Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[C:3]([C:14]([O:16]C)=[O:15])=[C:4]1[CH:13]=[CH:12][CH2:11][CH2:10][N:5]12.[OH-].[K+].Cl>CO.O>[CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[C:3]([C:14]([OH:16])=[O:15])=[C:4]1[CH:13]=[CH:12][CH2:11][CH2:10][N:5]12
Reactant: COC(=O)c1c2n(c3ccccc13)CCC=C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1c2n(c3ccccc13)CCC=C2
Yield: 64 %

Procedure:
A stirred solution of methyl 6,7-dihydropyrido[1,2-a]indole-10-carboxylate (T. Teitei and L. K. Dalton, Australian J. Chem 1969, 22, 997) (1.0 g, 0.0044 mole) in methanol (40 ml) was treated with a solution of potassium hydroxide (3.0 g, 0.054 mole) in water (50 ml) and heated under reflux for 3 h. The solution was allowed to cool, then acidified with HCl acid and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated under vacuum to leave the title compound (D8) as a yellow solid (600 mg, 64%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]([OH:19])[CH2:10][CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:20]([C:22]1([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[CH2:21]>C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:15][C:14]([F:17])([F:16])[C:13]([NH:12][CH2:11][CH2:10][CH:9]([C:4]1[CH:3]=[C:2](/[CH:21]=[CH:20]/[C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:7]=[C:6]([F:8])[CH:5]=1)[OH:19])=[O:18]
Reactant: C=CC1(O)CCCCC1
Reactant: O=C(NCCC(O)c1cc(F)cc(Br)c1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=C(NCCC(O)c1cc(F)cc(/C=C/C2(O)CCCCC2)c1)C(F)(F)F
Temperature: 90 °C

Procedure:
A mixture of N-(3-(3-bromo-5-fluorophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide (0.58 g, 1.57 mmol), 1-vinylcyclohexanol (0.3 g, 2.38 mmol) and palladium acetate (0.03 g, 0.12 mmol) in tetrabutyl ammonium acetate (1.0 g) and DMF (1 ml) was heated at 90° C. for 1 h. After cooled to room temperature, the reaction mixture was partitioned between water (40 ml) and ethyl acetate (60 ml). Ethyl acetate portion was dried over Na2SO4. Purification by chromatography (40 to 60% EtOAc-hexanes gradient) gave (E)-2,2,2-trifluoro-N-(3-(3-fluoro-5-(2-(1-hydroxycyclohexyl)vinyl)phenyl)-3-hydroxypropyl)acetamide as a colorless oil. Yield (0.25 g, 54%): H NMR (400 MHz, DMSO-d6) δ 9.32 (t, J=5.6 Hz, 1H), 6.94-7.18 (m, 3H), 6.41-6.53 (m, 2H), 5.42 (d, J=4.4 Hz, 1H), 4.54-4.60 (m, 1H), 3.18-3.26 (m, 2H), 1.72-1.86 (m, 2H), 1.38-1.66 (m, 10H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1>CCOCC>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:8])=[CH:16][CH:17]=1)#[CH:22]
Reactant: C#Cc1ccc(N)cc1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: CCOCC
Product: C#Cc1ccc(NC(=O)NC(=O)c2c(F)cccc2F)cc1

Procedure:
With stirring, 3.2 g of 2,6-difluorobenzoylisocyanate are added dropwise to a ready prepared mixture of 2 g of 4-aminophenylacetylene in 20 ml of absolute ether. The precipitate is filtered with suction after 2 hours and recrystallised from ethanol, yielding N-(4-ethynylphenyl)-N'-(2,6-difluorobenzoyl)urea with a melting point of 213°-217° C. (Compound 1).
Reaction SMILES: [CH2:1]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][CH2:10][CH2:11][CH:5]2[CH2:4][N:3](C(OC(C)(C)C)=O)[CH2:2]1.Cl>ClCCl>[CH2:1]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][CH2:10][CH2:11][CH:5]2[CH2:4][NH:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ccccc3NCCC2C1
Agent: Cl
Solvent: ClCCl
Product: c1ccc2c(c1)NCCC1CNCCN21

