Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH3:14][C:15]1[C:24]2[C:19](=[C:20]([O:29][CH3:30])[C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[CH2:18][CH2:17][N:16]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([N:16]1[CH2:17][CH2:18][C:19]2[C:24](=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[C:20]=2[O:29][CH3:30])[C:15]1=[CH2:14])=[O:6]
Reactant: COc1ccc(OC)c(C(=O)Cl)c1
Reactant: COc1cc2c(c(OC)c1OC)CCN=C2C
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=C1c2cc(OC)c(OC)c(OC)c2CCN1C(=O)c1cc(OC)ccc1OC
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of compound 45 (746 mg, 3.7 mmol) in anhydrous benzene (2 mL) was slowly added at room temperature to a solution of compound 44 (880 mg, 3.7 mmol) in anhydrous benzene (10 mL) containing triethylamine (568 mg, 5.6 mmol, 0.78 mL). The resulting solution was heated at reflux with stirring under Ar for 2 h. White NH4Cl precipitated and was removed by filtration. The filtrate was evaporated to dryness and the residue was subjected to flash chromatography (ether:triethylamine, 99:1 by volume, silica gel 230-300 mesh) to give compound 46 as an oil (1.3 g, 87.8%): 1H NMR (CDCl3, 200 MHz) δ6.87 (s, 1H), 6.85 (d, 1H, J=10 Hz), 6.80 (d, 1H, J=3 Hz), 6.70 (d, 1H, J=10 Hz), 5.21 (s, br 1H), 4.55 (s, br, 1H), 3.90 (s, 6H), 3.88 (s, 3H), 3.84 (s, 3H), 3.75 (s, 3H), 3.41 (s, br, 2H), 2.88 (t, 2H, J=6 Hz). CIMS (isobutane) m/e 400 (MH+, 100).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[O:13])[CH:6]=[CH:5]2.[CH:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C>O1CCCC1>[C:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[O:13])[CH:6]=[CH:5]2)#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: C#CCCCCCCCC
Reactant: O=Cc1ccc2cc(Br)ccc2n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCC#Cc1ccc2nc(C=O)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.5 %

Procedure:
A solution of 6-bromo-2-quinolinecarboxaldehyde (18.9 g), 1-decyne (12.2 g) and triethylamine (24.3 g) in dry tetrahydrofuran (300 ml) was chilled to 5° C. and degassed, under nitrogen. bis(Triphenylphosphine)palladium (II) chloride (0.56 g) and copper (I) iodide (0.08 g) were added to the reaction mixture, which was degassed and stirred under nitrogen at room temperature for 30 mins, and then heated at 40° C. for 19 hrs. The mixture wits cooled to room temperature, the precipitate was filtered, and the filter cake was washed with ethyl acetate, and the filtrate wits evaporated. The residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate wits concentrated. The residue was chromatographed on silica gel, eluting with heptane to heptane:2% ethyl acetate. The appropriate fractions were collected and evaporated. A 2 g-portion of the residue (23.4 g) was chromatographed, eluting with hexane:dichloromethane/2:1 give 1.3 g (64.0%) of product, mp 46.5°-47.5° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH:17]=[CH2:18])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:23][CH:24]1[CH:32]=[CH:31][CH2:30][CH:29]2[CH:25]1[CH2:26][NH:27][CH2:28]2.C1N2CCN(CC2)C1.O>C(#N)C.CN(C)C=O>[NH2:23][CH:24]1[CH:32]=[CH:31][CH2:30][CH:29]2[CH:25]1[CH2:26][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([CH:17]=[CH2:18])[C:10]=1[F:16])[CH2:28]2
Reactant: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: NC1C=CCC2CNCC12
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: C=Cc1c(F)c(N2CC3CC=CC(N)C3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 77.8 %

