Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[C:11](=[O:14])([O-])[O-:12].[Na+].[Na+].C(O)(=O)[CH2:18][C:19]([CH2:24]C(O)=O)([C:21](O)=O)O>O1CCOCC1>[CH3:18][C:19]([CH3:24])([O:12][C:11]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1)=[O:14])[CH3:21]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.8 %

Procedure:
Boc-anhydride (2.30 ml, 4.19 mmol) was added to a solution of cis-4-amino cyclohexyl carboxylic acid (1.00 g, 6.99 mmol) in aqueous solution of sodium carbonate (6 ml, 5% w/w) in dioxane (14 ml) at 0° C. The reaction mixture was allowed to warm up to room temperature and stirred for 18 h. The reaction mixture was acidified to pH˜4 using citric acid. The compound was extracted with ethyl acetate (3×30 ml) and washed with brine (15 ml). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The solvent was evaporated and dried to afford 1.2 g (71.8%) of cis-4-[[(1,1-dimethylethoxy)carbonyl]amino]-cyclohexanecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([NH2:10])=[CH:8][C:7]([O:11][CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=1)=O.B(F)(F)F.CCOCC.[CH:24]([NH2:26])=O>>[CH3:1][C:2]1[C:4]2[C:9](=[CH:8][C:7]([O:11][CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=2)[N:10]=[CH:24][N:26]=1
Reactant: NC=O
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Agent: FB(F)F
Solvent: CCOCC
Product: COc1cc2ncnc(C)c2cc1OC
Temperature: 25 °C

Procedure:
2-Amino-4,5-dimethoxyacetophenone (5.0 g) and boron trifluoride etherate (1.5 mL) were heated in formamide (80 mL) at 140° C. for 18 h. The reaction mixture was cooled to room temperature and extracted three times with benzene. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. Flash chromatography on silical gel, eluting with a mixture of 98/2 dichloromethane/methanol gave 4-methyl-6,7-dimethoxyquinazoline (D-1) as a yellow solid, 3.43 g; 1H NMR (CDCl3, 300 MHz) 8.99 (s, 1H), 7.30 (s, 1H), 7.18 (s, 1H), 4.05 (s, 6H), 2.87 (s, 1H) ppm; MS (ES) 205 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10]([F:23])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1.[O:34]1[CH2:39][CH2:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH2:35]1>>[O:34]1[CH2:39][CH2:38][CH:37]=[C:36]([C:12]2[N:11]=[C:10]([F:23])[C:9]3[O:8][C:5]4[C:4]([C@:15]5([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]5)[C:14]=3[CH:13]=2)=[CH:3][C:2]([C:30]2[C:25]([F:24])=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:7][CH:6]=4)[CH2:35]1
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Reactant: NC1=N[C@]2(COC1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Reactant: OB(O)c1cccnc1F
Product: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1c2cc(C2=CCCOC2)nc1F

Procedure:
The titled compound was synthesized by steps analogous to those described in method A1 above, but using (Intermediate 17B), 2-fluoropyridin-3-ylboronic acid and 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:16])[NH:6][C:7]1C=C(C=CN=1)C(O)=O)([CH3:3])[CH3:2].N[C:18]1[CH:19]=[C:20]([CH:26]=[CH:27]N=1)[C:21]([O:23]CC)=[O:22].NC1C=CC(C(OC)=O)=CC=1>>[CH:1]([NH:4][C:5](=[O:16])[NH:6][C:7]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccnc(N)c1
Reactant: CC(C)NC(=O)Nc1cc(C(=O)O)ccn1
Agent: COC(=O)c1ccc(N)cc1
Product: CC(C)NC(=O)Nc1ccc(C(=O)O)cc1

Procedure:
This compound is prepared analogously to Intermediate Y by replacing ethyl 2-aminoisonicotinate in step 1 with methyl 4-aminobenzoate; [M+H]+ 237.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]([CH3:15])=[CH:4][N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[C:5]([CH3:15])=[CH:4][N:3]=[C:2]([NH:28][C:27]3[CH:26]=[CH:25][C:24]([CH2:23][N:20]4[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]4)=[CH:30][CH:29]=3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: Cc1cnc(Cl)nc1-c1ccc(F)cc1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Product: Cc1cnc(Nc2ccc(CN3CCN(C)CC3)cc2)nc1-c1ccc(F)cc1
Yield: 79 %

