Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:18]=3)=[CH:15][C:14]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([S:50]([CH3:53])(=[O:52])=[O:51])=[CH:46][CH:45]=3)=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][C:14]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([S:50]([CH3:53])(=[O:51])=[O:52])=[CH:46][CH:45]=3)=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cc4ccc(S(C)(=O)=O)cc4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(Cc3ccc(S(C)(=O)=O)cc3)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 75 °C
Reaction time: 8 h
Yield: 23.7 %

Procedure:
4-(2-(5-Fluoro-6-methoxypyridin-3-ylamino)-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (384.7 mg, 0.5228 mmol) was dissolved in trifluoroacetic acid (Aldrich redistilled 99+%, 5.0 mL, 65 mmol) and the reaction flask was fitted with a reflux condenser and placed in a preheated oil bath (75° C.) and stirred overnight. Then, the reaction was cooled to room temperature, concentrated, and treated with saturated sodium bicarbonate and 5N NaOH and then with 5N HCl to adjust the pH to 6. Then, DCM was added and the layers were separated. The aqueous phase was filtered, and the collected solid was combined with the organic phase. The aqueous phase was extracted with DCM, and these organic extracts were combined with the organic phase, concentrated, and purified on a silica gel column (30:1 DCM/2N ammonia in MeOH to 10:1 DCM/2N ammonia in MeOH). The solvent polarity was increased after most of the product had eluted. The fractions with product were collected, concentrated, treated with MeOH, and filtered. The solid was washed with MeOH, collected, and dried under high vacuum. The material was <95% pure by HPLC, so the solid was washed with EtOAc, filtered, collected, and dried under high vacuum in a water bath (40° C.) and then at room temperature overnight to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (61.3 mg, 24% yield) as a yellow powder. 1H NMR (d6-DMSO, 400 MHz) δ 11.89 (s, 1H), 8.65 (d, J=2.15 Hz, 1H), 8.40 (d, J=2.15 Hz, 1H), 8.38-8.30 (m, 2H), 7.86 (d, J=8.22 Hz, 2H), 7.90-7.84 (m, 1H), 7.74 (br s, 1H), 7.53 (d, J=8.22 Hz, 2H), 4.09 (s, 2H), 3.93 (s, 3H), 3.17 (s, 3H), 2.41 (s, 3H). m/z (ESI, +ve ion) 496 (M+H)+.
Reaction SMILES: C([C:3]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:5]=[CH:6][N:7](C)[CH3:8])#N.[ClH:15]>ClCCCl>[CH3:13][N:12]([CH3:14])[C:10]([C:3]1[C:8]([Cl:15])=[N:7][CH:6]=[CH:5][CH:4]=1)=[O:11]
Reactant: Cl
Reactant: CN(C)C=CC=C(C#N)C(=O)N(C)C
Solvent: ClCCCl
Product: CN(C)C(=O)c1cccnc1Cl
Temperature: 50 °C
Reaction time: 6 h
Yield: 72 %

Procedure:
The 1-cyano-1-dimethylaminocarbonyl-4-dimethylamino-1,3-butadiene (14.5 g, 0.075 mol) obtained in (a) above was dissolved in 1,2-dichloroethane (150 ml) and the resulting solution heated to 50° C. The solution was then stirred whilst hydrogen chloride gas was introduced. After a few minutes, a thick mass of crystals formed in the solution which later dispersed to leave a deep red solution. After about 6 hours, no more starting material could be detected. Nitrogen was then introduced to blow the excess hydrogen chloride gas out of the solution and the solution was then extracted with water (4×100 ml). The organic phase was then dried over sodium sulphate and reduced in a vacuum. The residue was then stirred in petroleum ether, filtered off under suction and dried to give 10 g 2-chloropyridine-3-carboxylic acid N,N-dimethylamide as pale yellowish crystals, m.pt. 70°-71° C. Yield: 72% of the theoretical.
Reaction SMILES: C[Mg]Br.[CH3:4][C:5]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][N:32]=[C:31](C(OCC)=O)[CH:30]=2)=[CH:25][CH:24]=1)([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:11][N:10]=1)[CH:6]([CH3:8])[CH3:7]>C1(C)C=CC=CC=1.C1COCC1.C1COCC1>[CH3:4][C:5]([C:23]1[CH:24]=[CH:25][C:26]([C:29]2[O:33][N:32]=[C:31]([C:12]([OH:15])([CH3:13])[CH3:11])[CH:30]=2)=[CH:27][CH:28]=1)([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:11][N:10]=1)[CH:6]([CH3:7])[CH3:8]
Reactant: CCOC(=O)c1cc(-c2ccc(C(C)(c3ccc(OCc4ccccn4)cn3)C(C)C)cc2)on1
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)C(C)(c1ccc(-c2cc(C(C)(C)O)no2)cc1)c1ccc(OCc2ccccn2)cn1
Reaction time: 1 h

