Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:10](=[O:11])[CH:9]2[CH:12]=[C:13](Br)[S:14][CH:8]2[C:7]1=[O:16])[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.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>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:10](=[O:11])[CH:9]2[CH:12]=[C:13]([C:23]3[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[S:14][CH:8]2[C:7]1=[O:16])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)CN1C(=O)C2C=C(Br)SC2C1=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: [Cs+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)CN1C(=O)C2C=C(c3ccc(OC)cc3)SC2C1=O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, (2-bromo-4,6-dioxo-3a,4,6,6a-tetrahydro-thieno[2,3-c]pyrrol-5-yl)-acetic acid ethyl ester, example 1-d (431 mg, 1.35 mmol), 4-methoxy-phenyl boronic acid (309 mg, 2.0 mmol), cesium carbonate (1.10 g, 3.4 mmol), and tetrakis(triphenylphosphine)palladium(0) (157 mg, 0.14 mmol) were suspended in 8 mL of ethylene glycol dimethyl ether. The reaction mixture was heated at reflux temperature for 5 hours, cooled to room temperature, and diluted with ethyl acetate. The organic mixture was successively washed with saturated sodium bicarbonate and brine solutions. The organic fractions were dried over anhydrous sodium sulfate and concentrated to a crude solid residue, which was then purified by column chromatography, eluting the title compound from silica gel with a gradient of (5-30%) ethyl acetate in hexanes to yield 197 mg of a white solid. MS: (+) m/z 348.05 (M+1).
Reaction SMILES: F[C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH2:20]([N:22](CC)CC)C.Cl.CN>C(O)(C)C>[Br:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[NH:12][C:8]1[C:9]2[CH:10]=[N:11][C:2]([NH:22][CH3:20])=[CH:3][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCN(CC)CC
Reactant: Fc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Agent: CN
Agent: Cl
Solvent: CC(C)O
Product: CNc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Temperature: 95 °C
Reaction time: 5 h
Yield: 65.8 %

Procedure:
A mixture of 7-fluoro-4-(3-bromoanilino)pyrido[4,3-d]pyrimidine (74 mg, 0.23 mmol), triethylamine (7 mL, 50 mmol) and methylamine hydrochloride (3.0 g, 44 mmol) in isopropanol (30 mL) contained in a steel bomb is stirred at 95° C. (oil bath) for 5 h. The resulting mixture is concentrated under vacuum, basified with aqueous Na2CO3, diluted with water and extracted with EtOAc (3×100 mL). Chromatography of this extract on silica gel (3% MeOH/CH2Cl2) gives 4-(3-bromoanilino)-7-methylaminopyrido[4,3-d]pyrimidine (50 mg, 65%) as a pale yellow solid. 1H NMR (DMSO) δ 9.93 (1H, brs), 9.37 (1H, s), 8.47 (1H, s), 8.18 (1H, s), 7.84 (1H, d, J=7.8 Hz), 7.34 (1H, t, J=7.9 Hz), 7.30 (1H, brd, J=8.1 Hz), 7.19 (1H, q, J=4.7 Hz), 6.35 (1H, s), 2.85 (3H, d, J=4.8 Hz).