Procedure:
The title compound was prepared according to procedure B from 2-chloro-4-(4-fluorophenyl)-5-methylpyrimidine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 79% yield (yellow solid) after purification by flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.28 (s, 1H), 7.63 (m, 2H), 7.55 (d, 2H, J=8.5 Hz), 7.22 (t, 2H, J=8.7 Hz), 7.14 (t, 2H, J=8.7 Hz), 3.44 (s, 2H), 2.42 (bs, 8H), 2.25 (s, 3H), 2.24 (s, 3H); MS (ESI): 392.0 [M+H]+, 196 [M+H]2+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:15][CH:14]3[O:16][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[N:3]=1.[CH3:17][NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1)=[O:20]>>[CH:11]12[O:16][CH:14]([CH2:13][CH2:12]1)[CH2:15][N:9]([C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:19]([NH:18][CH3:17])=[O:20])=[CH:27][CH:26]=3)[N:3]=1)[CH2:10]2
Reactant: Clc1nc(Cl)nc(N2CC3CCC(C2)O3)n1
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CNC(=O)Nc1ccc(-c2nc(Cl)nc(N3CC4CCC(C3)O4)n2)cc1
Yield: 29 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 4 using 3-(4,6-dichloro-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane and 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. Yield 5 g, 29% yield.
Reaction SMILES: C([O:4][C:5](=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH:14]([CH3:16])[CH3:15])[CH:8]=1)(C)C.[OH-].[Na+]>C(O)C.O>[CH:14]([O:13][C:9]1[CH:8]=[C:7]([CH2:6][C:5]([OH:17])=[O:4])[CH:12]=[CH:11][CH:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)OC(=O)Cc1cccc(OC(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1cccc(CC(=O)O)c1
Reaction time: 18 h

Procedure:
Combine 3-isopropoxy-phenyl-acetic acid isopropyl ester 10.2 g, 43.2 mmol) and sodium hydroxide (2.08 g, 51.8 mmol) in 1/1 ethanol/water (80 mL). Heat to reflux. After 18 hours, remove the ethanol by evaporation in vacuo and acidify to pH=1 using an aqueous solution with 1M hydrochloric acid solution. Extract the aqueous solution 3 times with ethyl acetate. Extract the combined organic layers with water and saturated sodium chloride solution. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to obtain 3-isopropoxy-phenyl-acetic acid.
Reaction SMILES: C([N:8]([CH3:19])[C:9]1([C:16]([NH2:18])=[O:17])[CH2:12][N:11]([C:13]([O-:15])=[O:14])[CH2:10]1)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C.C(O)C.Cl.ClCCl>[NH2:18][C:16]([C:9]1([NH:8][CH3:19])[CH2:10][N:11]([C:13]([O:15][C:9]([CH3:16])([CH3:12])[CH3:10])=[O:14])[CH2:12]1)=[O:17]
Reactant: CN(Cc1ccccc1)C1(C(N)=O)CN(C(=O)[O-])C1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCO
Product: CNC1(C(N)=O)CN(C(=O)OC(C)(C)C)C1
Yield: 186.1 %

Procedure:
10% wt Palladium on charcoal (160 mg) in ethyl acetate (2 ml) was added to a solution of 3-[benzyl(methyl)amino]-3-(aminocarbonyl)azetidine-1-carboxylate (500 mg, 1.57 mmol) in ethanol (45 ml). After addition of a few drops of saturated hydrogen chloride in dichloromethane, the reaction mixture was stirred at room temperature under 2 bars of hydrogen for 3 hours. Filtration of the catalyst and concentration under reduced pressure afforded tert-butyl 3-(aminocarbonyl)-3-(methylamino)azetidine-1-carboxylate (335 mg, 93%) as a white solid; 1H NMR Spectrum: (CDCl3) 1.44 (s, 9H), 2.35 (s, 3H), 3.71 (d, 2H), 4.29 (brd, 2H), 5.51 (brs, 1H), 6.95 (brs, 1H).
Reaction SMILES: Cl[C:2]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:21][N:5]2[N:6]=[C:7]3[C:12]([C:11]([C:13]4[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=4)=[CH:10][CH:9]=[CH:8]3)=[C:4]2[N:3]=1.[C:29]([O:33][C:34](=[O:55])[NH:35][C:36]1([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37]1)([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[C:29]([O:33][C:34](=[O:55])[NH:35][C:36]1([C:40]2[CH:41]=[CH:42][C:43]([C:2]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][N:5]4[N:6]=[C:7]5[C:12]([C:11]([C:13]6[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=6)=[CH:10][CH:9]=[CH:8]5)=[C:4]4[N:3]=3)=[CH:44][CH:45]=2)[CH2:37][CH2:38][CH2:39]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: N#Cc1ccc(-c2cccc3nn4cc(-c5ccccc5)c(Cl)nc4c23)cc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
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: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5c(-c6ccc(C#N)cc6)cccc5nn4cc3-c3ccccc3)cc2)CCC1

