Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:18]1([OH:24])C=CC=CC=1.C(Cl)(Cl)Cl>C(O)C.O.S(=O)(=O)(O)O>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:18]=[O:24])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
2,4-di-t-butylphenol (75 g, 0.36 mole) was dissolved in 200 ml absolute ethanol in a 1 L round bottom flask equipped with a water-cooled condenser. Sodium hydroxide (82 g, 2.0 moles) was dissolved in 80 ml water and added while still hot to the solution of phenol. Chloroform (156 g, 1.31 mole) was added in 2 ml portions over a 45-minute period. The resulting yellow-brown mixture was stirred 1 hour while cooling to ambient temperature. The mixture was diluted with 500 ml of 1M sulfuric acid and extracted with 200 ml of dichloromethane. The organic layer was isolated in a separatory funnel and dried over anhydrous magnesium sulfate. The mixture was filtered and rotoevaporated to a thick syrup. The yield was 33%. The IR spectrum of the crude product showed the characteristic aldehyde carbonyl (C=O) stretching frequency at 1648 cm-1. The product was used without further purification.
Reaction SMILES: [N:1](=[C:3]([C:7](=[O:10])[CH2:8][CH3:9])[C:4](=O)[CH3:5])O.[NH2:11][CH:12](C(O)=O)[CH2:13][CH2:14][CH3:15].C(C1NC(CCC)=NC=1C)(=O)C>C(O)CCC>[CH3:5][C:4]1[N:11]=[C:12]([CH2:13][CH2:14][CH3:15])[NH:1][C:3]=1[C:7](=[O:10])[C:8]#[CH:9]
Reactant: CCC(=O)C(=NO)C(C)=O
Reactant: CCCC(N)C(=O)O
Agent: CCCc1nc(C)c(C(C)=O)[nH]1
Solvent: CCCCO
Product: C#CC(=O)c1[nH]c(CCC)nc1C
Yield: 44.9 %

Procedure:
To 92.4 g (0.646 moles) of 3-oximino-2,4-hexanedione dissolved in 807 ml of n-butanol was added 90.75 g (0.775 moles) of d,l-norvaline. The mixture was refluxed 6.25 h, then cooled and concentrated in vacuo. The residue was taken up in ethyl acetate (500 ml), suction filtered and the filtrate washed with 10% aqueous sodium hydroxide (4×100 ml). Removal of the solvent in vacuo gave 0.29 moles (48% yield based on recovered amino acid) of 4-methyl-5-propinoyl-2-propylimidazole and 5-acetyl-4-methyl-2-propylimidazole (87:13 respectively).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.Cl.C([OH:25])C>>[CH3:15][C:14]1[C:3]2[C:2](=[O:25])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[N:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:13]=1
Reactant: CCO
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Agent: Cl
Product: Cc1nn(-c2ccccn2)c2[nH]c3ccccc3c(=O)c12
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution of 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (34.9 g, 0.12 mol) in ethanol (500 mL) was added 6N hydrochloric acid (50 mL, 0.30 mol), and the mixture was heated and under reflux for 2 hours. The solution was cooled to room temperature, and the reaction solvent was concentrated and evaporated under reduced pressure. The residue was made basic by the addition of an aqueous sodium hydroxide solution, and organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform:methanol=95:5) to give the title compound (25.8 g, 79% yield).
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.[CH3:19][O:20][C:21]([CH2:23]P(OC)(OC)=O)=[O:22].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[CH3:40][C:41]([C:43]1[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][CH:44]=1)=O.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[N+:49]([C:46]1[CH:47]=[CH:48][C:43](/[C:41](/[CH3:40])=[CH:23]/[C:21]([O:20][CH3:19])=[O:22])=[CH:44][CH:45]=1)([O-:51])=[O:50]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COC(=O)/C=C(\C)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 46 %

