Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]1[N:13]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=3)[N:15]=2)[C:12](=[O:26])[C:11]2[S:27][CH2:28][CH:29]([O:32][CH3:33])[CH2:30][S:31][C:10]1=2.Cl.Cl[C:36]([N:38]1[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]1)=[O:37].N1C=CC=CC=1>C(Cl)Cl>[CH3:33][O:32][CH:29]1[CH2:30][S:31][C:10]2[C:9](=[O:8])[N:13]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=4)[N:15]=3)[CH:12]([O:26][C:36]([N:38]3[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]3)=[O:37])[C:11]=2[S:27][CH2:28]1
Reactant: COc1ccc2ccc(N3C(=O)C4=C(SCC(OC)CS4)C3O)nc2n1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2ccc(N3C(=O)C4=C(SCC(OC)CS4)C3OC(=O)N3CCN(C)CC3)nc2n1
Temperature: 45 °C
Yield: 52.3 %

Procedure:
Triethylamine (34.5 cc) is added, at about 15° C., to a suspension of 6-hydroxy-3-methoxy-7-(7-methoxy-1,8-naphthyridin-2-yl)-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (10.7 g) and 1-chlorocarbonyl-4-methylpiperazine hydrochloride (16.4 g) in anhydrous methylene chloride (440 cc), and anhydrous pyridine (195 cc) is then added to the resulting mixture. The reaction mixture is heated for 3 hours at 45° C. After cooling, the mixture is diluted by adding methylene chloride (300 cc). The organic phase is washed three times with distilled water (total 600 cc), dried over anhydrous sodium sulphate and evaporated. The resulting residue (41.0 g) is treated with boiling methanol (150 cc). After cooling the mixture for 1 hour at 2° C., the crystals are filtered off, washed twice with ice-cooled methanol (total 40 cc) and dried under reduced pressure (20 mm Hg) at 20° C. The resulting product (9.0 g; m.p. 215° C.) is dissolved in boiling methanol (175 cc). After cooling the solution for 2 hours at 2° C., the resulting crystals are filtered off, washed twice with ice-cooled methanol (total 20 cc) and dried under reduced pressure (0.2 mm Hg) at 50° C. 3-Methoxy-7-(7-methoxy-1,8-naphthyridin-2-yl)-6-(4-methylpiperazin-1-yl)carbonyloxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (7.4 g), melting at 218° C., is obtained.
Reaction SMILES: [C:1]([S:5]([CH2:8][CH:9]([CH2:15][C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)[C:10]([O:12]CC)=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].S1C=CC(CC(C(OCC)=O)C(OCC)=O)=C1>>[C:1]([S:5]([CH2:8][C@@H:9]([CH2:15][C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)[C:10]([OH:12])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cc1ccsc1)CS(=O)(=O)C(C)(C)C
Agent: CCOC(=O)C(Cc1ccsc1)C(=O)OCC
Product: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccsc1)C(=O)O

Procedure:
This compound was prepared analogously to Example 1 by the enzymatic hydrolysis of ethyl (RS)-α-[(tert-butylsulphonyl)methyl]-3-thiophenepropionate which, in turn, was prepared starting from diethyl 3-thienylmethylmalonate [J. Am. Chem. Soc. 76, 4466 (1954)] analogously to the synthesis of ethyl (RS)-α-[(tert-butylsulphonyl)methyl]hydrocinnamate described in EPA 0236734, MS: 318 (M)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][N:6]([CH3:18])[C:7](=[O:17])[CH2:8][NH:9]C(=O)OC(C)(C)C.O.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[ClH:23].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:21]=[CH:20][CH:19]=[C:4]([CH2:5][N:6]([CH3:18])[C:7](=[O:17])[CH2:8][NH2:9])[CH:3]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CN(Cc1cccc(Br)c1)C(=O)CNC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(Cc1cccc(-c2ccc(Cl)cc2)c1)C(=O)CN
Product: Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 133.7 %