Procedure:
114 mg (0.3 mmol) 4-(2-Chloro-3-phenylpyrimido[1,2-b]indazol-10-yl)benzonitrile, 122.9 g (0.3 mmol) {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-cyclobutyl}carbamic acid tert-butyl ester, 34.6 mg (0.03 mmol) tetrakistriphenylphosphinepalladium(0) and 95 mg (0.90 mmol) sodium carbonate in 3.2 mL dioxane and 0.45 mL water were heated in a microwave vial which had been sealed with a microwave cap over night at 105° C. (heating block). After the usual work up, the crude mixture (235 mg) was used in the next step without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[C:23]3[C:18](=[N:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]([CH2:25][CH3:26])[C:16](=[O:27])[C:15]=2[CH2:28][CH2:29][C:30]([OH:32])=O)[CH:11]=[CH:12][CH:13]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.Cl>CN(C=O)C.C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[C:23]3[C:18](=[N:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]([CH2:25][CH3:26])[C:16](=[O:27])[C:15]=2[CH2:28][CH2:29][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH:11]=[CH:12][CH:13]=1
Reactant: CCn1c(=O)c(CCC(=O)O)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Reactant: C1COCCN1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCn1c(=O)c(CCC(=O)N2CCOCC2)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 0.3 ml portion of oxalyl chloride and one drop of DMF were added to a 20 ml THF solution containing 1.00 g of 3-[4-(3-chlorophenyl)-l-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoic acid, followed by stirring at room temperature for further 30 minutes. The reaction mixture was added dropwise to an ice-cooled 10 ml THF solution containing 1.0 ml of morpholine, followed by stirring for 30 minutes. To the reaction mixture was added 1M hydrochloric acid and the whole was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography (chloroform-methanol) and then recrystallized from diisopropyl ether-ethyl acetate to obtain 780 mg of 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-[3-(morpholin-4-yl)-3-oxopropyl]-1,8-naphthyridin-2(1H)-one as colorless crystals.
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](/[NH2:13])=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[NH2:2].[N+:14]([C:17]1[CH:32]=[CH:31][CH:30]=[CH:29][C:18]=1[CH:19]=[C:20]([C:26]([CH3:28])=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])([O-:16])=[O:15].C(OC(=O)C)C.CCCCCC>C(O)C>[C:1]([O:4][CH2:5][C:6]1[NH:13][C:26]([CH3:28])=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:19]([C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=2[N+:14]([O-:16])=[O:15])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[NH2:2]
Reactant: CCOC(=O)/C=C(\N)COC(N)=O
Reactant: CCOC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(COC(N)=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Yield: 58.1 %

Procedure:
9.4 g (50 millimoles) of ethyl 4-carbamoyloxy-3-aminocrotonate and 13.2 g (50 millimoles) of ethyl 2-(o-nitrobenzylidene)acetoacetate were dissolved in 200 ml of ethanol and reacted at a temperature of from 60° to 70° C. for 16 hours under stirring. The reaction mixture was concentrated under reduced pressure. The residue was crystallized from ethylacetate-hexane, whereby 12.6 g (yield: 58%) of 2-carbamoyloxymethyl-6-methyl-4-(o-nitrophenyl)-3,5-diethoxycarbonyl-1,4-dihydropyridine in crystal form was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22](Br)[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:40]1(B(O)O)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(Br)c1
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: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(-c2ccccc2)c1
Yield: 76.2 %

Procedure:
Ethyl 1-benzyl-3-[(3-bromo-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate (1.20 g), phenylboronic acid (0.37 g), tetrakis(triphenylphosphine)palladium (0.12 g), 2M aqueous sodium carbonate solution (3 mL), ethanol (5 mL) and toluene (20 mL) were stirred under an argon atmosphere while heating under reflux for 24 hrs. Ethyl acetate was added to the reaction mixture. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-phenylbenzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (0.91 g, 77%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 134-135° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[CH:9][O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[CH3:17][Sn:18](Cl)([CH3:20])[CH3:19].O>C1COCC1>[CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([Sn:18]([CH3:20])([CH3:19])[CH3:17])[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: C[Sn](C)(C)Cl
Reactant: COc1cccc2occc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2oc([Sn](C)(C)C)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 111.7 %