Procedure:
Methyl magnesium bromide (334 μL of a 1.4M solution in toluene:THF (75:25), 0.468 mmol) was added to a stirred solution of 1c (55.0 mg, 0.117 mmol) in THF (1.00 mL) at 0° C. After approximately 1 h, the reaction was quenched with water, and the resulting mixture was purified directly by flash chromatography on silica gel (gradient elution; 0%-100% EtOAc/hexanes as eluent) to afford the title compound 2a. m/z (ES) 457 (MH)+. 1HNMR (500 MHz, CDCl3): δ 8.61 (d, 1H, J=4.6 Hz), 7.67 (m, 1H), 7.67 (d, 2H, J=8.5 Hz), 7.58 (d, 1H, J=8.0 Hz), 7.36 (d, 2H, J=8.5 Hz), 7.25 (m, 1H), 7.19 (d, 2H, J=8.3 Hz), 6.92 (d, 2H, J=8.9 Hz), 5.22 (s, 2H), 2.72 (m, 1H), 1.68 (s, 6H), 1.63 (s, 3H), 0.89 (d, 3H, J=6.7 Hz), 0.86 (d, 3H, J=6.7 Hz).
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([O:18]CC)=[O:17])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].[Li+].[OH-].CO.Cl>O>[O:1]=[C:2]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([OH:18])=[O:17])[C:3](=[O:9])[C:4]([CH3:7])([CH3:8])[CH2:5][CH3:6]
Reactant: CCOC(=O)C1CCCCN1C(=O)C(=O)C(C)(C)CC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C)(C)C(=O)C(=O)N1CCCCC1C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylate (0.69 g; 2.43 mmol), 1 N LiOH (5 mL), and methanol (20 mL) was stirred at 0° C. for 30 min and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 50 mL of methylene chloride. The organic extract was washed with brine and concentrated to deliver 0.61 g (98%) of snow-white solid which did not require further purification.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7](Cl)=[O:8])(=[O:3])[CH3:2].[F:10][C:11]([F:34])([F:33])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:22][CH:21]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[NH:20][N:19]=2)=[CH:14][CH:13]=1.C(OCC)C>C1(C)C=CC=CC=1>[C:1]([S:4][CH2:5][CH2:6][C:7]([N:20]1[N:19]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:11]([F:34])([F:10])[F:33])=[CH:13][CH:14]=2)[S:22][CH:21]1[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCCC(=O)Cl
Reactant: O=C(OCc1ccccc1)C1NN=C(c2ccc(C(F)(F)F)cc2)S1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(=O)SCCC(=O)N1N=C(c2ccc(C(F)(F)F)cc2)SC1C(=O)OCc1ccccc1

