Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][CH2:8][CH3:9])=[N:4][C:3]=1[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.Cl[C:19]([O:21][CH3:22])=[O:20]>C1COCC1>[CH2:7]([C:5]1[O:6][C:2]([C:19]([O:21][CH3:22])=[O:20])=[C:3]([CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:4]=1)[CH2:8][CH3:9]
Reactant: CCCc1nc(COC2CCCCO2)c(Br)o1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Product: CCCc1nc(COC2CCCCO2)c(C(=O)OC)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To a solution of 5-bromo-2-propyl-4-(((2-tetrahydropyranyl)oxy)methyl)oxazole (2.376 g, 7.82 mmol), prepared as in Example 29c, in 60 mL of THF and cooled to -78° C. was added n-buthylithium (8.75 mmol). The resulting solution was stirred for 30 minutes at -78° C., and 1.0 mL (12.9 mmol) of methyl chloroformate was added. The reaction mixture was stirred at -78° C. for 5 minutes and at 0° for 30 minutes. The reaction was quenched by the addition of satd NaHCO3, the layers were separated, and the aqueous layer extracted with methylene chloride. The organic extracts were combined, dried, and concentrated. The residue was chromatographed on silica gel, eluting with 10 to 25% ethyl acetate in hexane, to afford 1.660 g of the title compound as an oil. MS m/z: 284 (M+H)+. NMR (CDCl3) δ:4.95 (d, J=12 Hz, 1H), 4.82 (t, J=3 Hz, 1H), 4.67 (d, J=12 Hz, 1H), 3.94 (m, 1H), 3.92 (s, 3H), 3.57 (m, 1H), 2.80 (t, J=7.5 Hz, 2H), 1.84 (sextet, J=7.5 Hz, 2H), 1.80-1.50 (m, 6H), 1.05 (t, J=7.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=O.C([SiH](CC)CC)C.FB(F)F.[OH-].[Na+]>ClCCl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([CH2:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ccc(Cl)cc1Cc1ccccc1Cl
Temperature: 25 °C
Yield: 47.1 %

Procedure:
To 10 g of (2-amino-5-chlorophenyl) (2-chlorophenyl)methanone dissolved in 100 ml of dichloromethane are added at room temperature 18.7 ml of triethylsilane and 14.4 ml of trifluoroborane etherate, and the mixture is refluxed for 18 hours and then maintained at room temperature for 72 hours. The resulting mixture is hydrolysed with 2M sodium hydroxide solution, and the phases are separated by settling. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a cyclohexane/ethyl acetate solvent mixture to give 4.46 g of the expected product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[C:11]1[CH:26]=[CH:25][C:14]([O:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][C:11]1[CH:26]=[CH:25][C:14]([O:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:13][CH:12]=1)=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: Brc1ccc(OCCOC2CCCCO2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=Cc1cccc(Oc2ccc(OCCOC3CCCCO3)cc2)c1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
A solution of 3-hydroxybenzaldehyde (1.27 g, 10.4 mmol), tetrahydro-2-(2-(4-bromophenoxy)ethoxy)-2H-pyran (6.26 g, 20.8 mmol), potassium carbonate (2.23 g, 16.12 mmol) and copper (330 mg, 5.2 mmol) in pyridine (10 mL) was refluxed for 5 days. It was then cooled to r.t., filtered through Celite, diluted with ethylacetate (50 mL), and washed with H2O (3×40 mL). The organic was dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, ether:hexanes, 2:3) to afford tetrahydro-2-(2-(4-(3-formylphenoxy)phenoxy)ethoxy)-2H-pyran (3.09 g, 87%) as a pale yellow oil.
Reaction SMILES: [C:1](Cl)(=O)C.C(N(CC)CC)C.CO.[C:14]([C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][C:19]([N+:27]([O-:29])=[O:28])([CH2:20]3)[CH2:18]1)[CH2:24]2)([OH:16])=[O:15]>CN(C=O)C>[CH3:1][O:15][C:14]([C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][C:19]([N+:27]([O-:29])=[O:28])([CH2:20]3)[CH2:18]1)[CH2:24]2)=[O:16]
Reactant: O=C(O)C12CC3CC(C1)CC([N+](=O)[O-])(C3)C2
Reactant: CC(=O)Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C12CC3CC(C1)CC([N+](=O)[O-])(C3)C2
Reaction time: 2 h
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1-carboxy-3-nitroadamantane obtained by the method of Example 42 was dissolved in 10ml of DMF. To the mixture, 15 mmole of acetyl chloride was added dropwise over 30 minutes. The mixture was heated to begin to reflux around the conclusion of the addition. After refluxing for 2 hours, the mixture was cooled, 20 mmole of triethylamine was added, and then 11 mmole of methanol was added dropwise over 30 minutes while retaining the temperature of the mixture at 10° C. or less followed by stirring for more 2 hours. As a result, the conversion of 1-carboxy-3-nitroadamantane was 99%, and 1-methoxycarbonyl-3-nitroadamantane (yield 95%) was formed.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20](O)=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[CH:4][N:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([N:24]3[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]3)=[O:21])=[CH:10][C:9]=2[F:23])=[N:6][CH:7]=1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3C(=O)O)cc2F)cn1
Reactant: OC1CCNCC1
Product: Nc1cnc(-c2ccc(-c3ccccc3C(=O)N3CCC(O)CC3)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Step C of Example 504 using 4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid and piperidin-4-ol. MS (ESI): mass calcd. for C22H21FN4O2, 392.16; m/z found, 393.1 [M+H]+. 1H NMR (400 MHz, CDCl3) Complex due to the presence of multiple conformations on the NMR time-scale, peaks listed for identification purposes only: δ 8.54 (d, J=13.9), 8.11-8.05 (m), 7.98-7.83 (m), 7.47-7.27 (m), 6.72 (s), 4.68 (s), 4.24-4.05 (m), 3.76-3.53 (m), 3.27-3.18 (m), 2.91-2.80 (m), 2.62-2.51 (m), 1.82 (m), 1.69 (m), 1.51-1.45 (m), 1.26-1.18 (m), 0.48-0.41 (m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:12]2[CH2:13][NH:14][CH2:15][CH2:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18][CH2:19][C:20](Br)=[O:21]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[C:12]2[CH2:13][N:14]([C:20](=[O:21])[CH2:19][Br:18])[CH2:15][CH2:16][N:11]2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2cc3n(n2)CCNC3)cc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Product: O=C(CBr)N1CCn2nc(OCc3ccccc3)cc2C1

