Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][OH:12])=[CH:8][C:9]=1[Br:10])=[O:4].I(O)(=O)(=O)=[O:14]>CC#N.CCOC(C)=O.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([OH:14])=[O:12])=[CH:8][C:9]=1[Br:10])=[O:4]
Reactant: COC(=O)c1sc(CO)cc1Br
Reactant: [O-][I+3]([O-])([O-])O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1sc(C(=O)O)cc1Br
Reaction time: 2 h
Yield: 101.3 %

Procedure:
A mixture of 3-Bromo-5-hydroxymethyl-thiophene-2-carboxylic acid methyl ester (0.19 g, 0.76 mmol) and Periodic Acid (0.38 g, 1.66 mmol) in MeCN (10 ml) was stirred for 30 min A solution of PCC (0.010 g, 0.015 mmol) in MeCN (0.2 ml) was added. After 2 h, the reaction mixture was diluted with EtOAc (50 ml), washed with sodium sulfite, brine, dried over sodium sulfate, filtered and evaporated. Isolate 0.204 g (100%) of yellow solid product.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[C:23]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.[BH3-]C#N.[Na+]>>[CH:23]1([NH:1][CH2:2][CH:3]2[CH2:12][CH2:11][CH2:10][C:9]3[C:8]([O:13][C:14]4[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=4)=[CH:7][CH:6]=[CH:5][C:4]2=3)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2cccc3c2CCCC3CNC2CCCC2)nc1
Yield: 37.5 %

Procedure:
Using a method similar to Example 204, using 6-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide (intermediate 20, 297 mg, 1.00 mmol), cyclopentanone (168 mg, 2.00 mmol), and NaBH3CN (125 mg, 2.00 mmol) gives the title compound (137 mg) as a white foam. Mass spectrum (ion spray): m/z=366 (M+1); 1HNMR (CDCl3): 8.56 (s, 1H), 8.15 (d, 1H), 7.22-7.15 (m 2H), 6.93-4.89 (m, 2H), 5.82 (br. s, 2H), 3.11 (m, 1H), 3.02 (m, 1H), 2.92-2.78 (m, 2H), 2.63-2.42 (m, 2H), 1.91-1.50 (m, 10H), 1.35 (m, 2H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[C:12]([F:13])=[C:11]([N+]([O-])=O)[CH:10]=[CH:9][N+:8]=1[O-:17].[OH-].[Na+]>ClCCl>[CH3:6][C:7]1[C:12]([F:13])=[C:11]([Cl:3])[CH:10]=[CH:9][N+:8]=1[O-:17]
Reactant: Cc1c(F)c([N+](=O)[O-])cc[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1c(F)c(Cl)cc[n+]1[O-]

