Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([OH:29])[CH3:28].[CH3:30][O:31][C:32]([C:34]1[S:35][C:36]([N:40]2[CH:44]=[CH:43][N:42]=[CH:41]2)=[CH:37][C:38]=1O)=[O:33].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:30][O:31][C:32]([C:34]1[S:35][C:36]([N:40]2[CH:44]=[CH:43][N:42]=[CH:41]2)=[CH:37][C:38]=1[O:29][CH:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[Cl:20])[CH3:28])=[O:33]
Reactant: COC(=O)c1sc(-n2ccnc2)cc1O
Reactant: CC(O)c1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1sc(-n2ccnc2)cc1OC(C)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
Triphenyl phosphine (304 mg, 1.16 mmol, 1.3 Eq.), 1-(2-Chloro-phenyl)-ethanol (182 mg, 1.16 mmol, 1.3 Eq.) and 3-Hydroxy-5-imidazol-1-yl-thiophene-2-carboxylic acid methyl ester (200 mg, 0.89 mmol, 1.0 Eq.) in anhydrous THF (5 mL) were cooled to 0° C. under nitrogen. Diethyl azodicarboxylate (183 μL, 1.16 mmol, 1.3 Eq.) was added dropwise. The reaction was stirred at 0° C. for 30 minutes then warmed to ambient temperature for 3.5 hours. The solvent was removed in vacuo and the residue re-dissolved in DCM and absorbed onto SiO2. The crude product wad purified by column chromatography (75% EtOAc/petroleum ether) to give the sub-title compound as a light yellow foam (290 mg, 0.80 mmol, 84%); 1H NMR (400 MHz, d-6 DMSO) δ 1.60 (3H, d), 3.80 (3H, s), 5.90 (1H, q), 7.14 (1H, d), 7.31-7.37 (1H, m), 7.43-7.49 (3H, m), 7.74-7.78 (2H, m), 8.29 (1H, d).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[CH3:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]Br>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:32][C:33]2[CH:40]=[CH:39][CH:38]=[C:35]([CH3:36])[CH:34]=2)[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: Cc1cccc(CBr)c1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3cccc(C)c3)[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 25, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as described in EXAMPLE 43, Part A, and 3-methylbenzyl bromide. The crude product is purified by column chromatography eluting with gradient of 40% EtOAc/hexanes to 50% EtOAc/hexanes to afford the title compound as a white foam.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[C:7]1([CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2C(O)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[Li]>C(Cl)Cl.CCOCC>[C:7]1([CH2:13][C:14]2[CH:15]=[CH:19][CH:20]=[CH:21][C:22]=2[C:1](=[O:5])[CH3:2])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccccc1Cc1ccccc1
Agent: [Li]C
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)c1ccccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
Oxalyl chloride (4.1 ml, 47 mmol) was added to a solution of 2-(phenylmethyl)benzoic acid (from Aldrich) in methylene chloride (100 ml) over 5 minutes at room temperature. The solution was allowed to stir at room temperature for 2 hours. The solution was concentrated and the resultant orange gum azeotroped with benzene (twice) and placed under high Vacuum for 1 hour. In a separate flask, methyl lithium (1.4M in THF, 100 ml, 140 mmol) was added over 10 minutes to a slurry of CuI2 (13.432 gm, 42.3 mmole) in ether (125 ml). The slurry was allowed to stir for 2 minutes. The above-prepared acid chloride in ether (50 ml) at -78° C. was cannulated over 20 minutes into the dimethyl lithiumcuprate solution, which was also cooled to -78° C. The solution stirred for an additional 20 minutes, then was quenched with methanol (30 ml) and warmed to room temperature. The solution was then added to saturated NH4Cl (200 ml), and the aqueous layer was extracted with ether (twice). The organic layers were combined and washed with brine, then dried over MgSO4, filtered and concentrated to afford an orange oil. The crude oil was purified by flash chromatography on Merck silica gel in 5% EtOAc in hexane. The fractions containing the product were combined and concentrated to afford the title compound as a pale yellow solid (3.090 gm, 63%).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>C1COCC1>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[CH:3]=2)[OH:17])=[CH:14][CH:13]=1
Reactant: COc1ccccc1Br
Reactant: O=Cc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cccc(C(O)c2ccc(Br)cc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a suspension of magnesium (2.4 g, 100 mmmol), in THF (20 mL) at room temperature was added dropwise a solution of bromoanisole (9.1 mL, 71.4 mmol) in THF (30 mL). The reaction mixture was stirred at room temperature for 2 h and at 60° C. for 2 h. The mixture was cooled to room temperature and a solution of 4-bromobenzaldehyde (13.2 g, 71.4 mmol) was added over 5 min. The reaction mixture was stirred at room temperature for 3 h and was quenched by addition of aqueous saturated ammonium chloride (NH4Cl) (30 mL). The aqueous layer was washed with ether (3×40 mL), dried over Na2SO4 and concentrated. Purification by flash chromatography with hexanes/EtOAc (10:1) afforded 16.95 g of (4-bromo-phenyl)-(3-methoxy-phenyl)-methanol. 1HNMR (400 MHz, CDCl3) δ 7.46-7.41 (comp, 2H), 7.27-7.18 (comp, 3H), 6.91-6.87 (comp, 2H), 6.81-6.78 (m, 1H), 5.73 (s, 1H), 3.76 (s, 3H); MS (M+1) 294.2.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH3:19])=[CH:13][C:12]=1[NH:20][C:21]1[C:30]2[C:25](=[CH:26][C:27](F)=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][C:22]=1[C:34]#[N:35]>CN(C=O)C>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH3:19])=[CH:13][C:12]=1[NH:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:3][C:4]3[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=3)=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][C:22]=1[C:34]#[N:35]
Reactant: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Reactant: Oc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3cc(Oc4ccncc4)c(OC)cc23)c(Cl)cc1Cl
Temperature: 100 °C
Yield: 54.5 %

