl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:39][C:33]2[CH:34]=[C:35]([CH2:37][OH:38])[CH:36]=[C:31]([Br:30])[CH:32]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: OCc1cc(O)cc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(CO)c2)c1CCC(=O)OCC
Temperature: 70 °C
Yield: 97.9 %

Procedure:
To a solution of 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (4.2 g, 8.9 mmol), 3-Bromo-5-hydroxymethyl-phenol (1.5 g, 7.4 mmol) in N,N-dimethylformamide (40 mL) and acetone (80 mL) was added potassium carbonate (10.2 g, 74.2 mmol) at room temperature. The resulting suspension was heated to 70° C. for 24 h. Then, the reaction mixture was cooled to room temperature and diluted with water and 10% aq. HCl. The organic compound was extracted into ethyl acetate and the combined organic extracts were washed with water and brine solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude material was purified by column chromatography (Isco™ 120 g) with 0-50% ethyl acetate/hexanes as eluting solvents to afford the title compound (4.3 g, 99%) as a colorless oil. HR-ES(+) calcd for C30H41O7Br [M+Na]+ 615.1928, observed 615.1926.
Reaction SMILES: C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O.[CH2:22]([O:29][C@@H:30]1[C@@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:34]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:33]([CH2:52][O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:32][C@H:31]1[O:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][OH:72])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(Cl)Cl.S(=O)(=O)(O)O>C(O)C>[CH2:22]([O:29][C@@H:30]1[C@@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:34]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C@@H:33]([CH2:52][O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:32][C@H:31]1[O:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH:71]=[O:72])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCCCCCCCCCCO[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCO
Product: O=CCCCCCCCCCO[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
PDC oxidation of 10-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyloxy)-n-decanol. Under an atmosphere of nitrogen, pyridinium dichromate (220 mg, 0.585 mmol) was added to a dry methylene chloride solution (6 mL) of 10-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyloxy)-n-decanol (275 mg, 0.395 mmol). The resulting brown slurry was stirred at room temperature under nitrogen. TLC analysis (visualization by UV and char with 10% sulfuric acid in ethanol) of the reaction mixture indicated complete consumption of the starting material and the formation of a new compound after 16 h. The reaction mixture was treated with ether (10 mL), filtered through silica gel and Celite with an ether wash (25 mL) and concentrated to an off-white oil. Chromatographic purification (silica gel, 20% ethyl acetate in hexanes) afforded 204 mg (0.294 mmol, 74%) of 10-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyloxy)-n-decanal as a clear oil. Rf=0.40 (silica gel, 30% ethyl acetate in hexanes); 1H NMR (CDCl3, 300 MHz) δ: 9.75 (t, J=1.8 Hz, 1H), 7.32 (m, 20H), 4.98 (dd, J=10.8, 9.6 Hz, 2H), 4.84 (t, J=10.5 Hz, 2H), 4.75 (d, J=10.8 Hz, 1H), 4.61 (d, J=8.4 Hz, 1H), 4.56 (dd, J=10.8, 6.0 Hz, 1H), 4.43 (d, J=7.8, 1H), 4.00 (m, 1H), 3.8-3.4 (m, 8H), 2.40 (dt, J=7.2, 1.5 Hz, 2H), 1.70 (m, 6H), 1.31, (m, 10H); MS (FAB+): 701.0 ((M+Li)+, 100), 609.0 (4), 455.0 (5), 423.1 (7), 181.1 (35), 160.0 (10), 107.0 (4), 105.0 (5).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](=[O:21])[CH2:11][P:12]([CH2:17][CH:18]1[CH2:20][CH2:19]1)(=[O:16])[O:13]CC)=O)(C)(C)C.C[Si](C)(C)[Br:24]>ClCCl.CO>[BrH:24].[NH2:8][CH2:9][C:10](=[O:21])[CH2:11][P:12]([CH2:17][CH:18]1[CH2:20][CH2:19]1)(=[O:13])[OH:16]
Reactant: C[Si](C)(C)Br
Reactant: CCOP(=O)(CC(=O)CNC(=O)OC(C)(C)C)CC1CC1
Solvent: ClCCl
Solvent: CO
Product: Br
Product: NCC(=O)CP(=O)(O)CC1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 0.64 g of ethyl 3-(N-tert.-butoxycarbonylamino)-2-oxo-propyl(cyclopropylmethyl)phosphinate in 10 ml of anhydrous dichloromethane under an inert atmosphere at room temperature is treated with 1.53 g of trimethylbromosilane. The pale yellow solution is stirred for 4 hours at room temperature and the volatile materials are removed under reduced pressure to give a pale yellow oil. This oil is redissolved in methanol containing 1% water and the clear pale yellow solution is stirred for 30 minutes at room temperature. The solvent is removed and the residue is dried in high vacuum at 50° C. for 24 hours to afford 3-amino-2-oxopropyl(cyclopropylmethyl)phosphinic acid hydrobromide salt as a yellow gum. This gum is dissolved in ethanol and treated with propylene oxide to afford, after filtration and drying 3-amino-2-oxo-propyl(cyclopropylmethyl)phosphinic acid as a pale yellow solid of m.p. 109°-110° C.; 1H-NMR (D2O): δ (ppm)=4.15 (2H, s, CH2N), 3.18 (2H, d, J=15 Hz, CH2P), 1.58 (2H, d, d, J=15+6 Hz, PCH2), 0.83 (1H, m, CH), 0.55 (2H, m, CH2), 0.17 (2H, m, CH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:25][CH3:26])=[C:19]([C:23]=1[Cl:24])[C:20](Cl)=[O:21].[Cl-].[Al+3].[Cl-].[Cl-].ClCCl>C(OCC)(=O)C.O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:25][CH3:26])=[C:19]([C:23]=1[Cl:24])[C:20]([C:4]1[C:5]([CH3:13])=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1])=[O:21]
Reactant: COc1ccc(Br)c(Cl)c1C(=O)Cl
Reactant: COc1cc(C)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C)c(C(=O)c2c(OC)ccc(Br)c2Cl)c(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3,4,5-trimethoxytoluene (0.83 g; 4.6 mmol), 4C (4.6 mmol), aluminium chloride (0.62 g, 4.6 mmol) and dichloromethane (20 ml) is stirred at room temperature for 3 hours. A mixture of water and ethyl acetate (1:1 v/v; 50 ml) is then added. The organic phase is concentrated and the residue is crystallized from diisopropylether and recrystallized from methanol. The solid material is collected by vacuum filtration, washed with water and dried yielding yellow crystals, 0.7 g, (35.4%) mp 87-88° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][Cl:7].[Zn:15].NC1C=CC(I)=CC=1C#N>C1COCC1>[Cl-:7].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][Zn+:15]
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: [Zn]
Agent: N#Cc1cc(I)ccc1N
Solvent: C1CCOC1
Product: COc1cc(C[Zn+])cc(OC)c1OC
Product: [Cl-]

