Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH:16][C:17](=[N:20][C:21]([O:23][CH3:24])=[O:22])[S:18][CH3:19])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[NH:1]=[C:2]1[C:15]([NH:16][C:17](=[N:20][C:21]([O:23][CH3:24])=[O:22])[S:18][CH3:19])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH:3]1[CH2:31][C:30]1[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)N=C(Nc1ccc(C(=O)c2ccccc2)cc1N)SC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)N=C(NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccc(OC)cc2)C1=N)SC
Reaction time: 3 h

Procedure:
To a mixture of 3-amino-4-(3-carbomethoxy-S-methylisothioureido)benzophenone (3.43 g.; 0.01 mol) in benzene (100 ml.) there is added p-methoxybenzaldehyde (1.36 g.; 0.01 mol) and p-toluenesulfonic acid monohydrate (0.1 g.). The mixture is refluxed and stirred for 3 hours. The water reaction is removed by a Dean-Stark distillation receiver. The mixture is poured into an excess of hexane and the suspension formed is filtered. The filter cake is dried to afford 3-imino-(4-methoxyphenyl)methyl-4-(3-carbomethoxy-S-methylisothioureido)benzophenone.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].[NH2:14][C:15]1[CH:37]=[CH:36][C:18]([C:19]([N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[CH2:24][C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]2=3)=[O:20])=[CH:17][CH:16]=1>>[CH:32]1[C:23]2[CH2:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[CH2:27][N:21]([C:19]([C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:7]([C:6]4[S:5][C:4]5[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=5[C:2]=4[Cl:1])=[O:8])=[CH:37][CH:36]=3)=[O:20])[C:22]=2[CH:35]=[CH:34][CH:33]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1sc2ccccc2c1Cl

Procedure:
As described for Example 9, 3-chlorobenzo[b]thiophene-2-carbonyl chloride is reacted with 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine to give the product. Recrystallization from dichloromethane-hexane gives crystals, m.p. 252°-254° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2].S(=O)(=O)(O)O.[I:24](O)(=O)=O.II>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([I:24])=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2]
Reactant: [O-][I+2]([O-])O
Reactant: CCOC(=O)c1ncc2[nH]c3ccccc3c2n1
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ncc2[nH]c3ccc(I)cc3c2n1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 400.7 %

Procedure:
2 g of 5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester (Example 3) in 20 ml of glacial acetic acid is combined with 0.5 ml of water, 0.12 ml of concentrated sulfuric acid, 336 mg of iodic acid, and 878 mg of iodine and agitated for 2.5 hours at 90° C. After concentrating the reaction mixture, the latter is combined with 50 ml of water, gently made alkaline with ammonia, and suctioned off, thus obtaining 2.81 g of 8-iodo-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester, mp 264°-266° C. under decomposition.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O)[C:6]([O:8][CH3:9])=[O:7])#[N:2].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:12]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)#[N:2]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccccc2)c(C#N)c1
Temperature: 150 °C
Yield: 81.2 %

Procedure:
The following reaction was split into two batches with half the amounts: methyl 3-cyano-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate (D19) (1.5 g, 4.85 mmol), phenylboronic acid (1.183 g, 9.70 mmol), potassium carbonate (2.011 g, 14.55 mmol) and palladium tetrakistriphenylphosphine(0) (0.561 g, 0.485 mmol) were dissolved in DMF (24 ml) and the mixture heated in the microwave for 30 min at 150° C. The two reactions were combined and diluted with ethyl acetate (50 mL) and the mixture filtered through kieselguhr to remove palladium residues. The filtrate was concentrated in vacuo to reduce the amount of DMF and then the residue partitioned between saturated aqueous sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The organic phase was washed with further sodium bicarbonate (50 mL) and then water (50 mL) before it was dried (MgSO4), filtered and the solvent removed in vacuo. The brown solid was purified by silica chromatography, eluting with 0-25% EtOAc in iso-hexane over 35 minutes to give the title compound as a white solid (935 mg, 3.94 mmol). δH (d6-DMSO, 400 MHz): 8.42 (1H, d), 8.29 (1H, dd), 7.81 (1H, d), 7.65 (2H, m), 7.60-7.50 (3H, m), 3.92 (3H, s).