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:24][CH2:25][CH2:26][CH3:27])[N:20]([CH2:21][CH2:22][NH2:23])[C:16]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1>>[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:24][CH2:25][CH2:26][CH3:27])[N:20]([CH2:21][CH2:22][NH:23][C:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4])[C:16]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: C/C=C/C(=O)Cl
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Product: C/C=C/C(=O)NCCn1c(CCCC)nc2c(N)nc3cccnc3c21
Yield: 81.1 %

Procedure:
Using the general method of Example 92, crotonyl chloride (68 μL, 0.7 mmol) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.2 g, 0.7 mmol) to provide 0.2 g of N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-(E)-2-butenamide as a white powder, m.p. 198-200° C. Analysis: Calculated for C19H24N6O: % C, 64.75; % H, 6.86; % N, 23.85; Found: % C, 64.25; % H, 6.68; % N, 23.99. HRMS (EI) calcd for C19H24N6O (M+) 352.2011 found 352.1996
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][S:11]([C:14]([F:17])([F:16])[F:15])(=[O:13])=[O:12])=[CH:5][CH:4]=1.[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][NH2:24])[CH3:20].O>C1(C)C=CC=CC=1>[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][NH:24][C:9](=[CH:10][S:11]([C:14]([F:17])([F:16])[F:15])(=[O:13])=[O:12])[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:20]
Reactant: CCOC(CN)OCC
Reactant: COc1ccc(C(=O)CS(=O)(=O)C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(CNC(=CS(=O)(=O)C(F)(F)F)c1ccc(OC)cc1)OCC

Procedure:
A solution of 4'-methoxy-2-[(trifluoromethyl)sulfonyl]acetophenone (6.0 g, 0.021 mol) in toluene is treated with aminoacetaldehyde diethyl acetal (2.8 g, 0.021 mol), heated at reflux overnight with removal of water, and concentrated in vacuo to obtain the title product as an oil. This oil is used in Example 4 without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.Cl.[NH2:27][N:28]1[CH2:35][CH:34]2[CH:30]([CH2:31][CH2:32][CH2:33]2)[CH2:29]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:27][N:28]3[CH2:35][CH:34]4[CH2:33][CH2:32][CH2:31][CH:30]4[CH2:29]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: NN1CC2CCCC2C1
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncnc(NN3CC4CCCC4C3)n2)cc1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 μL of triethylamine and 3-Amino-3-azabicyclo-[3,3,0]octane hydrochloride salt (19 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([NH2:11])[CH2:8][CH2:7][C@@H:6]1[N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]1=[O:28])(=[O:3])[CH3:2].[CH3:29][C:30]([CH3:32])=O.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>CO>[C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([NH:11][CH:30]([CH3:32])[CH3:29])[CH2:8][CH2:7][C@@H:6]1[N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:13]1=[O:28])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: CC(C)=O
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(=O)N[C@@H]1C[C@H](NC(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A stirring solution of benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-aminocyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (˜0.135 mol) in methanol (675 mL) was charged sequentially with acetone (37.8 g, 4 eq), sodium acetate (33.2 g, 3 eq), and sodium cyanoborohydride (16.9 g, 2 eq). The mixture was stirred at room temperature for 6 h and filtered. The filtrate was dissolved in dichloromethane (1 L); this solution was washed with 1N NaOH (1 L). The solids collected in the filtration were dissolved in 1N NaOH (1 L) at 0° C. and then extracted with dichloromethane (1 L). The organic extracts were combined and extracted with aqueous HCl (200 mL 1N HCl+800 mL water). The aqueous phase was basified with sat. NaHCO3 (500 mL) and then 1N NaOH (100 mL) until pH 11. The aqueous phase was extracted with dichloromethane (2 L). The organic extracts were combined, dried (Na2SO4), filtered, and concentrated in vacuo to give benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(isopropylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate as an oil. LC/MS found [M+H]+=431.45. 1H-NMR (400 MHz, d4-MeOH): δ 7.3-7.4 (m, 5H), 5.12 (s, 2H), 4.31 (m, 1H), 4.24 (t, J=9.4 Hz, 1H), 4.11 (m, 1H), 3.61 (t, J=9.1 Hz, 1H), 3.52 (q, J=8.6 Hz, 1H), 3.04 (br. s, 1H), 2.96 (sep, J=6.3 Hz, 1H), 2.40 (m, 1H), 2.15 (m, 1H), 1.92 (s, 3H), 1.7-1.9 (m, 5H), 1.65 (m, 1H), 1.12 (app. dd, J=6.3, 1.1 Hz, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.CCN(C(C)C)C(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:30])=[O:29]
Reactant: COC(=O)c1cc(CCO)cc2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc(CCOS(C)(=O)=O)cc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a dichloromethane (0.03 M) solution of methyl 3-(2-hydroxyethyl)-1-naphthalenecarboxylate (1 eq.) from Step 2, Amine 31 and Hunig's base (1.5 eq.) was added at 0 methanesulfonyl chloride (1.3 eq.). The resulting solution was stirred at 0° C. for 30 min and then at RT for 15 min. The reaction mixture was subsequently quenched with 10% aq. HCl. The aqueous wash was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, and filtered. Concentration of the filtrate in vacuo afforded the crude title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH2:11]Cl)=[C:6]([CH:9]=1)[CH2:7]Cl.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:9]=[C:6]2[C:5]([CH2:10][CH2:11][N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:7]2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: ClCCc1ccc(Cl)cc1CCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Clc1ccc2c(c1)CN(c1ccccc1)CC2
