Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@:10]1([CH:50]1[CH2:52][O:51]1)[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH:50]4[CH2:52][O:51]4)([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@@](C5CO5)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C5CO5)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(oxiran-2-yl)-6,8-dioxabicyclo[3.2.1]octane 10a (310 mg, 0.43 mmol, obtained from the synthetic method described in step 1 example 10) in a methanol/tetrahydrofuran mixture (v/v=4/1, 15 mL) were added o-dichlorobenzene (0.25 mL, 2.15 mmol) and 10% Pd/C (30 mg, 0.03 mmol) at room temperature. The mixture was stirred under H2 at room temperature for 6 hours and filtered. The filter cake was washed with an ethyl acetate/tetrahydrofuran mixture (v/v=4/1, 10 mL×2) and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=1/1 to give the title compound 26 as a white solid (34 mg, 17.6%, HPLC: 97.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 449.1[M+H]+; and 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.38 (m, 2H), 7.27 (m, 1H), 7.09 (d, 2H), 6.83 (d, 2H), 5.54 (d, 1H), 5.10 (d, 1H), 4.99 (d, 1H), 3.97 (m, 5H), 3.45 (t, 1H), 3.40 (m, 2H), 3.26 (m, 3H), 2.78 (t, 1H), 1.29 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH3:9].CCN(CC)CC.[F:17][C:18]1([F:33])[O:22][C:21]2[CH:23]=[CH:24][C:25]([C:27]3([C:30](Cl)=[O:31])[CH2:29][CH2:28]3)=[CH:26][C:20]=2[O:19]1>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:30]([C:27]2([C:25]3[CH:24]=[CH:23][C:21]4[O:22][C:18]([F:33])([F:17])[O:19][C:20]=4[CH:26]=3)[CH2:29][CH2:28]2)=[O:31])[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: Cc1ccc(N)nc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a solution of 6-chloro-5-methylpyridin-2-amine (11.1 g, 78.0 mmol) and Et3N (22.0 mL, 156 mmol) in dichloromethane (100 mL) was added a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (20.3 g, 78.0 mmol) in dichloromethane (50 mL). The resulting reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was then washed with 1N aqueous NaOH (2×200 mL), 1 N aqueous HCl (1×200 mL), and saturated aqueous NaHCO3 (1×200 mL). The organics were dried over sodium sulfate and evaporated to yield N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (26.9 g, 94%). ESI-MS m/z calc. 366.1. found 367.3 (M+1)+. Retention time 2.19 minutes. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 7.89-7.87 (m, 1H), 7.78-7.76 (m, 1H), 7.54-7.53 (m, 1H), 7.41-7.39 (m, 1H), 7.33-7.30 (m, 1H), 2.26 (s, 3H), 1.52-1.49 (m, 2H), 1.19-1.16 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=O.[F:17][C:18]([F:26])([F:25])[C:19](=[O:24])[CH2:20][C:21](=O)[CH3:22]>C(O)(=O)C.S(=O)(=O)(O)O>[F:17][C:18]([F:26])([F:25])[C:19]([C:20]1[C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[C:3]2[C:4]3[CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:21]=1[CH3:22])=[O:24]
Reactant: Nc1sc2c(c1C(=O)c1cccs1)CCC2
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2cccs2)c1C(=O)C(F)(F)F)CCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 21.5 %

Procedure:
To a stirred solution of 59 mg (0.24 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-thiophen-2-yl-methanone in 2 ml acetic acid was added 0.038 ml (0.24 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 20:1) afforded 19 mg (22%) 2,2,2-trifluoro-1-(2-methyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[4,5]thieno [2,3-b]pyridin-3-yl)-ethanone as a colorless oil. ES-MS m/e (%): 368 (M+H+, 100).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[N:10]=[CH:11][NH:12][CH:13]=1.[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])O.[Na+]>ClCCl>[Br:8][C:9]1[N:10]=[CH:11][N:12]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:13]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1c[nH]cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Brc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
0.3787 g of triethylamine is added dropwise over 15 minutes to a solution of 0.500 g of 4-bromoimidazole, 1.043 g of trityl chloride and 25 ml of dichloromethane. The reaction mixture is stirred at room temperature for 11 hours and then poured onto 50 ml of aqueous saturated sodium hydrogencarbonate solution. The mixture is extracted twice with 75 ml of dichloromethane. The combined organic phases are washed with 50 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.38 (1:3 EtOAc-heptane); Rt=5.02.
