Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][N:37]([CH3:48])[CH2:38][CH2:39][CH2:40][N:41]([CH3:47])[CH2:42][CH2:43][CH2:44][NH:45][CH3:46].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:45]([CH2:44][CH2:43][CH2:42][N:41]([CH2:40][CH2:39][CH2:38][N:37]([CH3:36])[CH3:48])[CH3:47])[CH3:46])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CNCCCN(C)CCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(N(C)CCCN(C)CCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 56.2 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (20 mg, 0.04 mmol) in CH2Cl2 (1 mL) were added N-[3-(dimethylamino)propyl]N,N′-dimethyl-1,3-propanediamine (0.004 mL, 0.02 mmol) and triethylamine (0.05 mL, 0.36 mmol). The resultant solution was stirred at room temperature over night. The reaction mixture was concentrated. Separation via a HPLC followed by treatment with t-amino SPE cartridge then provided the title compound as a white solid (7 mg, 29%). LC-MS m/z 609 (M+H)+; 1H-NMR (MeOD) δ 1.29 (d, 6H), 1.95 (m, 4H), 2.33 (s, 3H), 2.75 (s, 3H), 2.78 (s, 3H), 2.92 (s, 3H), 3.17 (m, 6H), 3.50 (m, 2H), 4.15 (s, 2H), 4.23 (m, 1H), 7.19 (m, 2H), 7.48 (d, 1H), 7.55 (m, 1H), 7.71 (s, 1H), 7.86 (d, 1H).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6](=O)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[N:9]=1.[BH4-].[Na+].CC(C)=O>CO>[Br:14][C:10]1[N:9]=[C:8]([CH2:7][CH:6]2[O:16][C:3](=[O:2])[CH2:4][CH2:5]2)[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CCC(=O)Cc1cccc(Br)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: O=C1CCC(Cc2cccc(Br)n2)O1
Temperature: 1.5 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 490 mg of 5-(6-bromo-2-pyridyl)-4-oxo-pentanoic acid methyl ester in 20 ml of methanol is mixed under ice cooling with 72 mg of sodium borohydride and stirred for 1 hour at 0-3° C. Then, 2 ml of acetone is added, stirred for 1 more hour and the reaction mixture is evaporated to dryness. The residue is distributed between water and ethyl acetate, the organic phase is dried on sodium sulfate and concentrated by evaporation. 421 mg of 5-[(6-bromo-2-pyridyl)-methyl]-tetrahydrofuran-2-one is obtained as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12](=[O:14])[CH3:13])[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[OH:9].Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:11][O:10][C:7]1[CH:6]=[C:5]([C:12](=[O:14])[CH3:13])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: COc1cc(C(C)=O)cc(OC)c1O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)cc(OC)c1OCCN1CCOCC1
Temperature: 80 °C
Yield: 69.8 %

Procedure:
In a vial, 500 mg (2.5 mmol) of 3′,5′-dimethoxy-4′-hydroxyacetophenone was combined with 4-(2-chloroethyl)morpholine hydrochloride (600 mg, 3.2 mmol), and powdered potassium carbonate (1.5 g, excess). Dimethylformamide (2 mL) was added, the vial was sealed, and the rxn was heated to 80° C. overnight. The reaction was diluted with water and extracted with diethyl ether. The organic extract was washed with brine, dried (Na2SO4), and evaporated in vacuo to afford 540 mg (67%) of 14 as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:17]2[C:12](=[C:13]([O:26]C(=O)C)[C:14]([O:22]C(=O)C)=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[S:11][C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[CH3:2].[OH-].[Na+].C(O)(=O)C>CC(C)=O>[C:1]([N:4]1[C:17]2[C:12](=[C:13]([OH:26])[C:14]([OH:22])=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[S:11][C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c2c(c3ccccc3c1OC(C)=O)N(C(C)=O)c1ccccc1S2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N1c2ccccc2Sc2c(O)c(O)c3ccccc3c21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 28 %

