Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]([OH:12])(=[O:11])[C:8]([CH3:10])=[CH2:9].[C:13]1([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][C:28]=2[O:37]CCO)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[O:23]CCO.CCCCCC>CC#N.C1COCC1>[C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]([OH:12])(=[O:11])[C:8]([CH3:10])=[CH2:9].[C:27]1([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=2[O:23][CH:1]([OH:6])[CH3:2])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[O:37][CH:7]([OH:11])[CH3:8]
Reactant: OCCOc1ccc2ccccc2c1-c1c(OCCO)ccc2ccccc12
Agent: C=C(C)C(=O)O
Solvent: CCCCCC
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(O)Oc1ccc2ccccc2c1-c1c(OC(C)O)ccc2ccccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 142.6 %

Procedure:
BMPDMS (260 mg), TASHF2 (100 microliters, 0.1 M. in CH3CH) and THF (125 mL) were added to a dry 250 mL 3-necked round-bottomed flask equipped with a magnetic stirrer, a thermocouple, a reflux condenser and a nitrogen bubbler and the mixture was cooled to 0° C. A solution of (±)-2,2'-((1,1'-binaphthalene)-2,2'-diylbis(oxy))-bis(ethanol) dimethacrylate (2.5 g, 4.9 mmole) and TASHF2 (100 μL, 0.1 M. in CH3CN) in THF (125 mL) were added dropwise (0.5 mL/min) to the solution in the 250 mL flask to give a yellow mixture. This mixture was stirred overnight at 0° C. and then condensed. Hexane was added, and the polymer which precipitated was dried to give 1.91 g of a white powdery solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:4]=1[CH:5]([OH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:18]([N:26]=[C:27]=[S:28])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO.C(N(CC)CC)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:3]([CH2:2][NH:1][C:27]([NH:26][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[S:28])=[C:4]([CH:5]([OH:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:13]=1
Reactant: NCc1ccc(Cl)cc1C(O)c1ccccc1
Reactant: S=C=NCCc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: OC(c1ccccc1)c1cc(Cl)ccc1CNC(=S)NCCc1ccccc1

Procedure:
2-aminomethyl-5-chlorobenzhydrol (10 g; 0.04 mole) in 100 ml methanol and 2 ml triethylamine was treated dropwise with a solution of phenethyl isothiocyanate (8.6 g; 0.053 mole) in 25 ml of methanol. After 16 hours at room temperature the reaction mixture was evaporated and the residue was extracted with petroleum ether. The residual oil was recrystallized from diisopropyl ether to yield 1-(4-chloro-2-(α-hydroxybenzyl)benzyl)-3-phenethylthiourea as a white powder (M.Pt. 97° -- 101° ).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:8][NH:7][C:6]2[CH:9]=[C:10](B3OC(C)(C)C(C)(C)O3)[CH:11]=[CH:12][C:5]=2[C:4](=[O:22])[NH:3]1.[NH2:23][C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([S:36]([NH:39][CH:40]3[CH2:42][CH2:41]3)(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[CH:26][C:25]=1Br>>[NH2:23][C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([S:36]([NH:39][CH:40]3[CH2:42][CH2:41]3)(=[O:37])=[O:38])=[CH:34][CH:35]=2)=[CH:26][C:25]=1[C:10]1[CH:11]=[CH:12][C:5]2[C:4](=[O:22])[NH:3][C@@H:2]([CH3:1])[CH2:8][NH:7][C:6]=2[CH:9]=1
Reactant: Nc1ncc(-c2ccc(S(=O)(=O)NC3CC3)cc2)cc1Br
Reactant: C[C@H]1CNc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C(=O)N1
Product: C[C@H]1CNc2cc(-c3cc(-c4ccc(S(=O)(=O)NC5CC5)cc4)cnc3N)ccc2C(=O)N1
Yield: 33 %

