Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14]2)#[N:10]>CCO>[OH:3][NH:2][C:9](=[NH:10])[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14]2
Reactant: NO
Reactant: CCOC(=O)c1cc2cc(C#N)ccc2[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(C(=N)NO)ccc2[nH]1
Temperature: 55 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
Hydroxylamine hydrochloride (172 mg) and sodium bicarbonate (415 mg) was added to a solution of ethyl 5-cyano-1H-indole-2-carboxylate (D21) (265 mg) in EtOH (15 mL), in that sequence. The reaction mixture was heated to 55° C. and stirred for 16 hours at that temperature. Another portion of hydroxylamine hydrochloride (69.4 mg) was added, followed by addition of sodium bicarbonate (125.5 mg). The resulting suspension was stirred at 55° C. for 12 hours. The inorganics was filtered off. The solid was washed with dichloromethane (30 mL) and methanol (30 mL). The filtrate was concentrated to afford ethyl 5-[(hydroxyamino)(imino)methyl]-1H-indole-2-carboxylate (D22) (280 mg) as a yellow solid. No purification was attempted. MS (ES): C12H13N3O3 requires 247; found 248.1 (M+H+).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1>C(#N)C>[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[N:22]([C:2]2[N:11]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:21]=1
Reactant: Clc1nc(Nc2ccccc2)c2ccccc2n1
Reactant: Cc1cc(C)[nH]n1
Solvent: CC#N
Product: Cc1cc(C)n(-c2nc(Nc3ccccc3)c3ccccc3n2)n1
Temperature: 130 °C
Yield: 48.5 %

Procedure:
(2-Chloro-quinazolin-4-yl)-phenyl amine (250 mg, 0.98 mmol) was dissolved in acetonitrile (4 mL) and 3,5-dimethylpyrazole (140 mg, 1.47 mmol) was added. The mixture was heated in a sealed tube at 130° C. for 12 hours. The mixture was concentrated and the residue basified with sodium hydrogencarbonate, extracted with chloroform dried over anhydrous sodium sulfate filtrated and evaporated. The crude product was purified by column chromatography (ethylacetate/hexane) to give [2-(3,5-dimethyl-pyrazol-1-yl)-quinazolin-4-yl]-phenyl-amine (150 mg, 49%). Mp. 262.4-265.3° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.Cl.[CH3:18][N:19]([CH3:30])[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH2:20][N:19]([CH3:30])[CH3:18])=[CH:28][CH:27]=1
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CCOc1ccc(N/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1
Yield: 81.8 %

Procedure:
(4E)-6-Bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (70 mg, 0.25 mmol) and 4-(2-dimethylamino-ethoxy)-phenylamine hydrochloride (50 mg, 0.23 mmol) were stirred in dimethylformamide (1 mL) and triethylamine (50 μL) at 70° C. The reaction mixture is quenched by the addition of water. The solid material is then collected, washed with diethyl ether, water, and methanol, and then dried under vacuum to give (4Z)-6-bromo-4-[({4-[2-(dimethylamino)ethoxy]phenyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione (81 mg, 82%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[F:25][C:26]([F:38])([F:37])[CH:27]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:36])[C:30]=2[CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:36][C:31]3[CH:32]=[CH:33][CH:34]=[C:35]4[C:30]=3[CH2:29][CH2:28][CH:27]4[C:26]([F:25])([F:37])[F:38])[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: Oc1cccc2c1CCC2C(F)(F)F
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)c1coc(Oc2cccc3c2CCC3C(F)(F)F)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 87.4 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 1-trifluoromethyl-indan-4-ol (53 mg, 0.26 mmol) to give the title compound (62 mg, 87%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([N+:21]([O-:23])=[O:22])[C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[N+:21]([C:20]1[C:14]2[C:15](=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:13]=2)[CH:17]=[CH:18][CH:19]=1)([O-:23])=[O:22]
Reactant: Brc1ccccn1
Reactant: C#CCCn1nc2cccc([N+](=O)[O-])c2n1
Product: O=[N+]([O-])c1cccc2nn(CCC#Cc3ccccn3)nc12
Yield: 31.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (76 mg, 0.48 mmol) and 2-but-3-ynyl-4-nitro-2H-benzo[d][1,2,3]triazole (95 mg, 0.44 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 40 mg (0.14 mmol, 31%) of 4-nitro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as an orange oil.
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]([C:8]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([C:18]([F:27])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:13][C:12]=2[CH2:28][CH3:29])=[O:9])=[CH:6][CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[Na+].Cl.[NH2:38][OH:39]>C(O)C.O>[CH2:28]([C:12]1[CH:13]=[C:14]([C:18]([F:27])([C:19]([F:22])([F:20])[F:21])[C:23]([F:25])([F:24])[F:26])[CH:15]=[C:16]([CH3:17])[C:11]=1[NH:10][C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([C:1](=[N:38][OH:39])[CH3:2])=[CH:31][CH:30]=1)[CH3:29]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C(C)=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C(C)=NO)cc1
Yield: 104.8 %