Procedure:
To a suspension of 12-acetyl-5,6-diacetoxy-12H-benzo[a]phenothiazine (450 mg) in acetone (10 ml) there was added 2N aqueous sodium hydroxide solution (10 ml) and the resulting mixture was stirred at room temperature for 45 minutes. It was then made slightly acidic by the addition of 10% aqueous acetic acid solution and the insolubles filtered and washed with water. The solid was swished in ethyl acetate to afford pure title compound (100 mg), m.p. 258°-260° C.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH:7]=[O:8])[CH2:3][CH2:4][C:5]#[N:6].[O-:10][Mn](=O)(=O)=O.[K+].C(Cl)Cl>CC(O)(C)C>[C:5]([CH2:4][CH2:3][C:2]([CH3:9])([CH3:1])[C:7]([OH:10])=[O:8])#[N:6]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)(C=O)CCC#N
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CC(C)(CCC#N)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4,4-dimethyl-5-oxopentanenitrile (1.0 g, 7.98 mmol) in t-BuOH (2 mL) was cooled to 0° C. and 5% aqueous NaH2PO4 solution (11 mL) was added dropwise. 1M KMnO4 solution (16 mL) was added dropwise to the reaction mixture at 0° C. followed by few drops of CH2Cl2 (0.5 mL). The reaction mixture was allowed to stir at 0° C. for 1 h, and quenched with sodium sulfite. 1.5N HCl was then added to adjust the pH of the solution to ˜3. The organic product was extracted with EtOAc and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure to get 4-cyano-2,2-dimethylbutanoic acid (0.9 g, crude), which was carried through without further purification. 1H NMR (300 MHz, CDCl3) δ 5.55 (br s, 1H), 2.43-2.37 (m, 2H), 1.99-1.94 (m, 2H), 1.28-1.27 (m, 6H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[C:14]([CH3:15])=[N:13][NH:12][C:11]=3[NH2:16])[S:9][C:5]=2[CH:4]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:15][C:14]1[C:10]([C:8]2[S:9][C:5]3[CH:4]=[C:3]([CH2:2][N:23]4[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]4)[CH:18]=[CH:17][C:6]=3[N:7]=2)=[C:11]([NH2:16])[NH:12][N:13]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(CBr)cc2s1
Reactant: CN1CCNCC1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(CN3CCN(C)CC3)cc2s1

Procedure:
The title compound (9 mg) was prepared starting from 20 mg of 4-(6-bromomethylbenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine and excess 1-methylpiperazine. MS (m/z, ES+): 343.1 (M+1, 20%), 244.1 (M−CH3N(CH2)4N+1, 100%).
Reaction SMILES: B(F)(F)F.CCOCC.C([SiH](CC)CC)C.[CH2:17]([O:24][C@H:25]1[C@H:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@H:29]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:28]([CH3:47])[O:27][C@@:26]1([CH2:49][P:50](=[O:57])([O:54][CH2:55][CH3:56])[O:51][CH2:52][CH3:53])O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH2:17]([O:24][C@H:25]1[C@H:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@H:29]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:28]([CH3:47])[O:27][C@@H:26]1[CH2:49][P:50](=[O:57])([O:51][CH2:52][CH3:53])[O:54][CH2:55][CH3:56])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOP(=O)(C[C@@]1(O)O[C@@H](C)[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)OCC
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Product: CCOP(=O)(C[C@H]1O[C@@H](C)[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)OCC
Temperature: 0 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
Boron trifluoride diethyl etherate (0.079 mL, 0.644 mmol, commercially available from Sigma Aldrich) and triethylsilane (0.103 mL, 0.644 mmol, Sigma Aldrich) were added to a stirred solution of diethyl (((2S,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)methyl)phosphonate (0.251 g, 0.429 mmol) in acetonitrile (2 mL) at 0° C. under an argon atmosphere. The reaction mixture was then stirred at 0° C. for 5 h. The reaction mixture was next partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography (30 to 100% EtOAc/hexanes gradient) to give diethyl (((2S,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)methyl)phosphonate as a colorless oil (0.220 g, 90% yield). 1H NMR (400 MHz, CDCl3): δ ppm 1.14 (d, J=6.26 Hz, 3 H) 1.26 (td, J=7.04, 1.96 Hz, 6 H) 1.92 (td, J=15.75, 9.78 Hz, 1 H) 2.29 (ddd, J=19.95, 15.36, 1.47 Hz, 1 H) 3.53 (q, J=6.39 Hz, 1H) 3.56-3.70 (m, 4 H) 3.98-4.11 (m, 4 H) 4.63-4.77 (m, 4 H) 4.97 (dd, J=11.44, 1.86 Hz, 2 H) 7.26-7.39 (m, 15 H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>>[C:11]([N:5]1[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8])([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C(Cl)OCc1ccccc1
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Yield: 58 %