Procedure:
General method C was applied to (S)-3-methyl-8-(4,4,5,5-tetra methyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-benzo[e][1,4]diazepin-5(2H)-one (303 mg, 0.7 mmol) and 4-(6-amino-5-bromopyridin-3-yl)-N-cyclopropylbenzenesulfonamide to give (S)-4-(6-amino-5-(3-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl)pyridin-3-yl)-N-cyclopropylbenzenesulfonamide as a yellow solid (180 mg, 33% yield) after purification by reverse phase preparatory HPLC. MS (EI) m/z=464.6 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([I:22])=[C:6]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[CH:15]=2)=[O:10])[CH:7]=1.CC(C)([O-])C.[K+].FC(F)(F)S(O[CH2:36][C:37]([F:40])([F:39])[F:38])(=O)=O.C([O-])(O)=O.[Na+]>CC1OCCC1>[Cl:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([I:22])=[C:6]([N:8]([CH2:36][C:37]([F:40])([F:39])[F:38])[C:9]([C:11]2[CH:12]=[N:13][N:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[CH:15]=2)=[O:10])[CH:7]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C(Nc1cc(Cl)c(F)cc1I)c1cnn(C2CCCCO2)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC1CCCO1
Product: O=C(c1cnn(C2CCCCO2)c1)N(CC(F)(F)F)c1cc(Cl)c(F)cc1I
Temperature: 65 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of N-(5-chloro-4-fluoro-2-iodophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxamide (1.26 g, 3.13 mmol) in 55 mL of anhydrous MeTHF heated to 65° C. are added potassium t-butoxide (421 mg, 3.76 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.54 mL, 3.76 mmol). The reaction mixture is stirred for 2 hours at 65° C., and then cooled, poured into saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic phase is washed with saturated aqueous NaCl solution, dried over Na2SO4 and concentrated to dryness. After purification by flash chromatography on silica (DCM/EtOAc: 100/0 to 95/5), 2.32 g of an orange-coloured solid are obtained (yield: 73%).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][C@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:9]([OH:11])=O)[CH2:3]1.C(Cl)(=O)C(Cl)=O.[CH3:28][O:29][CH2:30][CH2:31][N:32]1[CH:36]=[CH:35][C:34]([NH2:37])=[N:33]1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH3:28][O:29][CH2:30][CH2:31][N:32]1[CH:36]=[CH:35][C:34]([NH:37][C:9](=[O:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:7][C@H:4]2[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]2)=[N:33]1
Reactant: COCCn1ccc(N)n1
Reactant: O=C1CC[C@H](C[C@@H](C(=O)O)c2cccc(C(F)(F)F)c2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: COCCn1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
(R)-3-((R)-3-Oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionic acid (prepared in Example 118, 90 mg, 0.30 mmol) was dissolved in methylene chloride (3 mL) and N,N-dimethylformamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 160 μL, 0.32 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (3 mL) and added dropwise into a solution of 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared in Example 72, 42 mg, 0.20 mmol), 2,6-lutidine (70 μL, 0.60 mmol) and methylene chloride (3 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol and diluted with methylene chloride and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 100% ethyl acetate) to afford (R)—N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionamide (79 mg, 62%) as a pale yellow gum: [α]29589=−79.3° (c=0.14, methanol); ES-HRMS m/e calcd for C21H24N3O3F3 (M+H)+ 424.1843, observed 424.1841; 1H NMR (300 MHz, DMSO-d6) δ 1.51 (m, 1H, CH), 1.74-2.29 (m, 8H, 4×CH2), 3.19 (s, 3H, OCH3), 3.61 (t, J=5.3 Hz, 2H, OCH2), 3.94 (m, 1H, ArCHCO), 4.12 (t, J=5.3 Hz, 2H, NCH2), 6.42 (d, J=2.2 Hz, 1H, Ar), 7.54 (d, J=2.2 Hz, 1H, Ar), 7.60 (m, 2H, Ar), 7.69 (brd, 1H, Ar), 7.73 (brs, 1H, Ar), 10.80 (s, 1H, NH).
Reaction SMILES: C([C:4]1([O:28][C@H:27]([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:15]([O:16][CH3:17])[C@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:5])C=C.N12CCC(CC1)CN2>C(O)C.C1C=CC=CC=1.O.CC(C)=O.O>[CH2:8]([O:7][C@@H:6]1[C@@H:15]([O:16][CH3:17])[C@H:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@H:27]([CH2:29][O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:28][CH:4]1[OH:5])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C=CCC1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OC)[C@H]1OCc1ccccc1
Agent: C1CN2CCC1CN2
Solvent: CCO
Solvent: O
Solvent: CC(C)=O
Product: CO[C@H]1[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)OC(O)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
Allyl-3-O-methyl-2,4,6-tri-O-benzyl-glucopyranose (7.4 g) was refluxed for 5 hours in a mixture of ethanol/benzene/water (7:3:1) (500 mL) containing tris triphenylphosphine rhodium (I) chloride (1.05 g) and diazabicyclo[2.2.2]octane (445 mg). The isomerized product was hydrolyzed in acetone-water (9:1) (140 mL) using mercuric chloride (18.6 g) and mercuric oxide (383 mg) by stirring the reaction mixture at room temperature for 1 hour. The resulting solution was evaporated to dryness, diluted with methylene chloride (500 mL), filtered and washed with 30% KBr (3×500 mL) and water (3×500 mL), dried over Na2SO4, concentrated and purified by chromatography on silica gel using hexane-ethyl acetate (4:1) and (3:1) as eluents to provide 2,4,6-tri-O-benzyl-3-O-methyl-D-glucopyranose (5.0 g).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[F-:12].[K+]>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C.CCOCC>[F:12][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: [F-]
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: [Br-]
Agent: [K+]
Agent: c1ccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: Cc1cc([N+](=O)[O-])cnc1F
Yield: 61.9 %