Procedure:
3-Acetylthiopropanoyl chloride (0.36 g), poly (4-vinyl pyridine) (0.8 g) and the product from step b) (0.8 g) were stirred together in dry toluene (30 ml) under an atmosphere of nitrogen for 20 hours. Diethyl ether was added and the solid was filtered off and washed with diethyl ether. The filtrate was evaporated under reduced pressure and the resulting product was crystallised from ethanol to yield the sub-title product (0.9 g) as a white solid. mp 120°-121°.
Reaction SMILES: [CH:1]1([CH:6]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]([C:10]([CH3:12])=[O:11])=[CH2:9]>>[CH2:2]1[C:1]2([CH2:6][CH2:12][C:10](=[O:11])[CH:8]=[CH:9]2)[CH2:5][CH2:4][CH2:3]1
Reactant: C=CC(C)=O
Reactant: O=CC1CCCC1
Product: O=C1C=CC2(CCCC2)CC1
Yield: 54 %

Procedure:
Piperidine enamine was prepared by a method analogous to that described in Organic Syntheses, Collective Volume 7, p 473, using 221.84 g of cyclopentane carbaldehyde instead of cyclooctane carbaldehyde. Through Michael addition of piperidine enamine to methyl vinyl ketone, cyclization by aldol condensation, dehydration, hydrolysis, and vacuum distillation for purification, there was obtained 173.4 g (yield 54%) of spiro[4.5]dec-6-en-8-one.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:13](N(CC)CC)C.CO>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.3 %

Procedure:
To a mixture of indole-5-carboxylic acid (3.0 g) and triethylamine (1.9 g) in dry THF (100 mL) was added 1,1-carbonyldiimidazole (3.08 g). The mixture was stirred for 30 minutes at room temperature, at which time methanol (25 mL) was added. The mixture was stirred at room temperature for 1 h, partitioned between water and ethyl acetate. The layers were separated and the organic layer washed twice with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography on silica gel (200 mL) using CH2Cl2 as eluent to give 0.794 g of the title compound: 1H NMR (CDCl3) δ 3.93, 6.66, 7.28, 7.41, 7.91, 8.34, 8.42.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].Br[CH2:20][CH:21]1[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH:21]1([CH2:20][C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6])[CH2:23][CH2:22]1
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: BrCC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CC1CC1)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.4 g of bromomethylcyclopropane were dissolved in 10 ml of dimethyl sulfoxide, 1.4 g of potassium carbonate was added, and the mixture was stirred at room temperature for 2 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.35 g of 2-cyclopropylmethyl-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (72)).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][OH:10].[OH-].[K+]>CN(C=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:10][CH3:9])=[N:3][CH:4]=1
Reactant: CO
Reactant: Brc1ccc(Br)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc(Br)cn1
Temperature: 100 °C

Procedure:
To a solution of 2,5-dibromopyridine (1.4 g, 5.9 mmol) in DMF (10 mL) was added MeOH (4 mL), and 8N aqueous KOH (1 mL). The solution was heated to 100° C. for 2 h, then cooled and partitioned between Et2O and H2O. The organic layer was washed with brine, dried over MgSO4 and concentrated to provide 840 mg of the title compound, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[C:19]([C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[S:30])[CH:25]=[CH:26][CH:27]=1)(=[O:21])[CH3:20]>>[C:19]([C:22]1[CH:23]=[C:24]([NH:28][C:29](=[S:30])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:25]=[CH:26][CH:27]=1)(=[O:21])[CH3:20]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: CC(=O)c1cccc(N=C=S)c1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cccc(C(C)=O)c1
Yield: 67.6 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.971 g, 4.00 mmol) and 3-acetylphenyl isothiocyanate (0.709 g, 4.00 mmol) to afford the product (1.135 g); m.p. 176-177° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8].[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:2]1[CH:3]=[C:4]([O:9][CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC1COc1cnc(Cl)c(-c2cccs2)c1
Yield: 18.6 %