Procedure:
To a suspension of tert-butyl {2-[(3-bromobenzyl)(methyl)amino]-2-oxoethyl}carbamate (293 mg) in toluene (4 ml) were added water (2 ml), (4-chlorophenyl)boronic acid (192 mg), sodium carbonate (173 mg), and tetrakis(triphenylphosphine)palladium (28 mg), followed by stirring at 80° C. overnight. The reaction mixture was cooled to room temperature, and then water was added thereto, followed by extraction with EtOAc. The organic layer was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/EtOAc=10/0 to ½). The purified product was dissolved in EtOAc (5 ml), and then 4 M hydrogen chloride/EtOAc (10 ml) was added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then MeCN was added thereto. The precipitated solid was collected and washed with MeCN to obtain N-[(4′-chlorobiphenyl-3-yl)methyl]-N-methylglycinamide hydrochloride (267 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:11][C:12]([O:14][CH2:15][C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>O1CCCC1>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[CH2:15][O:14][C:12]([NH:11][C:5]1([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:13]
Reactant: COC(=O)C1(NC(=O)OCc2ccco2)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(NC1(C(=O)O)CCCCC1)OCc1ccco1
Reaction time: 18 h
Yield: 74.4 %

Procedure:
28.13 g (0.1 mol) of 1-[[(2-furanylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid methyl ester was added to a mixture solution of 150 ml of 2N-sodium hydroxide aqueous solution and 200 ml of tetrahydrofuran, and the mixture was refluxed under heating for 18 hours. After the solvent was distilled off, water was added to the residue and the mixture was washed with diethyl ether. After potassium hydrogensulfate was added to the aqueous layer to acidify it, the layer was extracted with ethyl acetate twice. After the organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the mixture was stirred for 18 hours. The obtained crystal was collected by filtration to give 19.89 g (74%) of the title compound.
Reaction SMILES: [CH3:1][NH:2]/[C:3](/[C:10]([F:13])([F:12])[F:11])=[CH:4]\[C:5]([O:7]CC)=O.[H-].[Na+].[Cl:16][C:17]1[CH:35]=[C:34]([F:36])[C:33]([N:37]=[C:38]=[S:39])=[CH:32][C:18]=1[C:19]([N:21](CCC)[S:22]([NH:25][CH2:26][CH:27]=[CH2:28])(=[O:24])=[O:23])=[O:20].Cl.[CH3:41][CH2:42][CH2:43]CCC>CN(C)C=O>[Cl:16][C:17]1[CH:35]=[C:34]([F:36])[C:33]([N:37]2[C:5](=[O:7])[CH:4]=[C:3]([C:10]([F:11])([F:12])[F:13])[N:2]([CH3:1])[C:38]2=[S:39])=[CH:32][C:18]=1[C:19]([NH:21][S:22]([N:25]([CH:42]([CH3:43])[CH3:41])[CH2:26][CH2:27][CH3:28])(=[O:23])=[O:24])=[O:20]
Reactant: CCCCCC
Reactant: C=CCNS(=O)(=O)N(CCC)C(=O)c1cc(N=C=S)c(F)cc1Cl
Reactant: CCOC(=O)/C=C(\NC)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(C(C)C)S(=O)(=O)NC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=S)c(F)cc1Cl
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Under nitrogen, a mixture of 30 ml of N,N-dimethylformamide and 50 ml of n-hexane was heated to reflux with stirring for 1 hour and the hexane was subsequently distilled off at an internal temperature of 80-90° C. The mixture was allowed to cool to 30° C. and 0.75 g (3.828 mmol) of ethyl 3-methylamino-4,4,4-trifluorocrotonate was added with stirring, the reaction mixture was cooled to −20° C. and 0.2 g (7.92 mmol) of 95% sodium hydride was added in 3 portions with stirring to form a yellow precipitate. The mixture was stirred at −15° C. for a further 15 minutes and then 1.5 9 (3.828 mmol) of N-(2-chloro-4-fluoro-5-isothiocyanatobenzoyl)-N′-allyl-(1-propyl)sulfamide were added at −15° C. to the mixture. After stirring,for 15 minutes, a brown solution formed. Stirring was then continued at −15° C. for 1 hour and than at 22° C. for 8 hours. The reaction mixture was poured with stirring into 100 ml of 1 N hydrochloric acid and the aqueous mixture was extracted three times with methyl tert-butyl ether. The combined organic phases were reextracted with 1 N hydrochloric acid, then the organic phase was washed with water and the organic phase was dried over magnesium sulfate. After the drying agent had been filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3×20 cm column, eluent: dichloromethane) and, after the eluate had been concentrated under reduced pressure, 0.65 g (31.3% of theory) of the title compound having a melting point of 74-75° C. was obtained. According to the 1H NMR spectrum, a rotamer mixture was present in a ratio of 7:3. According to HPLC analysis, the product peaks for these were at 5.3 and 5.48 minutes having 70 and 25 area percent respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-])=O)=[C:6]([CH2:8][NH:9][CH2:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[O:19][CH3:20])[CH:7]=1.[N:24]#[C:25]Br>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:21]=[C:25]([NH2:24])[N:9]([CH2:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:8]2
Reactant: COc1cccc(OC)c1CNCc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: N#CBr
Solvent: C1COCCO1
Product: COc1cccc(OC)c1CN1Cc2cc(Cl)ccc2N=C1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 122.3 %

