Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].S(Cl)([Cl:21])=O>>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([Cl:21])=[O:18])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)O)CC2)CC1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)Cl)CC2)CC1
Reaction time: 1 h

Procedure:
10 ml of thionyl chloride was added to 0.02 mol (5.0 g) of trans-4-(trans-4'-propyl cyclohexyl)-cyclohexane carboxylic acid and heated. They became homogeneous within about 1 hour, and then they were treated further for about an hour. Thereafter, excess thionyl chloride was removed under reduced pressure to leave trans-4-(trans-4'-propyl cyclohexyl)-cyclohexane carboxylic acid chloride. On the other hand, 3.9 g of 4-4'-cyanophenyl phenol is dissolved in 10 ml of pyridine and the acid chloride was added therein. It was stirred well and left to stand for one night. 200 ml of toluene was added thereto, and the toluene layer was washed with 6N HCl at first, then with 2N aqueous NaOH solution, and finally with water until the wash washing water became neutral. After it was dried with anhydrous sodium sulfate, toluene was removed completely under reduced pressure. The yielded crystals were then recrystallized from acetone to obtain 5.8 g of crystals of trans-4-(trans-4'-propyl cyclohexyl)-cyclohexane carboxylic acid 4"'-cyanobiphenyl ester. Yield: 68%. Its physical properties and elemental analysis are shown n Table 1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:12][CH2:13][CH:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]([CH3:17])[CH3:16].O>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:12][CH2:13][CH:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH:15]([CH3:17])[CH3:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)C(CO)NC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC(NC(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
4-Methylbenzenesulfonyl chloride (0.2222 mol) was added portionwise at 10° C. to a mixture of 1,1-dimethylethyl [1-(hydroxymethyl)-2-methylpropyl]carbamoate (0.202 mol) in pyridine (65 ml). The mixture was stirred at 10° C. for 2 hours. H2O (75 ml) was added at 10° C. The precipitate was filtered off, washed with H2O and taken up in CH2Cl2. The organic solution was washed with H2O, dried, filtered and the solvent was evaporated, yielding 49 g of (±)-1,1-dimethylethyl [1-[[[(4-methylphenyl)-sulfonyl]oxy]methyl]-2-methylpropyl]carbamate (68%) (interm. 13).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].C(N(CC)CC)C.[Cl-].[CH:12]([NH:15][P:16]([CH2:19][CH2:20][Cl:21])(=[O:18])[OH:17])([CH3:14])[CH3:13]>C1C=CC=CC=1>[CH:12]([NH-:15])([CH3:14])[CH3:13].[CH2:1]([S:3][P:16]([CH2:19][CH2:20][Cl:21])(=[O:17])[OH:18])[CH3:2]
Reactant: CCS
Reactant: CC(C)NP(=O)(O)CCCl
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)[NH-]
Product: CCSP(=O)(O)CCCl
Reaction time: 2 h

Procedure:
13 g (0.2 mole) ethylmercaptan and 20 g (0.2 mole) triethylamine are added to 41 g (0.2 mole) 2-chloroethanephosphonic acid N-monoisopropylamide chloride in 100 ml benzene. Stirring was afterwards effected for 2 hours at 40° C; the salts were then filtered off with suction, the reaction solution was washed with water, and drying with sodium sulfate was carried out. After the solvent had been drawn off, there remained behind a crystalline residue, m.p. 51° C, yield: 15 g (33%) 2-chloroethanethiophosphonic acid S-ethyl ester N-monoisopropylamide.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:35])[CH2:18][CH:17]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[C:16]2[CH:29]=[C:30]([C:33]#[N:34])[CH:31]=[CH:32][C:15]=2[O:14]1>ClCCl>[C:33]([C:30]1[CH:31]=[CH:32][C:15]2[O:14][C:13]([CH3:35])([CH3:12])[CH2:18][CH:17]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N+:20]=3[O-:9])[C:16]=2[CH:29]=1)#[N:34]
Reactant: CC1(C)CC(c2ccc3ccccc3n2)c2cc(C#N)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)CC(c2ccc3ccccc3[n+]2[O-])c2cc(C#N)ccc2O1
Reaction time: 2 h
Yield: 69.7 %