Procedure:
A solution of 2-(benzyloxy)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.02 g, 0.087 mmol) in a DCM (1 mL) was treated with bromoacetyl bromide (7.6 μL, 17.6 mg, 0.087 mmol) at 0° C. The solvents were evaporated in vacuo to yield 1-(2-benzyloxy-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-2-bromo-ethanone as a white solid, that was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([N:10]=[N+]=[N-])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[F:1][C:2]([F:13])([F:14])[CH:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [N-]=[N+]=NC(c1ccccc1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NC(c1ccccc1)C(F)(F)F
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a solution of α-(trifluoromethyl)benzylazide (849 mf, 4.22 mmol) in ether (10 mL), lithium aluminum hydride (160 mg, 12.7 mmol) was added. The reaction mixture was stirred at room temerature for 2 hours. Then 0.46 ml H2O, 0.51 mL of 15% NaOH and 1.06 mL of H2O were added. The solid was filtered. The liquid was concentrated under reduced pressure to give desired product (647 mg, 88%). EI-MS m/z 176 (M+).
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]1([CH2:11][N:12]2[CH2:17][CH:16]([C:18]([O:20][CH3:21])=[O:19])[C:15](=O)[CH:14]([CH3:23])[CH2:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>CO>[C:5]1([CH2:11][N:12]2[CH2:17][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:14]([CH3:23])[CH2:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C1CN(Cc2ccccc2)CC(C)C1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CN(Cc2ccccc2)CC(C)C1Nc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.5 %

