Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[CH2:19][CH:18]3[CH:15]([C:16](OC)([O:20]C)[CH2:17]3)[C:14]=2[C:24]([O:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl>C(Cl)Cl.C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([C:13]2[CH2:19][CH:18]3[CH:15]([C:16](=[O:20])[CH2:17]3)[C:14]=2[C:24]([O:26][CH:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])(=[O:12])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC1(OC)CC2CC(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)=C(C(=O)OC(c3ccccc3)c3ccccc3)C21
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC2CC(=O)C12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 200 mg of 3-(p-nitrophenylsulfonyl)-7,7-dimethoxybicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester, in 5 mL of methylene chloride was diluted with 20 mL of acetic acid. Aqueous hydrochloric acid (4N, 3 mL) was added, the mixture was stirred for 1 hr at room temperature, and then evaporated to dryness at 25°. The residue was partitioned between methylene chloride and water and the organic layer was washed with brine, dried (Na2SO4), and evaporated. The residue was dissolved in a small amount of 5% methanol in methylene chloride and treated with an excess of diphenyldiazomethane to esterify any free acid present. After nitrogen evolution ceased, the reaction mixture was evaporated to dryness and the residue was dissolved in methylene chloride-ether to give a solution from which precipitated 127 mg (69.3%) of 3-(p-nitrophenylsulfonyl)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenyl methyl ester, as colorless crystals. IR (Nujol mull): 1730, 1780 cm-1 ; NMR (80 MHz; CDCl3): δ 2.5-3.6 (5H, m), 4.7 (1H, m), 7.0 (1H, s), 7.2-7.5 (10H, m), 8.0 (2H, d, J=9), and 8.23 (2H, d, J=9). ##STR26##
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([C:31]2[CH:32]=[C:33](/[C:43](=[CH:47]\[CH:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)/[C:44]([OH:46])=O)[CH:34]=[CH:35][C:36]=2[S:37]([CH:40]2[CH2:42][CH2:41]2)(=[O:39])=[O:38])[CH2:30][CH2:29]1.[CH3:54][N:55]1[CH:59]=[CH:58][C:57]([NH2:60])=[N:56]1>ClCCl.N1C=CC=CC=1.O>[CH:28]1([C:31]2[CH:32]=[C:33](/[C:43](=[CH:47]\[CH:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)/[C:44]([NH:60][C:57]3[CH:58]=[CH:59][N:55]([CH3:54])[N:56]=3)=[O:46])[CH:34]=[CH:35][C:36]=2[S:37]([CH:40]2[CH2:41][CH2:42]2)(=[O:38])=[O:39])[CH2:30][CH2:29]1
Reactant: Cn1ccc(N)n1
Reactant: O=C(O)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: Cn1ccc(NC(=O)/C(=C/C2CCOCC2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)n1
Reaction time: 0.25 h
Yield: 80.2 %

Procedure:
To a solution of triphenylphosphine (131 mg) in dichloromethane (2 mL) was added N-bromosuccinimide (89 mg) under ice-cooling, followed by stirring for 15 minutes under ice-cooling. A solution of (2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)acrylic acid (100 mg) in dichloromethane (1 mL) was added thereto, followed by stirring at room temperature for 30 minutes. A solution of 1-methyl-1H-pyrazol-3-amine (39 mg) in dichloromethane (1 mL) and pyridine (0.086 mL) were added thereto at room temperature, followed by stirring at room temperature for 15 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was sequentially washed with 1 M hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography to obtain (2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)acrylamide (97 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C:13]([F:16])([F:15])[F:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:17](C1C=C(C=C(OC(C)C)C=1)C(OC)=O)#[N:18]>>[C:17]([C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C:13]([F:16])([F:15])[F:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])#[N:18]
Reactant: COC(=O)c1cc(Br)cc(OC(F)(F)F)c1
Reactant: COC(=O)c1cc(C#N)cc(OC(C)C)c1
Product: COC(=O)c1cc(C#N)cc(OC(F)(F)F)c1