Procedure:
A mixture of 5-bromo-6-chloro-3-(1-BOC-2(R)-pyrrolidinylmethoxy)pyridine from Example 69a (310 mg, 0.87 mmol), 2-thienylboronic acid (167 mg, 1.3 mmol), 2M Na2CO3 (3 mL) and Pd(0) (32 mg) were mixed together in toluene (6 mL), and the mixture was heated at reflux for 4 hours. The mixture was cooled and extracted with chloroform. The CHCl3 was removed under reduced pressure, and the residue was chromatographed on a silica gel column, eluting with hexane/ethyl acetate 1:1 to afford the title compound (64 mg, 20% yield). MS (DCI/NH3) m/z 287 (M+H)+. 1 H NMR (CDCl3, 300 MHz) δ: 1.47 (s, 9H), 1.84-2.11 (m, 3H), 3.31-3.48 (m, 2H), 3.82-4.30 (m, 3H), 7.12 (dd, J=4.5, 6, 1H), 7.34-7.42 (m, 3H), 7.46-7.57 (m, 1H), 8.23 (d, J=3, 1H).
Reaction SMILES: [OH:1][C:2]1[C:7](C(C)(C)C)=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]2=[N:14]1.CC(C1C=C(N2N=C3C(C=CC([Cl:42])=C3)=N2)C(O)=C(C(C)(C)C)C=1)(C)C>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N:14]=[C:15]2[CH:21]=[C:20]([Cl:22])[C:19]([Cl:42])=[CH:18][C:16]2=[N:17]1
Reactant: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Reactant: Cc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Product: Cc1ccc(O)c(-n2nc3cc(Cl)c(Cl)cc3n2)c1

Procedure:
2-(2'-hydroxy-3'-t-butyl-5'-methylphenyl)-5- chlorobenzotriazole which are commercially available from Ciba-Geigy under the designations Tinuvin 327 and 326 respectively.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([O:15][CH3:16])([O:13][CH3:14])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:28]=[CH:29][CH:30]=2)O1>>[CH3:14][O:13][C:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:29]3[CH:28]=[C:27]([C:31]4[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:26]=[CH:25][CH:30]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([O:15][CH3:16])[CH3:12]
Reactant: COC(C)(OC)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Product: COC(C)(OC)c1ccn2c(-c3cccc(-c4ccccc4C#N)c3)cnc2n1
Yield: 76 %

Procedure:
3-Bromo-7-(1,1-dimethoxyethyl)imidazo[1,2-a]pyrimidine (197 mg, 0.50 mmol) was coupled with 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3′-[7-(1,1-dimethoxyethyl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2-carbonitrile (200 mg, 76%) as a white powder: δH (360 MHz, CDCl3) 1.72 (3H, s), 3.30 (6H, s), 7.39 (1H, d, J 7), 7.49-7.73 (6H, m), 7.78-7.84 (2H, m), 7.97 (1H, s), 8.95 (1H, d, J 7); m/z (ES+) 385 (M++H).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][C:12]([NH2:15])=[N:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[C:20](N)=[CH:21][CH:22]=[CH:23][CH:24]=1>C(O)(=O)C>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=1[NH:15][C:12]1[CH2:13][CH2:14][N:10]([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:16])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[N:11]=1
Reactant: COc1ccccc1N
Reactant: Cc1ccc(S(=O)(=O)N2CCC(N)=N2)cc1
Solvent: CC(=O)O
Product: COc1ccccc1NC1=NN(S(=O)(=O)c2ccc(C)cc2)CC1

Procedure:
A mixture of 4,5-dihydro-1-(4-toluenesulphonyl)-1H-pyrazol-3-amine (8.08 g) (Organic Synthesis 48,8, (1968)), o-anisidine (8.0 g) and glacial acetic acid (80 ml) was heated on a steam bath for 4 hours. The reaction mixture was cooled, filtered and washed with ether to give the sub-title product, 7.6 g, mp 176°-9°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1(Br)[CH:9]=[CH:8][CH:7]=[N:6][CH2:5]1.[S:12]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13]1>O1CCOCC1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([C:14]2[CH:15]=[CH:16][S:12][CH:13]=2)[CH:7]=[N:6][CH:5]=1
Reactant: COC(=O)C1(Br)C=CC=NC1
Reactant: OB(O)c1ccsc1
Solvent: C1COCCO1
Product: COC(=O)c1cncc(-c2ccsc2)c1
Temperature: 90 °C

