Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]/[C:2](/[CH:19]=[CH:20]/[CH:21]=[C:22](\[CH3:28])/[CH:23]=[CH:24]/[C:25]([O-:27])=[O:26])=[CH:3]\[CH:4]=[CH:5]\[CH:6]=[C:7](/[CH3:18])\[CH:8]=[CH:9]\[CH:10]=[C:11](/[CH3:17])\[CH:12]=[CH:13]\[C:14]([O-:16])=[O:15].[K+].[K+]>O>[CH3:18]/[C:7](/[CH:8]=[CH:9]/[CH:10]=[C:11](\[CH3:17])/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:6]\[CH:5]=[CH:4]\[CH:3]=[C:2](/[CH3:1])\[CH:19]=[CH:20]\[CH:21]=[C:22](/[CH3:28])\[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26]
Reactant: CC(/C=C/C=C(C)/C=C/C(=O)[O-])=C\C=C\C=C(C)\C=C\C=C(C)\C=C\C(=O)[O-]
Agent: [K+]
Solvent: O
Product: CC(/C=C/C=C(C)/C=C/C(=O)O)=C\C=C\C=C(C)\C=C\C=C(C)\C=C\C(=O)O

Procedure:
Coloration of milk. A 6.6& solution of pure potassium norbixin (so-called "cheese color") was diluted to 1.1% with water, and the dilute solution added with agitation to whole milk to give a level of 100 ppm norbixin in the milk. The resulting color was light orange.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[C:16]2[CH:17]=[N:18][CH:19]=[C:20](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[CH3:10])=[CH:5][CH:4]=1.[C:31]([O:35][C:36]([N:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40](Br)=[CH:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>C(O)C>[C:31]([O:35][C:36]([N:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]([C:20]2[CH:19]=[N:18][CH:17]=[C:16]([C@@H:12]3[CH2:13][CH2:14][CH2:15][N:11]3[CH:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH3:10])[CH:21]=2)=[CH:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: COc1ccc([C@@H](C)N2CCC[C@H]2c2cncc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Reactant: CC(C)(C)OC(=O)n1cc(Br)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)N2CCC[C@H]2c2cncc(-c3cn(C(=O)OC(C)(C)C)c4ccccc34)c2)cc1
Temperature: 80 °C
Yield: 58.6 %

Procedure:
A mixture of 3-{(S)-1-[(R)-1-(4-Methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine 4 (crude, 6.93 mmole), 3-bromo-indole-1-carboxylic acid tert-butyl ester (2.46 g, 8.32 mmole), Na2CO3 (35 mL, 35 mole, 1 M aqueous) in a mixed solution of 50 mL of toluene and 20 mL of ethanol was degased under vacuum. After heat at 80° C. for 1.5 hours, the reaction mixture was cooled to room temperature and dilutied with 150 mL of EtOAc, and washed by 2×100 mL of water. The organic layer was filtered and concentrated. The crude producte was purified by flash chromatography (Hexane 70%, EtOAc 30%) to give 3-(5-{(S)-1-[1-(4-Methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridin-3-yl)-indole-1-carboxylic acid tert-butyl ester 5 (2.02 g, 59% in two steps) as light brown gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN(C)C=O.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:19])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)Cc1ccc(F)cc1
Temperature: 400 °C
Yield: 89.5 %

Procedure:
A solution of 150 g (0.974 mol) of 4-fluorophenylacetic acid an 1 mL of N,N-dimethylformamide in 500 mL of toluene at 40 ° C. was treated with 20 mL of thionyl chloride and heated to 400° C. An additional 61.2 mL of thionyl chloride was added dropwise over 1.5 hours. After the addition, the solution was heated at 50° C. for 1 hour, the solvent was removed in vacuo and the residual oil was distilled at reduced pressure (1.5 mmHg) to afford 150.4 g (89.5%) of the title compound, bp=68°-70 ° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:24][CH3:25])[C:10]([S:11]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:26])[CH:3]=1.[CH3:27][NH:28][CH3:29]>CCO>[CH3:27][N:28]([CH3:29])[C:2]1[N:7]2[N:8]=[C:9]([S:24][CH3:25])[C:10]([S:11]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:26])[CH:3]=1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc2ccccc2c1
Reactant: CNC
Solvent: CCO
Product: CSc1nn2c(N(C)C)cc(C)nc2c1S(=O)(=O)c1ccc2ccccc2c1