Procedure:
Prepared from methyl 3-bromo-5-(trifluoromethoxy)benzoate according to the procedure for methyl 3-cyano-5-isopropoxybenzoate. LCMS-ESI (m/z) calculated for C10H6F3NO3: 245.2; no m/z observed, tR=4.43 min. 1H NMR (400 MHz, CDCl3) δ 8.27 (t, J=1.4 Hz, 1H), 8.16-8.07 (m, 1H), 7.73-7.65 (m, 1H), 3.99 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:24]=[C:23]3[C:19]([CH:20]=[CH:21][NH:22]3)=[CH:18][CH:17]=2)=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27][O:28][CH2:29][CH2:30]Br>CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:24]=[C:23]3[C:19]([CH:20]=[CH:21][N:22]3[CH2:30][CH2:29][O:28][CH3:27])=[CH:18][CH:17]=2)=[O:14])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccc3cc[nH]c3c2)cc1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1ccc2ccc(NC(=O)/C=C/c3ccc(C(C)(C)C)cc3)cc21
Reaction time: 2 h

Procedure:
To a round-bottomed flask was added, (2E)-3-[4-(tert-butyl)phenyl]-N-indol-6-ylprop-2-enamide, Example 189, (320 mg, 1.0 mmol) and anhydrous DMF (20 mL). The solution was stirred magnetically and treated with sodium hydride (0.10 g, 2.5 mmol, 60% dispersion in mineral oil, Aldrich) followed by 2-bromoethyl methyl ether (140 mg, 1.0 mmol, Aldrich). Stirring was continued at 25° C. for 2 h, then the reaction mixture was quenched by the addition of water (50 mL) and extracted with EtOAc. The organic extract was concentrated in vacuo. Purification by silica gel chromatography (60:40 hexane:EtOAc) provided the title compound as a yellow solid. MP 133° C. MS (ESI, pos. ion) m/z: 377 (M+1).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][O:6][C:7](=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][OH:23])[C:16]=1[CH3:24]>O.O1CCOCC1.O>[CH3:5][O:6][C:7](=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([OH:23])[C:3]([NH:2][CH3:1])=[O:4])[C:16]=1[CH3:24]
Reactant: COC(=O)c1ccccc1Nc1cccc(CNO)c1C
Reactant: CN=C=O
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)N(O)Cc1cccc(Nc2ccccc2C(=O)OC)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
Methyl isocyanate (0.33 g, 5.8 mmol) is added dropwise to 2-[[3-(N-hydroxyamino)methyl-2-methylphenyl]amino]benzoic acid methyl ester (1.5 g, 5.2 mmol) in 33% water/dioxane (60 mL) with ice bath cooling. The reaction mixture is stirred at 0° C. for 30 minutes and then at room temperature for 1 hour. It is then diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The organic layer is washed with water (50 mL) and dried over magnesium sulfate. Evaporation of the ethyl acetate gives the crude product which is purified by recrystallization first from ether and then from ethyl acetate to give 2-[[3-[[hydroxy[(methylamino)carbonyl]amino]methyl]2-methylphenyl]amino]benzoic acid methyl ester (0.68 g, 38%). mp=173-175° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[CH3:11][C:12]([S:15]([NH2:17])=[O:16])([CH3:14])[CH3:13].O>C1COCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5](/[C:8](=[N:17]/[S:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])/[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)nn1
Reactant: CC(C)(C)S(N)=O
Solvent: C1CCOC1
Solvent: O
Product: C/C(=N\S(=O)C(C)(C)C)c1ccc(Cl)nn1
Temperature: 60 °C

Procedure:
To a solution of 1-(6-chloro-pyridazin-3-yl)-ethanone (34 mg, 0.22 mmol) in dry THF (1.0 mL) was added 2-methyl-propane-2-sulfinic acid amide (29 mg, 0.24 mmol). Ti(OEt)4 (0.090 mL, 0.43 mmol) was added in one portion and the reaction was heated to 60° C. for 1 h. Water was added to the reaction mixture and the resulting slurry was filtered through a pad of diatomaceous earth. The filtrate was dried over Na2SO4 and was concentrated to provide 2-methyl-propane-2-sulfinic acid[1-(6-chloro-pyridazin-3-yl)-eth-(E)-ylidene]-amide as a crude residue that was used without purification, m/z 260.5 [M+H]+.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[CH:30][N:31]([CH3:33])[CH3:32])=[C:25]([C:34]#[N:35])[CH:24]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Na+].O>[C:34]([C:25]1[CH:24]=[C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])[CH:28]=[CH:27][C:26]=1[N:29]=[CH:30][N:31]([CH3:32])[CH3:33])#[N:35]
Reactant: CN(C)C=Nc1ccc(N)cc1C#N
Reactant: CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC#CC(=O)Nc1ccc(N=CN(C)C)c(C#N)c1
Reaction time: 0.25 h
Yield: 89 %