Procedure:
2-Chloro-3-methyl-5-nitropyridine (15.0 g, 86.9 mmol; from Maybridge Chemical Co.), KF (12 g, 258 mmol), and tetraphenylphosphonium bromide (20 g, 47.7 mmol) were combined in 200 mL of acetonitrile and heated at reflux for 4 days. The mixture was diluted with Et2O (500 mL), filtered, and the solution was concentrated. The residue was triturated with hot hexane, then the combined hexane solutions were concentrated to give 8.4 g (60%) of the title compound: 1H NMR (DMSO-d6, 300 MHz) δ8.95 (dd, J=1.6 Hz, 1H), 8.43 (m, 1H), 2.42 (s, 1H); MS (CI/NH3) m/z: 157 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[N:7]=[C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2Br)[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=2[N:9]1[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)([CH3:4])([CH3:3])[CH3:2].[C:37]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6](=[O:36])[N:7]=[C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:47]2[CH2:48][CH2:49][N:44]([CH2:43][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:45][CH2:46]2)[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=2[N:9]1[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1ccccc1Br
Reactant: c1ccc(-c2ccccc2CN2CCNCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1ccccc1N1CCN(Cc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 38.3 %

Procedure:
To a degassed solution of [1-(2-bromo-benzyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-ylidene]-carbamic acid tert-butyl ester (200 mg, 0.36 mmol) in anhydrous toluene (4 ml) was added Pd(OAc)2 (0.7 mg, 1.8 □mol). Nitrogen was bubbled through the suspension for 10 min before BINAP (17 mg, 27 □mol) was added. After a further 2 min 1-biphenyl-2-ylmethyl-piperazine (99 mg, 0.36 mmol) in degassed toluene (4 ml) was introduced and then after a additional 2 min Cs2CO3 (0.86 g, 2.6 mmol) was added and the reaction was stirred for 2 min. Throughout all of the additions nitrogen was continuously bubbled through the reaction mixture. To After 2.75 h the reaction was cooled to rt and filtered through Celite®. Purification by chromatography on silica gave [1-[2-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-ylidene]-carbamic acid tert-butyl ester (100 mg) which was used without purification in the next step.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCC[N:40]=[C:39]1[CH2:38][CH2:37][CH2:36]CC2.Cl.NCC1CC1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:40][CH2:39][CH:38]2[CH2:37][CH2:36]2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Agent: Cl
Agent: NCC1CC1
Solvent: CCO
Solvent: O
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NCC4CC4)ncnc32)[C@]1(C)F
Yield: 72.2 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.30 g, 0.64 mmol) in ethanol (about 5 ml) was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (about 0.14 ml, 0.97 mmol) and aminomethyl cyclopropane hydrochloride (about 0.14 g, 1.2 mmol) at room temperature and refluxed for about 30 minutes. Completion of the reaction monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water, brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 5% methanol in dichloromethane as eluent furnished title compound (0.23 g) as a colorless solid. Yield: 67%; 1H NMR (300 MHz, CDCl3): δ 8.39 (s, 1H), 8.06-8.04 (m, 2H), 7.99 (d, 1H, J=3.6 Hz), 7.60-7.55 (m, 1H), 7.47-7.42 (m, 2H), 6.54 (d, 1H, J=23.1 Hz), 5.93 (bs, 1H), 4.84-4.78 (m, 2H), 4.49-4.42 (m, 1H), 3.49 (bs, 2H), 2.16 (s, 3H), 1.89 (d, 3H, J=2.4 Hz), 1.44 (d, 3H, J=23.1 Hz), 1.19-1.08 (m, 1H), 0.59-0.55 (m, 2H), 0.34-0.31 (m, 2H); ES Mass: [M+1]+ 498 (100%), [M+Na] 520 (45%); HPLC: 96%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:25]=[CH:24][C:15]3[N:16]([CH:21]([CH3:23])[CH3:22])[C:17](=[O:20])[N:18]([CH3:19])[C:14]=3[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.ClC1C(C2C=CC3N(C(C)C)C(=O)NC=3C=2)=NC=C(C(F)(F)F)C=1.BrC[C:52]([O:54][CH2:55][CH3:56])=[O:53]>>[Cl:1][C:2]1[C:3]([C:12]2[CH:25]=[CH:24][C:15]3[N:16]([CH:21]([CH3:22])[CH3:23])[C:17](=[O:20])[N:18]([CH2:19][C:52]([O:54][CH2:55][CH3:56])=[O:53])[C:14]=3[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CC(C)n1c(=O)n(C)c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Reactant: CCOC(=O)CBr
Agent: CC(C)n1c(=O)[nH]c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Product: CCOC(=O)Cn1c(=O)n(C(C)C)c2ccc(-c3ncc(C(F)(F)F)cc3Cl)cc21
Yield: 68 %