Procedure:
In an analogous manner to that described in Example 6, from 7-chloro-5-methyl-2-methylsulphanyl-3-(naphthalene-2-sulphonyl)-pyrazolo[1,5-a]pyrimidine and dimethyl-amine in EtOH there was obtained dimethyl-[5-methyl-2-methylsulphanyl-3-(naphthalene-2-sulphonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-amine as colorless crystals, m.p.>230°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:17][C:18]([F:41])([F:40])[C:19]([C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=1)([OH:24])[C:20]([F:23])([F:22])[F:21].C(=O)([O-])[O-].[K+].[K+].COCCOC>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO.O>[F:17][C:18]([F:40])([F:41])[C:19]([C:25]1[CH:26]=[CH:27][C:28]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:29][CH:30]=1)([OH:24])[C:20]([F:21])([F:23])[F:22]
Reactant: CC1(C)OB(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1)c1ccc(Br)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=S(=O)(c1ccccc1)c1ccc(-c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)cc1
Temperature: 100 °C
Yield: 41.9 %

Procedure:
A 100 mL pressure vessel was charged with 1-bromo-4-(phenylsulfonyl)benzene (1.00 g, 3.37 mmol, Example 17, step 1), 1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-propanol (1.62 g, 4.37 mmol), potassium carbonate (1.40 g, 10.10 mmol), tetrakis(triphenylphosphine)palladium (0) (0.194 g, 0.168 mmol), 20 mL of 1,2-dimethoxyethane, and 5 mL of water. The vessel was sealed and the reaction was heated to 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with EtOAc (30 mL), separated, dried (MgSO4) and concentrated to give an oil. Purification via column chromatography (40 g of silica, 0 to 50% EtOAc in hexanes) produced a yellow solid that was slurried with cold (0° C.) MeOH (25 mL) to give 1,1,1,3,3,3-hexafluoro-2-(4′-(phenylsulfonyl)-4-biphenylyl)-2-propanol (0.650 g). 1H NMR (400 MHz, CD3OD) δ 8.08-7.95 (m, 4H), 7.91-7.74 (m, 6H), 7.69-7.54 (m, 3H). m/z (ESI, +ve ion) 461.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=1.66 μM; GK-GKRP EC50 (LC MS/MS)=3.96 μM.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]([NH:10][CH:11]=[O:12])([CH3:9])[CH:5](O)[CH:6]=[CH2:7].S(Br)(Br)=O.[P:18]([O:25]CC)([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>>[CH3:1][O:2][C:3](=[O:13])[C:4]([NH:10][CH:11]=[O:12])([CH3:9])/[CH:5]=[CH:6]/[CH2:7][P:18]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:25]
Reactant: C=CC(O)C(C)(NC=O)C(=O)OC
Reactant: CCOP(OCC)OCC
Agent: O=S(Br)Br
Product: CCOP(=O)(C/C=C/C(C)(NC=O)C(=O)OC)OCC