Procedure:
203 mg of m-chloroperbenzoic acid were added at room temperature to a solution of 314 mg of 3,4-dihydro-2,2-dimethyl-4-(2-quinolyl)-2H-1-benzopyran-6-carbonitrile in 10 ml of dichloromethane. After stirring for 2 hours the mixture was washed with sodium bisulphite solution and sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated. The residue was recrystallized from diethyl ether to give 230 mg of 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)quinoline 1-oxide of melting point 183°-185° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([NH2:13])=[CH:10][CH:11]=[CH:12][C:3]1=2.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:24]=2[C:25]([NH:27][CH2:28][CH3:29])=[O:26])[C:19]([Cl:35])=[CH:18][N:17]=1>>[Cl:35][C:19]1[C:20]([NH:22][C:23]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:24]=2[C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[N:21][C:16]([NH:13][C:9]2[C:4]3[O:5][CH2:6][CH2:7][CH2:8][C:2]([CH3:14])([CH3:1])[C:3]=3[CH:12]=[CH:11][CH:10]=2)=[N:17][CH:18]=1
Reactant: CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCCOc2c(N)cccc21
Product: CCNC(=O)c1cccc(F)c1Nc1nc(Nc2cccc3c2OCCCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared from 5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-ethyl-3-fluoro-benzamide in an analogous manner to Example 179. Product isolated as a tan solid (30 mg, 30%). LCMS (m/e) 484 (M+H); 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.08 (s, 1H), 7.92 (d, 1H, J=8 Hz), 7.78 (s, 1H), 7.33 (m, 3H), 6.84 (d, 1H, J=7.8 Hz), 6.74 (t, 1H, J=8, 7.8 Hz), 6.05 (m, 1H), 3.96 (m, 2H), 3.38 (m, 2H), 2.04 (m, 2H), 1.66 (m, 2H) 1.34 (s, 6H), 1.11 (t, 3H, J=7.3 Hz).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:9]([Cl:12])(Cl)[Cl:10]>>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][C:9]1([Cl:12])[CH2:1][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClC(Cl)Cl
Solvent: C=Cc1ccccc1
Product: ClC1(Cl)CC1c1ccccc1

Procedure:
312 g of styrene are reacted with chloroform as described in (I). Afer a post-reaction time of 5 hours, fractional distillation gives 45 g of styrene and 444 g of 2,2-dichloro-1-phenyl-cyclopropane of boiling point 103°-104° C./11 mm. This corresponds to 79.2% of theory or 93% based on styrene converted.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:8][O:9][CH2:10][CH2:11][OH:12])[CH:2]=1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCNCC1)=O)=NC(N1CCNCC1)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:8][O:9][CH2:10][CH2:11][O:12][C:14]2[CH:46]=[CH:45][C:17]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:44])=[CH:16][CH:15]=2)[CH:2]=1
Reactant: OCCON=Cc1cccnc1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCNCC1)N1CCNCC1
Product: O=C1NC(=O)C(Cc2ccc(OCCON=Cc3cccnc3)cc2)S1
Yield: 85.9 %