Procedure:
A mixture of sodium hydride (128 mg, 3.2 mmol) and 4-hydroxypyridine (750 mg, 7.89 mmol) in 5 mL of N, N′-dimethylformamide is heated at 100° C. for 1 hour. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile (200 mg, 0.51 mmol) is added and the reaction mixture is heated at 130° C. for 2 hours. An additional 21 mg of sodium hydride is added and the reaction mixture is heated at 130° C. for an additional 30 minutes. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by heating with methanol and dichloromethane to provide 130 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-(pyridin-4-yloxy)-3-quinolinecarbonitrile, mp 267-269° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11](Cl)(=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>O1CCCC1.N1C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:11](=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1ccc([N+](=O)[O-])cc1
Yield: 90 %

Procedure:
In a three necked flask equipped with a dropping funnel, a thermometer and a reflux condenser, p-nitroaniline (138 g) was dissolved in a mixed solution of tetrahydrofuran (200 ml) with pyridine (140 ml) in a nitrogen atmosphere. To the solution, octadecanoyl chloride (333 g) was added through the dropping funnel over a time span of 20 minutes, while stirring the reaction mixture. After the completion of the dropwise addition, the reaction mixture was stirred for 2 hours. The resultant solid product was removed by filtering, and the filtrate was concentrated under reduced pressure, to produce crystals. The crystals were collected and recrystallized from ethanol. 4'-nitro-n-octadecaneanilide (364 g) was obtained at a yield of 90%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=1)=[O:6].C([O:24][P:25]([CH2:30]/[CH:31]=[CH:32]/[C:33]1[CH:38]=[C:37]([CH3:39])[C:36]([CH:40]=O)=[C:35]([CH3:42])[CH:34]=1)(=[O:29])[O:26]CC)C>>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5]([C:4]2[CH:18]=[CH:19][C:20]3[N:21]=[C:40]([C:36]4[C:35]([CH3:42])=[CH:34][C:33]([CH2:32][CH2:31][CH2:30][P:25](=[O:24])([OH:29])[OH:26])=[CH:38][C:37]=4[CH3:39])[NH:1][C:2]=3[CH:3]=2)=[O:6])=[CH:9][CH:10]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOP(=O)(C/C=C/c1cc(C)c(C=O)c(C)c1)OCC
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(N)c(N)c2)cc1
Product: Cc1cc(CCCP(=O)(O)O)cc(C)c1-c1nc2ccc(C(=O)Nc3ccc(C(C)(C)C)cc3)cc2[nH]1

