Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].C1OCCOCCOCCOCCOCCOC1.[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26](Cl)=[O:27].[Cl:34][C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([O:45][C:46]2[C:52]([Cl:53])=[CH:51][C:49]([NH2:50])=[CH:48][C:47]=2[Cl:54])=[CH:37][CH:36]=1>CC#N.O>[Cl:34][C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([O:45][C:46]2[C:47]([Cl:54])=[CH:48][C:49]([NH:50][C:2]([NH:3][C:26](=[O:27])[C:25]3[C:24]([F:23])=[CH:32][CH:31]=[CH:30][C:29]=3[F:33])=[S:1])=[CH:51][C:52]=2[Cl:53])=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: N#C[S-]
Reactant: Nc1cc(Cl)c(Oc2ccc(Cl)c3ccccc23)c(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(NC(=S)Nc1cc(Cl)c(Oc2ccc(Cl)c3ccccc23)c(Cl)c1)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1.4 g of potassium thiocyanate and 1.0 mg of 18-Crown-6 in 15 ml CH3CN which was cooled to 0° C. and placed under an atmosphere of nitrogen was slowly added a solution of 23 g of 2,6-diflurobenzoyl chloride in 15 ml of CH3CN. The reaction mixture was stirred for 0.5 hr at 0° C. and then allowed to warm to room temperature. After 0.5 hr at an IR spectrum of an aliquot indicated complete disappearance of the acid chloride. To the reaction mixture was then added 4.0 g of 4-(4-chloro-1-naphthoxy)-3,5-dichloroaniline as a powder. After 0.5 hr at ambient temperature the reaction mixture was poured into 125 ml of cold water. A buff colored solid precipitated and was filtered. The filter cake was then washed with 120 ml of a 5:1 H2O:CH3CN solution. The crystals were then dried overnight in a vacuum oven at 50° C. This afforded 5.6 g of the desired thiourea as a pale yellow crystalline powder. mp 193°-195° C. NMR (D6 -DMSO): 6.43 (d, J-10 Hz, 1H), 7.0-817 (m, 10H contains singlet at 8.13), 12.35 (s, 1H), 12.62 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][C:2]2[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=2)[CH2:13][CH2:12]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Product: O=[N+]([O-])c1ccc(NC2CC2)cn1

Procedure:
Using analogous procedures to those described in the portion of Note [9] immediately above that is concerned with the preparation of starting materials, 5-bromo-2-nitropyridine (0.41 g) was reacted with cyclopropylamine (0.21 ml) to give 5-cyclopropylamino-2-nitropyridine (0.322 g); 1H NMR: (CDCl3) 0.62 (m, 2H), 0.91 (m, 2H), 2.57 (m, 1H), 4.96 (br s, 1H), 7.19 (m, 1H), 7.99 (d, 1H), 8.16 (m, 1H); which in turn was converted into 5-(N-tert-butoxycarbonyl-N-cyclopropylamino)-2-nitropyridine (0.48 g); 1H NMR: (CDCl3) 0.59 (m, 2H), 1.05 (m, 2H), 1.53 (s, 9H), 3.02 (m, 1H), 8.05 (m, 1H), 8.22 (d, 1H), 8.64 (m, 1H); which in turn was converted into 2-amino-5-(N-tert-butoxycarbonyl-N-cyclopropylamino) pyridine (0.349 g); 1H NMR: (CDCl3) 0.5 (m, 2H), 0.79 (m, 2H), 1.44 (s, 9H), 2.95 (m, 1H), 4.39 (br s, 2H), 6.46 (d, 1H), 7.24 (m, 1H), 7.87 (m, 1H); Mass Spectrum: M+H+ 250; and which in turn was converted into N-[5-(N-tert-butoxycarbonyl-N-cyclopropylamino) pyridin-2-yl]-2-[4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]acetamide; Mass Spectrum: M+H+ 572.
Reaction SMILES: [F:1][C:2]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:3]=1[O:4][C:5]1[C:13]2[N:12]=[CH:11][N:10]([CH3:14])[C:9]=2[C:8]([CH:15]=C)=[CH:7][C:6]=1[C:17]1[C:18]2[CH:27]=[N:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:19]=2[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1.I([O-])(=O)(=O)=[O:42].[Na+]>O.O1CCCC1.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:3]=1[O:4][C:5]1[C:13]2[N:12]=[CH:11][N:10]([CH3:14])[C:9]=2[C:8]([CH:15]=[O:42])=[CH:7][C:6]=1[C:17]1[C:18]2[CH:27]=[N:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:33])[CH3:34])[C:19]=2[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1
Reactant: C=Cc1cc(-c2cn(C)c(=O)c3c2cnn3COCC[Si](C)(C)C)c(Oc2ccc(F)cc2F)c2ncn(C)c12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc(C=O)c3c(ncn3C)c2Oc2ccc(F)cc2F)c2cnn(COCC[Si](C)(C)C)c2c1=O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
A mixture of 4-[4-(2,4-difluorophenoxy)-1-methyl-7-vinyl-1H-benzimidazol-5-yl]-6-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (0.076 g, 0.13 mmol) and sodium metaperiodate (0.0865 g, 0.404 mmol) in water (0.23 mL) and tetrahydrofuran (3.10 mL) was treated with 0.16M solution of osmium tetraoxide in water (0.172 mL, 0.0270 mmol). The resultant reaction mixture was stirred at 60° C. for 30 min. The reaction mixture was diluted with water and ethyl acetate. Layers were separated and the organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to give a crude residue. Purification by flash column chromatography (100% hexanes to 100% EtOAc [EtOAc contained 5% MeOH]) gave the desired product (50.6 mg, 66%). LCMS calculated for C28H30F2N5O4Si (M+H)+: m/z=566.2. found: 566.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH2:20])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:21](Cl)(=[O:23])[CH3:22].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH:20][C:21](=[O:23])[CH3:22])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(C)cc(-c2nc(N)sc2-c2ccncc2)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc(-c2cc(C)cc(C)c2)c(-c2ccncc2)s1
Temperature: 80 °C
Reaction time: 14 h
Yield: 29.5 %