Procedure:
Following a procedure similar to that described in Example 3(a), but using 0.90 g of 2-(3-pyridylmethyleneaminooxy)ethanol (prepared as described in Preparation 5), 2.00 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 1.32 ml of tributylphosphine and 1.23 g of 1,1'-(azodicarbonyl)dipiperazine, 1.37 g of the title compound were obtained as a crystalline powder, melting at 155°-157° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>C1COCC1>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][C:4]2[O:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=2)=[CH:11][CH:10]=1
Reactant: Cc1ccoc1C
Reactant: BrCc1ccc(Br)cc1
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccc(Br)cc2)oc1C
Yield: 41.5 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 1 using commercial 2,3-dimethylfuran (5.00 g, 52.0 mmol), commercial 4-bromobenzylbromide (13.0 g, 52.0 mmol) and 2.5M n-BuLi/hexanes (20.8 mL, 52.0 mmol) in THF. Purification on Biotage KP-Sil eluting with 1% EtOAc/pet. ether gave 5.72 g (41%) of the title compound. 1H NMR (DMSO-d6) δ1.84 (s, 3H), 2.09 (s, 3H), 3.83 (s, 2H), 5.87 (s, 1H), 7.17 (d, 2H), 7.49 (d, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[Si:16]([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:17][Si:16]([CH3:19])([CH3:18])[O:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][N:11]([Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]2=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][Si:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: C[Si](C)(C)Cl
Reactant: O=C1NCCN1c1ccc(O)c(O)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)Oc1ccc(N2CCN([Si](C)(C)C)C2=O)cc1O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3.4 g (17.5 mmol) of 1-(3,4-dihydroxyphenyl)-2-imidazolidinone in 10 ml of ethyl acetate was added 7.6 g (70 mmol) of chlorotrimethylsilane, and subsequently 7.0 g (70 mmol) of triethylamine. After stirring overnight at room temperature, the precipitate was filtered off under nitrogen and the filtrate evaporated to dryness in vacuo; yield: 7.14 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:11]C(=O)C(C)(C)C)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[NH2:11]
Reactant: CC(C)(C)C(=O)Nc1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Nc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A mixture of N-(3-fluoro-4-nitro-phenyl)-2,2-dimethyl-propionamide (87.0 g, 0.36 mol) in CH2Cl2 (400 mL) and 6N hydrochloric acid (800 mL) was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with 1000 mL of ethyl acetate and potassium carbonate (500.0 g) was added portion wise. The aqueous solution was separated and the organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed by evaporation under reduced pressure; the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 30:1) to afford 3-fluoro-4-nitroaniline (56.0 g, 99%). 1H NMR (300 MHz, CDCl3) δ 8.07 (t, J=8.7 Hz, 1H), 7.86 (dd, J=2.1, 13.2 Hz 1H), 7.59 (brs, 2H), 7.22 (s, 1H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23]3=[C:24]([NH:26][C:27](=[S:28])[N:22]3[CH2:21][CH2:20][CH2:19]2)[CH:25]=1.[OH-].[Na+]>CCO>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23]3=[C:24]([N:26]=[C:27]([S:28][CH2:3][C:4]4[CH:13]=[CH:12][C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[N:5]=4)[N:22]3[CH2:21][CH2:20][CH2:19]2)[CH:25]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: COc1cc2c3c(c1)[nH]c(=S)n3CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2c3c(c1)nc(SCc1ccc4ccccc4n1)n3CCC2
Temperature: 25 °C
Yield: 61.2 %