Procedure:
The title compound was prepared from 3,4-diamino-N-(4-tert-butylphenyl)-benzamide (from Example 6-26) and [(E)-3-(4-formyl-3,5-dimethylphenyl)-allyl]-phosphonic acid diethyl ester analogous to Example 6-32. 1H NMR (Methanol-d4, 400 MHz): δ 8.25 (dd, 1H), 7.92 (dd, 1H), 7.72 (dd, 1H), 7.63 (m, 2H), 7.42 (m, 2H), 7.06 (s, 2H), 2.73 (t, 2H), 2.14 (s, 6H), 1.95 (m, 2H), 1.69 (m, 2H), 1.33 (s, 9H). MS (m/z) 520.2 (M+1); Retention time: 1.19 min (Method 10).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](/[C:8](=[C:11](/N(C)C)\[CH3:12])/[C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.Cl.C[OH:20]>>[F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](/[C:8](=[C:11](/[OH:20])\[CH3:12])/[C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1
Reactant: CO
Reactant: C/C(=C(/C#N)C(=O)c1ccc(F)cc1)N(C)C
Agent: Cl
Product: C/C(O)=C(/C#N)C(=O)c1ccc(F)cc1

Procedure:
A solution of 1.35 g. (0.006 m) of 2-(p-fluorobenzoyl)-3-dimethylaminocrotononitrile in a mixture of 15 ml. methanol and 8 ml. of 1 N HCl was heated on the steam bath in an open beaker for 45 minutes. Upon cooling in an ice bath, a solid formed, was collected, and then recrystallized from cyclohexane-petroleum ether with charcoal treatment, giving 0.7 g. (64%) of light pinkish crystals, m.p. 65°-67° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([F:33])=[C:12]([C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][N:25]([S:28]([CH:31]=[CH2:32])(=[O:30])=[O:29])[CH2:24][CH2:23]3)=[N:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C[O:37][CH2:36]C1.CO.[OH-].[Na+]>C(Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[C:11]([F:33])=[C:12]([C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:23][CH2:24][N:25]([S:28]([CH2:31][CH2:32][O:37][CH3:36])(=[O:30])=[O:29])[CH2:26][CH2:27]3)=[N:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: C=CS(=O)(=O)N1CCN(c2ncc(-c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COCCS(=O)(=O)N1CCN(c2ncc(-c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-[4-(vinylsulfonyl)piperazin-1-yl]pyrimidine (360 mg) was mixed with THF (3 ml) and MeOH (4 ml), and a 1M aqueous NaOH solution (1.46 ml) was added thereto, followed by stirring at room temperature for 3 hours. CHCl3 was added to the reaction mixture, which was washed with water and saturated brine, and dried over Na2SO4. Then, the organic layer was concentrated under reduced pressure to obtain 5-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-{4-[(2-methoxyethyl)sulfonyl]piperazin-1-yl}pyrimidine (353 mg).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[S:27](Cl)(=[O:29])=[O:28].C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([N:5]([CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[S:27]([C:23]1[S:22][CH:26]=[CH:25][CH:24]=1)(=[O:29])=[O:28])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1cccs1

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with 2-thiophenesulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give thiophene-2-sulfonic acid isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amide as a light yellow solid. MS: 487.0 ([M+NH4]+)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH3:17])[C:10](=[N:13][C:14]#[N:15])SC)=[CH:4][CH:3]=1.[CH3:18][NH2:19]>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH3:17])[C:10]([NH:19][CH3:18])=[N:13][C:14]#[N:15])=[CH:4][CH:3]=1
Reactant: CCN(Cc1ccc(Cl)nc1)C(=NC#N)SC
Reactant: CN
Solvent: CC#N
Product: CCN(Cc1ccc(Cl)nc1)C(=NC#N)NC
Yield: 81.4 %