Procedure:
1-(5-Chloro-2-nitrophenyl)-N-(2,6-dimethoxybenzyl)methanamine (6.50 g, 21.2 mmol) was dissolved in 160 mL dioxane and cyanogen bromide (3.24 g, 29.6 mmol) dissolved in 20 mL dioxane was added. A slightly yellowish suspension was formed immediately. The reaction mixture was heated for 2 hours at reflux. The entire reaction mixture was completely dissolved at 85° C. and a colorless precipitate began to form at 75° C. The mixture was cooled to room temperature and stirring was continued for 12 hours. The resulting precipitate was filtered out and rewashed with dioxane (2×), isolating the crude product (8.6 g) after drying in a vacuum drying cabinet at 40° C. For purification and release of the hydrobromide salt, the solids were dissolved in dichloromethane again and alkalized with 2N sodium hydroxide solution. A portion of the product was precipitated immediately, filtered out and dried. The two phases of the mother liquor was separated and the resulting organic phase was washed with water (3×), whereupon a crystal product was again formed from it. The organic aqueous phase was concentrated in vacuo and the solids were filtered out. The two solids that were isolated in succession were combined.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]([CH3:18])[C:14](OC)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:27][OH:28].C[O-].[Na+]>CO>[OH:28][NH:27][C:14](=[O:15])[CH:13]([N:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:18]
Reactant: NO
Reactant: COC(=O)C(C)N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C(C)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(a) Methyl 2-[[4-methoxybenzenesulfonyl](benzyl)amino]propionate (2.1 g, 6.01 mmol) is dissolved in methanol (20.0 mL). To this solution is added hydroxylamine hydrochloride (0.84 g, 12.0 mmol), followed by the addition of sodium methoxide (7.0 mL of a 4.37M solution). The reaction is stirred overnight at room temperature. The reaction is worked up by first removing all the solvent, and partitioning between ethyl acetate/hexane (2/1) and saturated sodium bicarbonate. The aqueous phase is extracted well with ethyl acetate/hexane, the combined organic layers are dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (ethyl acetate) to give N-hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]propionamide, m.p. 149°-151° C.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[NH2:21][C:22]([NH2:24])=[S:23]>CN(C=O)C>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]2[N:21]=[C:22]([SH:23])[NH:24][C:17]=2[C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: NC(N)=S
Reactant: O=Cc1ccc(F)cc1
Reactant: CN(C)c1ccc(C=O)cc1
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2nc(S)[nH]c2-c2ccc(F)cc2)cc1