Procedure:
Phosphoryl chloride (19 ml) in dichloromethane (50 ml) was added dropwise to a stirred solution of 2-methyl-3-fluoro-4-nitropyridine-N-oxide (12 g) in dichloromethane (50 ml). The reaction mixture was heated under reflux for a total of 8 hours. After cooling and pouring onto ice, the mixture was basified (NaOH) to pH 9 and extracted with dichloromethane. After drying (K2CO3) and removal of solvent, the crude product was purified by column chromatography (silica gel; 1% MeOH/CHCl3) to give 2-methyl-3-fluoro-4-chloro-pyridine-N-oxide (6.78 g) m.p. 63°-65°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:18])=O>CN1CCCC1=O>[Cl:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(N2CCCC2)cc1Cl
Solvent: CN1CCCC1=O
Product: O=C(Cl)c1ccc(N2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-chloro-4-pyrrolidinylbenzoic acid (1 g) is added thionyl chloride (10 ml), and a drop of N-methylpyrrolidone is added to the mixture. The mixture is stirred at room temperature for one hour. Subsequently, the mixture is concentrated under reduced pressure, and the residue is dissolved in toluene (10 ml), and further concentrated under reduced pressure to give 2-chloro-4-pyrrolidinylbenzoyl chloride (acid chloride) as a pale yellow powder. Separately, (5R)-5-isopropylaminocarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepine (1 g) is dissolved in dichloromethane (20 ml), and thereto is added pyridine (1.64 ml). To the mixture is added drowpise with stirring a solution of the above obtained acid chloride in dichloromethane (5 ml) at room temperature. The mixture is stirred for one hour, and thereto is added 1N aqueous sodium hydroxide solution (10 ml), and then stirred for 30 minutes. The mixture is extracted with ethyl acetate (20 ml), and the extract is dried over sodium carbonate, crystallized from acetonitrile, and further recrystallized from acetone--n-hexane to give (5R)-5-isopropylaminocarbonylmethyl-1-[4-(1-pyrrolidinyl)-2-chlorobenzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.45 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=1.[Mg].II.[Br:14][C:15]1[CH:16]=[C:17]([C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]#[N:37])=[N:23]S(C(C)(C)C)=O)[CH:18]=[CH:19][C:20]=1[F:21]>C(OCC)C.O1CCCC1>[Br:14][C:15]1[CH:16]=[C:17]([C:22]2([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=3)[C:30]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:36]([NH2:37])=[N:23]2)[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: CC(C)(C)S(=O)N=C(c1ccc(F)c(Br)c1)c1ccccc1C#N
Reactant: COc1ccc(Br)cc1C
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C2(c3ccc(F)c(Br)c3)N=C(N)c3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
A solution of 4-bromo-1-methoxy-2-methylbenzene (1.21 g, 6.0 mmol) in diethyl ether (10 mL) was added dropwise to magnesium (0.22 g, 9.0 mmol) and iodine. The resulting mixture was heated to reflux for 2 h and was then allowed to cool to room temperature. The prepared reagent was added to a solution of N-((3-bromo-4-fluorophenyl)(2-cyanophenyl)methylene)-2-methylpropane-2-sulfinamide (Scheme #11 F, 0.82 g, 2.0 mmol) in tetrahydrofuran (20 mL) at 0°. The mixture was stirred at 0° C. for 1 h and then quenched by addition of saturated aqueous ammonium chloride. The reaction mixture was partitioned between water and ethyl acetate, the organic phase was dried over magnesium sulfate and evaporated. The residue was dissolved in methanol (20 mL) and was treated with hydrochloric acid (2M in diethyl ether, 2 mL) overnight. The solvent was evaporated and the residue was partitioned between saturated aqueous sodium bicarbonate and chloroform, the organic phase was dried over magnesium sulfate and evaporated. Purification by flash chromatography using chloroform:methanol (9:1) afforded 0.53 g (63% yield) of the title compound. 1H NMR (DMSO-d6) δ 7.90-7.74 (m, 1 H), 7.74-7.67 (m, 1 H), 7.59-7.42 (m, 3 H), 7.35-7.21 (m, 2 H), 7.12-7.00 (m, 2 H), 6.97-6.71 (m, 3 H), 3.74 (s, 3 H), 2.06 (s, 3 H); MS (ESI) m/z 425, 427 [M+1]+.
Reaction SMILES: O=[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:6]=1)[CH:3]=O.I.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:28][NH2:29])=[NH:27])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[N:28]=[N:29][CH:3]=[C:2]([C:5]3[CH:6]=[C:7]([N:11]4[CH2:15][CH2:14][CH2:13][C:12]4=[O:16])[CH:8]=[CH:9][CH:10]=3)[N:27]=2)=[CH:24][CH:25]=1
Reactant: O=CC(=O)c1cccc(N2CCCC2=O)c1
Reactant: COc1ccc(C(=N)NN)cc1
Agent: I
Product: COc1ccc(-c2nncc(-c3cccc(N4CCCC4=O)c3)n2)cc1

Procedure:
Oxo[3-(2-oxopyrrolidin-1-yl)phenyl]acetaldehyde was reacted with 4-methoxybenzenecarboximidic hydrazide hydriodide salt (0.72 g, 2.46 mmol) using the method described in Example 1 to give 1-{3-[3-(4-methoxyphenyl)-[1,2,4]triazin-5-yl]phenyl}pyrrolidin-2-one as a yellow solid (0.47 g): δH (400 MHz, d6-DMSO) 2.09-2.17 (2H, m), 2.57 (2H, t, J 8.0 Hz), 3.88 (3H, s), 3.99 (2H, t, J 7.0 Hz), 7.16-7.21 (2H, m), 7.64 (1H, t, J 8.0 Hz), 7.98-8.01 (1H, m), 8.18 (1H, d, J 8.2 Hz), 8.51-8.55 (2H, m), 8.66 (1H, t, J 1.8 Hz), 9.95 (1H, s); m/z (ES+) 347.
Reaction SMILES: C1(S([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[CH:21][C:20]=4[CH:28]=3)[CH2:12][CH2:11]2)(=O)=O)C=CC=CC=1.S(=O)(=O)(O)O.[OH-].[NH4+]>>[N:13]1([C:16]2[CH:17]=[CH:18][C:19]3[O:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[CH:21][C:20]=3[CH:28]=2)[CH2:12][CH2:11][NH:10][CH2:15][CH2:14]1
Reactant: COC(=O)c1cc2cc(N3CCN(S(=O)(=O)c4ccccc4)CC3)ccc2o1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)c1cc2cc(N3CCNCC3)ccc2o1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Methyl 5[4-(benzenesulfonyl)-1-piperazinyl]benzofuran-2-carboxylate (10 g) was added to sulfuric acid (25 g) at 25-30° C. and the mixture was heated to 98-102° C., followed by stirring for 15 minutes at the same temperature. The reaction mass was cooled to 25-30° C. and then poured into ice cold water (80 ml). The pH of the resulting aqueous layer was adjusted to 9-10 with ammonium hydroxide solution, followed by extracting with ethyl acetate (3×200 ml) and then distilling off the solvent under vacuum to produce 6.5 g of methyl 5-(1-piperazinyl)benzofuran-2-carboxylate (Yield: 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:38])([F:37])[C:13]([CH2:32][NH:33][CH2:34][CH2:35][CH3:36])([OH:31])[CH2:14][NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:33]([CH2:34][CH2:35][CH3:36])[CH2:32][C:13]([OH:31])([CH2:14][NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([F:37])([F:11])[F:38])=[O:6]
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: O=C(O)c1ccccc1Cl
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1Cl