Procedure:
To a solution of [4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.50 g, 1.78 mmol) and 4-dimethylaminopyridine (0.06 g, 0.51 mmol) in N,N-dimethylacetamide (5 mL) was added acetyl chloride (0.21 g, 2.67 mmol) and the mixture was stirred at 80° C. for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate. The precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.17 g, yield 29%).
Reaction SMILES: C([O:4][CH2:5]/[CH:6]=[CH:7]/[CH2:8][N:9]1[C:14]([C:15](=[O:24])[C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)=[C:13]([CH2:25][CH3:26])[C:12](=[O:27])[NH:11][C:10]1=[O:28])(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[OH:4][CH2:5]/[CH:6]=[CH:7]/[CH2:8][N:9]1[C:14]([C:15](=[O:24])[C:16]2[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=2)=[C:13]([CH2:25][CH3:26])[C:12](=[O:27])[NH:11][C:10]1=[O:28]
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)n(C/C=C/COC(C)=O)c(=O)[nH]c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(C/C=C/CO)c(=O)[nH]c1=O
Reaction time: 1 h
Yield: 58.4 %

Procedure:
To a stirred solution of 50 mg (0.13 mmol) of the compound obtained from Example 80 in 5 ml of methanol was added 20 mg (0.37 mmol) of sodium methoxide at room temperature. After 1 hour, the reaction mixture was neutralized with acetic acid and evaporated under reduced pressure to give a yellow-colored residue, which was purified by flash chromatography using a mixture of ethyl acetate and hexane (4:1) as an eluent to afford 26 mg (yield 56%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.F[C:17]1[C:18]([C:24]#[N:25])=[N:19][C:20]([F:23])=[CH:21][N:22]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:17]1[C:18]([C:24]#[N:25])=[N:19][C:20]([F:23])=[CH:21][N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1nc(F)cnc1F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#Cc1nc(F)cnc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
In 5 ml of toluene was dissolved 0.5 g f 3,6-difluoro-2-pyrazinecarbonitrile. After adding 0.41 mL of benzyl alcohol and 0.74 mL of triethylamine successively, the mixture thus obtained was stirred at 80° C. for one hour. The reaction mixture was cooled to room temperature and then purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=10:1] to obtain 0.58 g of 3-(benzyloxy)-6-fluoro-2-pyrazinecarbonitrile as a white-colored solid product.
Reaction SMILES: [CH2:1]([C:8]1([OH:14])[CH2:12][CH2:11][O:10][C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C@H:16]([C:21]([NH:23][CH3:24])=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18].N1C=CC=CC1=O>ClCCCl>[CH2:1]([C@:8]([OH:14])([CH2:12][CH2:11][OH:10])[C:9]([NH:15][C@H:16]([C:21](=[O:22])[NH:23][CH3:24])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([C@@:8]([OH:14])([CH2:12][CH2:11][OH:10])[C:9]([NH:15][C@H:16]([C:21](=[O:22])[NH:23][CH3:24])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C1OCCC1(O)Cc1ccccc1
Agent: O=c1cccc[nH]1
Solvent: ClCCCl
Product: CNC(=O)[C@@H](NC(=O)[C@@](O)(CCO)Cc1ccccc1)C(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)[C@](O)(CCO)Cc1ccccc1)C(C)(C)C
Temperature: 80 °C
Yield: 38 %
Yield: 25 %