Procedure:
To a solution of 2.01 g (23.9 mmol) of 2-butynoic acid and 2.9 ml (22.3 mmol) isobutyl chloroformate in 30 ml tetrahydrofuran was stirred at 0° C. under nitrogen as 2.42 g (2.63 ml, 22.3 mmol) of N-methyl morpholine was added over 3 min. After stirring for 15 min., a solution of N'-(4-amino-2-cyanophenyl)-N,N-dimethylformamidine and 1.6 g (1.75 ml, 15.9 mmol) of N-methyl morpholine in 25 ml tetrahydrofuran was added over 4 min. The mixture was stirred 30 min. at 0° C. and 30 min. at room temperature. The mixture was diluted with 70 ml of ethyl acetate and poured into a mixture of brine and saturated sodium bicarbonate. The organic layer was dried (MgSO4) and filtered through a pad of silica gel. The solvent was removed and the residue was stirred with 50 ml of ether. The suspended solid was collected to give 3.61 g (89%) of an off-white solid. mass spectrum (m/e): 255.0 (M+H, electrospray).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])[CH:6]=[CH:5][N:4]=1)[NH2:2].[Si:14]([O:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[C:29]([CH:32]=O)[CH:28]=[CH:27]2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CCO>[Si:14]([O:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[C:29](/[CH:32]=[N:2]/[NH:1][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])[CH:6]=[CH:5][N:4]=1)[CH:28]=[CH:27]2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16]
Reactant: COCCOc1ccnc(NN)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(C=O)nc12
Solvent: CCO
Product: COCCOc1ccnc(N/N=C/c2ccc3cccc(O[Si](C)(C)C(C)(C)C)c3n2)c1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
2-Hydrazinyl-4-(2-methoxyethoxy)pyridine (0.076 g, 0.415 mmol) and 8-(tert-butyldimethylsilyloxy) quinoline-2-carbaldehyde (0.119 g, 0.415 mmol) were heated to reflux in EtOH (2 mL) for 16 hours. After cooling to ambient temperature the reaction mixture was filtered and washed with EtOH to provide 105 mg (56%) of desired product as an orange solid.
Reaction SMILES: CC(C)=O.[CH2:5]([O:9][C:10]1[N:15]=[C:14]([CH3:16])[C:13]([C:17]([O:19]CC)=[O:18])=[CH:12][N:11]=1)[CH2:6][CH2:7][CH3:8].[OH-].[Na+]>O>[CH2:5]([O:9][C:10]1[N:15]=[C:14]([CH3:16])[C:13]([C:17]([OH:19])=[O:18])=[CH:12][N:11]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCOc1ncc(C(=O)OCC)c(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCOc1ncc(C(=O)O)c(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To 50 ml of acetone, 10.0 g (42 mmol) of ethyl 2-butoxy-4-methylpyrimidine-5-carboxylate was dissolved, followed by adding 50 ml of water, then adding drop-wise 13.4 g (84 mmol) of a 25% sodium hydroxide aqueous solution, and stirring at room temperature for 1 hour. The reaction liquid was concentrated at 40° C. under reduced pressure to remove acetone, and 10% hydrochloric acid was added to make acidic. The crystal precipitated was filtered, washed with water and dried to obtain 8.00 g (yield: 91%) of 2-butoxy-4-methylpyrimidine-5-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][NH2:22].[OH:23][CH2:24][CH:25]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][N:22]=[CH:25][CH2:24][OH:23]
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccncc1
Reactant: O=CCO
Product: CC1=C(CCON=CCO)c2cc(F)ccc2/C1=C\c1ccncc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-pyridyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with hydroxyacetaldehyde by the method of Example 1.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>C(#N)C>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[C:15]4[S:16][CH:17]=[CH:18][C:14]=4[O:13][N:12]=3)[CH:6]=2)=[CH:28][CH:27]=1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(CNCCOc2cccc(-c3noc4ccsc34)c2)cc1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 4-fluorobenzylamine and acetonitrile essentially as described above in example 18 except that the column is eluted using a solvent gradient of 40% ethyl acetate in heptane, to 100% ethyl acetate. Purity by LC/MS (APCI)=100%, [M+H]+=369.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@@H:2]([CH3:4])[OH:3].I[CH2:9][CH2:10][CH3:11]>[Ag]=O.CCOCC>[CH2:9]([O:3][C@H:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])[CH2:10][CH3:11]
Reactant: CCCI
Reactant: COC(=O)[C@@H](C)O
Agent: O=[Ag]
Solvent: CCOCC
Product: CCCO[C@H](C)C(=O)OC
Reaction time: 96 h
Yield: 63.1 %