Procedure:
A solution of 14.1 g of 2-isocyanopropionic acid methyl ester and 8.5 g of freshly distilled acrolein in 50 ml of tetrahydrofuran is added within a period of 20 minutes at 0°-5° under nitrogen to a solution of 17 g of anhydrous zinc chloride in 75 ml of tetrahydrofuran, and the whole is stirred for 45 hours at 0°-5°. The whole is poured onto 500 ml of 10% sodium hydrogen carbonate solution and extracted with 200 ml of dichloromethane. The organic phase is dried over sodium sulphate and concentrated by evaporation. Filtration of the residue over silica gel (ethyl acetate as eluant) yields 4-methyl-5-vinyl-2-oxazoline-4-carboxylic acid methyl ester. By hydrolysis of the 4-methyl-5-vinyl-2-oxazoline-4-carboxylic acid methyl ester in a manner analogous to that described in Example 1, 2-formylamino-2-methyl-3-hydroxy-4-pentenoic acid methyl ester is obtained. By reaction of the 2-formylamino-3-hydroxy-2-methyl-4-pentenoic acid methyl ester with thionyl bromide and subsequent treatment with triethyl phosphite in the manner described in Example 1, E-2-formylamino-2-methyl-5-diethylphosphono-3-pentenoic acid methyl ester is obtained in the form of a yellow oil:
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH3:12])[CH3:11])(C)C.[C:13]1([CH:20]=CC=C(O)[CH:15]=1)O.[O-]O>>[CH:10]([C:5]1[CH:4]=[CH:9][CH:8]=[C:7]([CH:13]([CH3:20])[CH3:15])[CH:6]=1)([CH3:11])[CH3:12]
Reactant: CC(C)c1ccccc1C(C)C
Reactant: Oc1cccc(O)c1
Agent: [O-]O
Product: CC(C)c1cccc(C(C)C)c1

Procedure:
By well-known processes, diisopropylbenzene (DIPB) is oxidized to produce, among other products, the dihydroperoxides (DHP) and hydroxyhydroperoxides (HHP) of diisopropylbenzene, for the preparation of resorcinol. Almost all acid-catalyzed decompositions of m-DHP to resorcinol require the use of pure m-DHP. For example, U.S. Pat. No. 3,928,469 disclosed that a crude hydroperoxide mixture which is obtained from the oxidation product of m-diisopropylbenzene, and which has a composition consisting of 72% m-DHP, 20% m-HHP, and 8% others, is cleaved in a usual manner, using a mineral acid catalyst, to give only a low cleavage yield of about 70 to 73% resorcinol based on moles m-DHP used. Yet, there is no practical way to make pure DHP by the hydroperoxidation of m-DIPB and there is no economical way to separate HHP and other products from the hydroperoxidation product to obtain pure DHP.
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][CH:14]=[O:15])[C:3]([NH:5][C:6]1[S:7][C:8]([CH3:11])=[N:9][N:10]=1)=[O:4].Cl>O>[CH3:11][C:8]1[S:7][C:6]([N:5]2[CH:14]([OH:15])[CH2:13][CH2:12][N:2]([CH3:1])[C:3]2=[O:4])=[N:10][N:9]=1
Reactant: Cc1nnc(NC(=O)N(C)CCC=O)s1
Agent: Cl
Solvent: O
Product: Cc1nnc(N2C(=O)N(C)CCC2O)s1

Procedure:
The dimethyl acetal of 3-[1-methyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde (15 grams), water (400 ml) and hydrochloric acid (4 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. The reaction mixture is then filtered while hot and the filtrate is cooled to form a precipitate. The precipitate is recovered by filtration, is dried and is recrystallized to yield the desired product tetrahydro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C@:7]([CH3:16])([CH2:14][OH:15])[CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C=O)C>CCOCC.O>[CH2:24]([O:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C@:7]([CH3:16])([CH2:14][OH:15])[CH2:6][CH2:5]2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CO)O2
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CO)O2

Procedure:
A mixture of 0.55 g. (2.33 mmol) of (S)-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-methanol, 790 mg. (5.72 mmol) of anhydrous K2CO3, 0.68 ml. (748 mg; 5.93 mmol) of benzyl chloride (distilled from and stored over K2CO3) and 4.5 ml. of DMF was stirred for 22 hrs. at room temperature then poured into H2O and worked up with ether in the usual manner. There was obtained 0.89 g. of a yellow oily product which was chromatographed on silica gel (35 g.). Elution with 19:1 and 9:1 benzene-ethyl acetate gae 724 mg. (97.1%) of (S)-(-)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-methanol as a colorless solid, mp 66°-69.5°; [α]25D-2.35° (c 1.2, CHCl3).
Reaction SMILES: C[O:2][C:3]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[C:10]([CH3:16])=[C:9]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:8]4[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:7]=4[C:6]=3[C:5]=2[CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[C:10]([CH3:16])=[C:9]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:8]4[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:7]=4[C:6]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c3c(C)c(-c4ccccc4)c4c(c3c2c1)C(=O)NC4=O
Agent: BrB(Br)Br
Product: Cc1c(-c2ccccc2)c2c(c3c1[nH]c1ccc(O)cc13)C(=O)NC2=O
Yield: 90 %