Procedure:
0.93 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxylic acid, 0.62 g of 4-amino-1,3,3a,4,7,7a-hexahydro-isoindole and 0.34 g of DABCO are refluxed for 1 hour in a mixture of 6 ml of acetonitrile and 3 ml of dimethylformamide. The reaction mixture is treated with 20 ml of water, and the product is filtered off with suction, washed with water and dried. 1 g of 7-(4-amino-1,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxylic acid is obtained.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1)=[O:3].C(N(C(C)C)C(C)C)C.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26]>C(Cl)Cl>[C:2]([C:4]1[CH:5]=[C:6]([NH:10][C:25]([C:21]2[O:20][CH:24]=[CH:23][CH:22]=2)=[O:26])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:1]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(=O)c1cccc(N)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cccc(NC(=O)c2ccco2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1 g of 3-aminoacetophenone in 20 mL of CH2Cl2 was added 5 mL of ethyl-di-iso-propylamine. To the stirred reaction mixture was then added 1 mL of 2-furoyl chloride which was allowed to stir at 25° C. for 8 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (CH2Cl2) to yield 900 mg of furan-2-carboxylic acid (3-acetyl-phenyl)-amide as a white solid. 1H NMR (CDCl3, 500 MHz) δ 8.11 (1 H, br s), 8.09 (1H, t, J=2 Hz), 7.93 (1 H, m), 7.66 (1H, m), 7.47 (1 H, m), 7.20 (1 H, m), 6.52 (1 H, m), 2.56 (3H, s) ppm.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Cl[CH2:18][C:19]([O-:21])=[O:20].[Na+].Cl>CS(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:18][C:19]([OH:21])=[O:20])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CCOC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
16.50 g of sodium hydride with 64% purity and 350 ml of dry dimethyl sulfoxide were supplied to a well dried 1-litre 4-necked flask. Then 101.30 g of ethyl 3,4-dichlorophenylacetate obtained in Example 6 was added dropwise, the solution being stirred at room temperature even after the end of the dropwise addition. Thereafter, 48.61 g of sodium chloroacetate was added and the solution was further stirred at room temperature. At this point, the reaction solution changed from a yellow to a red suspension. The reaction solution was stirred overnight at room temperature, then poured into a mixture of 500 ml of 1N hydrochloric acid and 300 ml of ice water, and stirred vigorously. The reaction mixture was extracted with 800 ml of ether and the organic layer was washed with 500 ml of water (three times) and 500 ml of a saturated saline solution (once). This organic layer was then dried over approximately 50 g of anhydrous sodium sulfate, concentrated to approximately 50 ml solvent and crystallized by treating it with approximately 300 ml of an ether/hexane mixed solvent. The precipitated crystals were filtered out and dried to give 106.07 g of primary crystals of the title substance. Meanwhile, the filtrate was concentrated to produce an oily substance, and it was crystallized by adding 20 ml of ether and 60 ml of hexane. Further, after additional supply of hexane, the precipitated crystals were filtered out and dried to obtain 3.09 g of the secondary crystals (109.16 g when combined with the primary crystals, yield 84.0%) of the title substance.
Reaction SMILES: [C:1]([C:4]1[C:12]2[NH:11][C:10]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>C(O)C>[NH:9]1[CH:8]=[CH:12][N:11]=[C:10]1[CH:13]=[CH:2][C:1]([C:4]1[C:12]2[NH:11][C:10]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1cccc2nc(CCc3ccccc3)[nH]c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ncc[nH]1)c1cccc2nc(CCc3ccccc3)[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
Ethanol (15 mL) was added to 4-acetyl-2-(2-phenylethyl)benzimidazole (1 g) obtained in Reference Example 1 and 2-imidazolecarboxyaldehyde (304 mg) . Sodium hydroxide (405 mg) was added to the mixture and the mixture was stirred overnight at room temperature. The reaction solution was poured into ice water, adjusted to pH 8 with 4 N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous sodium sulfate. After evaporation of the solvent under a reduced pressure, the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound (0.35 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][CH2:8][C:9]1[N:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)([O-])=O.Cl.[OH-].[NH4+].C(OCC)(=O)C.CCCCCC>O.C(OCC)(=O)C>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[N:18][C:9]=1[CH2:8][O:7][C:6]1[CH:5]=[C:4]([NH2:1])[CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1cccc(OCc2ncc3ccccc3n2)c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1cccc(OCc2ncc3ccccc3n2)c1
Temperature: 90 °C
Yield: 55.3 %