Procedure:
18-Crown-6 (41.6 g) was added to a toluene (484 ml) solution of trimethyl phosphonoacetate (22.6 ml) in a nitrogen atmosphere. An 11% potassium hexamethyldisilazide (hereinafter referred to as “KHMDS”)/toluene solution (315 ml) was added thereto, and the obtained mixture was stirred for 1 hour. Under ice-cooling, 4-nitroacetophenone (20 g) was added thereto, and the mixture was stirred for 1 hour. After the reaction was over, the reaction was stopped with a saturated ammonium chloride solution. The reaction mixture was separated with ethyl acetate and water. The organic layer was washed three times with water and once with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was suspended in methanol (40 ml) and stirred. The precipitated solid was filtered off and washed with cold methanol. Thus, Compound 6a (12.4 g, 46%) was obtained as an opalescent solid.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1([CH3:28])[C:12](=[O:13])[CH:11]2[C:6](=[C:7]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][C:19]=4[O:26][CH3:27])[N:15]=[C:8]3[C:9](=[O:14])[CH2:10]2)[CH:5]=[N:4]1.Br.[CH2:30]([N:32]([CH2:36][CH3:37])[CH2:33][CH2:34]Br)[CH3:31]>>[ClH:1].[ClH:1].[CH3:2][C:3]1([CH3:28])[C:12](=[O:13])[CH:11]2[C:6](=[C:7]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][C:19]=4[O:26][CH3:27])[N:15]=[C:8]3[C:9](=[O:14])[CH:10]2[CH2:31][CH2:30][N:32]([CH2:36][CH3:37])[CH2:33][CH3:34])[CH:5]=[N:4]1
Reactant: COc1cc(SC)ccc1C1=NC2=C3C=NC(C)(C)C(=O)C3CC(=O)C2=N1
Reactant: CCN(CC)CCBr
Agent: Br
Agent: Cl
Product: CCN(CC)CCC1C(=O)C2=NC(c3ccc(SC)cc3OC)=NC2=C2C=NC(C)(C)C(=O)C21

Procedure:
Prepared analogously to Example 23 from 2.9 gm of 7,7-dimethyl-2-(2-methoxy-4-methylmercapto-phenyl)-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione hydrochloride and 2 gm of 2-diethylamino-ethyl bromide hydrobromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[NH:8][CH2:7][CH2:6]2.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])/[C:9](=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)/[N:8]([C:31](=[O:32])[C:30]1[CH:29]=[C:28]([O:27][CH3:26])[C:36]([O:37][CH3:38])=[C:35]([O:39][CH3:40])[CH:34]=1)[CH2:7][CH2:6]2
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1ccc(C=C2NCCc3cc(OC)c(OC)cc32)cc1OC
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(/C=C2/c3cc(OC)c(OC)cc3CCN2C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OC

Procedure:
A suspension of 6 parts of 3,4-dihydro-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methylene]isoquinoline and 6 parts of 3,4,5-trimethoxybenzoyl chloride in 50 parts of pyridine is heated at the boiling point under reflux in a nitrogen atmosphere for 45 minutes, whereupon 180 parts of chloroform is introduced. The resultant solution is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residue is taken up in benzene; and the benzene solution is chromatographed on silica gel, using benzene and mixtures thereof with increasing amounts of ethyl acetate as developing solvents. From an eluate comprising 30% ethyl acetate in benzene, on evaporation of solvent, (Z)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-(3,4,5-trimethoxybenzoyl)-1-[(3,4-dimethoxyphenyl)methylene]isoquinoline melting at 195°-200° is obtained as the residue.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH2:11])[CH:2]=1.[F:12][C:13]([F:31])([F:30])[C:14]([C:17]1[CH:26]=[CH:25][C:24]2[CH2:23][C@H:22]([C:27](O)=[O:28])[CH2:21][CH2:20][C:19]=2[N:18]=1)([CH3:16])[CH3:15].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C1C=NC2N(O)N=NC=2C=1>CN1CCCC1=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:27]([C@@H:22]2[CH2:21][CH2:20][C:19]3[N:18]=[C:17]([C:14]([CH3:16])([CH3:15])[C:13]([F:31])([F:30])[F:12])[CH:26]=[CH:25][C:24]=3[CH2:23]2)=[O:28])[CH:2]=1
Reactant: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)O)C2)C(F)(F)F
Reactant: Nc1cnc2ccccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)Nc1cnc3ccccc3c1)C2)C(F)(F)F
Temperature: 60 °C
Reaction time: 0.03 h
Yield: 74.7 %

