Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH2:18][O:19][CH2:20][CH3:21])([C:14]([O:16]C)=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>O1CCCC1.CO.O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH2:18][O:19][CH2:20][CH3:21])([C:14]([OH:16])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC[C@]1(C(=O)OC)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOC[C@]1(C(=O)O)C=C[C@@H](NC(=O)OC(C)(C)C)C1

Procedure:
To a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]-1-(ethoxymethyl)cyclopent-2-ene-1-carboxylate (3.25 g, 10.8 mmol) in tetrahydrofuran (58.7 mL), methanol (58.7 mL) and water (12.6 mL) was added lithium hydroxide monohydrate (0.731 g, 17.42 mmol). The pink mixture was heated to reflux overnight. The organic solvents were removed in vacuo and the aqueous layer was washed once with ether and then acidified slowly with concentrated HCl until the pH reached 4. The resulting suspension was extracted with methylene chloride three times. The combined organic layers were dried over MgSO4, filtered and concentrated to give the desired product as a mixture of cis/trans isomers (2.75 g, 89%). MS calculated for C14H24NO5: (M+H) 286.2; found 186.2 (M+H-Boc).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[CH2:11]([NH2:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(OCC)(=O)C>[Cl-].[Na+].O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:19][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: CCCCCCCCN
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCNc1ccccc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
157.6 g (1 mol) of 2-nitrochlorobenzene and 280 g (2.2 mol) of octylamine were mixed. The reaction mixture was heated to a temperature of 150° C. for 3 hours to undergo reaction, and then allowed to stand overnight. To the reaction solution was then added a mixture of ethyl acetate and saturated brine. The reaction solution was then subjected to separation. The organic phase thus extracted was dried and concentrated to obtain 235 g (0.93 mol) of the desired aniline derivative (yield: 93%).
Reaction SMILES: Cl.[CH3:2][C:3]1(O)[C:7]([CH3:9])(O)[NH:6][C:5]([CH2:10][CH2:11][CH3:12])=[N:4]1.Cl.[OH2:15]>>[CH3:2][C:3]1[NH:4][C:5]([CH2:10][CH2:11][CH3:12])=[N:6][C:7]=1[CH2:9][OH:15]
Reactant: O
Reactant: CCCC1=NC(C)(O)C(C)(O)N1
Agent: Cl
Product: CCCc1nc(CO)c(C)[nH]1

Procedure:
The product from Example 6 is dissolved in 900 ml. of water and 350 ml. of concentrated hydrochloric acid, heated on a steam bath for 5 hours and then chilled. The solution is concentrated in vacuo and a mixture of 100 ml. of acetone and 100 ml. of ethanol is added. The mixture is filtered. The filtrate is evaporated and the residue is dissolved in 50 ml. of water and neutralized with a concentrated solution of K2CO3, until bubbling ceases. The top layer is separated and combined with 5 ml. of methanol. On standing, a precipitate forms. The solid is collected and the filtrate is diluted with acetone to give a second precipitate which is also collected. The solids are combined and recrystallized from hot acetone giving the desired product, m.p. 134°-136° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=O)[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH2:26][OH:27]>C(O)C>[Cl:1][C:2]1[C:3]([C:9](=[N:26][OH:27])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(NCC(=O)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Reactant: NO
Agent: Cl
Solvent: CCO
Product: O=C(NCC(=NO)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 96 h
Yield: 96.2 %

Procedure:
To 2.8 g of N-[2-(3,5-dichloropyridin-2-yl)-2-oxoethyl]-2-(trifluoromethyl)benzamide in 19 ml of ethanol, 1.0 g of hydroxylamine hydrochloride was added, and the mixture was stirred at room temperature for 96 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, the resulting residue was mixed with 50 ml of water and extracted with ethyl acetate (50 ml×2), the resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 2.8 g of the desired product as pale yellow crystals.
Reaction SMILES: [Na:1].Cl[CH2:3][C:4]([O-:6])=[O:5].[Na+].[CH2:8]([OH:11])[CH2:9][OH:10]>>[C:4]([O:6][O:10][CH2:9][CH2:8][OH:11])(=[O:5])[CH3:3].[Na:1]
Reactant: OCCO
Reactant: O=C([O-])CCl
Agent: [Na+]
Agent: [Na]
Product: CC(=O)OOCCO