Procedure:
In a similar manner to the preparation of 5-(3-chloro-5-trifluoromethylpyridin-2yl)-3-methyl-1-(1-methylethyl)benzimidazol-2-one described above, 2.5 g of 5-(3-chloro-5-trifluoromethyl-pyridin-2yl)-1-(1-methylethyl)benzimidazol-2 -one and 1.23 g of ethyl bromoacetate gave 2.1 g (68%) of colorless crystals. Yield: 68%, m.p.L 125-127° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+].C(Cl)Cl>C(O)C.O>[N:11]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)=[N+:12]=[N-:13]
Reactant: COc1ccc(CCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(CN=[N+]=[N-])cc1
Yield: 75 %

Procedure:
64 mmol 1-(chloromethyl)-4-methoxybenzene and 90 mmol sodium azide were dissolved in 20 ml ethanol and 5 ml water, and stirred overnight at room temperature. CH2Cl2 and water were added. The organic layer was separated, dried and evaporated to give 48 mmol 1-(azidomethyl)-4-methoxybenzene.
Reaction SMILES: Br[C:2]1[C:25]([F:26])=[CH:24][C:5]2[O:6][C:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.C([Li])CCC.[C:32](=[O:34])=[O:33]>C(OCC)C>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[C:7]1([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[O:6][C:5]2[CH:24]=[C:25]([F:26])[C:2]([C:32]([OH:34])=[O:33])=[CH:3][C:4]=2[O:8]1
Reactant: Fc1ccc(C2(c3ccc(Cl)cc3Cl)Oc3cc(F)c(Br)cc3O2)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(O)c1cc2c(cc1F)OC(c1ccc(F)cc1)(c1ccc(Cl)cc1Cl)O2
Temperature: 20 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a cooled (−78° C.) solution of 5-bromo-2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole (16.5 g, 36.0 mmol) in diethyl ether (250 mL) was slowly added a solution of n-butyl lithium in hexanes (1.6M, 23 mL, 36.0 mmol, 1.0 eq.). After 1 h at −78° C., solid carbon dioxide (50 g approx.) was added to the solution and the reaction was allowed to warm up to 20° C. After 16 h at 20° C. the reaction mixture was partitioned between water (150 mL), ethyl acetate (1.5 L) and hydrochloric acid (1N, 150 mL). The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water. The volatiles were removed in vacuo. Purification by flash chromatography afforded the title compound (10.73 g, 69%) as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([OH:17])=O.C(Cl)Cl.[CH2:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:22].S(Cl)(Cl)=O>C(N(CC)CC)C>[CH3:22][CH2:21][N:23]([C:15]([C:3]1[C:4](=[O:14])[N:5]([CH3:13])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([Cl:12])[C:11]=2[C:2]=1[OH:1])=[O:17])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cn1c(=O)c(C(=O)O)c(O)c2c(Cl)cccc21
Reactant: CCNc1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Temperature: 7.5 °C
Reaction time: 4 h
Yield: 55.1 %