Procedure:
Sodium cyanoborohydride (0.69 g, 11 mmole) and 26 g of 30A molecular sieves were slowly added at room temperature to a stirred solution of 1-phenylmethyl-3-methyl-5-methoxycarbonyl-4-piperidone (5.04 g, 18.3 mmole) from Example 3 in 200 ml of methanol, 10.22 g (110 mmole) of aniline and 9.48 ml of 3.86N hydrochloric acid (36.6 mmole) in methanol. The reaction mixture was stirred at room temperature for 3 days, after which time the molecular sieves were filtered off and the solution was made acidic with 10 ml of 20% hydrochloric acid. The methanol was evaporated under vacuum and the residue was diluted with 100 ml of water then extracted with ether. The aqueous layer was then made alkaline with dilute aqueous sodium hydroxide and extracted with 3×100 ml of ether. The combined organic layers were concentrated under vacuum to yield 3.87 g (60%) of crude 1-phenylmethyl-3-methyl-5-methoxycarbonyl-4 -(N-phenylamino)piperidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCCc1coc(-c2ccc(F)cc2)n1
Product: O=C(NCCc1coc(-c2ccc(F)cc2)n1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 27 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (45 mg, yield 27%). 1H NMR (400 MHz, DMSO-d6) δ 8.91 (t, J=5.4 Hz, 1H), 8.51 (s, 1H), 8.20 (d, J=7.9 Hz, 1H), 8.12 (d, J=8.2 Hz, 1H), 8.00-7.97 (m, 3H), 7.74-7.70 (t, J=7.8 Hz, 1H), 7.37-7.32 (t, J=8.8 Hz, 2H), 3.61-3.56 (m, 2H), 2.84-2.80 (t, J=7.0 Hz, 2H). MS (ESI) m/z: Calculated for C21H14F4N4O3: 446.10. found: 447.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9]Br)[CH:3]=1.C([S:14][CH2:15][C@@H:16]([CH3:20])[C:17]([OH:19])=[O:18])(=O)C.[OH-].[Na+].CCOC(C)=O>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[CH2:9][S:14][CH2:15][C@@H:16]([CH3:20])[C:17]([OH:19])=[O:18]
Reactant: Cc1cc(Br)cc(CBr)c1
Reactant: CC(=O)SC[C@@H](C)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc(CSC[C@@H](C)C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.55 g (21 mmol) 1-bromo-3-bromomethyl-5-methyl-benzene and 2.90 ml (21 mmol) (S)-3-acetylsulfanyl-2-methyl-propionic acid in 32 ml methanol is cooled in an ice bath and 4N aqueous sodium hydroxide (15.8 ml, 63 mmol) are added. The reaction mixture is stirred at rt for 3 hrs. EtOAc is added to the mixture and the organic layer is washed with water and brine and evaporated. Filtration over silica gel (flashmaster, hexane to hexane/EtOAc 4/6) gives the title compound.
Reaction SMILES: [CH2:1]([C:6]1[N:7]([CH2:34][CH2:35][CH3:36])[N:8]=[C:9]2[C:18]=1[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[N:11]=[C:10]2[N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:2][CH2:3][C:4]#[CH:5].Cl[CH2:38][CH:39]=[N:40][OH:41]>>[CH3:38][C:39]1[CH:5]=[C:4]([CH2:3][CH2:2][CH2:1][C:6]2[N:7]([CH2:34][CH2:35][CH3:36])[N:8]=[C:9]3[C:18]=2[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=[C:10]3[N:19]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[O:41][N:40]=1
Reactant: C#CCCCc1c2c3c(nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2nn1CCC)CCCC3
Reactant: ON=CCCl
Product: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3c(c2c1CCCc1cc(C)no1)CCCC3
Yield: 34.8 %

Procedure:
Using the method of Example 595 Part B, di(tert-butyl) 1-pent-4-ynyl-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (4.00 g, 8.05 mmol), prepared as described in Example 615, was reacted with α-chloroacetaldoxime (1.13 g, 12.1 mmol). The crude product was purified by chromatography (silica gel, elution with a gradient of 20-40% ethyl acetate in hexanes) to provide 1.55 g of di(tert-butyl) 1-[3-(3-methylisoxazol-5-yl)propyl]-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate as a glassy solid.
Reaction SMILES: [Cl:1][C:2](Cl)([Cl:6])C([O-])=O.[Na+].[C:9]([O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:11])[CH3:10].O>COCCOCCOC>[C:9]([O:12][CH2:13][C@H:14]1[C@H:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:2]1([Cl:6])[Cl:1])(=[O:11])[CH3:10]
Reactant: O=C([O-])C(Cl)(Cl)Cl
Reactant: CC(=O)OC/C=C/c1ccccc1
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: CC(=O)OC[C@H]1[C@H](c2ccccc2)C1(Cl)Cl
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A solution of sodium trichloroacetate (27.8 g, 150 mmol) in diglyme (20 ml) was added dropwise over 1 hour to a solution of trans-cinnamyl acetate (8.81 g, 50 mmol) in diglyme (80 ml) at 120° C. to 135° C. and the reaction mixture was heated at 120° C. to 125° C. for 1 hour. The reaction mixture was cooled to room temperature, poured into water (300 ml), extracted with n-hexane (300 ml+3×50 ml) and dried over MgSO4. The solvent was removed and the residue was distilled under vacuum affording the title compound (11.0 g, 76% yield, b.p. 104-105° C. (0.15 mmHg)).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([CH3:7])([OH:6])[CH3:5].C(N(CC)CC)C.[N-:15]=[N+:16]=[N-:17].[Na+]>C(Cl)Cl.O>[N:15]([CH2:2][CH2:3][C:4]([CH3:7])([OH:6])[CH3:5])=[N+:16]=[N-:17]
Reactant: CC(C)(O)CCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(O)CCN=[N+]=[N-]
Reaction time: 8 h
Yield: 65 %