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][OH:4].[CH2:7]([OH:12])[CH:8]([OH:11])[CH2:9][OH:10].[CH2:13]([OH:18])[CH:14]([OH:17])[CH2:15][OH:16].[CH2:19]([OH:24])[CH:20]([OH:23])[CH2:21][OH:22].[C:25]([OH:32])(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].ON1[C:38](=O)[CH2:37][CH2:36][C:35]1=O.CC(N=C=NC(C)C)C>CS(C)=O>[CH2:27]([CH:26]([CH2:35][CH2:36][CH2:37][CH3:38])[C:25]([OH:32])=[O:31])[CH2:28][CH2:29][CH2:30][CH2:1][CH3:2].[OH:12][CH2:7][CH:8]([CH2:9][OH:10])[OH:11].[OH:18][CH2:13][CH:14]([CH2:15][OH:16])[OH:17].[OH:24][CH2:19][CH:20]([CH2:21][OH:22])[OH:23].[OH:6][CH2:1][CH:2]([CH2:3][OH:4])[OH:5]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: OCC(O)CO
Solvent: CS(C)=O
Product: CCCCCCC(CCCC)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 250 mL vessel, tetraglycerol (5.0 g, 15.91 mmol) was added and dissolved into anhydrous DMSO (50 mL). Hexanoic acid (11.96 mL, 95.44 mmol) was also dissolved into the reaction mixture which was stirred magnetically at room temperature for one hour to fully dissolve the reagents. N,N-dimethylaminopyridine (0.194 g, 1.59 mmol) and N-hydroxysuccinimide (0.183 g, 1.59 mmol) were both dissolved in the solution. When the catalysts were fully dissolved, N,N-diisopropylcarbodiimide (15.0 mL, 97.03 mmol) was pipetted into the vessel and was sealed to keep the reaction dry. The reaction proceeded overnight at 55° C. The solution was dialyzed in SpectraPor7 MWCO 1000 dialysis tubing to remove the DMSO and unreacted monomer. The polymer crashed out in water into a thick white liquid. After 3 days of dialysis, the solution was placed into a separatory funnel and the organic portion was dissolved into chloroform. The water layer was removed and the organic layer was dried with sodium sulfate. The solvent was stripped via rotoevaporation to leave a clear thick liquid product. NMR analysis supported full conversion of hydroxyl groups to the hexanoic esters.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[C:10]([CH3:12])[CH:9]=[CH:8][CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.NC1C=CNN=1.[NH2:32][C:33]1[CH:37]=[C:36]([C:38]2[O:39][CH:40]=[CH:41][CH:42]=2)[NH:35][N:34]=1>O1CCCC1>[O:39]1[CH:40]=[CH:41][CH:42]=[C:38]1[C:36]1[NH:35][N:34]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[CH3:12])[NH:5][C:4]2=[O:13])[CH:37]=1
Reactant: Cc1cccc2c1/C(=C/O)C(=O)N2
Reactant: Nc1cc(-c2ccco2)[nH]n1
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: Cc1cccc2c1C(=CNc1cc(-c3ccco3)[nH]n1)C(=O)N2

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-4-methyl-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and substituting 3-amino-5-(2-furyl)-pyrazole for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-4-methyl-1,3-dihydro-indol-2-one (0.110 gms.) is reacted with 0.2065 gms. of 3-amino-5-(2-furyl)-pyrazole by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: O.[OH-].[Li+].[O:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]3[CH2:18][C@H:17]([N:19]([C:29](=[O:35])[CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=4)[CH2:16][C@H:15]3[C:36]([O:38]C)=[O:37])=[CH:12][C:7]=2[O:6][CH2:5]1.CO>O>[O:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]3[CH2:18][C@H:17]([N:19]([C:29](=[O:35])[CH2:30][C:31]([CH3:34])([CH3:32])[CH3:33])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=4)[CH2:16][C@H:15]3[C:36]([OH:38])=[O:37])=[CH:12][C:7]=2[O:6][CH2:5]1
Reactant: COC(=O)[C@@H]1C[C@@H](N(Cc2cccc(OC)c2)C(=O)CC(C)(C)C)CN1Cc1ccc2c(c1)OCO2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(CN(C(=O)CC(C)(C)C)[C@@H]2C[C@@H](C(=O)O)N(Cc3ccc4c(c3)OCO4)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
Lithium hydroxide monohydrate (17 mg, 0.405 mmol) was added to a solution of methyl (2S,4R)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]tetrahydro-1H-2-pyrrolecarboxylate (10) (100 mg, 0.20 mmol) in 66% v/v methanol in water (1.0 mL). The mixture was stirred overnight at room temperature, then the solvent was removed under reduced pressure and the residue partitioned between dichloromethane (1.0 mL) and water (1.0 ml). The aqueous phase was acidified with 1.0 M aqueous citric acid and the two layers were vigorously stirred for 10 min at room temperature. The layers were separated and the aqueous layer was back-extracted with dichloromethane. The combined dichloromethane extracts were dried (MgSO4) and evaporated under reduced pressure to give the title acid (11) (70 mg, 72%) as an off-white solid:
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])SCCCS2)[CH2:3][CH2:2]1.BrN1C(=[O:22])CCC1=O>CC#N.O>[CH:1]1([CH2:4][C:5](=[O:22])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1(CC2CC2)SCCCS1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(=O)CC1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A solution of ethyl 2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate (19.6 g, 79.67 mmol) in CH3CN (20 mL) was slowly added, over 30 minutes, to a well-stirred suspension of NBS (N-bromosuccinimide) in CH3CN (210 mL) and water (55 mL). After the mixture was stirred for 1 h, the resulting red solution was poured into an ice-cold CH2Cl2-Hexane solution (1:1 500 mL). The resulting mixture was washed with saturated aqueous NaHSO3 and water. The colorless organic phase was carefully washed with saturated aqueous K2CO3 and water. The organic phase was dried over MgSO4, then evaporated to give 6.88 g (55%) of ethyl 3-cyclopropyl-2-oxopropanoate as a yellow oil. 1H NMR (CDCl3): δ 4.29 (2H, q, J=8 Hz), 2.71 (2H, d, J=9 Hz), 1.35 (3H, t, J=8 Hz), 1.05-0.98 (1H, m), 0.59-0.54 (2H, m), 0.17-0.14 (2H, m).
Reaction SMILES: CN(C=O)C.[CH3:6][C@H:7]1[O:12][C@@H:11]([CH3:13])[CH2:10][NH:9][CH2:8]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:21]1[CH:26]=[CH:25][C:24]2=[N:27][C:28]([C:30]3[CH:31]=[CH:32][C:33]([C:43]([F:46])([F:45])[F:44])=[C:34]([NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[CH:35]=3)=[CH:29][N:23]2[N:22]=1>O>[CH3:13][C@H:11]1[O:12][C@@H:7]([CH3:6])[CH2:8][N:9]([C:21]2[CH:26]=[CH:25][C:24]3=[N:27][C:28]([C:30]4[CH:31]=[CH:32][C:33]([C:43]([F:44])([F:45])[F:46])=[C:34]([NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[CH:35]=4)=[CH:29][N:23]3[N:22]=2)[CH2:10]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: CC(C)(C)C(=O)Nc1cc(-c2cn3nc(Cl)ccc3n2)ccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2ccc3nc(-c4ccc(C(F)(F)F)c(NC(=O)C(C)(C)C)c4)cn3n2)C[C@H](C)O1
Temperature: 120 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
An 8 mL vial is charged with DMF (1 mL), cis-2,6-dimethylmorpholine (0.034 g), Cs2CO3 (0.130 g), and N-[5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-(trifluoromethyl)phenyl]-2,2-dimethyl-propanamide (0.0396 g, 0.1 mmol). The mixture is stirred at 120° C. for 16 hr, then diluted with H2O (5 mL) and extracted with Et2O (3 mL×2). Organics are dried and concentrated onto celite, purified by silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (0.027 g, 57% yield). LCMS m/z=476.6 [M+H]+, tR=2.77 min. (compound same as Example 250)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C@H:6]1[CH2:28][C@@:27]2([CH3:29])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:26]2[C:25](=[O:30])[CH2:24][C@@:23]2([CH3:31])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17]2(OCC[O:19]2)[CH3:18])[CH2:8][C@@H:7]1[OH:32].O.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[OH:32][C@@H:7]1[C@@H:6]([O:5][CH2:4][CH2:3][CH2:2][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:28][C@@:27]2([CH3:29])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:26]2[C:25](=[O:30])[CH2:24][C@@:23]2([CH3:31])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17](=[O:19])[CH3:18])[CH2:8]1
Reactant: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](OCCCCl)C[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1
Reactant: C1COCCN1
Solvent: O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCCN5CCOCC5)C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
2β-(3'-Chloropropoxy)-20,20-ethylenedioxy-3α-hydroxy-5α-pregnan-11-one (500 mg.) was dissolved in morpholine (5 ml.) and the solution heated on a steambath for 8 hours. The solution was poured into water and the precipitate extracted into ether (70 ml.). The ethereal solution was washed with water, dried over anhydrous sodium sulphate and evaporated to a white foam (480 mg.) which was dissolved in 35% aqueous acetic acid and the solution heated on a steam-bath for 3 hours. The solution was cooled in ice and an ice-cooled solution of 10N-potassium hydroxide added to the stirred solution in the presence of ether (100 ml.) until the aqueous layer was basic. The aqueous layer was extracted with ether (50 ml.) and the combined ether extracts washed with water, dried over anhydrous sodium sulphate and evaporated to a white foam (390 mg.) which was purified by preparative TLC in acetone to give the title compound (250 mg.) as a white foam, [α](c D + 65.0° (C 1.02).