Procedure:
Silver oxide (87.5 g, 0.38 mol) was added to a mixture of (R)-methyl lactate (52.1 g, 0.5 mol) with 1-iodopropane (100 g, 0.59 mol) over 3 hours, followed by allowing the mixture to stand at room temperature for 4 days, adding ether (200 ml) for dilution, filtering the mixture, distilling off ether, washing the residue with 2N-NaOH aqueous solution, drying over anhydrous sodium sulfate, distilling it under reduced pressure to obtain (R)-methyl 2-propoxypropionate (46.1 g, b.p. 33°-34° C./5 mmHg). To this (R)-methyl 2-propoxypropionate (28.2 g) were added water (60 ml) and NaOH (10 g), followed by agitating the mixture at room temperature for 3 hours, pouring the mixture in 6N-hydrochloric acid (80 ml), extracting the resulting organic layer with ether, washing the resulting organic layer with water and distilling off ether to obtain 2-propoxypropionic acid (18.0 g).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:11]=2[N:10]=[CH:9]1)=O)(C)(C)C.[OH-].[Na+]>CO>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][C:11]2[N:10]=[CH:9][NH:8][C:12]=2[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCc2ncn(C(=O)OC(C)(C)C)c2CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2nc[nH]c2CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of 4,5,7,8-tetrahydro-imidazo[4,5-d]azepine-1,6-dicarboxylic acid di-tert-butyl ester (Preparation 26, 6.87 g, 20.37 mmol) in methanol (60 mL) was added an aqueous 1M solution of sodium hydroxide (40.7 mL, 40.7 mmol). The resulting mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was partitioned between DCM (100 mL) and water (100 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to give the title compound as a brown foam (4.8 g) in a 99% yield.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6](C=O)=[CH:5][CH:4]=1.[CH:11](OC)([O:14][CH3:15])[O:12][CH3:13].CC1C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>CO>[CH3:13][O:12][CH:11]([C:6]1[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1)[O:14][CH3:15]
Reactant: COC(OC)OC
Reactant: CSc1ccc(C=O)cc1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccc(SC)cc1
Reaction time: 0.08 h