Procedure:
To a mixture of 4-bromo-2-methylbutan-2-ol (0.4 g, 2.4 mmol) and triethylamine (1 ml, 7 mmol, 3 eq.) in CH2Cl2 (15 ml) was added sodium azide (0.47 g, 7 mmol, 3 eq.) in H2O (5 ml) and the mixture was allowed to stir overnight. The mixture was quenched with water and extracted with CH2Cl2 (3×50 ml). The combined organic layer was washed with water, brine and dried over sodium sulphate. The solvent was distilled off to afford the product in 65% yield (0.2 g). 1H NMR (300 MHz, DMSO-d6): δ 4.39 (br s, 1H), 3.40-3.32 (m, 2H), 1.15 (t, 2H), 1.23-1.04 (m, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:30][OH:31].C([O-])(O)=O.[Na+]>>[CH3:1][N:2]([CH3:28])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:30][OH:31])=[CH:5][CH:4]=1
Reactant: NO
Reactant: CN(C)c1ccc(C(CC(=O)c2ccncc2)c2c[nH]c3ccccc23)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)c1ccc(C(CC(=NO)c2ccncc2)c2c[nH]c3ccccc23)cc1

Procedure:
In analogy to example 1, step 2, from 3-(4-dimethylamino-phenyl)-3-(1H-indol-3-yl)-1-pyridin-4-yl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (2.8:1) as a yellow foam, MS (ESI+): m/z=385.4 ([M+H]+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[C:14]3[CH:20]=[CH:19][C:18]([S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)(=[O:23])=[O:22])=[CH:17][C:15]=3[O:16][C:10]=2[C:9]1([CH3:32])[CH3:31])=O)(C)(C)C.O1CCOCC1>Cl>[F:30][C:26]1[CH:25]=[C:24]([S:21]([C:18]2[CH:19]=[CH:20][C:14]3[C:11]4[CH2:12][CH2:13][NH:8][C:9]([CH3:32])([CH3:31])[C:10]=4[O:16][C:15]=3[CH:17]=2)(=[O:22])=[O:23])[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(oc3cc(S(=O)(=O)c4cccc(F)c4)ccc23)C1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)NCCc2c1oc1cc(S(=O)(=O)c3cccc(F)c3)ccc21
Reaction time: 4 h