Reaction SMILES: Br[C:2]1[C:19]2[C:20]3[C:5]([C:6]4[C:23]5[C:10](=[C:11]([C:25]([OH:27])=[O:26])[CH:12]=[C:13]([Cl:24])[C:14]=5[C:15]=3[C:16]([Cl:22])=[CH:17][C:18]=2Br)[C:9]([C:28](O)=[O:29])=[CH:8][C:7]=4[Cl:31])=[C:4]([Cl:32])[CH:3]=1.[C:33]1([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[Cl:24][C:13]1[CH:12]=[C:11]2[C:25](=[O:26])[O:27][C:28](=[O:29])[C:9]3[CH:8]=[C:7]([Cl:31])[C:6]4[C:5]5[C:4]([Cl:32])=[CH:3][C:2]6[C:45]7[C:40]([N:39]([C:33]8[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=8)[C:18]8[C:19]=6[C:20]=5[C:15]([C:14]=1[C:23]=4[C:10]2=3)=[C:16]([Cl:22])[CH:17]=8)=[CH:41][CH:42]=[CH:43][CH:44]=7
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: O=C(O)c1cc(Cl)c2c3c(Cl)cc(Br)c4c(Br)cc(Cl)c(c5c(Cl)cc(C(=O)O)c1c25)c43
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=c1oc(=O)c2cc(Cl)c3c4c(Cl)cc5c6c(cc(Cl)c(c7c(Cl)cc1c2c73)c46)c1ccccc1n5-c1ccccc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A suspension of 9,10-dibromo-1,6,7,12-tetrachloroperylene-3,4-dicarboxylic acid anhidride (1.24 g, 2.0 mmol), diphenylamine (0.40 g, 2.40 mmol), Pd(AcO)2 (10 mmol %), sodium-tert-butoxide (0.48 g, 5.0 mmol), tricyclohexylphosphine (20 mol %) in 70 ml toluene was stirred at 100° C. under argon atmosphere for 24 h. The solvent was removed under reduced pressure. The solid was dissolved in dichloromethane and acetic acid and stirred overnight at 70° C. The solvent was removed under reduced pressure. The crude product was purified by column chromatography using dichloromethane as eluent on silica. Yield 0.50 g (40%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1.O.[OH-].[Li+]>C1COCC1.O.CO.O>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(OCCCBr)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OCCCBr)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A mixture of 107A (2.44 g, 8.9 mmol) and lithium hydroxide monohydrate (750 mg, 17.9 mmol) in THF-H2O-MeOH (15:7:7, 29 mL) was stirred at 60° C. for 2.0 hr. After cooling to room temperature, the reaction mixture was diluted with water (30 mL) and concentrated in vacuo to remove most organic solvents. The mixture was washed with 1:1 mixture of ethyl acetate-ether and the aqueous layer was acidified with 2.0 N HCl to pH 5.0. The precipitate was collected by filtration, rinsed with water and dried under high vacuum to give 107B as a crystalline solid (1.64 g, 71%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][CH2:8][N:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27](=[O:29])[CH3:28])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[C:38]([N:40]=[C:41]([N:43]1CCNCC1)[S-])#[N:39].O.[NH2:50]N>>[NH2:50][C:41]1[N:40]=[C:38]([N:13]2[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27](=[O:29])[CH3:28])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH2:8][CH2:7][C:6]3[CH:30]=[CH:31][C:3]([Br:2])=[CH:4][CH:5]=3)[CH2:11][CH2:12]2)[NH:39][N:43]=1
Reactant: NN
Reactant: CC(=O)NS(=O)(=O)c1ccc(CN(CCc2ccc(Br)cc2)C2CCNCC2)cc1
Reactant: N#CN=C([S-])N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)NS(=O)(=O)c1ccc(CN(CCc2ccc(Br)cc2)C2CCN(c3nc(N)n[nH]3)CC2)cc1

Procedure:
N-((4-(((4-Bromophenethyl)(piperidin-4-yl)amino)methyl)phenyl)sulfonyl)acetamide hydrochloride obtained in Step 2 was reacted with K2CO3 and S,S′-dimethyl-N-cyano-dithioiminocarbonate, followed by the cyclization of the intermediate (N-cyanopiperazine-1-carbimidothioate) with hydrazine monohydrate in a manner described in Procedure 3.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([NH2:6])=[O:5].[P:13]([Cl:18])(Cl)(Cl)(Cl)[Cl:14].C(O)=[O:20]>C(Cl)(Cl)(Cl)Cl>[Cl:14][P:13]([Cl:18])([NH:6][C:4](=[O:5])[C:3]1[C:7]([CH3:12])=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=1[CH3:1])=[O:20]