Procedure:
3-Benzyl-3-hydroxy-dihydro-furan-2-one (21c) (0.961 g, 5.00 mmol), H-tLeu-NHMe (1.80 g, 12.5 mmol) and 2-pyridone (0.476 g, 5.0 mmol) was suspended in 10 mL 1,2-dichloroethane in a reaction tube. The vessel was sealed with a screw cap and heated in a metal heating block at 80° C. for 24 h. The solvent was evaporated and the residue was re-dissolved in the least amount of 25% acetonitrile in water and the mixture was purified and the diastereomers separated by column chromatography using RP(C-18)-silica and a manual 10-50% acetonitrile in water gradient (with 0.05% HCOOH). The resulting fractions were analyzed by analytical RP-LC-MS and pure fractions pooled together and the solvent was evaporated to give (2S)-2-Benzyl-N-((1S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-2,4-dihydroxy-butyramide (0.424 g, 25%) and (2R)-2-Benzyl-N-((1S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-2,4-dihydroxy-butyramide (0.631 g, 38%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([C:12]2N(C3C=CC(OC)=CC=3)C=CN=2)[NH2:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:33]C(/C=N\S(C(C)(C)C)=O)=[CH:35][N:36]=2)=[CH:28][CH:27]=1>>[ClH:25].[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[O:33][C:12]([CH:10]([NH2:11])[CH2:9][C:4]3[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:35][N:36]=2)=[CH:30][CH:31]=1
Reactant: COc1ccc(-n2ccnc2[C@@H](N)Cc2cc(F)cc(F)c2)cc1
Reactant: CC(C)(C)S(=O)/N=C\c1cnc(-c2ccc(Cl)cc2)o1
Product: Cl
Product: NC(Cc1cc(F)cc(F)c1)c1cnc(-c2ccc(Cl)cc2)o1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 5E of Example 5 utilizing 19D. MS (m/z) 335.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([NH2:12])=[CH:7]2.CN(C=O)C.[H-].[Na+].Br[CH2:21][CH2:22][O:23][CH3:24]>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([NH:12][CH2:21][CH2:22][O:23][CH3:24])=[CH:7]2
Reactant: COCCBr
Reactant: Nc1cnc2c(Cl)ccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COCCNc1cnc2c(Cl)ccnc2c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 33.1 %

Procedure:
A round bottom flask under nitrogen atmosphere was charged with 8-chloro-1,5-naphthyridin-3-amine (160 mg, 0.89 mmol), DMF (2.2 mL, 0.89 mmol). This was cooled to 0° C. and SODIUM HYDRIDE (60% dispersion in oil) (107 mg, 4.45 mmol) added portionwise. This was quickly followed by addition of 1-bromo-2-methoxyethane (0.12 mL, 1.25 mmol) dropwise via syringe. Ice bath removed and reaction mixture heated to 85° C. and stirred at this temperature for 16 hours. Reaction diluted with 5 mL of 5% MeOH/Dichloromethane, loaded onto silica gel column and eluted with 2% MeOH/DCM to afford 8-chloro-N-(2-methoxyethyl)-1,5-naphthyridin-3-amine (70 mg, 33% yield) as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13](O)[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:14]1[O:15][CH:6]([C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=2)[O:7][CH2:13]1
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=[N+]([O-])c1cc(C2OCCO2)ccc1O

