Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[C:28]1([NH:34]N)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([N:34]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([C:23]([F:24])([F:25])[F:26])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NNc1ccccc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)C(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(S(=O)(=O)C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-33) and phenylhydrazine according to the method described for example 1. MS: M=447.1 (M+H)+
Reaction SMILES: OC1C=CC(C=O)=CC=1.C1(CCO)CC1.[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O[C@@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:26][CH2:25]1>>[O:22]([C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:26][CH2:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)[C@H]1CC[C@@H](O)CC1
Agent: O=Cc1ccc(O)cc1
Agent: OCCC1CC1
Product: COC(=O)[C@H]1CC[C@H](Oc2ccccc2)CC1

Procedure:
Instead of 4-hydroxybenzaldehyde and 2-cyclopropylethanol, phenol (1.43 g) and methyl cis-4-hydroxycyclohexanecarboxylate (2.00 g) were respectively used and treated by the same technique as in Reference Example 11-1 to give methyl trans-4-phenoxycyclohexanecarboxylate as a colorless oil (1.33 g).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CC(=O)OCC>>[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[N:17]1[CH2:18][CH2:19][N:20]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:21][CH2:22]1
Reactant: c1csc(N2CCNCC2)n1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCOC(C)=O
Product: c1cnc2sc(CN3CCN(c4nccs4)CC3)nc2c1

Procedure:
The product from Example 38A (200 mg, 1.1 mmol), 1-(1,3-thiazol-2-yl)piperazine (219 mg, 1.3 mmol), and D1 EA (340 μL, 2.1 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.71 (m, 4H) 3.46 (m, 4H) 4.06 (s, 2H) 6.86 (d, J=3.73 Hz, 1H) 7.17 (d, J=−3.73 Hz, 1H) 7.56 (dd, J=8.14, 4.75 Hz, 1H) 8.33 (dd, J=8.14, 1.70 Hz, 1H) 8.59 (dd, J=4.58, 1.53 Hz, 1H). (ESI) m/z 318 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[C:13]([Br:15])[C:12]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][C:10]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:8])[CH3:2].Cl.[NH2:35]O.O>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[C:13]([Br:15])[C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:11][C:10]=2[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:8][N:35]=1)=[O:33])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cc(Br)c(OCc3ccccc3)cc2OCc2ccccc2)on1

Procedure:
69.3 g of 4-(2,4-Bis-benzyloxy-5-bromo-phenyl)-2,4-dioxo-butyric acid ethyl ester (0.135 mol, 1 eq) were dissolved in 750 ml ethanol. 14.11 g hydroxylamine hydrochloride (0.203 mol, 1.5 eq) were added. The mixture was refluxed for 2.5 hours and cooled down. It was then poured onto 1000 ml water, the precipitate was filtered off. The filter cake was washed with 500 ml of water followed by 75 ml diethyl ether and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(O)(C(F)(F)F)=O>C(Cl)Cl.C(O)(C(F)(F)F)=O.O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(C2CCNCC2)n1
Reaction time: 8 h
Yield: 82 %

Procedure:
(S)-tert-butyl 4-(4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazol-2-yl)piperidine-1-carboxylate (0.3 g, 0.540 mmol) and TFA (0.768 g, 6.73 mmol) was dissolved in a mixture of DCM/TFA/H2O and stirred overnight. The reaction mixture was diluted with DCM, washed with saturated Na2CO3 and with water. The organic layer was evaporated. Yield 82%. 1H-NMR (400 MHz; DMSO-d6): δ 1.24 (d, 3H), 1.52 (dd, 1H), 1.58 (dd, 1H), 1.91-1.97 (m, 2H), 2.54-2.62 (m, 2H), 2.97-3.03 (d, 2H), 3.04-3.11 (m, 1H), 4.33 (dd, 1H), 4.41 (dd, 1H), 4.44-4.51 (m, 1H), 6.96 (d, 1H), 7.85 (d, 1H), 7.94 (dd, 1H), 7.99 (d, 1H), 8.07 (d, 1H), 8.08 (s, 1H), 8.28 (d, 1H).
Reaction SMILES: [C:1]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[K+].[CH:16](=[O:19])[CH2:17][CH3:18].C(O)(=O)C>CO>[C:1]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[C:17]([CH3:18])[CH:16]=[O:19])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)c1ccc(C=O)cc1
Reactant: CCC=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCC(C)(C)c1ccc(C=C(C)C=O)cc1
Temperature: 40 °C