Procedure:
To a mixture of 3-quinolinamine (26 mg, 0.18 mmol), (R)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (40 mg, 0.14) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (79 mg, 0.21 mmol) in N-methylpyrrolidinone (0.7 mL), followed by N,N-diisopropylethylamine (73 μL, 0.42 mmol) was added. Aliquot after 2 min: LCMS showed formation of the HOAt and Me ester, and some amide. After 1.3 h, the reaction was heated at 60° C. Aliquot after 25 h: LCMS showed the reaction was complete—all HOAt ester had been consumed. The material was filtered and purified by reverse-phase HPLC (20-80% ACN in 10 mM Et2NH/H2O; 3 injections of 400 μL, each) to afford the amide (43 mg, 75%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.95 (d, J=2.4 Hz, 1H), 8.76 (d, J=2.4 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.92 (dd, J=1.1, 8.0 Hz, 1H), 7.68-7.54 (m, 3H), 7.40 (d, J=8.0 Hz, 1H), 3.08-3.00 (m, 2H), 2.99-2.87 (m, 3H), 2.29-2.20 (m, 1H), 2.03-1.91 (m, 1H), 1.56 (s, 6H); m/z=414.1 (M+1)+.
Reaction SMILES: C[Si](C)(C)[O:3][C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C:13]([N:14]([Si:24]([CH3:27])([CH3:26])[CH3:25])[C:15](=[O:23])[CH2:16][CH2:17]1)=[CH:12][C:11]3=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[OH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C:13]([N:14]([Si:24]([CH3:26])([CH3:25])[CH3:27])[C:15](=[O:23])[CH2:16][CH2:17]1)=[CH:12][C:11]3=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)C=C1C=C2N([Si](C)(C)C)C(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](O[Si](C)(C)C)CC[C@H]3[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C=C1C=C2N([Si](C)(C)C)C(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The diene disilane prepared above is redissolved in THF (300 mL) and treated with tetrabutylammonium fluoride (1.0 M in THF; 35.0 mL, 35.0 mmole). The desilylation reaction occurs over 20 minutes with stirring at ambient temperature. The reaction mixture is then diluted with EtOAc (500 mL) and washed with brine (3×400 mL). The crude product solution is dried over MgSO4, filtered and evaporated to dryness. The crude product is purified by flash chromatography (1:1 EtOAc/CH2Cl2) to afford 17β-hydroxy-4-trimethylsilyl-7-ethyloxycarbonylmethylene-4-aza-androst-5-en-3-one as a mixture of the E and Z isomers (diolefin). The diolefin is then hydrogenated in a manner similar to that described in Example 7H to give 7β-ethoxycarbonylmethyl-17β-hydroxy-4-aza-5α-androstan-3-one. The compound has the following structure:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[O:14]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8]/[C:9](=[CH:25]\[C:24]3[CH:27]=[CH:28][C:21]([O:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:22][CH:23]=3)/[C:10](=[O:11])/[C:12](=[CH:25]/[C:24]3[CH:27]=[CH:28][C:21]([O:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:22][CH:23]=3)/[O:13][C:4]=2[CH:3]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Product: Cc1ccc2c(c1)O/C(=C\c1ccc(Oc3ccccc3)cc1)C(=O)/C(=C/c1ccc(Oc3ccccc3)cc1)O2

Procedure:
Calone is reacted with 4-phenoxybenzaldehyde analogously to the reaction conditions of Example 1, giving 7-methyl-2,4-bis[1-(4-phenoxyphenyl)meth-(Z)-ylidene]benzo[b]-1,4-dioxepin-3-one.
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[CH:10]2)=[CH2:4].Br[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19].O>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[CH:3]=[CH2:4])[CH:10]=[CH:11]1)[CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: C=CCCCBr
Reactant: C=Cc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCCCn1ccc2cccc(C=C)c21
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
Add sodium hydride (60% dispersion in mineral oil) (3.5 g, 87.3 mmol) to a 0° C. solution of 7-vinylindole (5.0 g, 34.9 mmol) in 140 mL of dimethylformamide. Warm the resulting mixture to 20-24° C. and stir an additional 30 minutes. Add 5-bromo-1-pentene (20 mL, 175 mmol) dropwise and stir for 3 hours. Pour the reaction mixture into a mixture of 150 mL of water and 150 mL of ethyl acetate. Wash the aqueous layer with ethyl acetate (3×100 mL). Combine the organic layers, wash with saturated aqueous sodium chloride, dry over sodium sulfate, filter, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 5-10% ethyl acetate in hexanes. Combine fractions containing product and concentrate them under reduced pressure to provide the desired compound as a clear oil (5.39 g, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C:43]([CH3:46])([OH:45])[CH3:44])[CH2:10]2)=[CH:5][CH:4]=1.[H-].[K+].[CH3:49][N:50]([CH3:54])[C:51](Cl)=[O:52].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C:43]([O:45][C:51](=[O:52])[N:50]([CH3:54])[CH3:49])([CH3:46])[CH3:44])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)C(=O)Cl
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(C)(C)O)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(C)(C)OC(=O)N(C)C)C[C@@H]3c3ccc(OC)cc3)cc21
Reaction time: 1 h