Procedure:
A solution of 4-methylsulfanylbenzaldehyde 1 (10 g, 66 mmol), (MeO)3CH (8.6 mL, 79 mmol) and p-TsOH (0.25 g, 1.3 mmol) in MeOH (130 mL) was stirred for 18 h. The remaining pTsOH was decomposed by addition of NaOMe. After 5 min, the mixture was evaporated in vacuo, and passed through a pad of SiO2 (95:5 hexane/Et2O) to afford 1-(1,1-dimethoxy-methyl)-4-methylsulfanyl-benzene 2. The residue after evaporation was dissolved into CH2Cl2 (360 mL) and treated with MCPBA (41 g, 240 mmol). After 18 h, the mixture was filtered and the filtrate evaporated. The residue was partitioned between EtOAc and 1 M NaOH. The organic layer was washed with 1 M NaOH (2×), washed with brine, dried (MgSO4), filtered and evaporated to afford 1-(1,1-dimethoxy-methyl)-4-methanesulfonylbenzene 3. The residue was dissolved into THF (130 mL) and treated with 2% H2SO4 (3.4 mL). After 2 h, the solvent was evaporated, and the residue was partitioned between EtOAc and NaHCO3. The organic layer was dried (MgSO4), filtered and evaporated to afford 12 g (98% for three steps) of 4-methylsulfonylbenzaldehyde 4 as a white solid; 1H NMR δ 3.11 (s, 3H), 8.09 (d, 2H, J=8.6), 8.14 (d, 2H, J=8.6), 10.15 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([C:19]#[N:20])[CH:14]=[C:15]([C:17]#[N:18])[CH:16]=2)[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26](COCC[Si](C)(C)C)[C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[C:13]([C:19]#[N:20])[CH:12]=2)[C:4]=1[F:21])=[O:29]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: N#Cc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 71.8 %

Procedure:
5-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-1,3-benzenedicarbonitrile (0.054 g, 0.181 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.050 g, 0.181 mmol) and DIPEA (0.063 mL, 0.361 mmol) were combined in THF (2 mL) and treated with HATU (0.076 g, 0.199 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. for 3 days. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The resultant solid was recrystallized from boiling IPA, cooled in an ice bath and filtered to give 4-chloro-N-({4-chloro-3-[(3,5-dicyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.056 g, 0.130 mmol, 72.1% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.19 (br. s., 1H), 8.20-8.36 (m, 2H), 7.94 (d, J=0.82 Hz, 2H), 7.78 (s, 1H), 7.33-7.55 (m, 2H), 4.54 (d, J=3.43 Hz, 2H). LC-MS (ES−) m/z 428.03, 430.02 [M−1]. LC-MS (ES+) m/z 430.27, 431.98 [M+H].
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH3:16][CH:7]([O:6][C:5]1[CH:17]=[CH:18][C:2]([C:24]2[CH:25]=[CH:26][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=2)=[CH:3][CH:4]=1)[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11]
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(C=O)cc2)cc1
Yield: 30.3 %

Procedure:
The title compound (82 mg, 30%, yellow foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (252 mg, 0.749 mmol, prepared in example 1), 4-formylbenzeneboronic acid (135 mg, 0.900 mmol), dichlorobis(triphenylphosphine)palladium(II) (21 mg, 0.030 mmol), 2 M sodium carbonate (270 mg in 1.3 mL water), and 1,2-dimethoxyethane (5 mL) in a manner analogous to the procedure described in Example 8.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:4]=1)#[N:2].C[N:40](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].N.CCN(C(C)C)C(C)C>CN(C=O)C.O1CCOCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([NH2:40])=[O:17])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)(=[O:32])=[O:31])[CH:4]=1)#[N:2]
Reactant: CC1=C(C(=O)O)C(c2ccc(C#N)cc2S(=O)(=O)c2ccccc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC1=C(C(N)=O)C(c2ccc(C#N)cc2S(=O)(=O)c2ccccc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 88.6 %

Procedure:
The reaction was carried out under argon. (rac)-4-{4-Cyano-2-[phenylsulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (166 mg, 0.307 mmol) and HATU (5 eq., 583 mg, 1.53 mmol) were initially charged in dry DMF (3.5 ml) at 0° C., and ammonium chloride (5 eq., 82 mg, 1.53 mmol) [alternatively: 1.23 ml of a 0.5 M solution of ammonia in dioxane] and DIEA (10 eq., 369 mg, 3.07 mmol) were added after brief stirring (20 minutes). The mixture was stirred at RT for 6 h (HPLC control) and then concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a solid (147 mg, 89% of theory).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[CH3:21][C:22]1([CH3:27])[CH2:26][O:25][CH2:24][NH:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([N:23]3[C:22]([CH3:27])([CH3:21])[CH2:26][O:25][CH2:24]3)=[O:20])=[N:8][C:9]=2[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Reactant: CC1(C)COCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COCN1C(=O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 5 g)) was reacted with 4,4-dimethyloxazolidine (CAN 51200-87-4) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=355.5 [MH+].