Procedure:
162.2 g of p-tert.amyl-benzaldehyde are added under nitrogen gasification to a solution of 1.56 g of potassium hydroxide in 113 ml of methanol and 48.8 g of propionaldehyde are subsequently added dropwise at 40° C. over a period of 6 hours. The mixture is subsequently stirred at 40° C. for an additional hour, 2 ml of acetic acid are added and the mixture is concentrated on a rotary evaporator. The oily suspension is taken up in ether, washed neutral with water, dried and evaporated. By distillation there is obtained pure 3-(p-tert.amyl-phenyl)-2-methyl-acrolein of boiling point 117°-120° C./0.035 Torr.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Temperature: 0 °C

Procedure:
To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (6.0 g, 34.68 mmol) in DCM was added by Et3N. The mixture was cooled to 0° C. and methanesulfonyl chloride was slowly added. After addition was complete, the reaction mixture was warmed to RT and stirred until starting material was completely consumed as indicated by TLC (40% EtOAc/hexanes). The reaction mixture was filtered and CH2Cl2 was added to the filtrate (100 mL). The organics were washed with water (2×30 mL), brine solution (30 mL), dried (Na2SO4), filtered, and concentrated to obtain crude product, which was purified by silica gel chromatography (5% EtOAc/hexanes, then 15% EtOAc/hexanes). 1-(tert-Butoxycarbonyl)azetidin-3-yl methanesulfonate was isolated as an off-white solid (2.2 g, 36% yield); ES-MS: 252.08 (M+H).
Reaction SMILES: C(Cl)(Cl)Cl.CCCCCC.[CH:11]1[C:21]2[CH:20]=[CH:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16](=[O:26])[C:15]=2[CH:14]=[CH:13][C:12]=1[CH2:27][C:28](N)=[O:29].CC(C)=[O:33].CCCCCC>>[CH:11]1[C:21]2[CH:20]=[CH:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16](=[O:26])[C:15]=2[CH:14]=[CH:13][C:12]=1[CH2:27][C:28]([OH:29])=[O:33]
Reactant: NC(=O)Cc1ccc2c(=O)c3ccccc3ccc2c1
Reactant: CC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: O=C(O)Cc1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
3.0 Gm. of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionamide is refluxed in a mixture of 20 ml. of acetic acid and 30 ml. of concentrated hydrochloric acid for 3 hours. The solution is cooled and poured into water. The mixture is extracted with ethyl acetate and the extract is washed, dried and evaporated to yield 90% of 2-(5H-dibenzo[a,d] cyclohepten-5-on-2-yl)propionic acid., m.p. (chloroform-hexane) 138°-139°C.; m.p. (acetone-hexane) 113°-115°C. Use of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetamide gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid, m.p. (acetone-hexane) 148°-149.5°C.
Reaction SMILES: [C:1]1([CH:7]([NH2:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]1[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:24]=1[CH2:33][C:34](O)=[O:35]>>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([CH:26]=[CH:25][C:24]=1[CH2:33][C:34]([NH:20][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:35])[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)c1ccc(CC(=O)O)c(OC)c1
Reactant: NC(c1ccccc1)c1ccccc1N1CCCCC1
Product: COC(=O)c1ccc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)c(OC)c1

Procedure:
Prepared from α-phenyl-2-piperidino-benzylamine and 2-methoxy-4-methoxycarbonyl-phenylacetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:7]1=[N:8][NH:9][C:10](=[O:12])[CH2:11][C:6]1([CH3:16])[CH2:5]2.[CH3:17][S:18][C:19](SC)=[N:20]C#N.[N:25]1C=CC=C[CH:26]=1>>[C:26]([N:1]([C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:7]1=[N:8][NH:9][C:10](=[O:12])[CH2:11][C:6]1([CH3:16])[CH2:5]2)[C:19](=[NH:20])[S:18][CH3:17])#[N:25]
Reactant: CSC(=NC#N)SC
Reactant: c1ccncc1
Reactant: CC12CC(=O)NN=C1c1ccc(N)cc1C2
Product: CSC(=N)N(C#N)c1ccc2c(c1)CC1(C)CC(=O)NN=C21