Procedure:
According to the literature procedure (J. Am. Chem. Soc. 189 (1957)), trans-4-hydroxy-L-proline (5.12 g, 0.039 mol) was treated with benzyl chloroformate (8.5 mL, 0.06 mol) to provide the title compound (6.0 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][CH2:9][CH:10]([F:12])[F:11])[CH:3]1[C:14]([OH:16])=[O:15].[C:18]([CH:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)#[CH:19]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][CH2:9][CH:10]([F:11])[F:12])[C@H:3]1[C:14]([O:16][C@H:20]([C:18]#[CH:19])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)=[O:15]
Reactant: C#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(/C=C\C(=O)OCC(F)F)C1C(=O)O
Solvent: ClC(Cl)Cl
Product: C#C[C@@H](OC(=O)[C@@H]1[C@H](/C=C\C(=O)OCC(F)F)C1(C)C)c1cccc(Oc2ccccc2)c1

Procedure:
Using the procedure of Step F of Example 9, (1R, cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2,2-difluoroethoxy)-1-propenyl]-cyclopropane-carboxylic acid and α-ethynyl-3-phenoxy-benzyl alcohol were reacted to obtain (R)α-ethynyl-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2,2-difluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+47°±1.5° (c=1% in CHCl3).
Reaction SMILES: [C:1]([C:9]1[O:10][C:11]2[C:17]([O:18]C)=[CH:16][CH:15]=[C:14]([C:20]([NH:22][C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])=[O:21])[C:12]=2[CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.O>ClCCl>[C:1]([C:9]1[O:10][C:11]2[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([C:20]([NH:22][C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])=[O:21])[C:12]=2[CH:13]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cccc2Cl)c2cc(C(=O)c3ccccc3)oc12
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc2c(C(=O)Nc3c(Cl)cccc3Cl)ccc(O)c2o1
Temperature: -78 °C
Yield: 46.9 %

Procedure:
Under a nitrogen atmosphere, Compound 168 (0. 04 g) obtained in Example 168 was dissolved in dry dichloromethane (2 ml) and the solution was cooled to −78° C. A 2.4M solution (0.125 ml) of boron tribromide in dichloromethane was slowly and dropwise added to the solution, and then the mixture was warmed to the room temperature and stirred one night. Distilled water (5 ml) was added to the mixture followed by stirring for one hour. The reaction solution was extracted with chloroform, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Compound 169 (0.02 g, 46.9%) as a pale-yellow solid.
Reaction SMILES: [OH-:1].[Na+].OO.[CH3:5][C:6]1[C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH:11]=1>CO.O>[CH3:5][C:6]12[O:12][CH:7]1[CH2:8][CH2:9][CH2:10][C:11]2=[O:1]
Reactant: CC1=CCCCC1=O
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC12OC1CCCC2=O
Reaction time: 0.17 h
Yield: 66.8 %

Procedure:
At room temp., 2N aqueous sodium hydroxide (7.00 mL, 14.0 mmol), followed by 30% aqueous hydrogen peroxide (11.0 mL, 112 mmol) was added to a stirred solution of commercially available 2-methylcyclohex-2-enone (2.20 g, 20.0 mmol) in methanol (250 mL), upon which the resulting red color of the solution faded within 10 min. After stirring at room temp. for 24 h, the reaction mixture was diluted with water (200 mL) and extracted with dichloromethane (3×150 mL). The combined organic extracts were washed with water (200 mL) and dried with sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue purified by chromatography on silica gel [40 g; pentane-Et2O (9:1); Rf=0.29] to furnish 1-methyl-7-oxabicyclo[4.1.0]heptan-2-one (1.18 g, 47%) as a colourless liquid.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[CH:9][CH:10]([OH:12])[CH3:11])[CH3:8].[H][H]>[Pd].C(O)C>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH2:9][CH:10]([OH:12])[CH3:11])[CH3:8]
Reactant: [H][H]
Reactant: CC(=CC(C)O)c1ccccc1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(O)CC(C)c1ccccc1-c1ccccc1