Procedure:
A suspension of 10 g (0.036 mol) of 2-[(3-nitrophenoxy)methyl]quinazoline in a solution of 105 g (0.38 mol) of ferrous sulfate heptahydrate and 0.5 ml of concentrated hydrochloric acid in 175 ml of water is heated on a steam bath to 90° C. Concentrated ammonium hydroxide is added in increments of 25 ml, and 3×10 ml over a period of 15 minutes. Heating is discontinued and the reaction mixture is allowed to cool over a period of 45 minutes while vigorously stirring. The reaction mixture is diluted with 500 ml of water/500 ml of ethyl acetate and filtered through Celite. The layers are separated and the ethyl acetate solution is charcoaled, filtered and concentrated to obtain an oil, which is subjected to high pressure liquid chromatography (ethyl acetate/hexane as eluent). Fractions 14-20 are combined and concentrated to obtain 5 g (56%) of off-white crystals, m.p. 103°-7° C.
Reaction SMILES: [CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:16][C:15]([C:17](OCC)=[O:18])=[N:14][N:13]=1)=[CH:8]2.O1CCCC1.[BH4-].[Na+]>CO>[OH:18][CH2:17][C:15]1[S:16][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)(=[O:24])=[O:23])=[N:13][N:14]=1
Reactant: CCOC(=O)c1nnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cccc2cc(-c3nnc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a mixture of ethyl 5-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3,4-thiadiazole-2-carboxylate (1.38 g), tetrahydrofuran (20 ml) and methanol (4 ml) was added sodium borohydride (0.26 g), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated, and water was added to the residue. The resulting crystals were collected by filtration, washed with water, and dried to give the title compound (1.18 g, yield 94%) as colorless crystals. melting point 259-260° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)[N:12]=[C:11]([C:21](O)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:45]3[CH2:49][C:48](=[O:50])[NH:47][CH2:46]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)[N:12]=[C:11]([C:21]([N:45]3[CH2:49][C:48](=[O:50])[NH:47][CH2:46]3)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cncc(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cncc(Cl)c3)n2)CN1

Procedure:
75 mg (0.21 mmol) of the compound of Example 26A is reacted analogously to the synthesis of the compound of Example 1 with 29 mg (0.23 mmol) of 4-imidazolinone-hydrochloride. 74 mg (82% of theory) of the title compound is obtained.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:27]1[N:28]=[C:29]([NH:32]C(=O)C(F)(F)F)[S:30][CH:31]=1)[C:5]([NH:7][CH:8]1[C:25](=[O:26])[N:10]2[C:11]([C:22]([OH:24])=[O:23])=[C:12]([CH2:15][S:16][C:17]3[S:18][CH:19]=[N:20][N:21]=3)[CH2:13][S:14][C@H:9]12)=[O:6].O.O.O.C([O-])(=O)C.[Na+].Cl>O>[CH3:1][O:2][N:3]=[C:4]([C:27]1[N:28]=[C:29]([NH2:32])[S:30][CH:31]=1)[C:5]([NH:7][CH:8]1[C:25](=[O:26])[N:10]2[C:11]([C:22]([OH:24])=[O:23])=[C:12]([CH2:15][S:16][C:17]3[S:18][CH:19]=[N:20][N:21]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.2 %

Procedure:
7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (23 g) was suspended in a solution of sodium acetate trihydrate (74.8 g) in water (230 ml) and the suspension was stirred for 15 hours at ambient temperature. The reaction mixture was adjusted to pH 5.0 with conc. hydrochloric acid and insoluble material was filtered off. The filtrate was adjusted to pH 2.5 and precipitating crystals were collected by filtration and dried to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (14 g), mp 172° to 175° C. (dec.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](Cl)=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:13][C@@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17]>>[O:3]1[C:4]2[CH:9]=[C:8]([C:10]([NH:13][C@H:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:19]([OH:21])=[O:20])=[O:11])[CH:7]=[CH:6][C:5]=2[O:1][CH2:2]1
Reactant: CC(C)C[C@@H](N)C(=O)O
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Product: CC(C)C[C@@H](NC(=O)c1ccc2c(c1)OCO2)C(=O)O
Yield: 55 %

Procedure:
Prepared in a similar manner to example 1 using benzo[d][1,3]dioxole-5-carbonyl chloride and D-Leucine. Yield: 55%. MS (M+H, 280.2).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][CH2:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])=[NH:11])[S:7][CH:8]=1.CN1CCOCC1.[CH3:31][O:32][C:33](Cl)=[O:34]>C1COCC1>[CH3:31][O:32][C:33](=[O:34])[NH:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][CH2:13][C:14]2[C:15]([O:22][CH3:23])=[CH:16][CH:17]=[CH:18][C:19]=2[O:20][CH3:21])=[NH:11])[S:7][CH:8]=1
Reactant: COC(=O)Cl
Reactant: COc1cccc(OC)c1CNC(=N)Nc1nc(CN)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)NCc1csc(NC(=N)NCc2c(OC)cccc2OC)n1