Procedure:
To 650 g of ethylene glycol, 210.2 g (2.50 mol) of the monosodium salt of ethylene glycol obtained by the operation described above in (1) was added with stirring and dissolved at 70 to 80° C. Then, 285.5 g (2.45 mol) of sodium monochloroacetate was charged over 1 hour at the same temperature and then stirred at the same temperature for 2 hours to obtain 1145.0 g of sodium β-hydroxyethoxy acetate solution in ethylene glycol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[C:11]([F:16])([F:15])[CH2:12][O:13][CH3:14])=[N:6][CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]([F:16])([F:15])[CH2:12][O:13][CH3:14])=[N:9][N:8]=2)[CH:7]=1
Reactant: COCC(F)(F)C(=O)NNc1ccc(Br)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COCC(F)(F)c1nnc2ccc(Br)cn12

Procedure:
N′-(5-bromopyridin-2-yl)-2,2-difluoro-3-methoxypropanehydrazide (0.25 g, 0.81 mmol) and p-toluenesulfonic acid monohydrate (0.12 g, 0.65 mmol) in 1,4-dioxane (3.5 mL) were put onto microwave at 160° C. for 80 min. The reaction mixture was diluted with EtOAc and washed sequentially with NaHCO3 aqueous solution and brine. The organic layer was dried over Na2SO4. Evaporation of the solvent and purification by HPLC gave 6-bromo-3-(1,1-difluoro-2-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:4][C:5]([N+:22]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.O.NN>C(O)C.[Ni]>[NH2:22][C:5]1[CH:4]=[C:3]([O:25][CH:26]([CH3:27])[CH3:28])[C:2]([CH3:1])=[CH:7][C:6]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1OC(C)C
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1OC(C)C
Temperature: 45 °C
Yield: 80 %

Procedure:
A suspension/solution of 1,1-dimethylethyl 4-({5-methyl-4-[(1-methylethyl)oxy]-2-nitrophenyl}amino)-1-piperidinecarboxylate (D74) (0.2 mmol, 80 mg) in ethanol (10 mL) was treated with Raney Nickel, then hydrazine hydrate (2 mmol, 100 mg, 10 eq) was added dropwise over 5 min under argon at room temperature. The mixture was then heated at 45° C. for 30 min. The catalyst was then filtered off and washed with ethanol and methanol. The filtrate was concentrated under reduced pressure to give the title compound as a solid (0.16 mmol, 60 mg, 83% yield). M+H 364.3, 308.2, 264.2 (full molecule and fragments for loss of tert-butyl group and loss of Boc group).
Reaction SMILES: [CH2:1]([O:3][C:4](=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)[C:5]([OH:7])=[O:6])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][CH:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CCOC(Cc1ccc(N)cc1)C(=O)O
Reaction time: 0.17 h

Procedure:
2-Ethoxy-3-(4-nitrophenyl)acrylic acid (18.4 g wet, approx. 77.5 mmol) was dissolved in MeOH (1.1 L) and 10% Pd on C (wet basis) (1.84 g) was added. The mixture was hydrogenated at 12 psi for 10 mins, followed by repeated refill to 20-28 psi every 10-20 mins for 5 hr then 46 psi for 18 hr. The mixture was filtered through GF/F paper and the residue was slurried in IMS (100 ml), filtered, washed with heptane (100 ml), and suction dried on the filter. Thus (±)-2-ethoxy 3-(4′-Aminophenyl)-propionic acid was obtained as an off-white solid (11.2 g, 69%).
Reaction SMILES: C[C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([Cl:11])[CH:5]=1)=[O:3].Br[O-].[Na+].S([O-])(O)=[O:16].[Na+].Cl>>[Cl:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[F:10])[C:2]([OH:3])=[O:16]
Reactant: CC(=O)c1ccc(F)c(Cl)c1
Reactant: O=S([O-])O
Agent: Cl
Agent: [Na+]
Agent: [O-]Br
Product: O=C(O)c1ccc(F)c(Cl)c1
Yield: 74 %