Procedure:
A mixture of 7-amino-4,4a,-dihydro-4a-methyl-[5H]-indeno[1,2-c]pyridazin-3[2H]-one (0.78 g), dimethyl cyanodithioiminocarbonate (1.02 g) in dry pyridine (20 ml) were stirred under reflux for 3 hours. The reaction mixture was evaporated to dryness, azeotroped several times with water and the residue triturated with acetone to give 7-(N-cyano-S-methylisothioureido)-4,4a,-dihydro-4a-methyl-[5H]-indeno[1,2-c]pyridazin-3[2H]-one (0.28 g) as a solid, m.p. 240° (d).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].C(N(CC)CC)C.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:6])[CH2:4][NH:5][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[Cl:14]
Reactant: COC(=O)CN
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Amino-acetic acid methyl ester (5 g, 40 mmol) was suspended in DMF and treated with triethylamine (13.9 mL, 100 mmol) and 2-chloro-benzoyl chloride (5 mL, 40 mmol). The reaction mixture was stirred at room temperature overnight. Water was added to the reaction, and the mixture was extracted with ethyl acetate three times. The organic layers were combined and dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography using ethyl acetate/hexane to yield (2-chloro-benzoylamino)-acetic acid methyl ester as a light yellow solid. LCMS calcd for C10H10ClNO3 (m/e) 227, obsd 228 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:14]3[N:15]=C[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.NN.[CH2:21](O)[CH3:22]>[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:17]=[CH:18][C:13]3[N:12]([C:21]([CH3:22])=[N:15][N:14]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCO
Reactant: O=[N+]([O-])c1cccc(-c2nnc3cccnn23)c1
Agent: [Pd]
Agent: NN
Product: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Temperature: 20 °C

Procedure:
A 103.0 g portion of 3-methyl-6-(3-nitrophenyl-1,2,4-triazolo[4,3-b]pyridazine and 1.0 g of 10% palladium on carbon were suspended in 2 liters of ethanol. The mixture was heated to reflux and 140 ml of anhydrous hydrazine added via a syringe pump over 24 hours. The solution was cooled to 20° C., filtered and the filtrate concentrated in vacuo. The residue was dissolved in 3 liters of hot dichloromethane and passed through a short column (200 g) of hydrous magnesium silicate with dichloromethane as the eluent. The fractions containing product were combined and evaporated, giving 83 g of the desired compound as yellow needles, mp 206°-208° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].[Li+].CC([N-]C(C)C)C.I[CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>C1COCC1.COC1SC(=O)N(CSP(OC)(OC)=S)N=1>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)(=[O:13])=[O:14])=[CH:10][CH:11]=1)[CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH3:2]
Reactant: ICC1CCCC1
Reactant: CCOC(=O)Cc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1
Agent: CC(C)[N-]C(C)C
Agent: COc1nn(CSP(=S)(OC)OC)c(=O)s1
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)N2CCN(C)CC2)cc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of the title C compound, [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester (15 g, 0.046 mol) in a mixture of THF (60 mL) and DMTP (10 mL) is cooled to −78° C. under nitrogen. The resulting solution is stirred at −78° C. for 45 min and to this is added LDA (25.6 mL, 6.40 g, 0.059 mol, 25% solution in THF/Hexane). A solution of iodomethylcyclopentane (11.60 g, 0.055 mol) in a mixture of DMTP (12 mL) and THF (20 mL) is added over a period of 15 min at −78° C. and reaction mixture stirred at −78° C. for 3 h further, followed by stirring at 25° C. for 12 h. The reaction mixture is then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (50 mL) and is concentrated in vacuo. The residue is diluted with water (50 mL) and extracted with ethyl acetate (3×100 mL). The organic solution is washed with a saturated aqueous sodium chloride (2×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography over silica gel (60-120 mesh), using 50% ethyl acetate in hexane as an eluent to afford 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid ethyl ester as a white solid: 1H NMR (400 MHz, CDCl3) δ 0.9-2.1 (m, 11H), 1.2 (t, J=7.1, 3H), 2.3 (s, 3H), 2.5 (br s, 4H), 3.0 (br s, 4H), 3.6 (m, 1H), 4.1 (q, J=7.1, 2H), 7.5 (d, J=8.3, 2H), 7.7 (d, J=8.3, 2H); MS 409 [M+1]+.
Reaction SMILES: C(#N)C.[C:4]1([P:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:23][CH2:24][CH:25]=[CH:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>C1(C)C=CC=CC=1>[Br-:23].[C:28]([C:27]([F:32])([F:31])[CH2:26][CH2:25][CH2:24][P+:10]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([OH:30])=[O:29]
Reactant: O=C(O)C(F)(F)C=CCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C(O)C(F)(F)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 5 °C
Reaction time: 30 h
Yield: 96.5 %