Procedure:
3,4,5-Trimethoxybenzylzinc chloride was prepared from 3,4,5-trimethoxybenzyl chloride (867 mg, 4 mmol) and reactive metallic zinc suspension (0.76 M in THF, 6.3 mL, 4.8 mmol). The supernatant was transferred via a cannula into a solution of 9 (244 g, 1 mmol) in THF, followed by the usual workup; pale-yellow oil (127 mg, 43%): 1H NMR (CDCl3) δ 3.78 (s, 2H, CH2), 3.81 (s, 6H, 3′- and 5′-OMe), 3.82 (s, 3H, 4′-OMe), 4.28 (br s, NH2), 6.30 (s, 2H, H-2′ and H-6′), 6.69 (d, J=8.4 Hz, 1H, H-3), 7.16 (d, J=8.4 Hz, 1H, H-4), 7.19 (s, 1H, H-6).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43]C)=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][NH2:54])[CH2:48][CH2:47]1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:54][CH2:53][CH2:52][N:49]4[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: CN1CCN(CCN)CC1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(NC(=O)NCCN5CCN(C)CC5)cc4)nc32)CC1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 2-(4-methylpiperazin-1-yl)-ethanamine as the aniline component. (17%, MS=633.4 (M+H))
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[Cl:11].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([N:10]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)[CH:7]=[CH:6][C:5]=1[Cl:11]
Reactant: COC(=O)c1cc(N)ccc1Cl
Reactant: O=Cc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N=Cc2cccc(Br)c2)ccc1Cl
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture solution of 5-amino-2-chloro-benzoic acid methyl ester (21 g, 113.2 mmol), 3-bromo-benzaldehyde (21 g, 113.2 mmol) and p-toluenesulfonic acid (431 mg, 2.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 5-[(3-bromo-benzylidene)-amino]-2-chloro-benzoic acid methyl ester (39.8 g, quant.) as a pale-white solid: MS calcd. for C15H11BrClNO2 353.62, obsd. (ESI+) [(M+H)+] 351.9 & 353.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=1.CN1CCCC1=O.[CH2:26]([Mg]Br)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>O.C1COCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:5]=1
Reactant: Br[Mg]CCc1ccccc1
Reactant: COC(=O)c1cccc(OS(=O)(=O)C(F)(F)F)c1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(CCc2ccccc2)c1