Procedure:
Demethylation of (803) prepared as described in example 406 with BBr3 using the procedure described in example 69 gave (804) (90%), mp 270–280° C. 1H NMR δ [(CD3)2SO] 11.60 (s, 1H), 10.82 (s, 1H), 9.22 (s, 1H), 8.31 (d, J=2.0 Hz, 1H), 7.47–7.42 (m, 4H), 7.36–7.23 (m, 2H), 7.06 (dd, J=8.7, 2.0 Hz, 1H), 2.32 (s, 3H). EIMS found M+:342.1005. C21H14N2O3 requires: 342.1004.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[F:14][C:15]1[CH:16]=[C:17](O)[CH:18]=[CH:19][CH:20]=1>>[F:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][CH:16]=1)[O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: Oc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc(F)c2)C1
Yield: 98.1 %

Procedure:
The title compound (D46) (294.6 mg) was prepared according to the experimental procedure described in Description 40 starting from (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (200 mg, 1.068 mmol, available at Aldrich#532169) and 3-Fluorophenol (0.096 ml, 1.068 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:37])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:25][CH:24]=3)[C@@H:14]([CH3:38])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:48](Cl)(=[O:50])[CH3:49]>ClCCl>[C:48]([N:34]1[CH2:35][CH2:36][CH:31]([CH2:30][O:29][C:26]2[CH:27]=[CH:28][C:23]([C:22]([N:15]3[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C@H:12]([N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:9](=[O:11])[CH3:10])[CH2:13][C@@H:14]3[CH3:38])=[O:37])=[CH:24][CH:25]=2)[CH2:32][CH2:33]1)(=[O:50])[CH3:49]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCC3CCNCC3)cc2)c2ccccc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(COc2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-{2-methyl-1-[4-(piperidin-4-ylmethoxy)-benzoyl]-1,2,3,4-tetrahydro-quinolin-4-yl}-acetamide (0.075 g, 0.14 mmol) was dissolved in dichloromethane at room temperature. DIEA (0.1 mL, 0.56 mmol) and acetyl chloride (0.2 mL, 2.8 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (10% methanol/90% dichloromethane) to afford the product (0.049 g, 49%).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C-:36]#[N:37].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.C(OCC)(=O)C.N.CO>[C:36]([C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[N:37]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(F)nc3)CC2)C1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: N
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
N-({1-[4-(6-fluoro-pyridin-3-yl)-4-hydroxy-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide 6a (70 mg, 0.14 mmol), KCN (Aldrich, 46 mg, 0.70 mmol) and 18-crown-6 (Aldrich, 190 mg, 0.70 mmol) in DMF (1 mL) were heated to 150° C. in a sealed tube overnight. The reaction solution was loaded on a silica gel column with a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][N:5]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=12.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)CCC>O1CCOCC1.C(Cl)Cl.[Pd](Cl)Cl.C1(P(C(C)C(P(C2C=CC=CC=2)C2C=CC=CC=2)C)C2C=CC=CC=2)C=CC=CC=1.[Ag]=O>[Cl:11][C:9]1[CH:8]=[CH:7][C:6]2[N:5]([N:4]=[C:3]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:2]=2[C:24]2[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(S(N)(=O)=O)cc1
Reactant: Fc1ccc(-c2nn3cc(Cl)ccc3c2Br)cc1
Agent: Cl[Pd]Cl
Agent: O=[Ag]
Agent: CC(C(C)P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3cc(Cl)ccc23)cc1
Yield: 33.7 %