Procedure:
A solution of 0.40 g (1.28 mmoles) of 4-(4-dimethylaminophenyl)-5-(4-fluorophenyl)-2-mercaptoimidazole, a Formula (IV) compound, [obtained by treatment of the corresponding Formula (VIII) compound (prepared from 4-dimethylaminobenzaldehyde and 4-fluorobenzaldehyde as described by Ide et al., in "Organic Reactions"; John Wiley and Sons, (1948) Chapter 5) with thiourea in DMF by the method described in Bender et al., J. Med. Chem., 28, 1169 (1985) (therein designated as the general method for preparation of 4,5-diarylimidazole-2-thiones)] in 15 ml of dry DMF was treated with 0.061 g (1.28 mmoles) of a 50% sodium hydride dispersion. 0.18 g (1.28 mmoles) of 1-bromo-2-chloroethane was added after 0.5 hours stirring at ambient temperature. After an additional 12 hours stirring, 0.18 g (1.28 mmoles) of powdered potassium carbonate was added, and the mixture heated to 150° C. for 2 hours. The solvent was removed in vacuo and the residue extracted with chloroform. The solution was washed with water, dried over MgSO4 and concentrated in vacuo. Column chromatography on silica afforded two isomers eluting with 10% and 20% CH3CN in CH2Cl2. Evaporation of the solvents followed by recrystallization from methanol gave 5-(4-dimethylaminophenyl)-6-(4-fluorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole, mp 163°-164.5° C., (TLC, silica, 10% CH3CN in CH2Cl2, Rf 0.17) and 6-(4-dimethylaminophenyl)-5-(4-fluorophenyl)-2,3-dihydroimid azo[2,1-b]thiazole, mp 195°-201° C., (TLC, silica, 10% CH2CN in CH2Cl2, Rf 0.3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[O:21]([C:28]1[N:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>>[O:21]([C:28]1[N:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:3]=1)=[O:31])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1.[O:21]([C:28]1[C:29]([C:30]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]3[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]3)[CH:5]=[CH:6][CH:7]=2)=[O:31])=[CH:33][CH:34]=[CH:35][N:36]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1cccnc1Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(NC(=O)c3cccnc3Oc3ccccc3)c2)CC1
Product: O=C(Nc1cccc(C2CCNCC2)c1)c1cccnc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of tert-butyl 4-[3-(amino)phenyl]-1-piperidinecarboxylate (0.15 mmol), 2-phenoxynicotinoyl chloride (0.23 mmol) and triethylamine (0.30 mmol) in 3 mL of solvent (CH2Cl2:THF, 1:3) was stirred at room temperature for 12 hours. The reaction mixture was purified by preparative TLC (silica, EtOAc:hexane 1:1) to afford the desired product, tert-butyl 4-(3-{[(2-phenoxy-3-pyridinyl)carbonyl]amino}phenyl)-1-piperidinecarboxylate. Trifluoroacetic acid (1.0 mL) was added to the purified product dissolved in 1.0 mL of CH2Cl2 and the solution was stirred at room temperature for 1 minute. The reaction mixture was concentrated in vacuo to afford the TFA salt of the desired product. 1H NMR (400 MHz, CDCl3) δ 9.85 (s, 1H), 8.76-8.64 (br, 1H), 8.30-8.14 (br, 1H), 7.67 (s, 1H), 7.49 (t, 2H, J=7.8 Hz), 7.42-7.29 (m, 3H), 7.24 (t, 3H, J=5.2 Hz), 7.03 (d, 1H, J=7.2 Hz), 3.59 (bd, 2H, J=11.5), 3.16-3.02 (m, 2H), 2.9-2.79 (m, 1H), 2.14-2.01 (m, 4H); ESIMS m/e: 374.1 [M+H]+.
Reaction SMILES: Cl[S:2]([CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:11])[CH3:10])(=[O:4])=[O:3].C(N(CC)CC)C.[OH:19][CH2:20][C:21]([CH3:38])([CH3:37])[C@@H:22]([O:29][Si:30]([CH3:36])([CH3:35])[C:31]([CH3:34])([CH3:33])[CH3:32])/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26]>ClCCl.CN(C1C=CN=CC=1)C>[C:9]([NH:8][CH2:7][CH2:6][CH2:5][S:2]([O:19][CH2:20][C:21]([CH3:38])([CH3:37])[C@@H:22]([O:29][Si:30]([CH3:36])([CH3:35])[C:31]([CH3:32])([CH3:34])[CH3:33])/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26])(=[O:4])=[O:3])(=[O:11])[CH3:10]
Reactant: COC(=O)/C=C/[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)CO
Reactant: CC(=O)NCCCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)COS(=O)(=O)CCCNC(C)=O
Yield: 54.2 %