Procedure:
To a pressure vessel, mixture of 0.675 g. of 2-(p-biphenylyl)-2-penten-4-ol (obtainable by Example 1) and 0.5 g. 10% palladium on carbon in 175 ml. of ethanol, is added hydrogen at about 2 at. pressure via below pressure hydrogenation. The catalyst is then removed, and the solution is evaporated to give a colorless oil which solidifies on standing to give solid 2-(p-biphenylyl)-pentan-4-ol, m.p. 53° C., which may also be designated 4-(p-biphenylyl)-pentan-2-ol.
Reaction SMILES: [Cl:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([O:12]C)[N:11]=[C:6]2[CH:5]=[CH:4][N:3]=1.B(Br)(Br)Br.ClCCl>ClCCCl>[Cl:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([OH:12])[N:11]=[C:6]2[CH:5]=[CH:4][N:3]=1
Reactant: COc1cnc2c(Cl)nccc2n1
Agent: BrB(Br)Br
Solvent: ClCCCl
Solvent: ClCCl
Product: Oc1cnc2c(Cl)nccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 153.8 %

Procedure:
A pressure-resistant vessel was charged with 5-chloro-2-methoxypyrido[3,4-b]pyrazine (5.0 g, 26 mmol) and DCE (25 mL). To this was added a 1M solution of boron tribromide in dichloromethane (82 mL, 82 mmol) slowly via syringe. The vessel was sealed, and the reaction was stirred at ambient temperature overnight. After 16 hours, the reaction was quenched by slow addition of the reaction mixture into a beaker containing methanol (100 mL) and ice. The resulting yellow solution was concentrated to a tan slurry, which was triturated with ethyl acetate (50 mL). The off-white precipitate was collected by vacuum filtration, washed with ethyl acetate, and dried in vacuo to provide the title compound (7.2 g, 40 mmol, 155% yield) along with some bromide salts. LC/MS (ESI+) m/z: 182.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[BH4-].[Na+]>C(O)C>[OH:12][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:11])[C:2]1([CH3:13])[CH3:1]
Reactant: CC1(C)C(=O)c2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1(C)C(=O)c2ccccc2C1O

Procedure:
To a solution of 2,2-dimethyl-indan-1,3-dione (430 mg, 2.47 mmol), in ethanol (80 mL) at −30° C. is added a solution of NaBH4 (29 mg, 0.74 mmol) in ethanol (3 mL). After one h the reaction is quenched with saturated aqueous NH4Cl and the mixture is brought to room temperature. The reaction mixture is concentrated to approximately half of its original volume and then diluted with ethyl acetate and washed with water. The aqueous layer is then back-extracted twice with ethyl acetate. The organic layers are combined, dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:6) to afford 3-hydroxy-2,2-dimethyl-indan-1-one; MS (ESI) m/z 177.0 (M+H)+.
Reaction SMILES: [OH-].[K+].[C:3](=[S:5])=S.[NH2:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:8]=1[OH:16]>CCO.O>[N+:13]([C:12]1[C:7]2[NH:6][C:3](=[S:5])[O:16][C:8]=2[CH:9]=[CH:10][CH:11]=1)([O-:15])=[O:14]
Reactant: S=C=S
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cccc2oc(=S)[nH]c12
Yield: 78.6 %

Procedure:
A solution of KOH (3.31 g, 59.0 mmol) in EtOH and water was treated with carbon disulfide (10.4 g, 136.3 mmol) followed by 2-amino-3-nitrophenol (7.00 g, 45.4 mmol). The mixture was heated at reflux temperature overnight, cooled, concentrated, acidified with 1M HCl and filtered. The filtercake was washed with water and dried in vacuo to provide the title compound (7.0 g, 79%), characterized by NMR and mass spectral analyses.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[CH:18]1[C:23]([CH:24]=O)=[CH:22][C:21]2[O:26][CH2:27][O:28][C:20]=2[CH:19]=1>>[CH3:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]1[CH:24]([C:23]3[CH:18]=[CH:19][C:20]4[O:28][CH2:27][O:26][C:21]=4[CH:22]=3)[NH:5][CH:4]([C:3]([O:2][CH3:1])=[O:17])[CH2:6][C:7]2=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccc(C)cc12
Reactant: O=Cc1ccc2c(c1)OCO2
Product: COC(=O)C1Cc2c([nH]c3ccc(C)cc23)C(c2ccc3c(c2)OCO3)N1