Procedure:
4-Acetyl-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-benzamide (2.2 g) was dissolved in ethanol (15 ml) and water (15 ml). To the solution, sodium acetate (0.6 g) and hydroxylamine hydrochloride (0.30 g) were added and the mixture was refluxed under heating for 4 hours. The reaction solution was extracted twice with ethyl acetate. The organic phases were combined, washed with water and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-4-[N-hydroxyethaneimidoyl]benzamide (2.1 g, yield 96%).
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:25])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1.[CH:26]1([Mg]Br)[CH2:30][CH2:29][CH2:28][CH2:27]1.CCOCC>C1COCC1>[CH2:18]([O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][C:8]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:25])=[CH:16][CH:15]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Br[Mg]C1CCCC1
Reactant: O=C(CCc1ccc(OCc2ccccc2)cc1)Sc1ccccn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CCc1ccc(OCc2ccccc2)cc1)C1CCCC1
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 84 %

Procedure:
3-(4-Benzyloxyphenyl)thiopropionic acid S-pyridin-2-yl ester (3.00 g, 8.58 mmol) from Step 4 above was dissolved in dry THF (45 mL) and cooled to −78° C. A solution of cyclopentylmagnesium bromide in Et2O (2.0 M, 4.51 mL, 9.02 mmol) was added dropwise along the sides of the reaction vessel. After stirring 35 min, the cooling bath was removed. The reaction mixture was quenched with saturated aq. NH4Cl upon reaching ambient temperature and extracted with Et2O (500 mL). The organic phase was washed with brine (50 mL), dried over MgSO4 and evaporated. The residue was purified by flash column chromatography (10% EtOAc in hexanes) to give the product (2.22 g, 84%) as a white semi-crystalline material. 1H NMR (CDCl3) δ 1.48-1.83 (m, 8H), 2.69-2.77 (m, 2H), 2.79-2.88 (m, 3H), 5.03 (s, 2H), 6.86-6.92 (m, 2H), 7.07-7.12 (m, 2H), 7.28-7.45 (m, 5H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[Cl:14])C=C.C(N(CC)[C:18]1[CH:23]=CC=C[CH:19]=1)C.Cl>>[CH2:23]([C:10]1[CH:9]=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[C:6]([Cl:14])[C:5]=1[OH:4])[CH:18]=[CH2:19]
Reactant: C=CCOc1ccc([N+](=O)[O-])cc1Cl
Reactant: CCN(CC)c1ccccc1
Agent: Cl
Product: C=CCc1cc([N+](=O)[O-])cc(Cl)c1O
Temperature: 210 °C
Reaction time: 6 h