Procedure:
A solution of 4-hydroxy-3-nitrobenzaldehyde (known compound, 20.6 g, 124 mmol), benzene (150 ml), ethylene glycol (10.3 ml, 185 mmol) and p-toluenesulfonic acid hydrate (catalytic amount) was refluxed overnight removing the resulting water by azeotropic distillation with benzene.
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1O)(=[O:33])[CH3:32]>>[C:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:1][CH:2]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)(=[O:33])[CH3:32]
Reactant: CC(=O)c1ccccc1O
Reactant: COc1ccc(C(O)CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1
Product: COc1ccc(C(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)Oc2ccccc2C(C)=O)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-hydroxy-3-(4-methoxyphenyl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2-acetylphenol: ESMS m/e: 529.2 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:22](Cl)(=[O:24])[CH3:23]>C1COCC1.O>[C:1]([NH:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:22](=[O:24])[CH3:23])[CH:12]=[CH:11]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)NC(=O)c1ccc2[nH]ccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)n1ccc2cc(C(=O)NC(C)(C)C)ccc21
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 14.1 %

Procedure:
N-tert-Butyl indole-5-carboxamide was dissolved in dry THF and solution was cooled to −78° C. Butyllithium was added dropwise with continuous stirring. The reaction mixture was stirred at −78° C. for 40 minutes followed by dropwise addition of acetyl chloride. After addition was complete, the reaction mixture was stirred at −78° C. for 30 minutes and then stirred for 1 hour at room temperature. The reaction mixture was diluted with water and organic phase separated. The aqueous phase was saturate with sodium chloride and was extracted with ethyl acetate. The extracts were combined, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatrography to afford the title compound as a white solid (14.1% yield), melting point=186.8° C.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[Li]CCCC.[C:17]([S:21]([N:23]=[CH:24][CH2:25][CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[CH3:11][O:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[CH:24]([NH:23][S:21]([C:17]([CH3:19])([CH3:18])[CH3:20])=[O:22])[CH2:25][CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: COc1cccc(OC)c1I
Reactant: CCOC(=O)C(C)CC=NS(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)CC(NS(=O)C(C)(C)C)c1c(OC)cccc1OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A cooled (−78° C.) yellow solution of 2-iodo-1,3-dimethoxybenzene (8.553 g; 32.39 mmol) in anh. THF (175 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (20.25 ml; 32.40 mmol). The resulting slightly yellow solution was further stirred at −78° C. for 15 min. A yellow solution of ethyl 4-((tert-butylsulfinyl)imino)-2-methylbutanoate (6.410 g; 25.91 mmol) in anh. THF (15 ml) was then added dropwise to the cooled reaction mixture, and stirring at −78° C. was continued for 30 min. The resulting yellow reaction mixture was treated successively with aq. sat. NH4Cl (80 ml), Et2O (250 ml) and water (75 ml). The separated yellow organic layer was then washed with brine (75 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded ethyl 4-(2,6-dimethoxyphenyl)-4-(1,1-dimethylethylsulfinamido)-2-methylbutanoate as an orange oil. LC-MS (conditions B): tR=0.88 min. and [M+H]+: 386.15 g/mol; tR=0.89 min. and [M+H]+: 386.14 g/mol (mixture of diastereoisomers).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:21])[CH2:5]1.[C:22]1([CH2:28][CH2:29]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.CC(=O)OCC>[O:3]=[C:4]1[N:10]([CH2:29][CH2:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6](=[O:21])[CH2:5]1
Reactant: O=C1CC(=O)N(c2ccccc2)c2ccccc2N1
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CC(=O)N(c2ccccc2)c2ccccc2N1CCc1ccccc1
Reaction time: 0.33 h

