Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH2:33][CH2:32][CH2:31][CH2:30][C:8]2[C:9]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([N:20]=[N+:21]=[N-:22])[C:16]([O:23][CH3:24])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:34])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([OH:39])[CH2:36][C:37]#[CH:38].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].C(C(N(C(C1N=NNC=1)CC1C=CC=CC=1)C(C1N=NNC=1)CC1C=CC=CC=1)C1N=NNC=1)C1C=CC=CC=1>O.[O-]S([O-])(=O)=O.[Cu+2].C(O)C>[C:1]([N:5]1[CH2:33][CH2:32][CH2:31][CH2:30][C:8]2[C:9]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([N:20]5[CH:38]=[C:37]([CH2:36][CH2:35][OH:39])[N:22]=[N:21]5)[C:16]([O:23][CH3:24])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCCO
Reactant: COc1cc2c(cc1N=[N+]=[N-])-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1-n1cc(CCO)nn1)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 100 °C

Procedure:
In a microwave tube were mixed 52 mg of azide 20c, 10 ul of 3-butyn-1-ol, 2 ml of water, 2 ml of ethanol, 3.5 mg of CuSO4, 11 mg of sodium ascorbate and 11 mg of tris(benzyltriazolylmethyl)amine. The mixture was heated at 100° C. for 30 min., and then cooled and diluted with water. The product was extracted into ethyl acetate. The organic layer was washed, dried and concentrated, and the residue was purified by silicagel chromatography (using a gradient of heptane/ethyl acetate as eluent), and provided 29 mg of product 20d. LCMS-ESI: [M+1] 564.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][C:19](=S)[N:18]([CH:23]([C:25](OCC)=[O:26])[CH3:24])[C:17]=3[CH:30]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:32][NH2:33]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:30]=[C:17]3[C:16](=[CH:15][CH:14]=2)[O:21][CH2:20][C:19]2[N:18]3[CH:23]([CH3:24])[C:25](=[O:26])[NH:32][N:33]=2)[CH2:11]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NN
Reactant: CCOC(=O)C(C)N1C(=S)COc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc21
Solvent: CCO
Solvent: O
Product: CC1C(=O)NN=C2COc3ccc(OC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 49.4 %

Procedure:
To a solution of 3-[4-(1-ethoxycarbonyl-ethyl)-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-azetidine-1-carboxylic acid tert-butyl ester (0.530 g, 1.22 mmol) in EtOH (10 mL) was added hydrazine hydrate (0.486 g, 9.72 mmol) and the mixture was heated at reflux for 2 h. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 20% EtOAc in petroleum ether) to give 3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (0.234 g, 52%) as a white solid. LC/MS (Table 1, Method 3) Rt=1.332 min.; MS m/z: 389 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:10]=O>CN(C)C=O>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH:9]=[O:10]
Reactant: O=O
Reactant: CN(C)c1ccccc1
Solvent: CN(C)C=O
Product: CN(C=O)c1ccccc1
Yield: 15.4 %

Procedure:
By essentially the procedure of Example 1, a tube was charged with 20 g of dimethylaniline, 20 g of dimethylformamide, and 1.0 g of cupric chloride dihydrate. The reaction was run at 114°-115° C. for one hour while oxygen was injected incrementally at 200-400 psi. The oxygen absorption was about 0.12 mole. Analysis of the reaction mixture by GC/MS showed a 94.5% conversion of dimethylaniline and a 15.4% yield of N-methyl-N-phenylformamide.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([O:15]C)=[CH:7][C:6]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2].C[Si](I)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:9][C:8]([OH:15])=[CH:7][C:6]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: COc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Oc1c(C(C)(C)C)cc(O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 80 %

Procedure:
4-Acetoxy-3,5-di-tert-butylanisole (0.50 g) was dissolved in dichloromethane (2 ml). After cooling with ice, trimethylsilyl iodide (0.31 ml) was added dropwise. The mixture was allowed to warm slowly to room temperature and stirred for 2 days; thereafter, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture. The mixture was subjected to extraction with diethyl ether and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica Gel chromatography (15% ethyl acetate in n-hexane) to afford 4-acetoxy-3,5-di-tert-butylphenol [0.38 g (yield, 80%)] as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([O:8][C:9]([C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([CH3:20])[CH:14]=2)=[O:10])C>>[N:1]1([CH2:20][C:15]2[CH:14]=[C:13]3[C:18]([CH:19]=[C:11]([C:9]([OH:10])=[O:8])[NH:12]3)=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1cc2ccc(C)cc2[nH]1
Product: O=C(O)c1cc2ccc(Cn3ccnc3)cc2[nH]1