Procedure:
2-Chloromethylquinoline hydrochloride (0.845 g, 4.0 mmol) was added to a solution of 5,6-dihydro-8-methoxy-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione (0.871 g, 4.0 mmol) in 1 N-NaOH (8 ml) and EtOH (8 ml). The mixture was heated to reflux, cooled to room temperature, concentrated in vacuo, and the aqueous residue extracted with CH2Cl2 (50 ml). The extract was washed with 1NNaOH (2×30 ml), and brine (20 ml), dried (MgSO4), and evaporated in vacuo to give an oil which was purified by chromatography (SiO2, Et2O) and trituration with Et2O-petrol ether to give the title compound (0.885 g, 62%) as yellow crystals, mp 89°-91° C. (Found: C,70.1; H,5.4; N,11.4; C21H19N3OS requires C,69.8; H,5.3; N,11.6%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:32]2[CH2:43][CH2:42][N:41]3[C:34](=[CH:35][C:36]4[CH2:37][C:38]([CH3:45])([CH3:44])[CH2:39][C:40]=43)[C:33]2=[O:46])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:29]=[C:22]3[CH:23]([CH3:28])[N:24]([CH3:27])[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=1)(=O)C.[OH-].[Li+].C(O)(C)C.C1COCC1>O>[CH3:28][CH:23]1[N:24]([CH3:27])[CH2:25][CH2:26][N:21]2[N:20]=[C:19]([NH:18][C:16]3[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=[C:12]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([N:32]5[CH2:43][CH2:42][N:41]6[C:34](=[CH:35][C:36]7[CH2:37][C:38]([CH3:44])([CH3:45])[CH2:39][C:40]=76)[C:33]5=[O:46])[C:6]=4[CH2:5][OH:4])[CH:17]=3)[CH:29]=[C:22]12
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4C)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC1c2cc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4CO)cn(C)c3=O)nn2CCN1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 318a (200 mg, 1.0 eq., 0.32 mmol), lithium hydroxide (38 mg, 5.0 eq., 1.60 mmol), i-propanol/THF (8/8 mL), and water (2 mL). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was added partitioned between water and dichloromethane. The combined organic layer was concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford racemic mixture 318b as a yellow solid (91 mg, 43%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[CH3:37]>[I-].[K+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=3[CH3:37])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(OCCCCl)c(C)c1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: [I-]
Agent: [K+]
Product: CC(=O)c1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(C)c1
Yield: 76 %

Procedure:
Following the procedure of Example 1, [α,α-bis(p-fluorophenyl)]-4-piperidinemethanol and 1-[4-(3-chloropropoxy)-3-methylphenyl]ethanone were reacted using potassium iodide catalyst to give the white title compound (recrystallizing from isopropyl alcohol) in 76% yield, m.p. 116°-117° C.
Reaction SMILES: C(ON=O)(C)(C)C.N[C:9]1[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:12]=[C:11]([C:26]#[N:27])[C:10]=1[S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29].C(Br)(Br)[Br:36]>>[Br:36][C:9]1[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:12]=[C:11]([C:26]#[N:27])[C:10]=1[S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)C(F)(F)F
Reactant: BrC(Br)Br
Agent: CC(C)(C)ON=O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1S(=O)(=O)C(F)(F)F
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 79 %

Procedure:
t-Butylnitrite (84 ml, 0.662 mol) was added to a suspension of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfonylpyrazole (100 g, 0.221 mol) in bromoform (320 ml). The resulting mixture was heated to 60-70° C. for 3 hours. Another portion of t-butylnitrite (84 ml, 0.662 mol) was added and the mixture stirred at 60-70° C. for a further 2.5 hours. It was then cooled, washed with hexane, hexane-toluene, and then filtered. The solid was washed with pentane and vacuum dried to give 5-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfonylpyrazole as a yellow solid (96.69 g, 79% yield), mp 142° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[CH3:21])=[CH:18]/[CH2:19][OH:20])=[CH:13][CH:12]=1.[CH2:22]([O:24][C@@H:25]([CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:23]>>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:11]1[CH:12]=[CH:13][C:14](/[C:17](/[CH3:21])=[CH:18]/[CH2:19][O:20][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][C@H:25]([O:24][CH2:22][CH3:23])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:37][CH:36]=2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: COc1cccc(OC)c1-c1ccc(/C(C)=C/CO)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3c(OC)cccc3OC)cc2)cc1)OCC
Yield: 46.2 %