Procedure:
3-Bromo-6-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (397 mg, 1.22 mmol), 4-(tri-n-butylstannyl)phenylsulfonamide (1.09 g), bis(diphenylphosphino)butane palladium(II) dichloride (100 mg) and silver oxide (283 mg) were stirred in anhydrous dioxan (15 ml) at reflux for 24 h. After cooling, the concentrated reaction mixture was taken up in DCM and concentrated onto silica gel which was loaded onto an SPE column and eluted with cyclohexane:ethyl acetate (8:1). This gave a white solid which was triturated with cyclohexane and filtered to give the title compound as a white solid (165 mg, 34%). MH+ 400 1H NMR (DMSO) δ 7.27 (2H, t, J 8 Hz); 7.4 (3H, m); 7.52 (4H, m); 7.7 (1H, d, J 9 Hz); 7.87 (2H, d, J 8 Hz); 9.18 (1H, s); Tlc SiO2 cyclohexane:ethyl acetate (3:1) Rf 0.12 detection uv254.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1CO.[CH3:14]C(C1C2C(=CC=CC=2)C=CC=1)=O>>[CH:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1)=[CH2:14]
Reactant: CC(=O)c1cccc2ccccc12
Reactant: Cc1ccc2ccccc2c1CO
Product: C=Cc1ccc2ccccc2c1

Procedure:
The crude hydrogenated product may therefore be treated to recover the desired methylnaphthyl carbinol in a relatively pure form. This may be effected by distilling the crude hydrogenation product at a pressure sufficiently below atmospheric to give a temperature below that which substantial dehydration of the methylnaphthyl carbinol takes place. Alternatively, it has been found that 2-methylnaphthyl carbinol which is produced can be dehydrated in the presence of 1-acetonaphthalene to yield 2-vinylnaphthalene. The 1-acetonaphthalene remains unreacted.
Reaction SMILES: CS(O[CH2:6][CH2:7][F:8])(=O)=O.[CH:9]1([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[CH:29]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([CH2:38][N:39]6[CH2:44][CH2:43]N(CCF)C[CH2:40]6)=[CH:34][N:33]=5)[S:31][C:24]=34)=[C:18]([F:48])[CH:17]=2)=[O:14])[CH2:11][CH2:10]1>>[CH:9]1([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[CH:29]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([CH2:38][N:39]6[CH2:44][CH2:43][CH:9]([N:12]([CH2:6][CH2:7][F:8])[CH3:13])[CH2:10][CH2:40]6)=[CH:34][N:33]=5)[S:31][C:24]=34)=[C:18]([F:48])[CH:17]=2)=[O:14])[CH2:11][CH2:10]1
Reactant: CS(=O)(=O)OCCF
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCN(CCF)CC5)cn4)sc23)c(F)c1)NC1CC1
Product: CN(CCF)C1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1

Procedure:
Compound 421 (example 269) was prepared in one step by reacting the amine precursor 401 (table 31) with compound 419, similarly to compound 420 (example 268, scheme 77). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.73 (s, 1H), 8.54 (d, J=1.6 Hz, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.33 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.85 (dd, J=8.0, 2.0 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.22-7.18 (m, 1H), 6.64 (d, J=5.2 Hz, 1H), 6.56 (bd, J=2.8 Hz, 1H), 4.51 (t, J=5.2 Hz, 1H), 4.39 (t, J=5.2 Hz, 1H), 3.54 (s, 2H), 2.90-2.82 (m, 2H), 2.77-2.63 (m, 2H), 2.59-2.50 (m, 1H), 2.40-2.30 (m, 1H), 2.22 (s, 3H), 2.02-1.91 (m, 2H), 1.69-1.61 (m, 2H), 1.50-1.38 (m, 2H), 0.68-0.62 (m, 2H), 0.45-0.40 (m, 2H). MS (m/z): 593.59 (M+H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](Cl)(=[O:11])[CH3:10]>[OH-].[Na+].O.O1CCCC1.C(Cl)(Cl)Cl>[C:5]([OH:11])(=[O:6])[CH3:7].[C:9]([OH:11])(=[O:2])[CH3:10].[C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2]
Reactant: CC(=O)Cl
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Hydroquinone (110 g) was dissolved in a solution of sodium hydroxide (80 g) in water (400 ml) and to the resulting solution was added dropwise a solution of acetyl chloride (157 g) in tetrahydrofuran (157 g) with ice-cooling (0° C.). The reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was poured into water (1 liter) and the crystals formed was filered and dissolved in chloroform. The solution was washed with dil. sodium hydroxide solution to remove unreacted hydroquinone. After removal of the solvent, the residue was recrystallized from water/ethanol to give hydroquinone diacetate (175 g). m.p. 121°-122.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4]1.[CH2:15](OC=O)C>C1(C)C=CC=CC=1>[CH3:15][NH:1][CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4]1
Reactant: CCOC=O
Reactant: COc1ccc2c(c1)OCCC2CN
Solvent: Cc1ccccc1
Product: CNCC1CCOc2cc(OC)ccc21