Procedure:
6-Imidazol-1-ylmethyl-1H-indole-2-carboxylic acid was prepared from imidazole and 6-methyl-1H-indole-2-carboxylic acid ethyl ester using the procedures described by Peter E Cross, et. al; Journal of Medicinal Chemistry 1986, 29(9), 1637-43.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:22](Cl)=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:24]1(B(O)O)[CH2:26][CH2:25]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]12([CH2:11][O:12][C:13]3[C:22]([CH:24]4[CH2:26][CH2:25]4)=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A mixture of methyl 6-(adamantan-1-ylmethoxy)-5-chloronicotinate (1.29 g, 3.84 mmol), cyclopropylboronic acid (0.43 g, 4.99 mmol), potassium phosphate (3.26 g, 15.40 mmol), tricyclohexylphosphine tetrafluoroborate (0.14 g, 0.38 mmol) and palladium acetate (0.04 g, 0.19 mmol) in degassed toluene (50 mL) and degassed water (5 mL) was refluxed under nitrogen for 7 h. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (100 mL), washed with water (50 mL), saturated ammonium chloride (50 mL) and brine (50 mL); dried over anhydrous sodium sulfate, filtered through diatomaceous earth and concentrated in vacuo. The residue was purified by flash chromatography eluting with 5% ethyl acetate in hexanes to afford the title compound as a white solid (1.17 g, 89%); 1H NMR (300 MHz, CDCl3) δ 8.57 (d, J=2.2 Hz, 1H), 7.67 (d, J=2.2 Hz, 1H), 3.95 (s, 2H), 3.85 (s, 3H), 2.09-1.96 (m, 4H), 1.78-1.63 (m, 12H), 0.99-0.91 (m, 2H), 0.72-0.65 (m, 2H); MS (ES+) m/z: 342.22 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[C:8]([CH2:13][OH:14])[N:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:6]=1)=[O:4].C([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[C:8]([CH:13]=[O:14])[N:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nn(-c2ccc(F)cc2)c(CO)c1C(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])O
Solvent: ClCCl
Product: COC(=O)c1nn(-c2ccc(F)cc2)c(C=O)c1C(C)C
Yield: 83.4 %

Procedure:
To a solution of 1-(4-fluoro-phenyl)-5-hydroxymethyl-4-isopropyl-1H-pyrazole-3-carboxylic acid methyl ester (13.6 g, 46.7 mmol) in CH2Cl2 (300 mL) at 25° C. was added solid NaHCO3 (19.6 g, 233 mmol) followed by Dess Martin reagent (20.8 g, 49.0 mmol; commercially available from Lancaster). The reaction was stirred at 25° C. for 4 hr after which time saturated sodium bisulfite (50 mL) was added and the organic layer was separated and washed with water and brine. The organic layer was dried over Na2SO4and concentrated to an oil that was purified by silica gel chromatography (15% EtOAc/Hex) to afford 1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid methyl ester (11.3 g, 84%): H-NMR (CDCl3) δ 9.95 (s, 1 H), 7.42-7.38 (m, 2 H), 7.17-7.13 (m, 2 H), 4.01-3.96 (m, 1 H), 3.92 (s, 3 H), 1.38 (d, 6 H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[N:5]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:4]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][N:5]2[C:6]([C:8]3[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=3)=[CH:7][C:3]([CH2:2][N:27]3[CH2:32][CH2:31][N:30]([CH2:2][C:3]4[CH:7]=[C:6]([C:8]5[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=5)[N:5]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)[N:4]=4)[CH2:29][CH2:28]3)=[N:4]2)[CH:22]=1
Reactant: COc1cc(-c2cc(CCl)nn2Cc2cccnc2)cc(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc(-c2cc(CN3CCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)n(Cc5cccnc5)n4)CC3)nn2Cc2cccnc2)cc(OC)c1OC