Procedure:
To a solution of Example 17A (50 mg, 0.165 mmol) in dichloromethane (5 mL) was added HCl (4 M in dioxane, 824 μL, 3.30 mmol). After reaction completion as indicated by LC/MS analysis, the solution was concentrated and purified by preparative HPLC to afford the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 7.48 (t, J=7.48 Hz, 1 H), 7.36 (d, J=7.02 Hz, 1 H), 7.19-7.29 (m, 2 H), 3.47-3.57 (m, 1 H), 3.35-3.44 (m, 2 H), 3.10-3.35 (m, 6 H), 1.76 (s, 2 H); MS (ESI) m/z 204.0 (M+H)+.
Reaction SMILES: [H-].[Na+].C(N(CC)CC)C.[O:10]=[C:11]1[NH:20][CH:19]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[C:18]2[C:17](=[O:29])[CH2:16][CH2:15][CH2:14][C:13]=2[N:12]1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>O1CCCC1>[CH3:40][S:41]([N:20]1[CH:19]([C:21]2[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=2)[C:18]2[C:17](=[O:29])[CH2:16][CH2:15][CH2:14][C:13]=2[N:12]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=2)[C:11]1=[O:10])(=[O:43])=[O:42]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% in mineral oil, 6 mg, 0.15 mmol) and triethylamine (26 μL, 182 μmol) are added to a solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 1, 25 mg, 61 μmol) in tetrahydrofuran (600 μL), and the mixture is stirred at room temperature for 15 min. Methanesulfonyl chloride (6 μL, 0.07 mmol) is added, and the mixture is stirred for 2.5 h and purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 13 mg; ESI mass spectrum [M+H]+=490; Retention time HPLC: 0.95 min (Z018_S04).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[NH:41][CH:42]=[C:43]([CH2:45][C:46]([F:49])([F:48])[F:47])[N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]5[NH:41][CH:42]=[C:43]([CH2:45][C:46]([F:49])([F:47])[F:48])[N:44]=5)=[O:59])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nc(CC(F)(F)F)c[nH]4)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nc(CC(F)(F)F)c[nH]4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[1-(2,2,2-trifluoroethylimidazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (150 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (79 mg) in dichloromethane (10 ml) at −78° C. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=1:1→ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[1-(2,2,2-trifluoroethylimidazol-2-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (60 mg) (Compound 344) as yellow amorphous.
Reaction SMILES: [OH-].[K+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]Br)=[CH:11][CH:10]=1>CN(C=O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[CH:11][CH:10]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: c1nc[nH]n1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Brc1ccc(Cn2cncn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
DMF and KOH (3.3 g, 58 mmol) were stirred together at rt for 5 minutes before adding 1,2,4-triazole (1 g, 14.5 mmol). After a further 30 minutes, the reaction mixture was cooled to 0° C. and 1-bromo-4-bromomethyl-benzene (7.2 g, 29 mmol) was added dropwise over 5 minutes. The reaction mixture was heated to 60° C., then cooled to rt, extracted with ethyl acetate and water, and subsequently dried over K2CO3. The solvent was evaporated to yield yellow-white crystals, which, upon repeated recrystallisation, (ethylacetate/isohexane) yielded 0.60 g of the sub-title compound as white crystals (62% isolated yield).
Reaction SMILES: I[Si](C)(C)[CH3:3].[C:6]([C:11]1[C:12](=[O:30])[CH2:13][CH:14]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH2:26][O:27][CH3:28])[C:19]=2[CH3:29])[CH2:15][C:16]=1[OH:17])(=[O:10])[CH2:7][CH2:8][CH3:9]>C(#N)C>[C:6]([C:11]1[C:16](=[O:17])[CH2:15][CH:14]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH2:26][O:27][CH2:28][CH3:3])[C:19]=2[CH3:29])[CH2:13][C:12]=1[OH:30])(=[O:10])[CH2:7][CH2:8][CH3:9]
Reactant: C[Si](C)(C)I
Reactant: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)c(COC)c2C)CC1=O
Solvent: CC#N
Product: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)c(COCC)c2C)CC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
Iodotrimethylsilane (0.5 ml) was added to a solution of 2-butyryl-3-hydroxy-5-(3-methoxymethyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (1.50 g; 4.36 mmole) (see Example 36) in dry acetonitrile (10 ml) under nitrogen and the mixture was stirred at room temperature for 15 minutes. The solvent was evaporated and the residue was stirred with an ethanolic potassium hydroxide solution at room temperature for 15 hours. The solution was poured into dilute hydrochloric acid and then extracted with diethyl ether. The ether extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Purification by column chromatography over silica gel (eluant dichloromethane) gave 2-butyryl-5-(3-ethoxymethyl-2,4,6-trimethylphenyl)-3-hydroxycyclohex-2-en-1-one (1.32 g; 84.7%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccccc1C
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C(=O)CCC(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 10 %