Procedure:
Methyl-3-bromo-nicotinate and 3-thiophene boronic acid were dissolved in degassed dioxane (25 mL). To the homogeneous solution was added Pd((Ph3)4P)). The reaction was heated to 90° C. for 18 hours and then cooled to room temperature and concentrated. The residue was taken up into EtOAc and water. The layers were then separated and the organics washed with brine and dried (MgSO4). Flash LC (60% Hexanes/EtOAc) gave the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9](=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=O)=[CH:5][CH:4]=1.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:49]([O:53][C:54]([CH2:56][O:57][C:58]1[CH:59]=[C:60]([CH:68]=[C:69]([O:71][CH2:72][C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH:70]=1)[CH2:61][NH:62][CH2:63][CH2:64][C:65]([OH:67])=[O:66])=[O:55])([CH3:52])([CH3:51])[CH3:50]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9](=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:26])[N:62]([CH2:61][C:60]2[CH:59]=[C:58]([O:57][CH2:56][C:54]([O:53][C:49]([CH3:52])([CH3:50])[CH3:51])=[O:55])[CH:70]=[C:69]([O:71][CH2:72][C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH:68]=2)[CH2:63][CH2:64][C:65]([OH:67])=[O:66])=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)COc1cc(CNCCC(=O)O)cc(OCC(=O)OC(C)(C)C)c1
Reactant: COc1ccc(COC(=O)CCCCCCCCCCCCCCC(=O)O)cc1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)CCCCCCCCCCCCCCC(=O)N(CCC(=O)O)Cc2cc(OCC(=O)OC(C)(C)C)cc(OCC(=O)OC(C)(C)C)c2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Hexadecanedioic acid mono-(4-methoxy-benzyl)ester (0.4 g, 0.98 mmol) was dissolved in ethyl acetate (10 mL). N-Ethyl-N-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.187 g, 0.98 mmol) and 1-hydroxy-7-azabenzotriazole (0.134 g, 0.98 mmol) was added and the mixture was stirred at 50° C. for 1 hour. After cooling to room temperature, diisopropylethylamin (0.50 mL, 2.95 mmol) was added followed by 3-(3,5-Bis-tert-butoxycarbonylmethoxybenzylamino)propionic acid (0.432 g, 0.98 mmol). The mixture was stirred overnight under nitrogen at room temperature. The mixture was separated between ethyl acetate (200 mL) and water (2×100 mL). The organic phase was dried (Na2SO4), solvent removed in vacuo. The crude product was purified by RP-HPLC on C18-column, buffer A: 0.1% TFA, buffer B: MeCN+0.1% TFA; gradient 80-100% B to yield the title compound.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([F:14])[CH:8]=1.[C:15](=[O:17])=[O:16].O>CCOCC>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:15]([OH:17])=[O:16])=[CH:8][C:9]=1[F:14]
Reactant: O=C=O
Reactant: Fc1cc(Br)ccc1Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1ccc(Cl)c(F)c1
Temperature: -78 °C