Procedure:
The product from Example 2 (5 g) was added to ethylformate (10 ml) and toluene (100 ml) then refluxed for 21/2 hrs. The solution was evaporated to dryness and then tetrahydrofuran (THF) (100 ml) and BH3.THF 25.9 ml of a IM THF solution) was added followed by heating for 11/2 hrs. The reaction was cooled and 6N HC1 (20 ml) was carefully added followed by heating for 1 hr. The THF was evaporated and the reaction made basic with aqueous KOH. The reaction was extracted with CH2Cl2, the organic layer then separated, dried (MgSO4), filtered and evaporated. The residue was chromatographed on silica gel and eluted with (EtOAc:H2O:HCO2H) (16:2:2), giving the product (1.4 g). Mass spec: (M+H)+ 208 1H NMR(CDCl3): 2.0 (m,2H); 2.49 (s,3H); 2.8 (m,2H); 3.75 (s,3H); 4.2 (m,1H); 6.38-7.25 (m,3H).
Reaction SMILES: [OH-:1].[K+].[NH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[N+:13]([O-:15])=O.Cl[O-].[Na+].Cl.[Cl-].[Na+]>C(O)C.O.C(O)(=O)C.CC(C)=O.C(Cl)(Cl)Cl>[N+:3]1([O-:1])[O:15][N:13]=[C:5]2[CH:6]=[C:7]([C:8]([OH:10])=[O:9])[CH:11]=[CH:12][C:4]=12
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: [OH-]
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)no[n+]2[O-]
Temperature: 67.5 °C
Reaction time: 0.75 h
Yield: 84.5 %

Procedure:
In a 3 L reactor fitted with mechanical stirring, reflux condenser, thermometer and nitrogen inlet, KOH (72.46 g) was dissolved in ethanol (250 ml) and water (250 ml). 4-Amino-3-nitrobenzoic acid (100 g) was added and the orange suspension was heated to 65-70° C. within 30 minutes. The resulting suspension was stirred at the same temperature for 45 minutes and cooled to 0° C.±5° C. within 30 minutes. A commercially available (13% w/w) solution of sodium hypochlorite (448.93 g) was added drop wise within 1.5 hours at 0° C.±5° C. The reaction mixture was stirred at the same temperature for 2 hours and controlled by TLC (CHCl3 100/acetone 2/acetic acid 1). Water (350 ml) was added within 15 minutes at 0° C. ±5° C. to give a fine yellow suspension. The reaction mixture was then acidified with a 6N HCl solution (239 ml) until 0.5<pH<1 was reached. Sodium chloride (58.44 g) was added and the resulting suspension was stirred at 0° C.±5° C. for 1.5 hours under nitrogen. The solid was collected by filtration, washed with 3×400 ml water and dried (40° C., 30 mbars, 12 hours) to yield 83.6 g (88.8% yield) of [2,1,3]-benzoxadiazole-5-carboxylic acid N-oxide.