Yield: 18.5 %

Procedure:
5-Chloro-2-(2-chloroethyl)benzyl chloride (8 g), was dissolved in chloroform (50 ml), then aniline (2.79 g,) and triethylamine (8.01 g,) were added to the solution. The mixture was refluxed for 18 hr. then cooled and washed with 2M sodium hydroxide solution (2×100 ml). The chloroform layer was dried (magnesium sulphate) and evaporated in vacuo. The residue was distilled in vacuo to afford 7-chloro-2-phenyl-1,2,3,4-tetrahydroisoquinoline (1.35 g), b.pt. 170°-180°/0.6-0.8 mmHg) characterised by its nmr spectrum.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C@H:14]([C:19]([OH:21])=O)[CH2:15][C:16](=[O:18])[NH2:17])=[O:12].[OH:22][C@H:23]([C@@H:41]([NH2:49])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:24][N:25]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.CN1CCOCC1>C1COCC1>[OH:22][C@H:23]([C@@H:41]([NH:49][C:19](=[O:21])[C@H:14]([CH2:15][C:16](=[O:18])[NH2:17])[NH:13][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12])[CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:24][N:25]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28]
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Reactant: CC(C)(C)OC(=O)NN(Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
At 0° C., 3.84 g (13.4 mmol) of quinoline-2-carbonyl-(L)-asparagine (hydrochloride salt) (Example 100A) b)) are added to 4.69 g (12.2 mmol) of 1-[2(S)-hydroxy-3(S)-amino-4-phenyl-butyl]-1-[phenylmethyl]-2-[tert-butoxycarbonyl]-hydrazine in 250 ml of THF. 2.18 g (13.4 mmol) of HOBT, 2.76 g (13.4 mmol) of DCC and 2.14 ml (19.5 mmol) of NMM are added to the suspension which is then stirred for 30 min at 0° C. and for 17 h at RT. The reaction mixture is filtered and the filtrate is concentrated by evaporation to a residual volume of approximately 50 ml. The fine suspension is taken up in methylene chloride and washed with NaHCO3 solution and brine, and the aqueous phases are extracted with 2 portions of methylene chloride. Filtration of the combined organic phases through cotton wadding, concentration by evaporation and precipitation from a concentrated solution in methanol/methylene chloride with DIPE and finally hexane yields the pure title compound: TLC Rf (P)=0.41; tRet (V)=14.8 min; FAB-MS (M+H)+ =655.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[CH:8][CH:7]=1)(=O)C.[OH-].[Na+]>CO.O>[OH:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc2cccc(COC(C)=O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2cccc(CO)c2c1

Procedure:
0.1 mole of the preceding 1-acetoxymethyl-7-methoxynaphthalene is saponified at room temperature, under argon, with a solution of 0.2 mole of sodium hydroxide diluted in 200 cm3 of methanol and 40 cm3 of water.
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)([O-:13])=[O:12].C(OCC)(=O)C>CCCCCC>[CH3:4][NH:6][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: CN
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a mixture of 40% aqueous solution of Methylamine hydrochloride (2.175 g, 33.2 mmol) and Triethyl amine (3.75 g, 37.18 mmol) at 0° C., added 4-Nitro-benzoyl chloride (4.6 g, 24.78 mmol) and stirred for 30 mins. The reaction was monitored by TLC (50% Ethyl acetate in Hexane). The solid precipitate so obtained was filtered, washed with ice cold water and dried to afford 4 g (89%) of N-Methyl-4-nitro-benzamide. 1H NMR: (DMSO-d6): δ 8.78 (s, 1H), 8.32 (d, 2H), 8.06 (d, 2H), 2.8 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[C:9]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([NH:1][CH2:2][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1CCCCCCCCCCCCCC1
Reactant: NCc1cccnc1
Product: c1cncc(CNC2CCCCCCCCCCCCCC2)c1

Procedure:
Following the general procedure of Example 33, but starting with 3-aminomethylpyridine and cylcopentadecanone, the title compound is produced, NMR (CDCl3, TMS) δ 8.58, 7.72, 7.25, 3.76, 2.56, 1.32.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>CN(C=O)C.C(OCC)C>[CH2:12]([O:11][C:4]1[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=[C:2]([Br:1])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1cc(Br)cn2nccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Brc1cc(OCc2ccccc2)c2ccnn2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-bromopyrazolo[1,5-a]pyridin-4-ol (1.10 g, 5.16 mmol) and benzyl bromide (0.676 ml, 5.68 mmol) were dissolved in DMF (20 ml) at 0° C. NaH (413 mg, 10.3 mmol, 60 wt %) was added in one portion and the mixture was allowed to stir at 0° C. After 30 minutes, additional benzyl bromide 0.068 ml, 0.57 mmol) was added and the mixture was allowed to stir 30 minutes at 0° C. The reaction mixture was diluted in diethyl ether, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/isohexane gradient) to afford 4-(benzyloxy)-6-bromopyrazolo[1,5-a]pyridine.