Procedure:
To a mixture of 0.42 g of 1-(6-chloro-3-pyridylmethyl)-3-cyano-1-ethyl-2-methylisothiourea and 5 ml of acetonitrile was added each 0.5 g of 40% methylamine aqueous solution at an hour interval in total six time (3.0 g), while refluxing and stirring. The reaction mixture was stirred for 6 hours in total. Then, the mixture was concentrated to afford 0.32 g of 1-(6-chloro-3-pyridylmethyl)-2-cyano-1-ethyl-3-methylguanidine (Compound No. 3).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH2:23]([O:25][C:26]1[CH:27]=[CH:28][C:29]([OH:39])=[C:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:31]=1)[CH3:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([O:25][C:26]1[CH:27]=[CH:28][C:29]([O:39][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)=[C:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:31]=1)[CH3:24]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)CCc1cc(OCC)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cc(OCC)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.44 g), ethyl 3-(5-ethoxy-2-hydroxyphenyl)propionate (1.0 g), anhydrous potassium carbonate (0.58 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give ethyl 3-[5-ethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate as an oil (1.57 g, 72%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[NH2:5][C:6]1[C:11]2[O:12][CH2:13][CH2:14][O:15][C:10]=2[C:9]([C:16]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:17])=[CH:8][C:7]=1[Cl:26]>C(N(CC)CC)C.CN(C=O)C>[NH2:5][C:6]1[C:11]2[O:12][CH2:13][CH2:14][O:15][C:10]=2[C:9]([C:16]([O:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([CH2:2][C:3]#[N:4])[CH2:24][CH2:25]2)=[O:17])=[CH:8][C:7]=1[Cl:26]
Reactant: N#CCCl
Reactant: Nc1c(Cl)cc(C(=O)OCC2CCNCC2)c2c1OCCO2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCN1CCC(COC(=O)c2cc(Cl)c(N)c3c2OCCO3)CC1
Temperature: 60 °C
Yield: 53 %

Procedure:
A mixture of chloroacetonitrile (2.15 ml) and (4piperidinyl)-methyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylate (11 g) in N,N-diethylethanamine (7 ml) and DMF (150 ml) was stirred at 60° C. until the reaction was complete. Then, the mixture was cooled. The solvent was evaporated. The residue was partitioned between DCM and water. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was crystallized from ACN and the precipitate was filtered off and dried (vacuum, 50° C.), yielding 6.6 g (53%) [1-(cyanomethyl)-4-piperidinyl]-methyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylate (intermediate 14).
Reaction SMILES: [H-].[K+].[C:3]([O:7][C:8]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]([CH2:20][OH:21])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:22](Br)[CH:23]=[CH2:24]>O1CCCC1>[C:3]([O:7][C:8]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]([CH2:20][O:21][CH2:24][CH:23]=[CH2:22])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(CO)Cc2ccccc21
Reactant: C=CCBr
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCOCC1Cc2ccccc2N(C(=O)OC(C)(C)C)C1
Reaction time: 0.5 h