Procedure:
A mixture of 1-(allyloxy)-2-chloro-4-nitrobenzene (55.2 g) and N,N-diethylaniline (50.0 mL) was stirred at 210° C. for 6 hours, and then followed by stirring at 175° C. overnight. At room temperature, the pH of the reaction mixture was adjusted to 1 by the addition of concentrated hydrochloric acid, followed by extraction with ether. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, the insoluble materials were separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 88:12) to obtain 2-allyl-6-chloro-4-nitrophenol (30.1 g) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[C:14]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:3][CH:4]=1
Reactant: O=C1CCCC1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)cc2)CCCC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a cold (−78° C.) solution of 1,4-dibromobenzene (33 g, 139.8 mmol) in tetrahydrofuran (200 mL) was added n-butyllithium (59.0 mL, 146.8 mmol, 2.49 M in hexane) dropwise. The viscous solution was stirred at −78° C. for 45 min, and cyclopentanone (13.6 mL, 153.8 mmol) was then added dropwise over 30 min. The resulting solution was stirred at −78° C. for 1 h and was then quenched by the addition of 0.5M HCl (200 mL) and ethyl acetate (200 mL). The layers were separated, and the organics were washed with water (1×100 mL), brine (1×100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with 5% ethyl acetate in hexane to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.71-1.76 (m, 2H), 1.78-1.88 (m, 6H), 4.85 (s, 1H), 7.39-7.43 (m, 2H), 7.44-7.49 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2]1.S(Cl)(Cl)=O.[CH2:19](O)[CH3:20]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([O:14][CH2:19][CH3:20])=[O:13])=[CH:2]1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCc1c[nH]c2ccccc12

Procedure:
A solution of 7.38 g of 3-indolepropionic acid and 5.9 g of thionyl chloride in 50 ml of ethanol is refluxed for 2 hours, cooled and evaporated. The residue is partitioned between ether and cold sodium bicarbonate solution. The organic phase is separated, dried over sodium sulfate and evaporated to yield ethyl 3-(3-indolyl)propionate; Rf (ether/SiO2)=0.51; IR (CH2Cl2) 1725 cm-1.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]3[CH:12]=[CH:13][O:14][C:8]3=[CH:7][C:6]=2[CH:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:4]1=[O:20])[CH3:2].[H][H]>[Pd]>[CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]3[CH2:12][CH2:13][O:14][C:8]3=[CH:7][C:6]=2[CH:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:4]1=[O:20])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1C(=O)N(CC)c2cc3ccoc3cc21
Agent: [Pd]
Product: CCOC(=O)C1C(=O)N(CC)c2cc3c(cc21)OCC3
Yield: 63 %

Procedure:
A mixture of 20 g. (73.3 mmoles) of ethyl 5-ethyl-6-oxo-6,7-dihydro-furo[2,3-f]indole-7-carboxylate and 4 g. of 10% palladium-on-carbon was shaken in a hydrogen atmosphere at an initial pressure of 50 psi. After 2 hours the catalyst was filtered and the filtrate evaporated. The residue was recrystallized from diethyl ether, 12.6 g. (63% yield), m.p. 82°-84° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13](N)=[O:14])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(=O)(O)(O)O.O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][OH:14])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1cc(-c2ccccc2)ccn1
Agent: O=P(O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1cc(-c2ccccc2)ccn1
Yield: 71 %