Procedure:
To a solution of 4-methoxybenzo(b)furan (2.50 g) in THF (50 ml) was added n-butyllithium (1.54 M hexane solution) (16.5 ml) at −78° C. and the mixture was stirred at the same temperature for 20 min. To this solution was added trimethyltin chloride (5.00 g) and the mixture was further stirred at the same temperature for 1 hr. The reaction mixture was warmed to room temperature and water (200 ml) was added. The mixture was extracted with ethyl acetate, and the obtained organic layer was washed with water and saturated brine and dried over magnesium sulfate. This solution was concentrated under reduced pressure to give the title compound (5.86 g) as pale-yellow crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([N:6]([CH2:15][C@@H:16]2[O:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH:29]=4)=[C:24]([F:34])[CH:23]=3)[CH2:17]2)[C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])=[N:2]1.C(N(CC)CC)C.[CH:42](OCC)=[O:43]>>[O:1]1[CH:5]=[CH:4][C:3]([N:6]([CH2:15][C@@H:16]2[O:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH2:33][CH2:32][N:31]([CH:42]=[O:43])[CH2:30][CH:29]=4)=[C:24]([F:34])[CH:23]=3)[CH2:17]2)[C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:12])[Cl:13])=[O:8])=[N:2]1
Reactant: CCOC=O
Reactant: O=C1O[C@@H](CN(C(=O)OCC(Cl)(Cl)Cl)c2ccon2)CN1c1ccc(C2=CCNCC2)c(F)c1
Solvent: CCN(CC)CC
Product: O=CN1CC=C(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)CC1
Yield: 117 %

Procedure:
To a suspension of 5(R)-[N-isoxazol-3-yl-N-(2,2,2-trichloroethyloxycarbonyl)aminomethyl]-3-[3-fluoro-4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl]oxazolidin-2-one (100 mg, 0.175 mmol) in ethyl formate (5 ml), with stirring was added, triethylamine (20 mg, 27 μl, 0.2 mmol), and the mixture was heated to reflux overnight. Ethyl formate was added and the mixture washed with 2M hydrochloric acid and saturated brine, dried over sodium sulfate and concentrated by rotary evaporation to give the crude title compound as a yellow gum (115 mg, 117%). M/z ES+(M+H)=561.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:7]=3[O:8][CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)(Cl)Cl>[CH3:21][O:20][C:19]1[C:6]2[C:5]3[CH:22]=[CH:23][C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:3][C:4]=3[CH:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:8][C:7]=2[CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc2c1-c1ccc(N)cc1C(c1ccccc1)O2
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1cccc2c1-c1ccc(NS(C)(=O)=O)cc1C(c1ccccc1)O2
Yield: 79 %

Procedure:
The solution of Example 5F (200 mg. 0.66 mmole), pyridine (300 mg) and methanesulfonyl chloride (227 mg., 2.00 mmole) in chloroform (3 mL) was stirred for 1 hour, washed with aqueous HCl (1M), dried (Na2SO4), filtered and concentrated under reduced pressure. Toluene was added and then concentrated. Heptane was added and concentrated under reduces pressure to provide the titled compound (199 mg. 80%). 1H NMR (300 MHz, CDCl3) δ 2.95 (s, 3H), 3.94 (s, 3H), 6.00 (s, 1H), 6.30 (s, 1H), 6.61 (d, J=2 Hz, 1H), 6.62 (dd, J=10 Hz, 2 Hz, 1H), 6.69 (dd, J=9 Hz, 1 Hz, 1H), 7.15 (t, J=9 Hz, 1H), 7.25 (dd, J=9 Hz, 2 Hz, 1H), 7.32-7.39 (m, 5H), 8.45 (d, J=9 Hz, 1H); MS (APCI) m/e 382 (M+H), 399 (M+NH4).
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:3]=1[O:4][C:5]1[C:6]([O:25][CH2:26][CH2:27][O:28][C:29](=[O:37])[NH:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[N:7][CH:8]=[N:9][C:10]=1[NH:11][S:12]([C:15]1[CH:24]=[CH:23][C:18]2[O:19][CH2:20][CH2:21][O:22][C:17]=2[CH:16]=1)(=[O:14])=[O:13].[CH3:44][I:45]>>[I-:45].[Cl:1][C:2]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:3]=1[O:4][C:5]1[C:6]([O:25][CH2:26][CH2:27][O:28][C:29]([NH:30][C:31]2[CH:32]=[N+:33]([CH3:44])[CH:34]=[CH:35][CH:36]=2)=[O:37])=[N:7][CH:8]=[N:9][C:10]=1[NH:11][S:12]([C:15]1[CH:24]=[CH:23][C:18]2[O:19][CH2:20][CH2:21][O:22][C:17]=2[CH:16]=1)(=[O:13])=[O:14]
Reactant: COc1ccc(Cl)c(Oc2c(NS(=O)(=O)c3ccc4c(c3)OCCO4)ncnc2OCCOC(=O)Nc2cccnc2)c1
Reactant: CI
Product: COc1ccc(Cl)c(Oc2c(NS(=O)(=O)c3ccc4c(c3)OCCO4)ncnc2OCCOC(=O)Nc2ccc[n+](C)c2)c1
Product: [I-]