Procedure:
24.5 g of O-methylanisole and 20.0 g of succinic anhydride were dissolved in 230 ml of methylene chloride. Holding the temperature of the reaction solution below 5° C., 84 g of aluminum chloride were slowly added. After the addition was complete, the reaction mixture was stirred for 1 hour at a temperature below 5° C. and for an additional 5 hours at room temperature. It was then allowed to stand for one day and overnight at room temperature, after which the reaction mixture was poured into ice-cooled dilute hydrochloric acid and the resulting precipitate was collected by filtration. The precipitate was washed and then dissolved in ethanol. This solution was dried by azeotropic distillation and then evaporated to dryness. 4.16 g of the title compound were obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20]Cl)[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33].C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:22][N:23]3[C:27](=[O:28])[C:26]4[C:25](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:24]3=[O:33])[N:14]([CH2:15][C:16]([OH:18])([CH3:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(O)Cn1c(CCl)nc2c(N)nc3ccccc3c21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(O)Cn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.4 %

Procedure:
A solution of 1-[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (1.00 g, 3.28 mmol) in DMF (3.0 mL) was added to a solution of N-hydroxyphthalimide (642 mg, 3.94 mmol) and triethylamine (0.915 mL, 6.56 mmol) in DMF (3.0 mL). The flask containing the solution of 1-[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol was rinsed with DMF (3.0 mL), which was added to the reaction solution. The solution was stirred at room temperature for 3 hours and a solid formed. The solid was isolated by filtration, washed with dichloromethane, and dried. The off-white solid was dissolved in hot DMF (20 mL). Acetonitrile (50 mL) was added to the solution, which was then placed in a freezer. Crystals formed and were isolated by filtration, washed with acetonitrile, and dried to provide 288 mg of 2-{[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}-1H-isoindole-1,3(2H)-dione as orange crystals, mp 270.0-272.0° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[H-].[Na+].[S:11]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[CH2:26][OH:27])([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>CN(C=O)C>[Br:8][C:6]1[CH:7]=[C:2]([O:27][CH2:26][C@@H:22]2[CH2:23][CH2:24][CH2:25][N:21]2[S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=2)(=[O:13])=[O:12])[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2COc2cncc(Br)c2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a suspension of 3,5-dibromopyridine (1.5 g, 6.05 mmol) and 60% NaH (307 mg, 7.7 mmol) in DMF (6 mL) was added 1-tosyl-2-(S)-pyrrolidinemethanol (1.4 g, 5.5 mmol), and the reaction mixture was stirred for 4 hours at room temperature and 1 hour at 60° C. The DMF was removed under reduced pressure, and the residue was chromatographed on a silica gel column, eluting with EtOAc/hexane 6:1 to afford the title compound (1.2 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]=[CH:12][NH:13][C:14](=[O:15])[C:5]=3[C:4]=2[CH:3]=1.[Al].C1C(=O)N([Br:24])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:24][C:11]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=3[C:5]=2[C:14](=[O:15])[NH:13][CH:12]=1
Reactant: O=c1[nH]ccc2[nH]c3ccc(F)cc3c12
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1[nH]cc(Br)c2[nH]c3ccc(F)cc3c12
Reaction time: 1 h