Procedure:
3-Chloromethyl-1-(3-pyridylmethyl) -5-(3,4,5-trimethoxyphenyl)pyrazole (110 mg) and piperazine (12 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:4]=[C:5]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH2:21][CH2:22][Cl:23])=[CH:14][C:6]3=[N:7][C:8]=2[N:9]=[CH:10][C:11]=1[C:12]#[N:13].[Cl:24][C:25]1[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:26]=1[NH2:27]>C(OCCO)C>[Cl:23][CH2:22][CH2:21][O:20][C:15]1[C:16]([O:18][CH3:19])=[CH:17][C:5]2[C:6]([CH:14]=1)=[N:7][C:8]1[N:9]=[CH:10][C:11]([C:12]#[N:13])=[C:2]([NH:27][C:26]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([Cl:32])=[CH:31][C:25]=3[Cl:24])[C:3]=1[CH:4]=2
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: COc1cc2cc3c(Cl)c(C#N)cnc3nc2cc1OCCCl
Solvent: CCOCCO
Product: COc1cc(Nc2c(C#N)cnc3nc4cc(OCCCl)c(OC)cc4cc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 41.2 %

Procedure:
A mixture of 4-chloro-8-(2-chloroethoxy)-7-methoxybenzo[b][1,8]naphthyridine-3-carbonitrile (500 mg, 1.43 mmol) and 2,4-dichloro-5-methoxyaniline (460 mg, 2.39 mmol) in 40 mL of 2-ethoxyethanol is heated at reflux for 20 minutes then cooled to room temperature. The solution is partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is partitioned between ethyl acetate and an aqueous solution of sodium hydroxide and sodium bicarbonate (pH 14). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Ethyl acetate and diethyl ether are added to the residue and the resultant orange solid is collected by filtration to provide 297 mg (41%) of 8-(2-chloroethoxy)-4-(2,4-dichloro-5-methoxyanilino)-7-methoxybenzo[b][1,8]naphthyridine-3-carbonitrile, mp 227–230° C. dec.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14](S(C)=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:20]([O:25][CH3:26])(=[O:24])[C@@H:21]([CH3:23])[OH:22].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:26][O:25][C:20](=[O:24])[C@@H:21]([O:22][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:16][N:15]=1)[CH3:23]
Reactant: CS(=O)c1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: COC(=O)[C@@H](C)O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)[C@H](C)Oc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reaction time: 48 h
Yield: 44.5 %

Procedure:
To a solution of 2-methanesulfinylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (40 mg, 0.14 mmol) in THF (1 mL) was added (R)-(+)-methyl lactate (20 μL, 0.21 mmol) followed by DBU (34 μL, 0.23 mmol). The solution was stirred for 2 days, quenched with 3% HCl and extracted with ethyl acetate. The organic layers were combined, washed successively with 5% NaHCO3, water, and brine, dried and concentrated in vacuo to afford 19.9 mg (46% yield) of the titled compound as a white solid shown to be 94% pure by HPLC. ESI-MS m/z 320 (MH+), 318 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[C:25]([F:28])([F:27])[F:26])[CH2:5][C@H:6]1[CH2:11][C@@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][N:7]1C(OC)=O.Br>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[C:25]([F:27])([F:26])[F:28])[CH2:5][C@H:6]1[CH2:11][C@@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][NH:7]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(C(F)(F)F)c(F)c1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](Cc3ccc(C(F)(F)F)c(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
(2R,4S)-Methyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (594 mg, 1.48 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 10 mL, 57.10 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(3-fluoro-4-(trifluoromethyl)benzyl)-piperidin-4-yl)isoxazol-3(2H)-one (338 mg, 66%). 1H NMR (600 MHz, dmso) δ 1.08 (q, 1H), 1.32 (qd, 1H), 1.71-1.79 (m, 2H), 2.45-2.72 (m, 4H), 2.72-2.80 (m, 1H), 2.96 (d, 1H), 5.68 (s, 1H), 7.23 (d, 1H), 7.35 (d, 1H), 7.65 (t, 1H). HRMS Calculated for [C16H16F4N2O2+H]+: 345.1226. Found: 345.1232
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]1([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25]I>O1CCCC1>[CH3:21][C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:25][CH2:24][C:23]([CH3:28])([CH3:27])[CH3:22])[C:18]([OH:20])=[O:19]
Reactant: CC(C)(C)CCI
Reactant: CC(C(=O)O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)CCC(C)(C(=O)O)c1ccccc1
Temperature: 50 °C