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:16]([OH:17])[C@H:15]([CH3:18])[O:14][C:13](=[O:19])[C@@H:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][CH3:33])(=[O:31])[C:29]#[CH:30]>C(Cl)Cl.C1N2CCN(CC2)C1>[CH2:1]([C@H:8]1[CH2:9][O:10][CH2:11][C@H:12]([NH:20][C:21]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:27])[C:13](=[O:19])[O:14][C@@H:15]([CH3:18])[C@@H:16]1[O:17]/[CH:30]=[CH:29]/[C:28]([O:32][CH3:33])=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CC(=O)OC
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1O
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: COC(=O)/C=C/O[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a solution of tert-butyl ((3S,7S,8R,9S)-7-benzyl-8-hydroxy-9-methyl-2-oxo−1,5-dioxonan-3-yl)carbamate (280 mg, 0.738 mmol, 1.00 equiv) in CH2Cl2 (7.4 mL) were added methyl propiolate (0.098 mL, 1.11 mmol, 1.50 equiv) and DABCO (4 mg, 0.04 mmol, 0.05 equiv). This solution was stirred at room temperature for 1 h, concentrated, and purified by automated silica gel column chromatography (5-25% acetone in hexanes) to provide (E)-methyl 3-(((3S,6S,7R,8S)-8-benzyl-3-((tert-butoxycarbonyl)amino)-6-methyl-4-oxo-1,5-dioxonan-7-yl)oxy)acrylate (312 mg, 91%) as a white solid: mp slow melt from 50-80° C., recrystallized at 98° C., remelt at 128-129° C.; IR (neat film) 3342, 2980, 2949, 1753, 1703, 1639, 1497, 1329, 1132, 910, 731 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J=12.2 Hz, 1H), 7.32-7.27 (m, 2H), 7.23-7.18 (m, 1H), 7.15-7.11 (m, 2H), 5.40 (d, J=12.2 Hz, 1H), 5.10 (d, J=8.3 Hz, 1H), 5.02 (dd, J=9.3, 6.4 Hz, 1H), 4.64 (dd, J=15.3, 7.5 Hz, 1H), 3.92 (dd, J=11.6, 7.6 Hz, 1H), 3.74 (d, J=9.1 Hz, 1H), 3.71 (s, 3H), 3.51 (d, J=11.1 Hz, 1H), 3.43 (dd, J=10.5, 6.4 Hz, 1H), 3.29 (dd, J=11.3, 7.5 Hz, 1H), 2.92 (dd, J=13.8, 3.5 Hz, 1H), 2.34 (t, J=12.5 Hz, 1H), 2.06 (s, 1H), 1.42 (s, 9H), 1.41 (d, J=6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.16, 167.97, 162.94, 154.91, 138.54, 129.09, 128.57, 126.48, 98.50, 89.01, 80.31, 73.94, 72.57, 71.33, 52.70, 51.26, 46.47, 35.18, 28.25, 18.73; HRMS-ESI (m/z) [M+Na]+ calc'd for C24H33NO8Na, 486.2098. found, 486.2104.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[CH:25](OC)(OC)OC.C1(O)O[C@H](C)[C@@H](O)C[C@H]1O>C1(C)C=CC=CC=1>[CH2:1]([CH:3]([N:6]1[C:7]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:8]=2[N:24]=[CH:25]1)[CH2:4][CH3:5])[CH3:2]
Reactant: COC(OC)OC
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1N
Agent: C[C@H]1OC(O)[C@H](O)C[C@@H]1O
Solvent: Cc1ccccc1
Product: CCC(CC)n1cnc2c(Oc3c(C)cc(C)cc3C)nc(C)cc21
Yield: 96.8 %

Procedure:
A mixture of N4-(1-ethylpropyl)-6-methyl-2-(2,4,6-trimethylphenoxy)-pyridine-3,4-diamine (160 mg, 0.49 mmol), trimethyl orthoformate (62 mg, 0.59 mmol) and paratosylalcohol (p-TsOH) (10 mg) in 20 ml of toluene was heated at reflux under a Dean-Stark trap apparatus for 24 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give the title compound (160 mg, 97%) as a light brown oil. The oil was purified through silica gel column chromatography using 2% methanol (MeOH) in chloroform as eluent to give a tan solid. Mp 127–131° C. 1H NMR (CDCl3) δ 7.82 (s, 1H), 6.90 (s, 2H, 6.81) (s, 1H), 4.02 (m, 1H), 2.37 (s, 3H), 2.32 (s, 3H), 2.13 (s, 6H), 1.98 (m, 4H), 0.87 (t, 6H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[CH2:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:20]([C:25]1[CH:26]=[C:27]([Cl:33])[C:28]([F:32])=[C:29]([Cl:31])[CH:30]=1)[C:21]([F:24])([F:23])[F:22].N1C=CC=CC=1C1C=CC=CN=1>ClC1C=CC=CC=1Cl.Cl[Cu]>[Cl:31][C:29]1[CH:30]=[C:25]([CH:20]([C:21]([F:24])([F:23])[F:22])/[CH:18]=[CH:17]/[C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[CH:26]=[C:27]([Cl:33])[C:28]=1[F:32]