Procedure:
8-Fluoro-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (10 g, 49 mmol) was dissolved in 400 mL DMF and covered with aluminum foil. NBS was added in a single portion and the solution was stirred for 1 hr at which time the reaction mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, filtered, concentrated. The crude residue purified on silica gel and eluted with EtOAc/hexanes (0 to 75% gradient elution).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[Br:13][CH2:14][C@@H:15]([CH3:18])[CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:16][C@H:15]([CH3:18])[CH2:14][Br:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: C[C@@H](CO)CBr
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)Cc1cccc(OC[C@H](C)CBr)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.5 %

Procedure:
To a stirring solution of (3-hydroxy-phenyl)-acetic acid methyl ester (0.75 g, 0.0045 mole) in anhydrous toluene (30 mL) was added (S)-(+)-3-bromo-2-methyl-1-propanol (0.90 g, 0.0059 mole). Polymer bound triphenylphosphine (2.4 g, 0.0072 mole, 3 mmol/g, Fluka Chemie) was then added, and the mixture was stirred for 15 minutes. The reaction mixture was then cooled to 0° C. and diisopropylazodicarboxylate (1.1 g, 0.00560 mole) was added In a dropwise fashion. After stirring at room temperature overnight, the crude reaction mixture was filtered, and the solid washed with toluene. After concentration of the filtrate in vacuo, the crude product was purified by column chromatography over silica gel (silica gel 60, EM Science) using 15% EtOAc:hexane as eluent to afford 0.86 g (63% yield) of the title compound as an oil: MS (ESI) 303.0 (M+2H+).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2I.[N:24]1([CH2:29][CH2:30][OH:31])[CH:28]=[CH:27][CH:26]=[N:25]1>C1(C)C=CC=CC=1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2[O:31][CH2:30][CH2:29][N:24]1[CH:28]=[CH:27][CH:26]=[N:25]1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(C3OCCO3)ccc21
Reactant: OCCn1cccn1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1nc(OCCn2cccn2)c2cc(C3OCCO3)ccc21
Temperature: 140 °C

Procedure:
The title compound was prepared from 300 mg (0.672 mmol) 5-(1,3-dioxolan-2-yl)-3-iodo-1-([2-(trimethylsilyl)ethoxy]methyl)-1H-indazole (Example 6A) in analogy to the procedure described in Example 21A. The procedure was modified by using 5 equivalents of 2-(1H-pyrazol-1-yl)-ethanol as the alcohol reactant and by switching to toluene as solvent. The reaction mixture was heated to 140° C. for 2 h using microwave irradiation, after which time the same amounts of catalyst and ligand were added again. This cycle was repeated one more time. The crude product thus obtained was purified by preparative RP-HPLC (acetonitrile/water gradient) to afford 153 mg (52% of th.) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1.Cl.Cl[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1
Reactant: ClCc1cccnc1
Reactant: CC(C)(C)CNc1nc(C#N)nc2ccc(O)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)CNc1nc(C#N)nc2ccc(OCc3cccnc3)cc12