Procedure:
Prepared similarly to Example 1 from 2-chlorobenzoic acid and 1,1,1-trifluoro-3-[(1-phenyl-1H-indazol-4-yl)amino]-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].CS(C)=O.[Na+].[CH3:16][S:17]([O-:19])=[O:18]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:17]([CH3:16])(=[O:19])=[O:18])[CH:5]=[O:6]
Reactant: CS(=O)[O-]
Reactant: O=Cc1ccc(F)c(F)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C=O)cc1F
Temperature: 90 °C

Procedure:
To a solution containing 0.5 g 3,4-difluorobenzaldehyde and 20 ml DMSO was added 0.71 g methanesulfinic acid sodium salt with stirring at 90° C. The solution was stirred 6 hours at 90° C. and then poured into water. Sodiumhydrogencarbonate was added and the product was extracted with ethyl acetate. The extract was evaporated to dryness in vacuo. The residue was triturated with 2-propanol, yield 0.93 g. 1H-NMR (DMSO-d6, 400 MHz): 3.52 (s, 3 H, CH3), 7.98-8.13 (m, 3 H, Ar), 10.22 (d, 1 H, CHO).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1>[Pd].C(O)C.C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cccc(Nc2ncc(C)cc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cccc(Nc2ncc(C)cc2N)c1
Reaction time: 8 h

Procedure:
Palladium on carbon (10%, 1.55 g, 1.456 mmol) was added to a Parr Hydrogenator bottle. The bottle was purged with nitrogen. Then, 5-methyl-3-nitro-N-(m-tolyl)pyridin-2-amine (15.5 g, 63.7 mmol) in 90 mL of ethanol and 90 mL of THF was added. The material was hydrogenated overnight on a Parr Hydrogenator. The mixture was filtered through Celite® to remove the palladium on carbon. The Celite® pad was washed with dichloromethane and evaporated to a solid (13.5 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:19][C:20]([NH2:22])=[O:21].[C:23](OCC)(=[O:29])[C:24](OCC)=[O:25].CC(C)([O-])C.[K+].Cl>CN(C)C=O.O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[C:19]1[C:20](=[O:21])[NH:22][C:24](=[O:25])[C:23]=1[OH:29]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC1(C2CCCC2)Cc2cc(CC(N)=O)c(Cl)c(Cl)c2C1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C2CCCC2)Cc2cc(C3=C(O)C(=O)NC3=O)c(Cl)c(Cl)c2C1=O