Procedure:
The 3-chloro-4-fluoroacetophenone is then reacted with an aqueous solution of sodium hypobromite, the aqeuous phase is treated with sodium hydrogensulfite and acidified with hydrochloric acid, and the precipitated product is recrystallized from benzene. 3-Chloro-4-fluorobenzoic acid obtained in a yield of 74%.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:9]1[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[C:11]([C:18]([OH:20])=O)[CH:10]=1)=[O:8].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:43]1([C@H:49]([NH2:52])[CH2:50][CH3:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C)C=O.O>[C:43]1([C@H:49]([NH:52][C:18]([C:11]2[CH:10]=[C:9]([C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[O:8])[N:17]3[CH2:16][CH2:15][O:14][CH2:13][C:12]=23)=[O:20])[CH2:50][CH3:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: C[C@H]1CCCN1C(=O)c1cc(C(=O)O)c2n1CCOC2
Reactant: CC[C@@H](N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccccc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 67 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (Comp. No. 7c) (300 mg, 0.914 mmol) in dimethylformamide (4 ml) was added 1-hydroxybenzotriazole (136 mg, 1 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (193 mg, 1 mmol). The mixture was stirred for 90 min at 50° C., then (R)-1-phenyl-propylamine (85 mg, 1 mmol) was added and the mixture was stirred at 25° C. overnight. An excess of water was added, the solid which precipitated was filtered off, washed with a small amount of water and purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 243 mg (67%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide (Comp. No. 16a; compounds with a compound number starting with “16” are compounds of the formula I) as white solid. LC/MS (method 4): Rt=1.12 min; m/z=396.22 (M+H+). 1H-NMR: δ (ppm)=8.07 (1H, d), 7.26-7.35 (5H, m), 7.19-7.22 (1H, m), 4.98 (1H, d), 4.81-4.89 (2H, m), 4.17-4.30 (2H, m), 3.92-3.99 (2H, m), 3.80-3.85 (1H, m), 3.68 (2H, bs), 2.03-2.09 (1H, m), 1.92-1.99 (1H, m), 1.74-1.84 (3H, m), 1.53-1.59 (1H, m), 1.18 (3H, d), 0.88 (3H, t).
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[CH2:11][O:12][C:13]1[CH:27]=[CH:26][C:16]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.Cl[CH2:29][CH2:30][CH2:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1.[OH-].[K+].C(O)C>O.CCCCCC.C(OCC)(=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:27]=[CH:26][C:16]([CH:17]=[CH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:29][CH2:30][CH2:31][C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:23][CH:24]=2)=[CH:15][CH:14]=1
Reactant: Oc1ccc(C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Reactant: ClCCCc1nnn[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: C(=Cc1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCCCc2nnn[nH]2)cc1

Procedure:
A mixture of (0.014 mol) 4-(4-(2-quinolinylmethyloxy)-styryl)phenol, (0.14 mol) 5-(3-chloropropyl)tetrazole, 2 g (0.036 mol) KOH in 5 ml water, and 50 ml ethanol is heated over a steam bath for a period of 3 hours. The reaction mixture is concentrated to dryness and slurried into water and extracted with methylene chloride. The methylene chloride extract is washed with water, dried over MgSO4 and concentrated under reduced pressure to obtain solid which is passed through a silica gel column using hexane/ethyl acetate as eluent. Evaporation of eluent gives 5-(3-(4-(4-(2-quinolinylmethyloxy)styryl)phenoxy)propyl)tetrazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH3:13])[N:6]([CH3:14])[C:5]2=[O:15].[Br:16]Br.O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]([Br:16])[CH3:13])[N:6]([CH3:14])[C:5]2=[O:15]
Reactant: CCc1nc2ccc(Br)cc2c(=O)n1C
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CC(Br)c1nc2ccc(Br)cc2c(=O)n1C
Temperature: 25 °C
Yield: 82.6 %