Procedure:
4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.25 mmol), 3-chloromethyl-pyridine hydrochloride (0.38 mmol) and cesium carbonate (2.5 mmol) are stirred in DMF (3 ml) at RT for 20 hours. Water is added until a clear solution is formed. Then more water is added until the solution gets turbide. The precipitate formed is filtered off, washed with water and dried (vacuum). A powder with mp. 156-158° C., Rf=0.35 (CH2Cl2/MeOH=15:1) is obtained.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]([F:33])([F:32])[C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=1)[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1>C1COCC1>[F:33][C:11]([F:10])([F:32])[C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=1)[O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[C:23]3=[N:28][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:24]3[CH:25]=[CH:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: Nc1ncccc1-c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4cccc(C(F)(F)F)c4)cc3)C2=N1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 210 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.331 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyridin-2-amine (347 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. carefully. Water was added to form precipitates which were washed with water and hexane, collected and dried in vacuo to give the title compound (234 mg) as a white powder. A part of this product was crystallized from MeCN-THF/IPE as colorless crystals.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:31])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:30]=[CH:29][C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=3)[CH:20]=2)[C:16]=1Cl)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[C:36]([CH3:43])=[C:37]2[C:42]=1[O:41][CH2:40][CH2:39][CH2:38]2.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:31])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:30]=[CH:29][C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=3)[CH:20]=2)[C:16]=1[C:35]1[C:36]([CH3:43])=[C:37]2[C:42](=[C:33]([F:32])[CH:34]=1)[O:41][CH2:40][CH2:39][CH2:38]2)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cc(F)c2c1CCCO2
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1-c1cc(F)c2c(c1C)CCCO2
Temperature: 120 °C
Yield: 41.6 %

Procedure:
A mixture of (S)-methyl 2-(tert-butoxy)-2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (50 mg, 0.113 mmol), 2-(8-fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (36.4 mg, 0.124 mmol) and 2M Na2CO3 (0.113 mL, 0.226 mmol) in DMF (1.5 mL) was added tetrakis(triphenylphosphine)pallafium(0) (13.07 mg, 0.011 mmol) and the mixture was subjected to microwave heating at 120° C. for 1 h. The mixture was then filtered and purified by prep HPLC to afford atrope isomer 1 (major, first eluting): (2S)-methyl 2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (27 mg, 0.047 mmol, 41.7% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ: 7.56 (d, J=7.9 Hz, 1H), 7.52 (s, 1H), 7.09 (d, J=7.9 Hz, 1H), 6.92 (d, J=10.7 Hz, 1H), 6.84 (s, 1H), 5.03 (s, 1H), 4.41-4.32 (m, 2H), 3.66 (s, 3H), 2.88-2.78 (m, 6H), 2.77 (s, 3H), 2.26-2.17 (m, 2H), 1.86 (s, 3H), 1.85-1.79 (m, 4H), 1.19 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH:24]3[CH2:28][OH:29])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:9]=1)(C)(C)C.[ClH:31].CO>>[ClH:31].[NH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:15]=[CH:16][C:17]([S:20]([N:23]3[CH2:27][CH2:26][CH2:25][C@@H:24]3[CH2:28][OH:29])(=[O:22])=[O:21])=[CH:18][CH:19]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(S(=O)(=O)N3CCCC3CO)cc2)n1
Agent: Cl
Solvent: CO
Product: Nc1cccc(-c2ccc(S(=O)(=O)N3CCC[C@@H]3CO)cc2)n1
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of {6-[4-(2-hydroxymethyl-pyrrolidine-1-sulfonyl)-phenyl]pyridin-2-yl}carbamic acid tert-butyl ester (15.0 g, 34.6 mmol) in HCl/MeOH (50 mL, 2M) was heated at reflux for 2 h. After cooling to room temperature, the reaction mixture was evaporated under vacuum and washed with EtOAc to give (R)-(1-(4-(6-aminopyridin-2-yl)phenylsulfonyl)pyrrolidin-2-yl)methanol hydrochloride (C-2; 11.0 g, 86%). 1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, J=8.7 Hz, 2H), 7.93-7.99 (m, 3H), 7.31 (d, J=7.2 Hz, 1H), 7.03 (d, J=8.7 Hz, 1H), 3.53-3.57 (m, 2H), 3.29-35 (m, 2H), 3.05-3.13 (m, 1H), 1.77-1.78 (m, 2H), 1.40-1.45 (m, 2H). MS (ESI) m/z (M+H)+334.2.