Procedure:
By alkylating the compound from Example 1, part a), with methyl iodide there was obtained 3-[2-[5-(2-chloro-5-methoxy-phenoxy)-6-(2,3-dihydro- 1,4-benzodioxin-6-ylsulfonylamino)-pyrimidin-4-yloxy]-ethoxycarbonylamino]- 1 -methyl-pyridinium iodide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[Cl:22][CH2:23][C:24](Cl)=[O:25].O>O1CCCC1>[Cl:22][CH2:23][C:24]([NH:14][C:11]1[CH:12]=[CH:13][N:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:10]=1)=[O:25]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCl)Nc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a solution, ice cooled, of 1-(3,4-dichlorophenyl)-1H-pyrazol-3-amine (0.36 g, 1.59 mmol) and triethylamine (0.24 g, 2.38 mmol) in dry tetrahydrofurane (5 ml), 2-chloroacetyl chloride (0.2 g, 1.79 mmol) was added. The mixture was stirred overnight at room temperature, water added and the organic solvent evaporated in vacuo. The resulting suspension was filtered and dried yielding 0.45 g of 2-chloro-N-(1-(3,4-dichlorophenyl)-1H-pyrazol-3-yl)acetamide as a beige colour solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH:11]2[CH2:13][CH2:12]2)=O)[CH:6]=[CH:7][CH:8]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:15]3[N:14]([CH:18]=[CH:17][N:16]=3)[CH2:12][CH2:13][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1c[nH]cn1
Reactant: COc1cccc(C(=O)C2CC2)c1
Solvent: ClCCl
Product: COc1cccc(C2=CCCn3ccnc32)c1

Procedure:
Combine 35 g of crude cyclopropyl 3-methoxyphenyl ketone with 60 g of imidazole, and heat to 200° C. for 18 hr. Dissolve the reaction mixture in 500 ml of methylene chloride, and wash with three 300 ml portions of water to remove the excess imidazole, further wash with two 100 ml portions of 10% sodium hydroxide. Dry the methylene chloride portion over magnesium sulfate, and remove the solvent in vacuo. Crystallize the residue from ether to provide the title compound.
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]([CH3:38])[C:15](=[O:37])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:30]3[N:29]=[C:28]([CH3:31])[NH:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)=[C:18]([O:32][CH3:33])[C:17]=1[N:34]=[C:35]=[O:36].[CH2:39]=O.[C:41]([BH3-])#[N:42].[Na+]>CO.C(Cl)(Cl)Cl>[CH3:39][N:42]([CH3:41])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]([CH3:38])[C:15](=[O:37])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:30]3[N:29]=[C:28]([CH3:31])[NH:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)=[C:18]([O:32][CH3:33])[C:17]=1[N:34]=[C:35]=[O:36]
Reactant: C=O
Reactant: COc1c(-c2cccc3[nH]c(C)nc23)ccc(C(=O)N(C)c2ccc(C)cc2OCCCCN)c1N=C=O
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1c(-c2cccc3[nH]c(C)nc23)ccc(C(=O)N(C)c2ccc(C)cc2OCCCCN(C)C)c1N=C=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
A mixture of N-[2-(4-aminobut-1-yloxy)-4-methylphenyl]-3-methoxy-N-methyl-4-(2-methyl-1H-benzimidazol-4-yl)-carbonylaminobenzamide (150 mg), 37% formaldehyde solution (43.7 mg) and sodium cyanoborohydride (18.3 mg) in methanol (10 ml) was stirred at ambient temperature for 6 hours. The mixture was diluted with chloroform and the solution was washed with saturated aqueous sodium hydrogen carbonate and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo. The crude product was purified by silica gel column (5% methanol in chloroform) to give N-[2-(4-dimethylaminobut-1-yloxy)-4-methylphenyl]-3-methoxy-N-methyl-4-(2-methyl-1H-benzimidazol-4-yl)-carbonylaminobenzamide (142 mg).