Procedure:
75A (1.14 g, 4 mmol), N-methylpyrrolidinone (2.2 mL), Fe(acac)3 (70 mg, 0.2 mmol) and dry THF (25 mL) were stirred under nitrogen at room temperature. Phenethylmagnesium bromide (1.0 M in THF, 5 mL) was added by syringe. After stirring for fifteen minutes, HCl (1 M, 10 mL) was slowly added. The mixture was diluted with water and extracted three times with EtOAc. The organic layers were combined, washed with water and then brine, were dried over MgSO4 and were concentrated. Purification was achieved using flash chromatography on SiO2 with hexanes/toluene 50:50. A colourless oil was obtained (660 mg, 69%). NMR 1H (ppm, CDCl3): 7.96-7.85 (m, 2H), 7.33-7.15 (m, 7H), 3.91 (s, 3H), 2.97-2.93 (m, 4H).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=[O:10])([CH3:5])[CH3:4])#[N:2].CO.O>O1CCCC1>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([OH:11])=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: COC(=O)c1cccc(C(C)(C)C#N)c1
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
To a solution of methyl 3-(1-cyano-1-methylethyl)benzoate (2.8 g, 14 mmol) in tetrahydrofuran (30 mL) were added lithium hydroxide•monohydrate (0.98 g, 24 mmol), methanol (10 mL) and water (10 mL), and the mixture was stirred at room temperature for 18 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with water (15 mL). 1N Hydrochloric acid was slowly added to the mixture to adjust the pH to 3. The precipitated white precipitate was collected by filtration, washed with water, and dried to give the title compound (2.5 g, 98%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](O)[CH:6]=[CH:5]2.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.S(=O)(O)[O-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH:6]=[CH:5]2
Reactant: Nc1ccc(O)cc1
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Nc2ccc3cc(Br)ccc3c2)cc1
Yield: 70 %

Procedure:
A mixture of 334 mg (1.50 mmol, Aldrich) of 6-bromo-2-naphthol, 218 mg (2.00 mmol, Aldrich) of 4-aminophenol, and 1.0 g of sodium bisulfite in 5 ml of H2O was heated to 150° in a closed Pyrex tube for 76 hours. The reaction was cooled, added to 25 ml of H2O and extracted with 25 ml of ethyl acetate. The organic extract was dried (MgSO4) and concentrated in vacuo to give a solid. The crude solid was purified by flash chromatography (10×5.0 cm, 1:4 EtOAc/petroleum ether) followed by recrystallization (EtOAc/petroleum ether) to afford 330 mg (70%) of title compound as small grey-white crystals, m.p. 179°-180°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:21]1[C:33]2[CH:32]([CH2:34]O)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1.C(N=C=NC(C)C)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([O:19][CH2:34][CH:32]2[C:33]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)OCC2c3ccccc3-c3ccccc32)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
To a solution of {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid (160 g) obtained in Example 3 in dichloromethane (500 mL) were added 9H-fluorene-9-ylmethanol (98 g) and 4-dimethylaminopyridine (3.1 g), diisopropylcarbodiimide (78 ml) was added dropwise under ice-cooling, and the mixture was stirred at 0° C. for 1 hr and further stirred at room temperature for 2 hr. The precipitate was removed from the reaction mixture by filtration, and the filtrate was concentrated under reduced pressure and purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (260 g) as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH:5]=[N:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[OH:35]>>[C@H:9]1([NH:8][C:6]2[N:7]=[C:2]([C:24]3[CH:23]=[CH:22][C:21]([OH:35])=[C:20]([O:19][CH3:18])[CH:25]=3)[CH:3]=[N:4][CH:5]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: Clc1cncc(N[C@@H]2CCc3ccccc32)n1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: COc1cc(-c2cncc(N[C@@H]3CCc4ccccc43)n2)ccc1O
Yield: 69.6 %

Procedure:
In a procedure analogous to Example 2, reaction of 6-chloro-N-[(1R)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine (136.8 mg, 0.56 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (153 mg, X0.61 mmol) furnished the product (130 mg, 70%).