Procedure:
Acetonitrile (23 ml) was added to a mixture of triphenylphosphine (6.7 g, 25.7 mmole) and Part (6) compound (4.6 g, 21.2 mmole). The solution was heated at gentle reflux under magnetic stirring for 30 hours. Toluene (46 ml) was then added and the reaction was brought to reflux for a brief period. The reaction was allowed to cool to 5° C. and kept overnight. The resulting white precipitates were collected, washed with cold acetonitrile/toluene (1/2), and dried in a heated vacuum oven (60° C.~5 mmHg) to give the title bromide (9.8 g, 20.4 mmole, 96.5%) as white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:21]1[O:29][CH:22]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[ClH:30]>C(OCC)(=O)C.CS(C)=O>[ClH:30].[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:21][CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[OH:29])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: OC(COC1CCN(Cc2ccccc2)CC1)c1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 5.00 g of 1-benzyl-4-hydroxypiperidine, 1.97 g of potassium tert-butoxide and 4 ml of dimethyl sulfoxide was heated to 80° C. Thereto was dropwise added 2.10 g of styrene oxide over 40 minutes. The resulting mixture was stirred for 3 hours at the same temperature. The reaction mixture was added to a mixture of 100 ml of ice water and 80 ml of ethyl acetate. The mixture was adjusted to pH 11.5 with 6N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/ethanol=10/1). The resulting oily product was dissolved in 8 ml of ethanol. To the solution were added 1 ml of a 6N dry hydrogen chloride-ethanol solution and 20 ml of diethyl ether. The mixture was stirred for 30 minutes at room temperature. The resulting crystals were collected by filtration, washed with a mixture of 2 ml of ethanol and 2 ml of diethyl ether, and dried to obtain 930 mg of 2-(1-benzylpiperidin-4-yloxy)-1-phenylethanol hydrochloride (compound No. 113).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4](Cl)[N:3]=1.[OH:11][C:12]1[CH:13]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:16][CH:17]=1.[H-].[Na+]>>[F:21][C:18]([F:19])([F:20])[C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[N:3]=1
Reactant: CSc1cc(Cl)nc(Cl)c1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Product: CSc1cc(Oc2cccc(C(F)(F)F)c2)nc(Oc2cccc(C(F)(F)F)c2)c1
Yield: 85.3 %

Procedure:
A mixture of 2,6-dichloro-4-methylthiopyridine (0.97 g; 0.005 mol), 3-hydroxybenzotrifluoride (1.3 ml; 10.4 mmol) and sodium hydride (0.2 g) was reacted and worked up according to the procedure of Example 1 above to give 2,6-di-(3-trifluoromethyl phenoxy)-4-methylthiopyridine (1.9 g; 85%)
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]>O1CCCC1.O.CCOC(C)=O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15](=[O:16])[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)COC(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromoaniline (10.0 g, 58.1 mmol) in tetrahydrofuran (230 mL) is treated with sodium bicarbonate (9.77 g, 116.2 mmol) and water (100 mL) followed by isobutyl chloroformate (8.3 mL, 63.9 mmol), and the mixture is stirred at ambient temperature for 2 h. The mixture is then diluted with water (100 mL) and EtOAc (100 mL), the layers are separated, and the organic phase is washed with water (50 mL) and saline (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Recrystallization of the resulting solid from EtOAc/hexanes provides the title compound, mp 95–96° C.; MS (ESI−) for C11H14NO2Br m/z 270 (M−H)−.
Reaction SMILES: [CH:1]1[C:10]2C(=CC=CC=2)C=C[CH:2]=1.C(C1C2C(=CC=CC=2)C=CC=1)(C)C.[CH:24]([C:27]1[C:28](C(C)C)=[C:29](C(C)C)[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2)([CH3:26])[CH3:25]>>[CH:24]([C:27]1[CH:28]=[CH:29][C:30]2[C:35](=[CH:34][CH:33]=[C:32]([CH:1]([CH3:10])[CH3:2])[CH:31]=2)[CH:36]=1)([CH3:25])[CH3:26]
Reactant: CC(C)c1cc2ccccc2c(C(C)C)c1C(C)C
Reactant: c1ccc2ccccc2c1
Agent: CC(C)c1cccc2ccccc12
Product: CC(C)c1ccc2cc(C(C)C)ccc2c1