Procedure:
To a solution of 6-bromo-2-ethyl-3-methyl-3H-quinazolin-4-one (2.6 g, 9.73 mmol) in glacial acetic acid (2 ml) cooled in an ice bath was added dropwise a solution of bromine (3.1 g, 19.46 mmol) in glacial acetic acid (5 ml). After addition was complete, the reaction was heated to reflux for 18 hours. At which time it was allowed to cool to room temperature. Water was then added to the solution and the mixture was extracted with dichloromethane. The organic layer was then washed with 10% sodium bisulfite solution, and then washed with saturated brine (2×30 ml). The combined organic phase was collected and dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield a brown crude product. The resulting residue was purified by silica gel chromatography with 50% dichloromethane in hexane. The product was collected and was dried under reduced pressure to give 6-Bromo-2-(1-bromo-ethyl)-3-methyl-3H-quinazolin-4-one (Yield 2.78 g, 82.5%). 1H NMR (400 MHz, CDCl3): δ 2.23 (d, 3H, J=6.82 Hz), 3.80 (s, 3H), 5.11 (q, 1H, J=13.14, 6.82 Hz), 7.64 (d, 1H, J=8.84 Hz), 7.87 (dd, 1H, J=8.59, 2.26 Hz), 8.46 (d, 1H, J=2.26 Hz). MS m/z calc. 345.9, found (ESI); 347.0 (M+1)+. Retention time 3.43 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: OCC1CCNCC1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: ClCCl
Product: O=C(O)c1cc(S(=O)(=O)N2CCC(CO)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-5-chlorosulfonylbenzoic acid (5.0 g.) is added to a solution of 4-piperidyl carbinol (6.9 g.) in 40 ml. of methylene chloride. The solution is refluxed for 2 hours, cooled to room temperature and stirred overnight. The solution is evaporated to dryness, the gummy residue dissolved in 1 N sodium hydroxide, and the alkaline solution extracted twice with ether. The aqueous solution is acidified with concentrated hydrochloric acid, and the precipitate recovered by filtration. Recrystallization from ethyl acetate yields crystals, m.p. 185°-187° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1.I[CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][N:19]1[CH:20]=[CH:21][C:16]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=3)[N:6]=[C:2]2[CH3:1])=[CH:17][C:18]1=[O:22]
Reactant: OCCI
Reactant: Cc1cccc(C#Cc2cn(-c3cc[nH]c(=O)c3)c(C)n2)c1
Product: Cc1cccc(C#Cc2cn(-c3ccn(CCO)c(=O)c3)c(C)n2)c1

Procedure:
The title compound, light yellow solid, MS: m/e=334.2 (M+H+), was prepared in accordance with the general method of example 3 from 4-(2-Methyl-4-m-tolylethynyl-imidazol-1-yl)-1H-pyridin-2-one and 2-iodoethanol.
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=[O:4].C(O)(=O)C=O.[CH2:12]1[O:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13]1>C1(C)C=CC=CC=1>[CH2:12]1[O:20][C:15]2[CH:16]=[CH:17][C:18]([CH:3]([OH:4])[C:2]([OH:6])=[O:5])=[CH:19][C:14]=2[O:13]1
Reactant: c1ccc2c(c1)OCO2
Reactant: O=CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)C(O)c1ccc2c(c1)OCO2
Reaction time: 3.5 h
Yield: 76.3 %

Procedure:
If, instead of glyoxylic acid monohydrate, an equivalent amount of 50% strength aqueous glyoxylic acid is employed and the mixture is stirred for 6 hours instead of 3.5 hours, 8.58 g of bis-3,4-methylenedioxyphenylacetic acid are obtained from the toluene phase and 73.4 g of 3,4-methylenedioxymandelic acid, corresponding to a yield of 76.3% of theory, relative to 1,2-methylenedioxybenzene employed, are obtained from the aqueous phase.
Reaction SMILES: C([O:9][C@@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([C:53]([O:55][CH3:56])=[O:54])=[N:33][C:34]=2[NH:38][CH2:39][CH:40]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[C:47]1([CH:40]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:39][NH:38][C:34]2[N:33]=[C:32]([C:53]([O:55][CH3:56])=[O:54])[N:31]=[C:30]3[C:35]=2[N:36]=[CH:37][N:29]3[C@H:11]2[C@H:10]([OH:9])[C@@H:14]([OH:15])[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12]2)[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](O)[C@H]1O
Yield: 97.6 %

Procedure:
A solution of methyl 9-{(2R,3R,4R,5S)-3,4-bis(benzoyloxy)-5-[(ethylamino)carbonyl]-tetrahydro-2-furanyl}-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 8) (3.4 g, 4.5 mmol) and sodium carbonate (50 mg) in dry methanol (60 ml) was stirred at room temperature for four hours Solvent was removed under reduced pressure and the residue taken up in a mixture of dichloromethane:methanol (95:5, by volume, 60 ml). Inorganic salts were filtered off and the filtrate evaporated under reduced pressure. The residue was triturated with diethyl ether, filtered off and dried to yield the title compound as a white solid, (2.4 g, 98%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:11]=[CH:12][CH:13]=2)[N:5]=[CH:6][C:7]=1[C:8]([NH2:10])=[O:9].Cl.[F:15][C:16]([CH3:21])([CH3:20])[C@H:17]([NH2:19])[CH3:18].C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.CO>[F:15][C:16]([CH3:21])([CH3:20])[C@H:17]([NH:19][C:2]1[C:3]2[N:4]([CH:11]=[CH:12][CH:13]=2)[N:5]=[CH:6][C:7]=1[C:8]([NH2:10])=[O:9])[CH3:18]
Reactant: NC(=O)c1cnn2cccc2c1Cl
Reactant: C[C@@H](N)C(C)(C)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CO
Product: C[C@@H](Nc1c(C(N)=O)cnn2cccc12)C(C)(C)F
Temperature: 25 °C
Yield: 32 %