Procedure:
The mixture of 1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid (1 gm) and methylene chloride (20 ml) was cooled to 5-10° C. under nitrogen atmosphere. Triethylamine (1.15 gm) was added to the resulting mass at 5-10° C. to form a clear solution. The solution was followed by addition of N-ethyl aniline (0.45 gm) in one portion at 5-10° C. and then thionyl chloride (0.48 gm) was added at 5-10° C. The resulting mixture was stirred for 4 hours followed by evaporation of methylene chloride under vacuum. The resulting residue was dissolved in ethyl acetate (100 ml) followed by washings with 5% sodium hydroxide solution (30 ml) at 25-30° C. The resulting aqueous layer was cooled to 10-15° C. and pH was adjusted to 2 by using 18% aqueous hydrochloric acid solution (20 ml). The resulting mass was stirred for 2 hours at 15-20° C. The resulting white colored solid was filtered and dried at 55-60° C. to yield 0.73 gm of laquinimod (HPLC Purity: 84.31%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[C:4]([Cl:11])[C:3]=1[Cl:12].C1COCC1.CCN(C(C)C)C(C)C.Cl[CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]>CCOC(C)=O>[Cl:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[C:6]=2[CH:5]=[C:4]([Cl:11])[C:3]=1[Cl:12]
Reactant: Clc1cc2[nH]cnc2c(Cl)c1Cl
Reactant: COCCOCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCOCn1cnc2c(Cl)c(Cl)c(Cl)cc21
Reaction time: 18 h

Procedure:
To a mixture of 4,5,6-trichloro-1H-benzoimidazole (0.098 g, 0.446 mmol) and THF (2.5 mL) was added DIPEA (0.155 mL, 0.892 mmol), followed by 1-chloromethoxy-2-methoxy-ethane (0.057 ml, 0.49 mmol) at 23° C. After stirring for 18 h, EtOAc was added. The organic layer was washed with saturated aqueous NaHCO3. The aqueous layer was further extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified (FCC) to yield the titled compound as a mixture of regioisomers (0.084 g, 61%). MS (ESI/CI): mass calcd. for C11H11Cl3N2O2, 308.0; m/z found, 309.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.59 (s, 1H), 8.58 (s, 1H), 8.09 (s, 1H), 8.04 (d, J=8.5 Hz, 1H), 5.84 (s, 2H), 5.71 (s, 2H), 3.59-3.57 (m, 2H), 3.56-3.53 (m, 2H), 3.42-3.38 (m, 4H), 3.18 (s, 3H), 3.17 (s, 3H).
Reaction SMILES: [Cl-].[CH3:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Zn+].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH2:42][CH2:43][O:44][CH3:45])[C:27]=2Cl)=[O:25])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][N:21]([C:24]([C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH2:42][CH2:43][O:44][CH3:45])[C:27]=2[CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[CH3:2])=[O:25])[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1ccccc1C[Zn+]
Reactant: COCCOc1ccccc1-n1c(Cl)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: COCCOc1ccccc1-n1c(Cc2ccccc2C)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
A solution of 2-methylbenzylzinc chloride (1.95 ml, 973 μmol, 0.5 M in THF) was added dropwise at −78° C. to a solution of B-OM-9-BBN (0.97 ml, 973 μmol, 1 M in hexane). The cooling bath was removed and the mixture was stirred at room temperature for 30 min. DMF (2 ml) was added, followed by the compound of step 5 (50 mg, 97.3 μmol), palladium(II) acetate (2.18 mg, 9.73 μmol) and S-PHOS (7.99 mg, 19.5 μmol). The reaction mixture was heated to 100° C. and stirred for 4 h. The mixture was diluted with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by preparative HPLC. The eluate was lyophilized overnight to give 14 mg of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:19]=[CH:18][C:10]3[S:11][C:12]([C:14]([O:16]C)=[O:15])=[CH:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[Li].O>C1COCC1.O>[C:1]1([C:7]2[CH:19]=[CH:18][C:10]3[S:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc2cc(-c3ccccc3)ccc2s1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(-c3ccccc3)ccc2s1
Yield: 99.1 %

Procedure:
A solution of compound 52b (510 mg, 1.9 mmol) and LiOH.H2O (319 mg, 7.6 mmol) in THF/H2O (10/10 mL) was stirred at room temperature overnight. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH˜4 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give 52c (479 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 255.0.