Procedure:
Substantially pure 2,6-diisopropylnaphthalene can be recovered from the diisopropylnaphthalene products in a multi-stage separation scheme. In one embodiment, the diisopropylnaphthalene product is first fractionally distilled to obtain a low boiling fraction which contains unreacted naphthalene and monoisopropylnaphthalene, a middle fraction containing the diisopropylnaphthalenes, and a high boiling fraction containing triisopropylnaphthalene and tetraisopropylnaphthalenes. 2,6-diisopropylnaphthalene is obtained from the middle fraction by cooling the liquid to a temperature between 0° C. and -20° C. to fractionally crystallize the 2,6-isomer from the other diisopropylnaphthalenes. The mother liquor from the crystallization can be subjected to a second crystallization step, or it can then be combined with the low boiling and high boiling fractions, and subjected to transalkylation before recycle to the alkylation reactor, along with fresh naphthalene.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:15][CH3:16])[C:8](=[O:14])[CH2:9][CH2:10][C:11](=O)[CH3:12])=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.C([O-])(=O)C.[Na+].[NH2:28][OH:29].Cl>C1COCC1.O.CCOC(C)=O>[Cl:1][C:2]1[C:6]([N:7]([CH2:15][CH3:16])[C:8](=[O:14])[CH2:9][CH2:10]/[C:11](=[N:28]/[OH:29])/[CH3:12])=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1
Reactant: NO
Reactant: CCN(C(=O)CCC(C)=O)c1cn(-c2cccnc2)nc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(C(=O)CC/C(C)=N/O)c1cn(-c2cccnc2)nc1Cl

Procedure:
To a solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-4-oxo pentanamide (0.10 g, 0.31 mmol) in THF (3.0 mL) was added a solution of sodium acetate (0.064 g, 0.78 mmol) and hydroxylamine.HCl salt (0.033 g, 0.47 mmol) in water (0.5 mL), and the mixture stirred for one hour. The mixture was diluted with EtOAc and water. The organic phase was separated, and the aqueous extracted with EtOAc. The combined organic phase was washed with brine, dried over MgSO4, and filtered. Removal of the volatiles under reduced pressure gave colorless gum, which was purified on silica gel eluting with MeOH/CH2Cl2 to give the title compound F105 as a colorless gum (0.088 g, 80%).
Reaction SMILES: [Sn](Cl)[Cl:2].[N+:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:15]=1[C:16]#[N:17])([O-])=O>Cl.C(O)C>[ClH:2].[F:23][C:22]([F:25])([F:24])[C:19]1[CH:20]=[CH:21][C:14]2[NH:13][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:4]=[C:16]([NH2:17])[C:15]=2[CH:18]=1
Reactant: N#Cc1cc(C(F)(F)F)ccc1Nc1ccccc1[N+](=O)[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CCO
Product: NC1=Nc2ccccc2Nc2ccc(C(F)(F)F)cc21
Yield: 89.9 %

Procedure:
Add a solution of tin(II) chloride (567 mg, 3 mmol) in 12 N hydrochloric acid (1.8 mL) to a solution of 2-(2-nitro-phenylamino)-5-trifluoromethyl-benzonitrile (307 mg, 1 mmol) in ethanol (10 mL). Reflux for 24 hours, then concentrate under vacuum, add water and filter. Wash the resulting solid with water and dichloromethane then dry under vaccum to yield the title compound as a yellow solid (282 mg, 90%): mp 334-336° C.; 1H NMR (DMSO-d6) δ 7.05-7.19 (m, 4H), 7.34 (d, 1H), 7.86 (dd, 1H), 7.87 (s, 1H), 8.79 (s, 1H), 9.26 (s, 1H), 9.75 (s, 1H), 12.40 (s, 1H). MS (ESI/neg) m/z (rel intensity) 276.1 (100).