Procedure:
Following the general procedure for the preparation of neopentyl sulfonylester intermediates of Description 10, N-[3-(chlorosulfonyl)propyl]acetamide (9) (4.0 g, 19.8 mmol) in 40 mL of dichloromethane (DCM) in the presence of 1.2 g (9.8 mmol) of 4-(N,N-dimethylamino)pyridine (DMAP) and 2.8 mL (2.0 g, 19-8 mmol) of triethylamine (Et3N, TEA) was reacted at ca. 0° C. with 3.0 g (9.9 mmol) of methyl (2E)(4S)-6-hydroxy-5,5-dimethyl-4-(1,1,2,2-tetramethyl-1-silapropoxy)hex-2-enoate (4). After work-up and isolation, the crude material was purified by silica gel column chromatography using ethyl acetate (EtOAc) and methanol (MeOH) mixtures (EtOAc/MeOH=9:1) to provide 2.5 g (55% yield) the title compound (19a) as a colorless oil. Rf=0.46 (EtOAc). 1H NMR (400 MHz, CDCl3): δ=0.01 (s, 3H), 0.08 (s, 3H), 0.93 (s, 9H), 0.97 (s, 6H), 2.06 (s, 3H) 2.07-2.11 (m, 2H), 3.14-3.18 (m, 2H), 3.40-3.45 (m, 2H), 3.77 (s, 3H), 3.98 (d, J=9.6 Hz, 1H), 4.06 (d, J=9.2 Hz, 1H), 4.09 (dd, superimposed, J=6.4, 1.6 Hz, 1H), 5.93 (br., 1H), 5.96 (dd, J=15.6, 1H), 6.90 (dd, J=15.6, 6.4 Hz, 1H) ppm. MS (ESI) m/z 466.10 (M+H)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([OH:16])=[CH:5][C:6]([C:12]([O:14][CH3:15])=[O:13])=[N:7]2.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([O:16][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:5][C:6]([C:12]([O:14][CH3:15])=[O:13])=[N:7]2
Reactant: COC(=O)c1cc(O)c2c(Cl)cccc2n1
Reactant: COC(=O)CBr
Product: COC(=O)COc1cc(C(=O)OC)nc2cccc(Cl)c12

Procedure:
The purified methyl 5-chloro-4-hydroxy-2-quinolinecarboxylate is alkylated with methyl bromoacetate as described in example 2 to produce methyl 5-chloro-4- methoxycarbonylmethyloxy-2-quinolinecarboxylate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH3:10][O-:11].[Na+].[CH3:13][OH:14]>>[Cl:9][C:4]1[CH:5]=[C:6]([O:11][CH3:10])[N:7]=[C:2]([O:14][CH3:13])[N:3]=1
Reactant: CO
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Product: COc1cc(Cl)nc(OC)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
In a 250 mL round bottom flask, 2,4,6-trichloro-pyrimidine (11.41 g, 62.2 mmol) was dissolved in 140 mL MeOH. The flask was cooled to 0° C. NaOMe (25% in MeOH, 28.44 mL, 124.4 mmol) was added to the flask dropwise (in 30 minutes). The reaction was stirred at 0° C. for 2 hours, then was warmed up to room temperature for 1 hour. The reaction mixture was concentrated down. Ethyl acetate was added, followed by washing with water. The organic layer was concentrated down after drying over anhydrous sodium sulfate to give white solid (10.68 g, 98.4%). LC-MS shows 175.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 6.52 (s, 1H), 4.0 (s, 6H); 13C NMR (300 MHz, CDCl3): δ 172.55, 164.96, 161.03, 99.94, 54.42, 53.76.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:20]2[C:21]3[C:16]([CH2:17][CH2:18][CH2:19]2)=[C:15]([F:22])[CH:14]=[CH:13][C:12]=3[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[F:22][C:15]1[CH:14]=[CH:13][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:20]3[C:21]=2[C:16]=1[CH2:17][CH2:18][CH2:19]3
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c3c2n1CCC3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C[C@H](N)c1nc2ccc(F)c3c2n1CCC3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.5 %