Reactant: O=CO
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1cc(C)c(C(N)=O)c(C)c1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(C)c(C(=O)NP(=O)(Cl)Cl)c(C)c1
Reaction time: 0.33 h

Procedure:
A suspension of 21 g (0.13 mole) of 2,4,6-trimethylbenzamide and 26.8 g (0.13 mole) of phosphorus pentachloride in 200 ml of AR carbon tetrachloride was heated at 70° for 30 min. The solution was cooled to 30° and 6.1 g (0.13 mole) of 97% formic acid added dropwise. Stirred for another 20 min., then filtered, washed with AR carbon tetrachloride and air-dried to give 20.5 g, m.p. 109°-110°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH2:9])[CH2:3][CH2:2]1.CO[C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]Br)[CH:14]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]2[C@:31]3([C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:33][C:32]3=[O:40])[CH2:30]2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C@@H:29]2[C@:31]3([C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH2:19][C:15]4[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=4)[C:12]([NH:9][CH2:8][CH2:7][N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[O:21])[C:32]3=[O:40])[CH2:30]2)=[CH:27][CH:28]=1
Reactant: NCCN1CCOCC1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Product: O=C(NCCN1CCOCC1)c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 60 starting from 2-morpholinoethanamine, 3-bromomethyl-benzoic acid methyl ester (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C30H30ClN3O3: 515, observed (M+H)+: 516.21H NMR (400 MHz, MeOD-d4) δppm 2.24 (d, J=8.59 Hz, 2 H) 3.20 (br. s., 2 H) 3.29 (s, 1 H) 3.42 (t, J=5.81 Hz, 2 H) 3.69 (br. s., 4 H) 3.80 (t, J=5.81 Hz, 2 H) 4.08 (br. s., 2 H) 5.14 (d, J=1.52 Hz, 2 H) 6.09 (d, J=7.33 Hz, 1 H) 6.73 (t, J=7.58 Hz, 1 H) 6.91 (d, J=8.08 Hz, 1 H) 7.04-7.13 (m, 1 H) 7.22-7.28 (m, 2 H) 7.29-7.36 (m, 2 H) 7.50 (t, J=7.71 Hz, 1 H) 7.55-7.62 (m, 1 H) 7.80 (d, J=7.58 Hz, 1 H) 7.90 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[O:20][CH2:19][CH2:18][C:17]3=[O:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1.OI(C1C=CC=CC=1)OS(C1C=CC(C)=CC=1)(=O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[O:20][CH:19]=[CH:18][C:17]3=[O:24])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)C(=O)CCO3)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)OI(O)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCCc2ccc3occc(=O)c3c2)cc1
Yield: 33.2 %

Procedure:
The compound was produced with reference to the method described in the literature (Synth. Commun., 1994, 24 (18), 2637). A solution of 2-(4-oxo-3,4-dihydro-2H-chromen-6-yl)ethyl 4-methylbenzenesulfonate (RE6) (15.0 g, 43 mmol), [hydroxy(tosyloxy)iodo]benzene (20.4 g, 52 mmol) and p-toluenesulfonic acid monohydrate (375 mg) in acetonitrile (750 mL) was stirred at 50° C. for 16 hours. The solvent was distilled off under reduced pressure. Ethyl acetate (500 mL) was added to the obtained concentrated residue, and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and brine in this order and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained concentrated residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1→1:2) to obtain the title compound (RE7) (4.92 g, 33%) as a pale yellow solid.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]=[C:5]([NH:17][CH3:18])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH2:16])[N:11]=1.CO[C:21]1[C:25](OC)=[N:24][S:23](=[O:28])[N:22]=1.[NH3:29]>>[NH2:29][C:21]1[C:25]([NH:16][CH2:15][CH2:14][S:13][CH2:12][C:10]2[N:11]=[C:7]([NH:6][C:5]([NH:17][CH3:18])=[N:4][CH3:3])[S:8][CH:9]=2)=[N:24][S:23](=[O:28])[N:22]=1