Procedure:
n-Butyl lithium (2.5M in hexanes, 176 ml) was added to a stirred solution of 1-bromo-4-chloro-3-fluorobenzene (83.38 g) in dry ether. Stirring was maintained for a further 2.5 hours at -78° C., and the mixture poured onto excess solid carbon dioxide pellets, allowed to reach room temperature and water added. The mixture was washed with ether, acidified, extracted (ethyl acetate) and dried (magnesium sulphate). After evaporation the residue was triturated with petroleum ether to give 4-chloro-3-fluorobenzoic acid (66.4 g) as a white solid, m.p. 192°-192.5° C.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([CH3:25])([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH3:27][C:28]1[O:32][C:31]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[N:30][C:29]=1[CH2:38][CH2:39][O:40]S(C1C=CC(C)=CC=1)(=O)=O>>[CH3:25][C:5]([O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][CH:20]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:40][CH2:39][CH2:38][C:29]2[N:30]=[C:31]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)[O:32][C:28]=2[CH3:27])=[CH:9][CH:8]=1)[C:4]([OH:26])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(C)(C)C)cc1
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(CC(C)(Oc2ccc(C(C)(C)C)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared, according to the procedure of Example 16, Step C, using 3-(4-hydroxyphenyl)-2-methyl-2-(4-tert-butylphenoxy)-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yloxazol-4-yl)-ethyl ester to produce a white solid (19%). MS [EI+] 520 (M+H)+, [EI−] 518 (M−H)+.
Reaction SMILES: [F:1][C:2]([Cl:6])([Cl:5])[S:3]Cl.[Cl:7][C:8]1[CH:9]=[C:10]([N:15]2[C:19](=[O:20])[CH2:18][NH:17][C:16]2=[O:21])[CH:11]=[CH:12][C:13]=1[CH3:14].C(N(CC)CC)C>C(OC(=O)C)C>[Cl:5][C:2]([Cl:6])([F:1])[S:3][N:17]1[CH2:18][C:19](=[O:20])[N:15]([C:10]2[CH:11]=[CH:12][C:13]([CH3:14])=[C:8]([Cl:7])[CH:9]=2)[C:16]1=[O:21]
Reactant: FC(Cl)(Cl)SCl
Reactant: Cc1ccc(N2C(=O)CNC2=O)cc1Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(N2C(=O)CN(SC(F)(Cl)Cl)C2=O)cc1Cl
Reaction time: 3 h

Procedure:
23.8 g of fluorodichloromethanesulphenyl chloride in 100 ml of acetic acid ethyl ester is added dropwise within 20 minutes at -10° C, with vigorous stirring, to a suspension of 22.5 g of 3-(3'-chloro-4'-methylphenyl)-imidazolidine-2,4-dione in 400 ml of acetic acid ethyl ester, and after one hour there is also added dropwise, at 0° C in the course of 10 minutes, 14.2 g of triethylamine in 100 ml of acetic acid ethyl ester; the cooling bath is subsequently removed and stirring is continued for 3 hours at room temperature. The triethylamine hydrochloride that has precipitated is filtered off and then washed with 100 ml of acetic acid ethyl ester; the solvent is evaporated off in vacuo to obtain, after recrystallisation in methanol, Compound No. 1 which melts at 166° - 167° C.
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:6]([OH:7])[C:5]=1O>>[CH3:3][C:4]1[CH:5]=[C:6]([OH:7])[CH:8]=[C:9]([CH3:11])[C:10]=1[OH:1]
Reactant: OO
Reactant: Cc1cc(C)c(O)c(O)c1
Product: Cc1cc(O)cc(C)c1O

Procedure:
By following in the same manner as in Example 53, except that 60 percent hydrogen peroxide was increased from 2.88 g. (50.8 m. moles) to 4.50 g. (79.4 m. moles), 4.69 g. (34.0 m. moles) of 3,5-dimethylcatechol and 2.75 g. (19.9 m. moles) of 2,6-dimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 67.9 percent.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([N:18]([CH2:23][C:24](O)=[O:25])[CH2:19][C:20](O)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:20](=[O:21])[CH2:19][N:18]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:23][C:24]2=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Reactant: NCCCc1ccccc1
Product: O=C1CN(Cc2ccccc2)CC(=O)N1CCCc1ccccc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
3-Phenyl-1-propylamine (3.63 g) and N-benzyliminodiacetic acid (6.0 g) was mixed and heated to 200° C. under a nitrogen atmosphere. The mixture was stirred at this temperature for 1 h, cooled and purified by column chromatography (SiO2, 40°-60° C. petroleum ether/chloroform) to give the title material as a pale orange liquid (5.53 g, 64%).