Procedure:
To a solution of 120 mg of 1-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2-methyl-propan-2-ol (from example 57b) in 0.5 ml of tetrahydrofuran are added 80 mg potassium hydride (35% dispersion in oil). The reaction mixture is stirred for 1 hour and then 163 μl dimethylcarbamoyl chloride are added. The mixture is stirred at room temperature for 18 hours. The mixture is treated with 2 ml water and extracted with 50 ml ethyl acetate (2×). The combined organic layers are washed with brine and dried with sodium sulfate. The organic layer is filtered and evaporated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow solid. Rf=0.45 (EtOAc-heptane 2:1); Rt=5.59.
Reaction SMILES: [C:1]([C@@H:3]([NH:22][C:23]([C:25]1([NH:31]C(=O)OC(C)(C)C)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[N:15]([CH3:21])[CH2:14]3)=[CH:7][CH:6]=1)#[N:2].C(O)=O.C(#N)C>CO.O>[NH2:31][C:25]1([C:23]([NH:22][C@H:3]([C:1]#[N:2])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[C:16](=[O:20])[N:15]([CH3:21])[CH2:14]4)=[CH:9][CH:10]=2)=[O:24])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CN1Cc2cc(-c3ccc(C[C@@H](C#N)NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)cc3)ccc2C1=O
Solvent: CC#N
Solvent: CO
Solvent: O=CO
Product: CN1Cc2cc(-c3ccc(C[C@@H](C#N)NC(=O)C4(N)CCOCC4)cc3)ccc2C1=O
Temperature: 50 °C
Yield: 60.3 %

Procedure:
To (S)-tert-butyl 4-(1-cyano-2-(4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 31, step (v), 436 mg) was added formic acid (9.7 mL) and the mixture heated to 50° C. for 15 min. The mixture was allowed to cool to room temperature, diluted with methanol and then evaporated to dryness. The material was purified by reversed phase HPLC (Waters X-Bridge column) eluting with methanol in aqueous 0.1% trifluoroacetic acid as eluent. The fractions containing the desired compound were combined, evaporated and then dissolved in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over magnesium sulfate and evaporated. The residue was triturated with diethyl ether and evaporated to give a product that was slurried in water (6.9 mL) and acetonitrile (0.36 mL) for 4 days. The solid was collected by filtration, washed with water and then dried under vacuum at 50° C. to afford the titled compound (212 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[NH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([OH:36])[CH2:31]1.C([O-])([O-])=O.[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([NH:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH:32]([OH:36])[CH2:31]3)=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: NC1CCCC(O)C1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(Cn2nc(NC3CCCC(O)C3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 100 °C
Yield: 48.2 %

Procedure:
A suspension of 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (100 mg, 0.204 mmol, obtained from Example 7, Step B), 3-aminocyclohexanol (70.5 mg, 0.612 mmol), Cu(I)I (7.77 mg, 0.0408 mmol), K2CO3 (141 mg, 1.02 mmol) and L-proline (9.39 mg, 0.082 mmol) was stirred in DMSO (5 mL) and heated to 100° C. for 12 hours. Water (5 mL) was added and the reaction mixture was extracted with CH2Cl2. The organic layer washed with water and brine, dried with Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (5% MeOH in CH2Cl2) to afford the product (47 mg, 48.3% yield) as a brown oil. LRMS (APCI pos) m/e 694.2 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[NH:17][C:18](=[S:22])[NH:19][C:20]=2[CH3:21])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[C:23](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]([S:22][CH3:23])[NH:19][C:20]=2[CH3:21])[CH:8]=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1[nH]c(=S)[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)[nH]1
Yield: 29.9 %