Reaction SMILES: C1(P(=[CH:20][C:21]#[N:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=2)=[CH:28][C:27]=1[C:41]([F:44])([F:43])[F:42]>C(Cl)Cl.O>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:40]=[CH:39][C:36](/[CH:37]=[CH:20]/[C:21]#[N:22])=[CH:35][CH:34]=2)=[CH:28][C:27]=1[C:41]([F:44])([F:43])[F:42]
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: N#C/C=C/c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
To the mixture of (triphenylphosphanylidene)acetonitrile (19.8 g, 51.9 mmol) and NaOH (2.59 g, 64.9 mmol) in DCM (30 mL) and water (60 mL) was added 4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}benzaldehyde (13.0 g, 43.2 mmol)) at 0° C. It was stirred at rt for 4 h. Purification via a flash chromatography afforded the title compound as a white solid (12 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][C:3]=1[N:14]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[N:15]1.S(=O)(=O)(O)O.[N+:26]([O-])([OH:28])=[O:27]>O>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][C:3]=1[N:14]1[C:18]([CH3:19])=[C:17]([N+:26]([O-:28])=[O:27])[C:16]([CH3:20])=[N:15]1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C)n(-c2cc(OS(C)(=O)=O)c(Cl)cc2F)n1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1nn(-c2cc(OS(C)(=O)=O)c(Cl)cc2F)c(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To 1-(2-fluoro-4-chloro-5-methylsulfonyloxyphenyl)-3,5-dimethylpyrazole (31.9 g) was added 95% sulfuric acid (35 ml) and then added dropwise an acid mixture of 95% sulfuric acid (7.5 ml) and 61% nitric acid (10.3 g) under cooling with iced water, and the reaction mixture was stirred at room temperature for further one hour, and was then poured into iced water. The reaction mixture was extracted with toluene and the resulting toluene layer was washed with 1N aqueous sodium hydroxide solution and then with water and dried over anhydrous sodium sulfate. Removal of the solvent from.the extract in toluene by distillation in vacuo gave the titled compound (33.1 g) as a yellowish brown crystalline solid. Recrystallization of the solid from a mixture of cyclohexane/acetone yielded a pale yellow crystalline solid. m.p. 150.5°-152.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)([C:14]([O:16]C)=O)[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CCOC(C)=O>[O:16]=[C:14]1[C@:12]2([CH:11]=[CH:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13]2)[CH2:18][CH2:19][O:20]1
Reactant: COC(=O)[C@@]1(CCO[Si](C)(C)C(C)(C)C)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@]2(CCOC2=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of Step D (1149 g, 2.875 mol) and THF (5.75 L) was added TBAF (1M in THF, 2.875 L) over ˜1 h. The reaction was stirred for 1 h at rt, and diluted with EtOAc. The organic layer was washed with brine, diluted with heptanes and the organic layer was further washed with water and brine. The organic layer was evaporated, the crystallized product was filtered, and washed with heptanes to provide the product of Step E as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) d=5.86-5.98 (m, 3H), 5.67 (d, J=5.4 Hz, 3H), 5.03-5.20 (m, 2H), 4.76-4.87 (m, 3H), 4.28 (t, J=7.0 Hz, 5H), 2.08-2.31 (m, 8H), 1.99 (d, J=2.4 Hz, 3H), 1.34 (s, 25H).