Procedure:
To 360 mg (1.12 mmol) N-[4-(aminomethyl)-1,3-thiazole-2-yl]-N′-(2,6-dimethoxybenzyl)guanidine hydrochloride, Example 154 free base, in 13.5 ml THF were added 0.2 ml NMM, and 0.1 ml chloroformic acid methyl ester in 1.5 ml THF were added drop-wise with stirring. Following completion of the reaction, the mixture was concentrated, was diluted with dichloromethane, was washed with saturated NaCl solution, was dried and was concentrated. Chromatography of the crude product on silica gel (dichloromethane/methanol 0-1%) yielded 140 mg; ESI-MS [M+H+]=380.05.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13](#[N:17])[CH:14]([CH3:16])[CH3:15].[CH3:18][O:19][CH2:20][O:21][CH2:22][C:23]1[CH:24]=[C:25](/[CH:29]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:26]=[CH:27][CH:28]=1>CCCCCC.C1COCC1.O>[C:13]([C:14]([CH3:16])([CH3:15])[CH:29]([C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][O:21][CH2:20][O:19][CH3:18])[CH:24]=1)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])#[N:17]
Reactant: CCOC(=O)/C=C/c1cccc(COCOC)c1
Reactant: CC(C)C#N
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)CC(c1cccc(COCOC)c1)C(C)(C)C#N
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, a solution (1.6 M, 1.50 mL) of n-butyllithium in hexane was added to a solution of diisopropylamine (336 μL) in THF (2 mL) at −78° C., to the reaction mixture was added isobutyronitrile (227 μL) at −78° C., and the mixture was stirred for 5 min. To the reaction mixture was added (E)-ethyl 3-(3-((methoxymethoxy)methyl)phenyl)acrylate (250 mg) at −78° C., and the mixture was stirred at room temperature for 20 min. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent of the reaction mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (210 mg) as a colorless oil.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](C)=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=O)C.COC1C=C(C=CC=1)C(Cl)=O.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:10]
Reactant: CC(=O)Oc1cccc(C(=O)O)c1C
Reactant: Nc1ccccc1
Agent: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)Nc2ccccc2)c1

Procedure:
WO 95/09843 describes a multistage process for the preparation of 3-acetoxy-2-methylbenzoic acid. This process starts from 3-methoxybenzoyl chloride. The 3-methoxybenzoyl chloride is reacted with aniline to give 3-methoxy-N-phenylbenzamide. In a second step, the 3-methoxy-N-phenylbenzamide is reacted with 2 equivalents of n-butyllithium and then alkylated using methyl iodide. 3-Methoxy-2-methyl-N-phenylbenzamide is formed here, which is then reacted with aqueous hydrochloric acid and aqueous hydrogen bromide in boiling acetic acid with hydrolysis of the amide group and cleavage of the methoxy group to give 3-hydroxy-2-methylbenzoic acid. The 3-hydroxy-2-methylbenzoic acid must be acylated with acetic anhydride in order to obtain the 3-acetoxy-2-methyl-benzoic acid. The individual reaction steps are described in greater detail in WO 95/09843 under Preparation 9 A, B and C and Example 81.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([S:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH:3]=1.[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:30][O:29][C:25](=[O:28])[CH:26]=[CH:27][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[S:16]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)(=[O:18])=[O:17]
Reactant: C=CC(=O)OC
Reactant: O=S(=O)(c1cc(F)ccc1OS(=O)(=O)C(F)(F)F)N1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C=Cc1ccc(F)cc1S(=O)(=O)N1CCOCC1
Temperature: 120 °C
Yield: 43 %