Procedure:
In a nitrogen atmosphere, (+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetamide (19.8 g., 0.0582 mole) and diethyl oxalate (9.14 g., 0.626 mole) are dissolved in dimethylformamide (100 ml.) and stirred in an ice bath. Potassium tert. butoxide (15.2 g, 0.136 mole) is added in two portions at a 10 minute interval. The reaction mixture is stirred at 25° C. for 18 hours, poured into water (600 ml) acidified with hydrochloric acid, extracted with ether, washed with water and brine and dried over MgSO4. Evaporation of the ether at reduced pressure gives (+)3-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione as the hemietherate in the form of a foam. Upon drying at reduced pressure, the analysis of the hemietherate is as follows:
Reaction SMILES: [CH2:1]([C:4]1([C:18]([O:20]C)=[O:19])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:2]=C.[OH-:22].[Na+]>CO>[OH:22][CH:2]1[CH2:1][C:4]2([N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[C:6]([CH3:10])([CH3:9])[O:7][CH2:8]2)[C:18](=[O:19])[O:20]1
Reactant: [OH-]
Reactant: C=CCC1(C(=O)OC)COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(C)(C)OCC12CC(O)OC2=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1.7 g of 3-tert-butyl 4-methyl 4-allyl-2,2-dimethyloxazolidine-3,4-dicarboxylate were dissolved in 20 ml of methanol and 8 ml of 1 N NaOH were added. The mixture was heated at 60° C. for 3 h, allowed to cool, and the methanol was removed in vacuo. The pH of the aqueous phase was adjusted to 2 with 1 N HCl, and it was extracted 3 times with 50 ml of dichloromethane each time. The combined organic phases were dried with MgSO4, and the solvent was removed in vacuo. The residue was taken up in 80 ml of dichloromethane and 10 ml of methanol. The solution was cooled to −78° C., and ozone was passed through until it assumed a pale blue color. Argon was then passed through until the blue color had completely disappeared. 3 ml of dimethyl sulfide were added, and the mixture was allowed to reach room temperature overnight. The solvents were then removed in vacuo. The crude product obtained in this way was employed directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[O:11]1[CH2:16][CH2:15][CH:14](OS(C)(=O)=O)[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CS(=O)(=O)OC1CCOCC1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1OC1CCOCC1
Yield: 21.3 %

Procedure:
In a manner similar to the method described in example 4a, 5-chlorosalicylaldehyde (6 g, 39 mmol) (Aldrich) was reacted with methanesulfonic acid tetrahydropyran-4-yl ester (10 g, 46 mmol) prepared in Example 32a and K2CO3 in N,N-dimethylformamide to give 5-chloro-2-(tetrahydro-pyran-4-yloxy)-benzaldehyde as a yellow solid (Yield 2 g, 64%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.O1CCCC1.[F:24][C:25]([F:34])([F:33])[CH:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[CH3:18][C@@:12]1([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH:29]4[CH2:30][CH2:31][CH:26]([C:25]([F:34])([F:33])[F:24])[CH2:27][CH2:28]4)[CH:3]=3)[CH:8]=2)[CH2:16][O:15][C:14](=[O:17])[NH:13]1
Reactant: OC1CCC(C(F)(F)F)CC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@]1(c2ccc3cc(OC4CCC(C(F)(F)F)CC4)ccc3c2)COC(=O)N1

Procedure:
(R)-4-(6-Hydroxynaphthalen-2-yl)-4-methyl-oxazolidin-2-one (0.1042 g, 0.0004284 mol) was dissolved in tetrahydrofuran (5.00 mL, 0.0616 mol) in a capped 40 mL vial. 4-Trifluoromethylcyclohexanol (0.101 g, 0.000600 mol) was added, followed by triphenylphosphine (0.180 g, 0.000685 mol) and the mixture was refluxed for 5 minutes. Diisopropyl azodicarboxylate (0.135 mL, 0.000685 mol) was then added and the mixture was heated at reflux overnight. TLC analysis showed that the reaction was complete. The mixture was concentrated to dryness under vacuum and purified by flash chromatography (0-20% EtOAc in methylene chloride).
Reaction SMILES: [S:1]1CC(O)S[CH2:3][CH:2]1O.[C:9]([CH2:11][C:12]([NH2:14])=[O:13])#[N:10].CO>O>[NH2:10][C:9]1[S:1][CH:2]=[CH:3][C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: OC1CSC(O)CS1
Reactant: N#CCC(N)=O
Solvent: O
Solvent: CO
Product: NC(=O)c1ccsc1N
Temperature: 37.5 °C
Yield: 143 %

Procedure:
1,4-Dithiane-2,5-diol (50 g, 328 mmol), and cyanoacetamide (55.2 g, 657 mmol) were added to a mixture of MeOH (150 mL), water (9 mL) and TEA (6.5 g, 50 mmol). The resulting mixture was heated at about 35-40° C. for 30 minutes while stirring, and then heated to about 50-60° C. for an additional 30 minutes with stirring. The reaction mixture was then cooled to RT and poured into a mixture of ice (70 g)/water (200 mL). A fine precipitate formed upon addition, which was filtered and dried overnight to give (66.7 g) of the title compound. MS (ES+): 143 (M+H)+.
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]2[N:23]4[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]4=[N:21][N:20]=2)[CH:15]=[CH:14]3)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:28][C:25]1[CH:26]=[CH:27][C:22]2[N:23]([C:19]([C:16]3[CH:15]=[CH:14][C:13]4[C:18](=[C:9]([O:8][C@H:7]5[CH2:6][CH2:5][NH:4][CH2:3][C@H:2]5[F:1])[CH:10]=[CH:11][CH:12]=4)[N:17]=3)=[N:20][N:21]=2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc3ccc(-c4nnc5ccc(F)cn45)nc23)[C@H](F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc2nnc(-c3ccc4cccc(O[C@H]5CCNC[C@H]5F)c4n3)n2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.1 %