Procedure:
To an ice-cooled solution of [(S)-1-(7-fluoro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)ethyl]carbamic acid tert-butyl ester (78 mg, 0.244 mmol) in DCM (4 mL) was added TFA (1.3 mL) and the mixture was stirred at RT for 1.5 h. Toluene was added and volatiles were removed under reduced pressure, the resulting residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 0.5M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording the title compound as a colourless gum (49.5 mg, 93%). LCMS (Method B): RT 1.78 min [M+H]+ 220
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH3:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:29][C:30]([CH3:32])=O.C(O)(=O)C>CN(C=O)C.O>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:30]([CH3:32])[CH3:29])[CH2:10][C@@H:9]1[CH3:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)=O
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Temperature: 60 °C

Procedure:
To (R)-1-Boc-2-methylpiperazine (200.0 mg, 0.999 mmol) and sodium triacetoxyborohydride (444.5 mg, 2.097 mmol) in DMF (5 mL) was added acetone (116 mg, 0.147 mL, 1.997 mmol) and acetic acid (90.0 mg, 86 μL, 1.498 mmol). The reaction mixture was heated at 60° C. for 1 h. The reaction mixture was diluted with water and extracted three times with diethyl ether. The combined organics were dried over sodium sulfate, filtered, concentrated, and used without further purification. LCMS-ESI+: calc'd for C13H27N2O2 (M+H+): 243.2; Found: 243.2 (M+H+).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]2)[CH2:15][CH2:14]1.[CH2:28]([N:30]([CH2:33]C)CC)C.ClC(Cl)([O:38]C(=O)OC(Cl)(Cl)Cl)Cl.CN>ClCCl>[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]2[CH2:22][CH2:23][C@H:24]([NH:27][C:28]([NH:30][CH3:33])=[O:38])[CH2:25][CH2:26]2)[CH2:15][CH2:14]1
Reactant: COc1ccc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)c(Cl)c1Cl
Reactant: CCN(CC)CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)N[C@H]1CC[C@H](CCN2CCN(c3ccc(OC)c(Cl)c3Cl)CC2)CC1
Reaction time: 20 h

Procedure:
1.38 g (3 mmol) trans-4-{2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine dihydrochloride was suspended in dry dichloromethane (100 ml), triethylamine (1.72 ml, 12.4 mmol) was added and 0.34 g (1.14 mmol) triphosgene dissolved in dichloromethane was dropped in. After one hour stirring at room temperature methylamine (33% solution in ethanol) was added and the stirring was continued for 20 hours. The mixture was evaporated. 20 ml water was added, the precipitate filtered, washed with water, dried. Recrystallizing the product from methanol gave trans-1-{4-[2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3-methyl-urea (0.86 g, 65%) melting above 250° C. This product was dissolved in dichloromethane (60 ml), then 10 ml (10 mmol) borontribromid solution (1M in CH2Cl2) was dropped in at 5° C. and the mixture stirred at room temperature for 24 hours. The reaction was monitored by TLC. 4 ml methanol was added and the mixture evaporated. 35 ml saturated NaHCO3 solution was added. The precipitate was filtered, washed with water and dried, recrystallized from methanol giving 0.34 g of title compound, melting at 237-41° C.