Procedure:
The cis and trans isomers of the title compound were prepared using the method described in Intermediate 1 but starting from racemic 5-methyl-tryptophan methyl ester and piperonal.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][CH:4]=1.[CH3:13][Mg]Cl.[Cl-].[NH4+]>C1COCC1>[F:12][C:2]([F:11])([F:1])[C:3]1[N:8]=[CH:7][C:6]([CH:9]([OH:10])[CH3:13])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C

Procedure:
To a solution of 2.0 g 6-trifluoromethyl-pyridine-3-carboxaldehyde in 20 mL of dry THF under inert atmosphere at −78° C. was added dropwise 6 ml of MeMgCl (3 M in THF). This mixture was allowed to warm up to room temperature slowly. Aqueous ammonium chloride was added to reaction mixture. The whole was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulphate. Purification by flash chromatography (silica, haptane/ethyl acetate) provided 0.85 g of 1-(6-trifluoromethyl-pyridin-3-yl)-ethanol.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.C1(C)C(S(O)(=O)=O)=CC=CC=1.[Cl:22][C:23]1[CH:30]=[C:29]([F:31])[C:28]([C:32]2[C:36]([Cl:37])=[C:35]([O:38][CH:39]([F:41])[F:40])[N:34]([CH3:42])[N:33]=2)=[CH:27][C:24]=1C=O.C(N(CC)CC)C>O1CCCC1>[Cl:37][C:36]1[C:32]([C:28]2[CH:27]=[C:24]([CH:1]([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])[C:23]([Cl:22])=[CH:30][C:29]=2[F:31])=[N:33][N:34]([CH3:42])[C:35]=1[O:38][CH:39]([F:41])[F:40]
Reactant: Cn1nc(-c2cc(C=O)c(Cl)cc2F)c(Cl)c1OC(F)F
Reactant: CCOC(OCC)OCC
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(OCC)c1cc(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc1Cl

Procedure:
20 ml of triethyl orthoformate and 0.1 g of toluenesulfonic acid were added to a solution of 3 g (8.8 mmol) of 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorobenzaldehyde in 50 ml of tetrahydrofuran. After the mixture had been refluxed for 2 hours, it was treated with 3 ml of triethylamine. The mixture was subsequently concentrated. The residue was treated with 50 ml of water. The product was subsequently extracted from the aqueous phase using ethyl acetate. The organic phase was then washed using saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and finally concentrated. The crude product was purified by means of column chromatography on silica gel (eluent: hexane/ethyl acetate=9:1). Yield: 1 g.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH:5]=[CH2:6])[CH:3]=[CH2:4].[C:8]1([PH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:15]1([P:14]([CH2:4][CH2:3][Si:2]([CH2:5][CH2:6][P:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH3:7])[CH3:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=C[Si](C)(C)C=C
Product: C[Si](C)(CCP(c1ccccc1)c1ccccc1)CCP(c1ccccc1)c1ccccc1

Procedure:
A mixture of 9.0 g (0.8 mole) dimethyl divinyl silane and 32.7 g (0.176) diphenyl phosphine (10% excess over equivalent amounts) was reacted for 22 hours in the manner described in Example 1. The reaction mixture was fractionated in vacuo to obtain minor amounts of the clear, colorless, slightly viscous liquid monoadduct, and major amounts of the clear, colorless, highly viscous liquid diadduct, i.e. the desired bis-(diphenylphosphinoethyl)dimethyl silane. The distillation yield of desired product was 84%. The bis-diphenylphosphinoethyl)dimethyl silane product had a boiling point of 238°-239° at 0.20 mm.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[N:7]=1.[OH:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]([C:23]2[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[CH:24]=2)=[O:22])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:12][CH2:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[CH:24]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[N:7][N:6]2[CH:8]=1
Reactant: OCc1cn2nc(I)ccc2n1
Reactant: Cc1cc(C(=O)Nc2cccc(O)c2)n(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(CO)cn4n3)c2)n(C)n1
Temperature: 150 °C
Reaction time: 16 h
Yield: 12.8 %

Procedure:
To a solution of (6-iodoimidazo[1,2-b]pyridazin-2-yl)methanol (400 mg, 1.45 mmol) in N,N-dimethylformamide (4.0 mL) were added N-(3-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (504 mg, 2.18 mmol) and potassium carbonate (402 mg, 2.91 mmol), and the mixture was stirred at 150° C. for 16 hr. After cooling the mixture to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/ethanol=100/0→10/1) to give the title compound (70 mg, 13%) as a white powder.