Reactant: Fc1c(Cl)cc(C(Br)C(F)(F)F)cc1Cl
Reactant: C=Cc1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: CC(C)(C)OC(=O)N1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 150 °C
Yield: 11.7 %

Procedure:
To a stirred solution of tert-butyl-5-vinylindoline-1-carboxylate (1.28 g, 5.23 mmol) in 1,2-dichlorobenzene (10.0 mL), was added 5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-fluorobenzene (3.4 g, 10 mmol), CuCl (103 mg, 1.05 mmol) and 2,2-bipyridyl (0.326 g, 2.092 mmol) and the resultant reaction mixture was degassed with argon for 30 min and heated to 150° C. for 1 h. The reaction mixture was cooled to ambient temperature and filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% ethyl acetate/petroleum ether) to afford the title compound as a pale yellow gummy solid (0.3 g, 61%): 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=6.0 Hz, 2H), 7.22 (s, 2H), 7.16 (d, J=8.4 Hz, 1H), 6.52 (d, J=16.0 Hz, 1H), 6.21 (dd, J=16.0, 7.6 Hz, 1H), 4.07 (m, 3H), 3.10 (t, J=8.4 Hz, 2H), 1.55 (s, 9H); ESIMS m/z 433.79 ([M−H]−); IR (thin film) 1168, 858 cm−1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:6]([CH:22]=1)[CH2:7][NH:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=1.[CH3:31][O:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:6]([CH:22]=1)[CH2:7][N:8]([C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=1)[CH2:40][C:37]1[CH:36]=[CH:35][C:34]([C:33]([O:32][CH3:31])=[O:42])=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CN(Cc2cc(Br)ccc2OCc2ccccc2)c2ccc(C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-Butyl 4-[5-bromo-2-benzyloxybenzylamino]benzoate (16.9 g) and methyl-4-bromomethylbenzoate were dissolved in in dimethylformamide (30 ml) and potassium carbonate (18 g) added. The mixture was stirred at ambient temperature for 24 hours and then poured into water (300 ml). The reaction mixture was extracted with ether (4×100 ml). The combined ether extracts were washed with water (3×100 ml) and brine (1×100 ml), dried over magnesium sulphate and evaporated. The residue was purified by MPLC eluting with 1:1 dichloromethane/hexane to give tert-butyl 4-[N-(5-bromo-2-benzyloxybenzyl)-N-(4-methoxycarbonylbenzyl)amino]benzoate (3.6 g) m.p. 154°-155° C.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH:9]([OH:11])[CH2:8][CH2:7][N:6]1[C:12](=[O:21])[N:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[CH3:14])=[O:4].[Li+].[OH-].Cl>O1CCCC1.O>[CH2:15]([N:13]([CH3:14])[C:12]([N:6]1[CH2:7][CH2:8][CH:9]([OH:11])[CH2:10][CH:5]1[C:3]([OH:4])=[O:2])=[O:21])[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]
Reactant: C=CCCCCN(C)C(=O)N1CCC(O)CC1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCCN(C)C(=O)N1CCC(O)CC1C(=O)O
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of compound 32 (2.03 g, 1 eq.) and LiOH (0.815 g, 5 eq.) in a mixture of tetrahydrofuran (30 mL) and water (30 mL) was stirred at room temperature until completion by TLC. HCl (1N, 50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). Dried organics were evaporated in vacuo to give compound 33 as a yellow gum in 100% yield. MS (ESI, EI+) m/z=285 (MH+).