Procedure:
The title compound (0.41 g, 80% yield) was prepared from (E)-3-(2′,6′-dimethoxy-biphenyl-4-yl)-but-2-en-1-ol (0.50 g, 1.76 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.44 g, 1.85 mmol) by a procedure analogous to that described in example 52 c.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:18][N:19]([CH3:22])[CH:20]=O>C(OCC)(=O)C>[CH3:8][C@H:6]1[CH2:20][N:19]([C:22]2[CH:9]=[CH:10][CH:11]=[CH:5][N:4]=2)[CH2:18][CH2:3][N:7]1[CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: C[C@H]1CN(c2ccccn2)CCN1Cc1nc2ccccc2[nH]1
Reaction time: 3 h
Yield: 46 %

Procedure:
The product of Example 25B (0.24 g, 1.33 mmol) in N,N-dimethylformamide (10 mL) was treated with 2-chloromethyl-1H-benzimidazole (0.21 g, 1.27 mmol) and cesium carbonate (0.41 mmol, 1.27 mmol) at 23° C. with stirring for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water (3×) and brine, dried over Na2SO4 filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on flash silica gel (1-3% methanol/dichloromethane gradient) to afford 178 mg (46% yield) of the title compound as a light yellow solid. mp 149-151° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.18 (d, J=6 Hz, 3H), 2.38 (m, 1H), 2.53 (m, 1H), 2.76 (dd, J=8, 11.2 Hz, 1H), 2.83 (m, 1H), 3.03 (m, 1H), 3.69 (d, J=14 Hz, 1H), 3.94 (m, 1H), 4.00 (m, 1H), 4.07 (d, J=14 Hz, 1H), 6.60 (dd, J=4.8, 6.4 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 7.13 (m, 2H), 7.60 (m, 3H), 8.08 (m, 1H), 12.22 (bs, 1H); MS (ESI) m/e 308 (M+H)+; Anal. calcd for C18H21N5: C, 70.33; H, 6.89; N, 22.78. Found: C, 70.21; H, 6.77; N, 22.62.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: BrCCc1ccccc1
Product: Cc1cc(C#Cc2cn(CCc3ccccc3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=302.2 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and (2-bromoethyl)benzene.
Reaction SMILES: COC1C=CC(C2C(C)(C)CC3C(=CC=C(OC)C=3)C=2)=C(N)C=1.Cl.[N:25]1([CH2:32][CH2:33][O:34][C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=O)=[CH:37][CH:36]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.N1(CCOC2C=C[C:57]([CH2:58][NH:59][C:60]3[CH:65]=[C:64]([O:66][CH3:67])[CH:63]=[CH:62][C:61]=3[C:68]3[C:77]([CH3:79])([CH3:78])[CH2:76][C:75]4[C:70](=[CH:71][CH:72]=[C:73]([O:80][CH3:81])[CH:74]=4)[CH:69]=3)=CC=2)CCCCCC1>>[N:25]1([CH2:32][CH2:33][O:34][C:35]2[CH:43]=[CH:42][C:38]([CH2:39][N:59]([CH2:58][CH3:57])[C:60]3[CH:65]=[C:64]([O:66][CH3:67])[CH:63]=[CH:62][C:61]=3[C:68]3[C:77]([CH3:79])([CH3:78])[CH2:76][C:75]4[C:70](=[CH:71][CH:72]=[C:73]([O:80][CH3:81])[CH:74]=4)[CH:69]=3)=[CH:37][CH:36]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1ccc2c(c1)CC(C)(C)C(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCCC3)cc1)=C2
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Agent: COc1ccc(C2=Cc3ccc(OC)cc3CC2(C)C)c(N)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1cc(OC)ccc1C1=Cc2ccc(OC)cc2CC1(C)C