Procedure:
To a solution of lithium bis(trimethylsilyl)amide in (154.48 g, 0.923 mol) in tetrahydrofuran (350 mL) was added 2-phenyl propionic acid (50.0 g, 0.333 mol) over 27 minutes maintaining the temperature below 25° C. Following a THF rinse (35 mL), the solution was heated to 50° C. for 23 minutes. The solution was then cooled below 25° C. and 3,3-dimethyl-1-iodobutane (110.3 g, 0.416 mol) was added. The reaction mixture was heated to 60° C. for 31 h, then was cooled to RT, and concentrated to a thick oil. Water (500 mL) was added and the solution was cooled to 10-15° C. and the pH was adjusted to <2 by the addition of 6 N HCl (75.59 g). The product was extracted with ethyl acetate (440 mL) and the organic layer was washed with 10% NaCl. The crude ethyl acetate solution (assayed for 66.8 g of 49-1, 85.6%) was concentrated to a thick oil and used in the resolution.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:23])[C:9]([C@H:13]2[C@H:18]([C:19]([CH3:21])=[CH2:20])[CH2:17][CH2:16][C:15]([CH3:22])=[CH:14]2)=[C:10]([OH:12])[CH:11]=1.[Si]([O:31][CH2:32][C:33]([O-:35])=[O:34])(C(C)(C)C)(C)C.F.F.F.C(N(CC)CC)C.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([OH:12])[C:9]([C@H:13]2[C@H:18]([C:19]([CH3:21])=[CH2:20])[CH2:17][CH2:16][C:15]([CH3:22])=[CH:14]2)=[C:8]([OH:23])[CH:7]=1.[C:33]([O-:35])(=[O:34])[CH2:32][OH:31]
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)[O-]
Agent: C=C(C)[C@@H]1CCC(C)=C[C@H]1c1c(O)cc(CCCCC)cc1O
Agent: F
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C([O-])CO
Temperature: -15 °C
Reaction time: 65 h

Procedure:
Cannabidiol (t-butyldimethylsilyloxy)acetate (80 mg) was dissolved in dry dichloromethane (0.25 mL), cooled to −15° C. and treated with 0.25 mL of cold 2 M solution of triethylamine trihydrofluoride in dichloromethane. The reaction mixture was left at 5° C. for 65 h. The mixture was poured to an excess of aqueous saturated sodium bicarbonate/ethyl acetate cooled to 0° C. with vigorous stirring. Aqueous layer was extracted twice with ethyl acetate, the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel with hexane-ethyl acetate (gradient 10:1, 4:1, 3:1) to afford 58 mg (95%) of cannabidiol glycolate (ALL00149) as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[N:8][C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)=[N:10][CH:11]=[C:6]2[CH2:5][NH:4][C:3]1=[O:24].FC(F)(F)C(O)=O.CC(C)([O-])C.[K+]>O1CCCC1>[CH3:1][N:2]1[C:7]2=[N:8][C:9]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:17][CH:18]=3)=[N:10][CH:11]=[C:6]2[CH:5]=[N:4][C:3]1=[O:24]
Reactant: CN1C(=O)NCc2cnc(Nc3ccc(-n4cccn4)cc3)nc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)ncc2cnc(Nc3ccc(-n4cccn4)cc3)nc21
Reaction time: 8 h
Yield: 69.4 %