Procedure:
(cis)-tert-butyl 3-fluoro-4-(2-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)piperidine-1-carboxylate (33 mg, 0.069 mmol) was dissolved in 2 mL DCM at ambient temperature. TFA (2 mL) was added and the mixture stirred at ambient temperature 1 hour. The reaction was evaporated under reduced pressure, and purified by preparative TLC eluting with 1:10 mixture of (0.5% NH4OH in MeOH):DCM to give the product (4.5 mg, 17% yield). MS APCI (+) m/z 382.1 (M+1) detected.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH:30]=[O:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][C:38]([Si:41]([CH3:55])([CH3:54])[O:42][CH2:43][C@@H:44]1[CH2:53][N:52]2[C@H:47]([CH2:48][O:49][CH2:50][CH2:51]2)[CH2:46][NH:45]1)([CH3:40])[CH3:39].[Cl-].[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:45]3[C@H:44]([CH2:43][O:42][Si:41]([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:54])[CH3:55])[CH2:53][N:52]4[C@H:47]([CH2:48][O:49][CH2:50][CH2:51]4)[CH2:46]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH:30]=[O:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1C=O
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCOC[C@@H]2CN1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H]3COCCN3C[C@H]2CO[Si](C)(C)C(C)(C)C)cc1-c1ccccc1C=O
Temperature: 90 °C
Yield: 18 %

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(2-formyl phenyl)-3-pyridinyl]-N,2-dimethylpropanamide (D59, 106 mg, 0.201 mmol), (7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)octahydropyrazino[2,1-c][1,4]oxazine (D51, 72 mg, 0.251 mmol) were dissolved in toluene (2 mL). Bis tritertbutylphosphine palladium (27 mg, 0.052 mmol), followed by hexadecyltrimethylammoium chloride (30 μL, 25% aq sol), and finally sodium hydroxide solution (0.25 mL, 50% aq sol) were added. The mixture was degassed for 5 minutes before heating at 90° C. for 2 hours. Reaction cooled to R.T., diluted with EtOAc, washed with sat NaHCO3 solution, dried (MgSO4). Filtered. Solvent evaporated. Residue purified eluting with 0-50% EtOAc/Pent. Solvent evaporated under reduced pressure to afford a pale yellow solid in 18% yield.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>C(O)(C)C>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([OH:16])[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: OC1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
5H-Dibenzo[a,d]cyclohepten-5-one (10 g) is dissolved in 80 ml of isopropyl alcohol and sodium borohydride (1.8 g) is added at once. The mixture is stirred at room temperature for two hr. 5 ml of water are added to quench the reaction and the solvent is evaporated. The residue is taken up in diethyl ether and washed with water, dried over MgSO4 and evaporated. (9.8 g 98% yield) of 5H-dibenzo-[a,d]-cyclohepten-5-ol is obtained.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]=[C:17]([CH:23]=[CH:24][C:25]=3[CH3:26])[C:18]([O:20]CC)=[O:19])=[CH:12][CH:13]=2)[CH:8]=[N:7][N:6]=1)([CH3:3])[CH3:2].[OH-].[K+]>C(O)C.O>[CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]=[C:17]([CH:23]=[CH:24][C:25]=3[CH3:26])[C:18]([OH:20])=[O:19])=[CH:12][CH:13]=2)[CH:8]=[N:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(C)c(-c2ccc3c(NC(C)C)nncc3c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-c1ccc2c(NC(C)C)nncc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of ethyl 3-(1-(isopropylamino)phthalazin-6-yl)-4-methylbenzoate (4 g, 11 mmol) (obtained by method D below) in ethanol/water (4:1) (50 mL) at RT was treated with potassium hydroxide (1 g, 23 mmol). The mixture was warmed to reflux and stirred for 2 h (M+1=322). The mixture was cooled to RT, then concentrated to remove the organic solvent. The mixture was diluted with 1 N aq. sodium hydroxide (20 mL), extracted with ether (2×50 mL). The combined ether extract was washed with 1N aq. sodium hydroxide (20 mL). The combined water layer was neutralized to pH 7 with conc. HCl. The white precipitate was collected and washed with water (20 mL), azotropically dried with toluene and placed under high vacuum to give 3-(1-(isopropylamino)phthalazin-6-yl)-4-methylbenzoic acid as pale yellow solid.