Procedure:
A solution of 4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 3, 50 mg, 0.26 mmol), (R)-2-Fluoro-1,2-dimethyl-propylamine hydrochloride salt (47 mg, 0.33 mmol, from step 3), and diisopropylethylamine (0.089 mL, 0.51 mmol) in NMP (0.5 mL) was heated to 100° C. for 1 hour in the CEM microwave. The mixture was cooled to rt, diluted with MeOH and purified by reverse-phase Prep HPLC (condition A). The fraction containing the major product was concentrated on the rotovap to remove the MeOH and the aqueous slurry of the product was neutralized by addition of ˜1 mL of saturated aq sodium bicarbonate. Sonication of the slurry followed by vacuum filtration and air drying in the funnel afforded 22 mg (33%) of a pale yellow solid as the title compound. HPLC (condition A): retention time=7.70 min. LCMS (condition B): m/z 265.2. 1H NMR (500 MHz, CD3OD) δ ppm 10.74 (1 H, br. s.), 8.16 (1 H, s), 7.41-7.80 (1 H, m), 7.01 (1 H, dd, J=4.72, 1.39 Hz), 6.72 (1 H, dd, J=4.58, 2.64 Hz), 4.28-4.64 (1 H, m), 1.46-1.55 (6 H, m), 1.44 (3 H, d).
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][CH2:15][CH3:16])=[N+:2]=[N-:3].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[C:18]#[CH:19]>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:5]1[CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:12]=[CH:13][C:4]=1[N:1]1[CH:19]=[C:18]([C:17]([O:21][CH2:22][CH3:23])=[O:20])[N:3]=[N:2]1)[CH3:16]
Reactant: C#CC(=O)OCC
Reactant: CCOc1cc(C(=O)OC)ccc1N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(C(=O)OC)cc2OCC)nn1
Temperature: 25 °C

Procedure:
A solution of methyl 4-azido-3-ethoxybenzoate (1.0 g) obtained in Example 320b) and ethyl propiolate (0.92 ml) in toluene (10 ml) was stirred at 100° C. overnight. After the reaction solution was allowed to cool to room temperature, the resultant precipitate was collected by filtration to give the title compound as a white solid (0.76 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19](C(=O)C)[CH2:18][CH2:17]4)=[CH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1.CO>Cl>[CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]4)=[CH:14][CH:15]=3)[CH2:6][CH2:7]2)[CH2:3]1
Reactant: CC(=O)N1CCN(c2ccc(N3CC[C@@H]4CN(C)C[C@@H]43)cc2)CC1
Agent: Cl
Solvent: CO
Product: CN1C[C@H]2CCN(c3ccc(N4CCNCC4)cc3)[C@H]2C1

Procedure:
The product of Example 49A (300 mg, 0.91 mmole) was dissolved in 6 ml of 2N hydrochloric acid and 3 ml of methanol and stirred at 60° C. for 3 hours. The mixture was concentrated to dryness under reduced pressure, diluted with water and extracted with dichloromethane (4×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure and purified by column chromatography (eluting with a mixture of 10% methanol and 1% ammonium hydroxide in dichloromethane) to provide the title compounds 1H NMR (300 MHz, CDCl3) δ ppm 6.84-6.94 (m, 2H) 6.53-6.60 (m, 2H) 4.00-4.07 (m, 1H) 3.44-3.51 (m, 1H) 3.11-3.20 (m, 1H) 2.99-3.09 (m, 9H) 2.88-2.96 (m, 1H) 2.68 (dd, J=9.66, 2.54 Hz, 1H) 2.48-2.59 (m, 2H) 2.31 (s, 3H) 2.09-2.19 (m, 1H) 1.89 (m, 1H). MS. (M+H)+=287.