Procedure:
Prepared from 200 mg (0.46 mmol) of 1-methyl-7-[4-(pyrazol-1-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, trifluoroacetic acid and 309 mg (2.76 mmol) of potassium tert-butoxide in 15 mL of tetrahydrofuran. The reaction mixture is stirred overnight. After the workup, the semi-solid is triturated in diethyl ether, and the powder is collected and dried to give 102 mg (65%) of the title compound: mp>290° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[N:10][C:5]2[S:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[H-].[Na+].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[F:25])[N:18]=[C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[C:16]=1[CH3:32]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[N:10][C:5]2[S:6][CH2:7][CH2:8][N:9]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][C:23]=4[F:25])[N:18]=[C:17]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:16]=3[CH3:32])[C:4]=2[CH:3]=1
Reactant: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Cl
Reactant: Clc1cnc2c(c1)NCCS2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cccc(F)c2c1N1CCSc2ncc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 7-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine (100 mg, 0.536 mmol) in DMF (2.0 mL) was added sodium hydride (28.0 mg, 0.643 mmol, 55% dispersion in oil) under a N2 atmosphere. The reaction was stirred at rt for 15 min. After this time 4-chloro-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (146 mg, 0.536 mmol) in DMF (3.0 mL) was added and the reaction was heated at 60° C. for 1 h and at 100° C. overnight. After this time more NaH (28.0 mg, 0.643 mmol, 55% dispersion in oil) was added and the reaction was heated at 120° C. for 3 h. The reaction was then cooled to rt and partitioned between EtOAc and water. The separated organic layer was washed with LiCl (1.0M aqueous solution) and then it was dried over MgSO4, filtered and evaporated in vacuo. Column chromatography (Hexanes:EtOAc, 1:0 to 1:1) gave 7-chloro-1-(5-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine as a yellow film. Mass Spectrum (ESI) m/e=423.0 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)[C:5](=[O:8])[NH:6][N:7]=1.[C:27]([O:30][CH2:31][C:32]1[C:33]([N:41]2[CH2:52][CH2:51][N:50]3[C:43](=[CH:44][C:45]4[CH2:46][C:47]([CH3:54])([CH3:53])[CH2:48][C:49]=43)[C:42]2=[O:55])=[N:34][CH:35]=[CH:36][C:37]=1B(O)O)(=[O:29])[CH3:28].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:27]([O:30][CH2:31][C:32]1[C:33]([N:41]2[CH2:52][CH2:51][N:50]3[C:43](=[CH:44][C:45]4[CH2:46][C:47]([CH3:54])([CH3:53])[CH2:48][C:49]=43)[C:42]2=[O:55])=[N:34][CH:35]=[CH:36][C:37]=1[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)[C:5](=[O:8])[NH:6][N:7]=1)(=[O:29])[CH3:28]
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(Cl)n[nH]c2=O)nc1
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)[nH]n2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 90 °C
Yield: 31.3 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 253d (172 mg, 0.46 mmol), (3-(acetoxymethyl)-2-(7,7-dimethyl-1-oxo-3,4,7,8-tetrahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2(6H)-yl)pyridin-4-yl)boronic acid 199e (0.91 g, 2.29 mmol), Pd(dppf)Cl2 (36 mg, 0.050 mmol), K3PO4 (195 mg, 0.92 mmol), sodium acetate (75 mg, 0.050 mmol), water (0.5 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 20:1 ethyl acetate/methanol to afford the 253e (100 mg, 31%) as brown solid. MS-ESI: [M+H]+ 694.3.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([O:22][CH3:23])[C:17]([N+:19]([O-])=O)=[CH:18][C:12]=2[NH:11][C:10](=[O:24])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Ni]>[NH2:19][C:17]1[C:16]([O:22][CH3:23])=[CH:15][C:13]2[CH2:14][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][C:10](=[O:24])[NH:11][C:12]=2[CH:18]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CN(Cc1ccccc1)C2
Agent: [Ni]
Solvent: CO
Product: COc1cc2c(cc1N)NC(=O)CN(Cc1ccccc1)C2
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A solution of 4-benzyl-7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (125 mg, 0.38 mmol) in methanol (25 mL) was treated with Ra—Ni (˜100 mg; 2800 grade) and shaken on a Paar apparatus under 40 psi H2. After one hour LCMS showed completion of the reaction. The mixture was filtered and concentrated to constant weight to afford 8-amino-4-benzyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (110 mg, 97%) as a mustard yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 7.34 (m, 5H), 6.66 (s, 1H), 6.33 (s, 1H), 4.84 (s, 2H), 3.74 (s, 3H), 3.65 (s, 2H), 3.49 (s, 2H), 2.98 (s, 2H); MS (m/e) 298 (M+1); mp 135° C. (dec.).