Procedure:
7-(3-Fluoro-benzenesulfonyl)-1,1-dimethyl-3,4-dihydro-1H-benzofuro[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (0.200 g, 0.435 mmol) in 4M HCl in dioxane (5.0 mL, 57.7 mmol) was stirred at rt. After 4 h, the heterogenous mixture was concentrated and triturated with Et2O. The resulting white precipitate was dried under vacuum at 80° C. for 15 h. mp 110-114° C.; MS m/z 360 [M+H]+. 1H-NMR (400 MHz, CDCl3): δ 1.7 (s, 6H), 3.0 (m, 2H), 3.5 (m, 2H), 7.5 (m, 1H), 7.7 (m, 1H), 7.9 (m, 4H), 8.3 (s, 1H), 10.0 (brs, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=O)=[CH:13][CH:12]=1.O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[C:5]2[CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH2:3][CH2:4]2)[C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:13][CH:12]=1
Reactant: CC1(C)CCC(=O)CC1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a three-neck round-bottomed flask equipped with two nitrogen inlets, reflux condenser, rubber septum, and magnetic stir bar were added zinc powder (0.53 g, 8.1 mmol) and THF (15 mL). To the stirred suspension was slowly added TiCl4 via syringe at room temperature under a nitrogen atmosphere (Note: significant fuming occurred upon addition of TiCl4). The reaction mixture was heated at reflux for 2 h. To the refluxing reaction mixture was added a solution of 4,4-dimethylcyclohexanone (20) (0.447 g, 3.54 mmol) and (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (0.314 g, 1.13 mmol) in THF (15 mL). The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 2 h. The reaction mixture was allowed to cool to room temperature. To the stirred reaction mixture was added water (8 mL) followed by 10% aqueous K2CO3 (8 mL). The mixture was filtered through a pad of Celite. The pad washed with EtOAc. The filtrate was transferred to a separatory funnel and washed with water. The organic phase was separated, washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated to give a pale tan solid. The intermediate aryl bromide was partially purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 3:1) to give 0.381 g of impure 4-[(4-bromophenyl)(4,4-dimethylcyclohexylidene)methyl]phenol as an oil. To the impure intermediate aryl bromide (0.37 g) were added tert-butyl acrylate (0.60 mL, 0.525 g, 4.1 mmol), Pd(OAc)2 (0.067 g, 0.30 mmol), Et3N (0.84 mL, 0.61 g, 6.03 mmol), P(o-tolyl)3 (0.134 g, 0.44 mmol) and CH3CN (15 mL). The stirred reaction mixture was heated overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and transferred to a separatory funnel. The reaction mixture was partitioned between EtOAc and H2O. The layers were separated and the organic phase was dried (MgSO4) and filtered. Silica gel was added to the filtrate and the solvent was removed in vacuo. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 1:1) as eluant to give 0.24 g (51% from (4-bromophenyl)(4-hydroxyphenyl)methanone) of compound 21 as an oil. 1H NMR (400 MHz, DMSO-d6): δ 0.93 (s, 6 H), 1.31 (m, 4 H), 1.45 (s, 9 H), 2.16 (m, 4 H), 6.43 (d, J=15.9 Hz, 1 H), 6.65 (d, J=8.4 Hz, 2 H), 6.84 (d, J=8.4 Hz, 2 H), 7.05 (d, J=8.2 Hz, 2 H), 7.48 (d, J=15.9 Hz, 1 H), 7.57 (d, J=8.1 Hz, 2 H), 9.32 (s, 1H). LRMS (ESI) m/z 417 (M−H)−.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17].[OH-].[Na+].Cl>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)CCC/C=C/c1ccc2ccccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCC/C=C/c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 42.4 %

Procedure:
To a solution of ethyl (E)-6-(2-quinolyl)-5-hexenoate (2.0 g) in methanol (10 ml) was added 3N aqueous sodium hydroxide solution (5 ml) under ice-cooling and the mixture was then stirred at room temperature for 6 hours. This reaction mixture was neutralized with 3N HCl and the solvent methanol was distilled off under reduced pressure. The resulting crude crystals were collected by filtration, rinsed with water, further rinsed with ether, and dried in vacuo to provide 0.76 g of (E)-6-(2-quinolyl)-5-hexenoic acid as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[CH3:23][OH:24]>>[CH3:23][O:24][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1
Reactant: CO
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1OC
Product: COc1ccc2c(OC)nc(Nc3cc(C)[nH]n3)cc2c1OC

Procedure:
Similar procedure as described in example 10 was used, starting from methanol and (1-chloro-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-methoxy-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 315(MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([N+:14]([O-])=O)[CH:10]=[CH:9][CH:8]=2>C(O)C.[Pd]>[NH2:14][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[C:4]([CH2:3][O:2][CH3:1])[N:5]=[CH:6]2
Reactant: COCc1cc2c([N+](=O)[O-])cccc2cn1
Agent: [Pd]
Solvent: CCO
Product: COCc1cc2c(N)cccc2cn1
Yield: 69.9 %

Procedure:
A catalyst (3% palladium-on-charcoal; 8 g) is added to a solution of 3-methoxymethyl-5-nitroisoquinoline (78 g) in ethanol (2 liters). The resulting suspension is stirred and hydrogen is bubbled through for 6 hours, whilst keeping the temperature between 20° and 25° C. with the aid of a bath of cold water. The mixture is then filtered and the filtrate is evaporated to dryness at 60° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is recrystallised from diisopropyl ether (500 cc). 5-Amino-3-methoxymethylisoquinoline (47 g), m.p. 105° C., is obtained.
Reaction SMILES: [NH2:1][C:2]([C:4]([NH2:6])=[S:5])=[S:3].[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=O>>[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[S:3][C:2]2[N:1]=[C:12]([C:8]3[O:7][CH:11]=[CH:10][CH:9]=3)[S:5][C:4]=2[N:6]=1
Reactant: NC(=S)C(N)=S
Reactant: O=Cc1ccco1
Product: c1coc(-c2nc3sc(-c4ccco4)nc3s2)c1

Procedure:
2,5-bis(furyl)thiazolo[5,4-d]thiazole was prepared from dithiooxamide and 2-furaldehyde. 2-furaldehyde (furfural) was purchased from Aldrich Chemical Company, Milwaukee, Wis.