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:20])([CH:17]([CH3:19])[CH3:18])[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5].C1C[O:24][CH2:23][CH2:22]1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:23]([NH:2][C:3]([CH3:20])([CH:17]([CH3:18])[CH3:19])[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5])(=[O:24])[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)NC(=O)C(C)(N)C(C)C)cc1
Reactant: C1CCOC1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NC(C)(C(=O)NS(=O)(=O)c1ccc(C)cc1)C(C)C

Procedure:
2-Amino2,3-dimethyl-N-(p-tolylsulfonyl) butyramide hydrochloride (45 g~0.4 mols) is completely dissolved in 160 mL of pyridine and 500 mL of THF is added. Acetic anhydride (45 mL) is then poured into the solution and the reaction mixture is heated at reflux for one hour. The solvents are removed under reduced pressure, and the oily residue is crystallized from EtOH/water affording 33.09 g of the title product having m.p. 198°-199° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]#[CH:6])[CH3:3].C(NC(C)C)(C)C.[C:14]([C:18]1[CH:23]=[CH:22][C:21](/[C:24](/[C:41]2[CH:46]=[CH:45][C:44](I)=[CH:43][CH:42]=2)=[CH:25]/[CH2:26][O:27][C:28]2[CH:39]=[CH:38][C:31]([O:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[C:30]([CH3:40])[CH:29]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:14]([C:18]1[CH:19]=[CH:20][C:21](/[C:24](/[C:41]2[CH:46]=[CH:45][C:44]([C:6]#[C:5][CH2:4][N:2]([CH3:3])[CH3:1])=[CH:43][CH:42]=2)=[CH:25]/[CH2:26][O:27][C:28]2[CH:39]=[CH:38][C:31]([O:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[C:30]([CH3:40])[CH:29]=2)=[CH:22][CH:23]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(C)(C)C)cc2)cc1C
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN(C)C)cc2)c2ccc(C(C)(C)C)cc2)cc1C
Temperature: 25 °C

Procedure:
1-(N,N-Dimethylamino)prop-2-yne (0.131 mL, 1.23 mmol) and diisopropylamine (0.40 mL, 2.85 mmol) were added to a solution of the methyl (Z)-[4-[3-(4-tert-butylphenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (350 mg, 0.614 mmol; prepared as described in example 30) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (10 mg, 0.053 mmol) and bis(triphenylphosphine)palladium(II) dichloride (22 mg, 0.031 mmol) were added. The reaction mixture was stirred at ambient temperature over night, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 98:2) yielding methyl (Z)-[4-[3-(4-tert-butylphenyl)-3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[C:9]1(=O)[O:14][CH:12]([CH3:13])[CH2:11][CH2:10]1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]2[C:3]=1[CH:12]([CH3:13])[CH2:11][CH2:10][C:9]2=[O:14]
Reactant: CC1CCC(=O)O1
Reactant: Fc1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC1CCC(=O)c2c(F)ccc(F)c21
Temperature: 110 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
1,4-Difluorobenzene (22 ml, 210 mmol) was mixed with gamma-valerolactone (4 ml, 42 mmol) and AlCl3 (28 g, 210 mmol) was added by portions to the stirred reaction mixture. The reaction mixture was then refluxed at stirring for 16 h (oil bath 110° C.). The reaction mixture was cooled down (ice/brine bath) and ice/conc. HCl was added and stirred until homogeneous mixture was obtained. The reaction mixture was then extracted into methylene chloride, washed with water (4×10 ml) and sodium bicarbonate solution (3×100 ml). The organic extract was dried over Na2SO4. Concentration by rotary evaporation gave 6.7 g of product as yellow powder. Yield 81%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.Br[CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([N:6]([CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: CNc1ccc(Cl)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C(C(=O)OCC)N(C)c1ccc(Cl)cc1
Yield: 32.8 %

Procedure:
p-Chloro-N-methylaniline (10.1 g), diethyl bromomalonate (8.5 g) and dry benzene (60 ml) were mixed, and heated under reflux for 7 hours with stirring. The reaction mixture was washed, dried and concentrated by the same procedure as in Example 2, (1). The residue was chromatographed on a silica gel column using benzene/hexane (1:1) as an eluent to give 3.5 g (yield 33%) of diethyl p-chloro-N-methylanilinomalonate having the following NMR data.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([N:23]2[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[C:24]2=[O:31])[CH:19]=[CH:20][C:21]=1[F:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:28]([CH:25]1[CH2:26][CH2:27][N:23]([C:18]2[CH:19]=[CH:20][C:21]([F:22])=[C:16]([F:15])[CH:17]=2)[C:24]1=[O:31])=[O:29]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)C1CCN(c2ccc(F)c(F)c2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2ccc(F)c(F)c2)C1=O
Yield: 25.2 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(3,4-difluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.108 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) to give 0.0446 g (25%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(3,4-difluorophenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.