Procedure:
0.5 g of a potassium hydride suspension (20% in oil) is added to a solution of 0.6 g of 1-tert-butoxycarbonyl-3(R,S)-hydroxymethyl-1,2,3,4-tetrahydroquinoline in 7 ml of tetrahydrofuran at 0° C., the mixture is stirred for 30 min and 0.58 ml of allyl bromide is then added. After the mixture has been stirred at 0° C. for 45 min, it is worked up in the customary manner and the crude product is purified over 50 g of silica gel (mobile phase F). 1-Tert-butoxycarbonyl-3(R,S)-allyloxymethyl-1,2,3,4-tetrahydroquinoline is obtained as a colourless oil (Rf (F)=0.40), which is then reacted analogously to Example 20a). Purification by means of FC over 50 g of silica gel with methylene chloride as the mobile phase gives 3(R,S)-allyloxymethyl-1,2,3,4-tetrahydroquinoline: Rf (F)=0.40; MS: M+ =203.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.Cl[CH2:26][CH2:27][S:28][CH3:29]>>[CH3:29][S:28][CH2:27][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)NC(C)c1cc2ccc(CCc3ccc(O)cc3)cc2o1
Reactant: CSCCCl
Product: CSCCOc1ccc(CCc2ccc3cc(C(C)NC(C)=O)oc3c2)cc1
Yield: 50 %

Procedure:
Using N-(1-{6-[2-(4-hydroxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (150 mg, 0.464 mmol) obtained in Example 165 and 2-chloroethylmethylsulfide (0.182 mL, 1.86 mmol) and in the same manner as in Example 158, the title compound was obtained (91.9 mg, yield 50%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[O:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][CH2:13]1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([C:20]1[CH:19]=[CH:18][C:17]2[O:12][CH2:13][CH2:14][O:15][C:16]=2[CH:21]=1)=[O:5]
Reactant: c1ccc2c(c1)OCCO2
Reactant: O=C(Cl)c1cc(I)ccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)OCCO2)c1cc(I)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a stirred solution of 2-bromo-5-iodo-benzoyl chloride (26.4 g, 76.56 mmol) in dichloromethane (250 mL) was added benzo(1,4)-dioxane (10.41 g, 76.26 mmol) at 0° C. To this reaction mixture, AlCl3 (40.78 g, 305.47 mmol) was added in portions. After stirring overnight at room temperature, the reaction mixture was poured into crushed ice. The resulting mixture was extracted with dichloromethane (500 mL×2). The dichloromethane layers were combined and washed with water (200 mL), saturated aqueous sodium bicarbonate solution (200 mL×2), and brine (200 mL), then dried over sodium sulfate and concentrated. The solid product was triturated with hexanes, and the triturated product was dried under vacuum to furnish (2-bromo-5-iodo-phenyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone (30 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][OH:22])[C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][O:22][S:37]([CH3:36])(=[O:39])=[O:38])[C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCO)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.0 g, 2.77 mmol), N,N-diisopropylethylamine (0.79 g, 6.1 mmol), and dichloromethane (10 mL). Cool in an ice bath. Add dropwise methanesulfonyl chloride (0.41 g, 3.6 mmol). After 1 hour, warm to ambient temperature and dilute the reaction mixture with dichloromethane. Extract with a 1 M aqueous hydrochloric acid solution and three times with saturated aqueous sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give 1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.58 (silica gel, ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[OH-].[Na+].[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=O>CC1CCCO1.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:7]=[C:31]([C:27]3[S:26][CH:30]=[CH:29][CH:28]=3)[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1cccs1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC1CCCO1
Product: Clc1ccc(-c2noc(-c3cccs3)n2)cc1
Temperature: 50 °C
Yield: 86.2 %

Procedure:
The 4-chlorobenzamidoxime (1.00 g, 5.8 mmol) was dissolved in 2-methyltetrahydrofuran (10.0 mL) and water (1.0 mL). A 40% aqueous solution of benzyltrimethylammonium hydroxide (100 uL) was added and the solution heated to 50° C. A 50% aqueous solution of sodium hydroxide (720 mg, 9.00 mmol) and 2-thiophenecarbonyl chloride (939.0 mg, 6.4 mmol) were added dropwise simultaneously over 15 minutes. The temperature of the mixture warmed to 70° C. The mixture was cooled to room temperature and water (40 mL) added. Solids formed and the 2-methyltetrahydrofuran was removed at reduced pressure. The solids were isolated by vacuum filtration. The 3-(4-chlorophenyl)-5-(2-thienyl)-1,2,4-oxadiazole (1.32 g, 5.0 mmol) was obtained as a white solid. (86% yield).