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-3,3-dimethyl-3,4-dihydronaphthalen-2-yl)phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxy-3,3-dimethyl-3,4-dihydronaphthalen-2-yl)phenyl]amine (454 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl[5-methoxy-2-(6-methoxy-3,3-dimethyl-3,4-dihydronaphthalen-2-yl)phenyl]amine (387 mg). This compound (385 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (345 mg).
Reaction SMILES: C(CCCC[C:8]1[CH:9]=[C:10](/[C:14](=[CH:48]\[CH:49]=[C:50]2/[C:51]([CH3:69])([CH3:68])[C:52]3[C:53](=[N:67]/2)[N:54]([CH2:59][CH2:60][CH2:61][CH2:62][S:63]([O-:66])(=[O:65])=[O:64])[CH:55]=[C:56]([Cl:58])[CH:57]=3)/[CH:15]=[CH:16]/[C:17]2[C:25]([CH3:27])([CH3:26])[C:24]3[C:23]4[CH:28]=[C:29]([S:36]([O-:39])(=[O:38])=[O:37])[CH:30]=[C:31]([S:32]([O-:35])(=[O:34])=[O:33])[C:22]=4[CH:21]=[CH:20][C:19]=3[N+:18]=2[CH2:40][CH2:41][CH2:42][CH2:43][S:44]([O-:47])(=[O:46])=[O:45])[CH:11]=[CH:12][CH:13]=1)(O)=O.[Na+:70].[Na+].[Na+].[OH:73][CH2:74][CH2:75][CH2:76][CH2:77][O:78]C1C=C(B(O)O)C=CC=1>>[Cl:58][C:56]1[CH:57]=[C:52]2[C:51]([CH3:69])([CH3:68])/[C:50](=[CH:49]\[CH:48]=[C:14](/[C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([O:73][CH2:74][CH2:75][CH2:76][CH2:77][OH:78])[CH:9]=3)\[CH:15]=[CH:16]\[C:17]3[C:25]([CH3:26])([CH3:27])[C:24]4[C:23]5[CH:28]=[C:29]([S:36]([O-:39])(=[O:37])=[O:38])[CH:30]=[C:31]([S:32]([O-:35])(=[O:33])=[O:34])[C:22]=5[CH:21]=[CH:20][C:19]=4[N+:18]=3[CH2:40][CH2:41][CH2:42][CH2:43][S:44]([O-:47])(=[O:45])=[O:46])/[N:67]=[C:53]2[N:54]([CH2:59][CH2:60][CH2:61][CH2:62][S:63]([O-:66])(=[O:65])=[O:64])[CH:55]=1.[Na+:70].[Na+:70].[Na+:70]
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(CCCCC(=O)O)c1
Reactant: OCCCCOc1cccc(B(O)O)c1
Agent: [Na+]
Product: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(OCCCCO)c1

Procedure:
Compound 51 is prepared analogously to compound 28, except with 3-(4-hydroxybutoxy)phenylboronic acid as a starting material.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH:13]([C:16]([O:18][CH3:19])=[O:17])[NH:12][C:11]2=[O:20])=[CH:6][CH:5]=1.[H-].[Na+].[H][H].[CH2:25](Br)[CH:26]=[CH2:27]>C(OCC)C.O>[CH2:27]([O:1][N:2]=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[CH:13]([C:16]([O:18][CH3:19])=[O:17])[NH:12][C:11]2=[O:20])=[CH:8][CH:9]=1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: COC(=O)C1NC(=O)N(c2ccc(C=NO)cc2)C1=O
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: C=CCON=Cc1ccc(N2C(=O)NC(C(=O)OC)C2=O)cc1
Reaction time: 2 h

Procedure:
A solution of 0.01 mol of 3-[4-(hydroxyiminomethyl)phenyl]-5-methoxycarbonylhydantoin in diethyl ether is treated with 0.01 mol of sodium hydride. After hydrogen evolutionstops, 0.011 mol of allyl bromide is added. The reaction mixture is stirredfor 2 hours. The reaction mixture is then poured into cold water, the layers are separated, and the aqueous layer is extracted with diethyl ether. The combined ether solutions are dried over MgSO4 and filtered, and the solvent is removed by rotary evaporator to yield 3-[4-(allyloxyiminomethyl)phenyl]-5-methoxycarbonylhydantoin.