Procedure:
By following the same procedure as in Example 10 using 0.32 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-thioxo-4-imidazoline, 10 ml of dry acetone, 0.15 g of potassium carbonate, and 0.15 g of methyl iodide and recrystallizing the product from cyclohexane, 0.1 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methylthioimidazole was obtained.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[N:6]=[C:7]([S:9][CH3:10])[S:8][C:4]=2[CH:3]=1.[Cl:13][C:14]1[C:19]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:18][C:17](B2CC(C)(C)C(C)(C)C2)=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:14]1[C:19]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:18][C:17]([C:2]2[CH:12]=[CH:11][C:5]3[N:6]=[C:7]([S:9][CH3:10])[S:8][C:4]=3[CH:3]=2)=[CH:16][N:15]=1
Reactant: CSc1nc2ccc(Br)cc2s1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(B3CC(C)(C)C(C)(C)C3)cnc2Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3ccc4nc(SC)sc4c3)cnc2Cl)cc1
Temperature: 90 °C
Yield: 10.9 %

Procedure:
In a 15 mL sealed-pressure tube was added 6-bromo-2-(methylthio)benzo[d]thiazole (60 mg, 0.231 mmol), N-(2-chloro-5-(3,3,4,4-tetramethylborolan-1-yl)pyridin-3-yl)-4-methoxybenzenesulfonamide (137 mg, 0.323 mmol), sodium carbonate (2M) (73 mg, 0.692 mmol) and 8 mol % Pd(PPh3)4 in 2.0 ml of EtOH. The tube was purged with argon for 10 minutes, back-filled with argon, sealed and placed in a pre heated oil bath at 90° C. for 2 hours. Analysis of an aliquot by LCMS shows a small amount of desired product (RT=2.66 min.), exhaustion of boronic ester starting material, remaining aryl bromide starting material, and an unidentified byproduct with mw 315. Added an additional 20 mg of Pd(PPh3)4 and 60 mg of boronic ester starting material. Continued to heat at 90° C. for two more hours. No additional conversion by LCMS. Stopped reaction and cooled to ambient temperature. Concentrated down in vacuo. Crude taken up in equal parts MeOH and DMSO, filtered and purified by Gilson RPHPLC with a 20-95% gradient of ACN in water with 0.1% TFA as a modifier. Following basification with saturated sodium bicarb and extraction with 10 ml DCM (2×), organic layer was dried over Na2SO4, filtered and concentrated in vacuo to afford N-(2-chloro-5-(2-(methylthio)benzo[d]thiazol-6-yl)pyridin-3-yl)-4-methoxybenzenesulfonamide (12 mg, 11% yield). MS (ESI pos. ion) m/z: 478 (MH+).
Reaction SMILES: [Br-].[CH3:2][O:3][CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:26][C:27]1[CH:28]=[CH:29][C:30]([CH3:35])=[C:31]([CH:34]=1)[CH:32]=O.CC#N.O>CC#N>[Br:26][C:27]1[CH:28]=[CH:29][C:30]([CH3:35])=[C:31]([CH:32]=[CH:6][CH2:5][CH2:4][O:3][CH3:2])[CH:34]=1
Reactant: COCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(Br)cc1C=O
Agent: [Br-]
Solvent: CC#N
Solvent: O
Product: COCCC=Cc1cc(Br)ccc1C

Procedure:
The title compound is prepared analogously as described for the title B compound in Example 45 using (3-methoxy-propyl)-triphenyl-phosphonium bromide and 5-bromo-2-methyl-benzaldehyde (prepared in Example 48; containing 20% of 3-bromo-2-methyl-benzaldehyde): Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 6.60 min.
Reaction SMILES: [CH2:1]([CH2:11][C:12](=[O:14])[CH3:13])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[CH3:15][C@@H:16]([CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:17][CH2:18][CH2:19][C:20](=[O:22])[CH3:21]>>[CH3:4][C@@H:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:2][CH2:1][CH2:11][C:12](=[O:14])[CH3:13].[CH3:15][C@H:16]([CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:17][CH2:18][CH2:19][C:20](=[O:22])[CH3:21]
Reactant: CC(=O)CC/C=C(\C)CCC=C(C)C
Agent: CC(=O)CCC[C@@H](C)CCCC(C)C
Product: CC(=O)CCC[C@H](C)CCCC(C)C

Procedure:
Specifically, it has been found that using the R-isomer of catalyst of formula (I) in the hydrogenation of E-geranyl acetone (=(E)-6,10-dimethylundeca-5,9-dien-2-one) the hydrogenation product (6S)-6,10-dimethylundecan-2-one is formed in more than 98% in respect to all of the possible stereoisomers (i.e. (6S)-6,10-dimethylundecan-2-one and (6R)-6,10-dimethylundecan-2-one) whereas the corresponding R-isomer is obtained only in amount of less than 2%.