Reactant: COC1=NS(=O)N=C1OC
Reactant: CN=C(NC)Nc1nc(CSCCN)cs1
Reactant: N
Agent: Cl
Product: CN=C(NC)Nc1nc(CSCCNC2=NS(=O)N=C2N)cs1

Procedure:
The product of Step A, above, was sequentially reacted with 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide and anhydrous ammonia by the general procedure of Example 117, Step B. The crude reaction mixture was evaporated under reduced pressure and the residue crystallized from methanol to give the title compound, mp 201°-203° (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].CI.[CH3:19]C(C)=O>O>[CH3:19][O:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(C)=O
Reactant: Cc1ccc(O)c(C(=O)c2ccccc2)c1
Solvent: O
Solvent: CI
Product: COc1ccc(C)cc1C(=O)c1ccccc1
Yield: 71.5 %

Procedure:
To a solution of 5.00 g (23.5 mmole) 2-hydroxy-5-methyl-benzophenone and 6.67 g (47.1 mmole) methyliodide in 50 ml abs. acetone 4.50 g (32.6 mmole) potassium carbonate are added. The reaction mixture is then heated for 5 hours with recycling. Following cooling, 50 ml water and 50 ml petroleum ether (30/60) are added to the suspension. The organic phase is separated off, the aqueous phase is extracted twice with 75 ml petroleum ether (30/60) and the purified organic phase is washed twice with 50 ml 10% NaOH solution. The organic phase is then dried through magnesium sulphate and the solvent is removed. 3.80 g (16.8 mmole, 71%) 2-methoxy-5-methyl-benzophenone are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2[CH:15]([CH3:16])[CH2:14][O:13][C:12]2=[O:17])=[C:4]([CH:8]=[CH:9][CH:10]=1)C(O)=O.[Cl:18][C:19]1[CH:30]=[CH:29][C:22]2[NH:23][C:24]([C@@H:26]([NH2:28])[CH3:27])=[N:25][C:21]=2[CH:20]=1.CN([C:34]([O:38]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:4][C:3]=1[N:11]1[CH:15]([CH3:16])[CH2:14][O:13][C:12]1=[O:17])[C:34]([NH:28][C@H:26]([C:24]1[NH:23][C:22]2[CH:29]=[CH:30][C:19]([Cl:18])=[CH:20][C:21]=2[N:25]=1)[CH3:27])=[O:38]
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC1COC(=O)N1c1c(Cl)cccc1C(=O)O
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1COC(=O)N1c1ccc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1f from 3-chloro-(4-methyl-2-oxo-oxazolidin-3-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and DIPEA in THF and purification of the residue by chromatography on aluminium oxide.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:28]=[CH:27][C:14]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][SH:26])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>C(Cl)Cl>[ClH:10].[ClH:10].[CH:1]1([NH:7][C:8](=[SH:26][CH2:25][CH2:24][CH2:23][N:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:28][CH:27]=3)[CH2:18][CH2:19]2)[OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: SCCCN1CCN(CCc2ccc(Cl)cc2)CC1
Reactant: O=C=NC1CCCCC1
Solvent: ClCCl
Product: Cl
Product: OC(NC1CCCCC1)=[SH]CCCN1CCN(CCc2ccc(Cl)cc2)CC1
Yield: 170.7 %

Procedure:
The procedure described in Example 35 was followed, using 1.7 g of cyclohexyl isocyanate, 4.0 g of 3-[4-(4-chlorophenethyl)piperazin-1-yl]propanethiol and 100 ml of methylene chloride, to give 3.8 g (58% of theory) of N-cyclohexyl-S-{3-[4-(4-chlorophenethyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 262°-267° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]([S:22]Cl)=[O:21].O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[C:11]1[O:12][C:20](=[O:21])[S:22][N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)SCl
Reactant: NC(=O)c1ccc(Cl)cc1OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1oc(-c2ccc(Cl)cc2OCc2ccccc2)ns1
Temperature: 90 °C
Yield: 98.8 %

Procedure:
To a solution of 2-(benzyloxy)-4-chlorobenzamide (0.103 g, 0.38 mmol) in toluene (5 ml) was added chlorocarbonylsulfenyl chloride (63 μL, 0.76 mmol) under nitrogen atmosphere and the resulting reaction mixture was refluxed at 90° C. for 2 h. After the completion of the reaction (TLC monitoring) water was added followed by extraction with ether (3×25 ml). The combined organics was then sequentially washed with water, 10% NaHCO3 (aqueous solution) and finally again with water. The organic layer was then dried over anhydrous Na2SO4, filtered and concentrated to get desired product (0.12 g, 94%) that was carried forward as such without further purification. MS: 320.21 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:23][NH2:24].[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl.O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:10]([C:11]([F:14])([F:12])[F:13])/[CH:9]=[CH:8]/[C:6]2[CH:7]=[CH:2][C:3]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])=[CH:4][CH:5]=2)[CH:20]=[C:19]([Cl:21])[CH:18]=1
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(=O)NCc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.2 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.3 g, 0.8 mmol) in DCM (10 mL) was added acetic anhydride (0.12 mL, 1.14 mmol), and TEA (0.217 mL, 1.52 mmol), and the resultant reaction mixture was stirred at ambient temperature for 6 h. The reaction mixture was diluted with H2O and extracted with DCM. The combined DCM layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 30-50% ethyl acetate in hexane) afforded the title compound as an off-white solid (0.2 g, 60%) mp 107-109° C.; 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 3H), 7.28 (m, 4H), 6.60 (d, J=16.0 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 5.75 (br s, 1H), 4.46 (d, J=6 Hz, 2H), 4.01 (m, 1H), 2.11 (s, 3H); ESIMS m/z 402.00 ([M+H]+).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([NH:12][CH2:13][CH2:14][O:15][CH2:16][CH3:17])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:4].[C:18]1([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC1C=CC=CC=1>[CH2:16]([O:15][CH2:14][CH2:13][NH:12][C:11]1[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:28]2[CH2:29][CH2:30][N:25]([CH2:24][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:26][CH2:27]2)=[N:7][CH:8]=[CH:9][CH:10]=1)[CH3:17]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCOCCNc1cccnc1NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOCCNc1cccnc1NC(=O)CN1CCN(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
A mixture of 3.62 parts of 2-chloro-N-[3-[(2-ethoxyethyl)amino]-2-pyridinyl]acetamide, 10.6 parts of 1-(phenylmethyl)piperazine, 6.4 parts of sodium carbonate and 90 parts of methylbenzene was stirred for 20 hours at 80° C. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 7.9 parts (100%) of N-[3-[(2-ethoxyethyl)amino]-2-pyridinyl]-4-(phenylmethyl)-1-piperazineacetamide as a residue (int. 25).