Procedure:
To a solution of the product of example 85 (100 mg 0.254 mmol) in dry DMF (3 ml) was added methyl acrylate (0.09 ml, 1.02 mmol), Pd(PPh3)2Cl2(17.83 mg, 0.0254 mmol), DPPP (10.5 mg, 0.0254 mmol) and DIPEA (0.2 ml, 1.02 mmol) successively at room temperature in sealed tube. The mixture was heated at 120° C. for about 24 h. After cooling to room temperature, the mixture was poured into ice water and extracted with EA three times. The combined extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA=5/1) to give the desire product (36 mg, yield 43%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@H:5]([C:8](Cl)=[O:9])[CH2:4][CH:3]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:18][C:19]=1[NH:20][CH:21]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:23][CH2:22]1)=[O:14].CCOC(C)=O>CN(C1C=CN=CC=1)C.ClC(Cl)C>[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:18][C:19]=1[N:20]([CH:21]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:23][CH2:22]1)[C:8]([CH:5]1[CH2:6][CH2:7][C:2]([CH3:1])=[CH:3][CH2:4]1)=[O:9])=[O:14]
Reactant: CC1=CC[C@@H](C(=O)Cl)CC1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCC2(CC1)OCCO2
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CC=C(C)CC1)C1CCC2(CC1)OCCO2
Temperature: 80 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
(1S)-4-Methyl-cyclohex-3-ene-1-carboxylic acid chloride (1.8 mmol), 5-(3,3-dimethyl-but-1-ynyl)-3-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylic acid methyl ester (336 mg, 0.89 mmol) and DMAP (217 mg, 1.8 mmol) were dissolved in dichloroethane (2.2 mL), sealed with a cap and heated to 80° C. After 2 h, the temperature was increased to 90° C., and the solution was stirred 16 h. The reaction mixture was further heated to 100° C., stirred 24 h and partitioned between water and ethyl acetate:hexanes (1:1). The layers were separated and the aqueous layer was extracted again with ethyl acetate:hexanes (1:1). The combined organic layers were dried over sodium sulfate, filtered and concentrated. Flash chromatography (5% EtOAc:hexanes 5 min then 5-40% EtOAc:hexanes, 20 min, 24 g column) afforded 250 mg (56% yield of the desired 5-(3,3-dimethyl-but-1-ynyl)-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(4-methyl-cyclohex-3-enecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester as a white foam.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[S:13][C:14]([C:18](=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][CH3:26])=[C:15]([CH3:17])[N:16]=1)(C)(C)C.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[S:34](Cl)(=[O:36])=[O:35]>>[CH2:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([C:14]1[S:13][C:12]([NH:11][CH2:10][CH2:9][CH2:8][NH:7][S:34]([C:30]2[S:29][CH:33]=[CH:32][CH:31]=2)(=[O:36])=[O:35])=[N:16][C:15]=1[CH3:17])=[O:27])[CH3:26]
Reactant: CCc1ccccc1C(=O)c1sc(NCCCNC(=O)OC(C)(C)C)nc1C
Reactant: O=S(=O)(Cl)c1cccs1
Product: CCc1ccccc1C(=O)c1sc(NCCCNS(=O)(=O)c2cccs2)nc1C

Procedure:
The title compound was prepared from {3-[5-(2-Ethyl-benzoyl)-4-methyl-thiazol-2-ylamino]-propyl}-carbamic acid tert-butyl ester and thiophene-2-sulfonyl chloride according to example BF. Off-white oil, 55%. MS (m/e): 448.1 (M+H, 100%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH:18]([F:20])[F:19])[N:3]=1.[NH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.[Li+].CC([N-]C(C)C)C.CC(O)=O>C1COCC1.O>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH:18]([F:20])[F:19])[N:3]=[C:2]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:7]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)cc(Cl)n1
Reactant: Nc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: FC(F)c1nc2ccccc2n1-c1nc(Cl)cc(Nc2cccnc2)n1
Reaction time: 0.17 h
Yield: 67 %

Procedure:
1-(4,6-Dichloro-2-pyrimidinyl)-2-(difluoromethyl)-1H-benzimidazole (International Publ. No. WO 2002/088112, the disclosure of which is incorporated herein by reference in its entirety) (0.315 g, 1 mmol) was added to a mixture of 3-aminopyridine (0.28 g, 3 mmol) and LDA (1.5 mL, 2 M in THF, 3 mmol) in 10 mL THF at room temperature. After 10 min, the mixture was neutralized with HOAc, diluted with water, extracted with EtOAc, and dried (Na2SO4). Chromatography on silica, eluting with CH2Cl2/EtOAc (3:2) gave a solid, which was recrystallized from i-Pr2O to give 0.252 g (67% yield) of 6-chloro-2-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-(3-pyridinyl)-4-pyrimidinamine: mp (i-Pr2O) 233-236° C.; 1H NMR (DMSO-d6) δ 10.42 (br, 1H), 8.72 (d, J=2.3 Hz, 1H), 8.43 (dd, J=4.7, 1.4 Hz, 1H), 8.26 (m, 1H), 8.01 (ddd, J=8.3, 2.5, 1.5 Hz, 1H), 7.86 (m, 1H), 7.62 (t, JHF′=52.9 Hz, 1H), 7.48-7.42 (m, 3H), 6.86 (s, 1H); Anal. Calcd. for C17H11ClF2N6: C, 54.8; H, 3.0; N, 22.55. Found: C, 54.75; H, 3.0; N, 22.7%.