Procedure:
The procedure of Example 1 was used except that the catholyte was prepared from the following weight parts: 4-phenylpicolinamide (0.3), phosphoric acid (0.9), water (2.0), and toluene (0.8). The reduction was carried out similarly to Example 1 to give a 71% yield of 4-phenyl-2-pyridylcarbinol at 5.8 F/mole charge passage. Repeating the reduction with no toluene added gave a 49% yield of carbinol at 6 F/mole charge passage. Addition of a titanium salt to the catholyte containing added toluene resulted in a 55% yield of 4-phenyl-2-picolylamine by HPLC analysis. Other cathode materials than lead were also used successfully such as cadmium or zinc with similar results.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][C@@H:8]([NH2:38])[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:37])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[O:26])=[C:20]([O:35][CH3:36])[CH:19]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[C:1]([O:5][C:6](=[O:39])[CH2:7][C@H:8]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:37])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[O:26])=[C:20]([O:35][CH3:36])[CH:19]=2)=[CH:13][CH:14]=1)[NH:38][S:48]([CH3:47])(=[O:50])=[O:49])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(CC(=O)Nc2ccc([C@H](N)CC(=O)OC(C)(C)C)cc2)ccc1NC(=O)Nc1ccccc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)Nc2ccc([C@@H](CC(=O)OC(C)(C)C)NS(C)(=O)=O)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of (R)-3-amino-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}-phenyl)-propanoic acid tert-butyl ester [100 mg, Reference Example 7(a)], dichloromethane (10 ml) and triethylamine (38 mg) was stirred at ambient temperature and then treated with methanesulphonyl chloride (22 mg). After stirring for 1 hour, the reaction mixture was diluted with dichloromethane (20 ml) and then washed with hydrochloric acid (20 ml, 1M), then with saturated aqueous sodium bicarbonate solution (20 ml). The organic layer was dried over magnesium sulphate and then evaporated to give the title compound (55 mg) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[NH:5][N:4]=1.[NH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:34])[CH2:19][CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[N:22]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]2[N:22]=[C:21]([CH2:20][CH2:19][C:18]([NH:17][CH2:16][CH2:15][NH:14][CH2:2][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6](=[O:13])[NH:5][N:4]=3)=[O:34])[O:25][N:24]=2)=[CH:27][CH:28]=1
Reactant: COc1ccc(-c2noc(CCC(=O)NCCN)n2)cc1
Reactant: O=c1[nH]nc(CCl)c2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2noc(CCC(=O)NCCNCc3n[nH]c(=O)c4ccccc34)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloromethyl-2H-phthalazin-1-one (9.7 mg, 0.05 mmol) in DMF (200 μL), N-(2-amino-ethyl)-3-[3-(4-methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-propionamide (14.4 mg, 0.05 mmol) and DIPEA (9 μL, 0.05 mmol) were added. The mixture was stirred overnight at rt and directly applied to preparative HPLC. The purity was determined by RPLC/MS.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].CI.CN(C=O)C>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[N:5]=[C:4]([N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[CH3:19])[N:3]=1
Reactant: N#Cc1nc(N)nc(Nc2cccc(F)c2F)n1
Reactant: O=C([O-])[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(c1nc(N)nc(C#N)n1)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To 2-amino-4 cyano-6-(2,3-difluorophenylamino)-[1,3,5]triazine (Intermediate 54, 332 mg, 1.34 mmol) were added potassium carbonate (203 mg, 1.46 mmol), methyl iodide (83 μL, 1.34 mmol) and anhydrous DMF (3 mL). The mixture was stirred at room temperature for 1 h and then diluted with 1M aq. citric acid (10 mL). The resulting mixture was extracted with ethyl acetate (2×10 mL) and the combined extracts washed with water (4×10 mL), saturated brine (10 mL) and dried further over anhydrous sodium sulfate. Evaporation of the solvent gave a gum which was loaded onto a silica column and eluted with heptane-30% ethyl acetate to give the desired compound (320 mg, 91%). Method B HPLC-MS: MH+ requires m/z=262. Found: m/z=262, Rt=1.76 min (98%).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:2]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=2[O:19][CH3:20])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.CCCCCC.S(Cl)([Cl:35])=O>>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:2]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([Cl:35])=[O:15])=[CH:12][C:11]=2[O:19][CH3:20])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(=O)O)ccc1NC(=O)c1ccccc1-c1ccccc1
Solvent: CCCCCC
Product: COc1cc(C(=O)Cl)ccc1NC(=O)c1ccccc1-c1ccccc1

Procedure:
A solution of 2.69 g of 4-[([1,1'-biphenyl]-2-carbonyl]amino]-3-methoxy benzoic acid in 5 ml of thionyl chloride is heated on a steam bath for 1 hour under Argon. The volatiles are removed in vacuo to give a residue which is stirred with hexane to give 2.58 g of crystalline solid, m.p. 121°-123° C. M+=361.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[CH2:10](O)[CH2:11][CH2:12][OH:13].O>C1(C)C=CC=CC=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:13][CH2:12][CH2:11][CH2:10][O:7]2)=[CH:4][N:3]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: OCCCO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc(C2OCCCO2)cn1
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 6-bromopyridine-3-carbaldehyde 7 (47.2 g, 254 mmol) in toluene (130 mL) in a 250 mL round-bottom flask was added 1,3-propanediol (38.6 g, 508 mmol) and 10-camphorsulfonic acid (2.95 g, 12.69 mmol). The reaction mixture was heated to reflux, with azeotropic removal of the evolved water, for 1 h, cooled down to r.t. and concentrated. The residue was partitioned between EtOAc (150 mL) and NaHCO3 soln (100 mL). Organic phase was collected and the aqueous phase was extracted with EA (2×150 mL). Combined organic fractions were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to yield a brown solid which was triturated with Et2O/Hex (10/150 mL) for 1 h, filtered to give 28 (53.98 g, 221 mmol, 87% yield) as a beige solid. MS (m/z): 243.1 (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]2[O:13][N:14]([CH3:22])[C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[C@:11]2([O:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:10][C@H:9]1[C:31]([OH:33])=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[Cl:21][C:20]1[C:15]2[N:14]([CH3:22])[O:13][CH:12]3[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:31]([OH:33])=[O:32])[CH2:10][C@@:11]3([O:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: [H][H]
Reactant: CN1O[C@H]2N(C(=O)OC(C)(C)C)[C@H](C(=O)O)C[C@@]2(OC(=O)OC(C)(C)C)c2cccc(Cl)c21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN1OC2N(C(=O)OC(C)(C)C)[C@H](C(=O)O)C[C@@]2(OC(=O)OC(C)(C)C)c2cccc(Cl)c21
Yield: 68.9 %

Procedure:
A solution of (2S,3aR,9bR)-3-(tert-butoxycarbonyl)-9b-[(tert-butoxycarbonyl)oxy]-6-chloro-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylic acid (Preparation 150, 25.4 g) in ethyl acetate (200 ml) was treated with 10% palladium on charcoal (5 g) and stirred under 50 p.s.i. of hydrogen gas for 170 hours. The reaction mixture was filtered through celite, evaporated and purified by flash column chromatography eluting with ethyl acetate:hexane (1:4) to give the product as a white foam (17.5 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11].C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>ClCCl>[C:25]([O:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])(=[O:27])[CH3:26]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1CCO
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCc1ccccc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 29.0 g of the product from Example 1 and 24 ml triethylamine in 290 ml of dichloromethane was cooled to 0° C. and treated with 13 ml acetic anhydride. The reaction mixture was stirred at room temperature for 22 hours. Dichloromethane (200 ml) was added and the organic layer washed with three 50 ml portions of water and one portion of brine. Drying the organic layer over magnesium sulfate followed by concentrating in vacuo gave the crude product. Purification by silica gel chromatography (elution with hexanes-ethyl acetate, 70:30) affoded 19.5 g of pure 2-[2-(acetyloxy)ethyl]-N-(1,1-dimethylethyl)benzenesulfonamide as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12].[OH:15][C:16]12[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[C:20]1([NH:29][C:30](=[O:32])[CH3:31])[C:19]1[CH:33]=[CH:34][C:35]([CH:37]([CH3:39])[CH3:38])=[CH:36][C:18]=1[O:17]2>C1COCC1>[C:8]([O:17][C:18]1[CH:36]=[C:35]([CH:37]([CH3:38])[CH3:39])[CH:34]=[CH:33][C:19]=1[C:20]1([NH:29][C:30](=[O:32])[CH3:31])[C:21](=[O:28])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]1=[O:15])(=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(=O)NC12C(=O)c3ccccc3C1(O)Oc1cc(C(C)C)ccc12
Reactant: CCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC(=O)Oc1cc(C(C)C)ccc1C1(NC(C)=O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.1 %

Procedure:
Triethylamine (0.24 ml, 1.77 mmol) and Valeroyl chloride (0.18 ml, 1.48 mmol) were added to N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-benzo[d]indeno[1,2-b]furan-9b-yl)acetamide (0.50 g, 1.48 mmol) in THF (10 ml). The reaction mixture was stirred at room temperature for 12 hrs, concentrated in a vacuum to remove solvent. The reaction mixture was extracted with water and methylene chloride, and purified through silica gel column chromatography (ethylacetate:hexane=1:2) to afford the title compound (0.20 g, 32%).