Procedure:
Sodium hydride 80% dispersion in oil (0.13 g) was added portionwise to a solution of the 2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (compound a) (1 g) in DMF (18 ml) previously cooled at 0°. The reaction was stirred for 20 min at 0°, then a solution of 2-phenylethyl bromide (0.85 ml) in DMF (2 ml) was added dropwise, the mixture was stirred at 23° for 15 h, then diluted with EA (80 ml) and washed with brine (3×100 ml), dried and concentrated "in vacuo". The crude product was purified by flash chromatography (eluting with CH-EA 1:1) to give the title compound as a white powder (0.85 g). T.l.c. CH-EA (1:1), Rf =0.27.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][CH:11]=[C:10]([CH:16]=[O:17])[C:9]2=[O:18])[CH2:2][CH2:3][CH3:4].[CH3:19][OH:20]>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][CH:11]=[C:10]([C:16]([O:20][CH3:19])=[O:17])[C:9]2=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc2occ(C=O)c(=O)c2c1
Reactant: CO
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCOc1ccc2occ(C(=O)OC)c(=O)c2c1
Reaction time: 0.5 h

Procedure:
6-Butoxy-4-oxo-4H-chromen-3-carbaldehyde (VI-2; 5 g, 0.02 mol) prepared by the method described in Steps 1 and 2 of the Reference Example 2 and N-bromo succinicimide (4.4 g) were refluxed in carbon tetrachloride (350 ml) for 1 h while it was irradiated externally with 250W Matsushita Electric tungsuten lamp. The mixture was allowed to cool in an ice-bath and anhydrous methanol (6 ml) was added slowly and stirred for additional 30 min. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed successively with water, 1 M sodium hydroxide, water and brine and dried. The solvent was evaporated under reduced pressure to give 6.2 g of an orange solid. Recrystallization from 95% ethanol afforded 4.3 g (77%) of compound (VII-3) as pale yellow prisms. m.p. 88-89° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[CH3:43][NH:44][CH2:45][C:46]([O:48]C(C)(C)C)=[O:47].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:44]([CH2:45][C:46]([OH:48])=[O:47])[CH3:43])=[O:24]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(=O)O)C(=O)CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and tert.-butyl methylamino-acetate with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:15]([NH2:17])=O>>[CH3:14][O:13][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[O:11][CH3:12])[N:1]=[CH:15][NH:17][C:4]2=[O:5]
Reactant: NC=O
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Product: COc1cc2nc[nH]c(=O)c2cc1OC
Temperature: 190 °C

Procedure:
A mixture of 2-amino-4,5-dimethoxybenzoic acid (9.9 mg, 0.050 mmol) and formamide (5 ml) was heated at 190° C. for 6 hours. The mixture was cooled to 80° C. and poured onto water (25 ml). Precipitated material was filtered off, washed with water and dried in vacuo. Yield 1.54 g (15%), brown powder. The structure was confirmed by 1H (500 MHz) and 13C NMR (125 MHz) analysis.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[Si]([O:13][C:14]1C=CC(C#N)=[C:16]([F:22])[CH:15]=1)(C(C)(C)C)(C)C.[CH:23]([Mg]Br)([CH3:25])[CH3:24].C1COCC1.Cl>[Cu](Br)Br.O>[F:22][C:16]1[CH:15]=[C:14]([OH:13])[CH:3]=[CH:2][C:1]=1[C:5](=[O:4])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)[Mg]Br
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C#N)c(F)c1
Reactant: C1CCOC1
Agent: Br[Cu]Br
Agent: Cl
Solvent: O
Product: CC(C)C(=O)c1ccc(O)cc1F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Under an argon atmosphere, dehydrated THF (5 mL; Manufactured by Kanto Chemical Co., Inc.) was added to 4-(tert-butyldimethylsilyloxy)-2-fluorobenzonitrile (14.02 g) that can be produced by the method described in Reference Example 1 or the like, and the mixture was cooled to 0° C. Subsequently, a 0.78 mol/L isopropylmagnesium bromide-THF solution (89 mL; manufactured by Kanto Chemical Co., Inc.) was added dropwise thereto. After completion of the dropwise addition, the reaction solution was stirred for 20 minutes while the temperature was raised to room temperature, copper bromide (140 mg; manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto, and the reaction solution was stirred for 1.5 hours at 60° C. The reaction solution was cooled to 0° C., water (21.4 mL) and 5 mol/L hydrochloric acid (21.4 mL) were added thereto, and the reaction solution was stirred to 6 hours at 60° C. 5 mol/L hydrochloric acid (21 mL) was further added, and the reaction solution was stirred for 13 hours at 60° C. The reaction solution was cooled to room temperature, and was extracted three times with ethyl acetate. The organic layer was washed with water and brine, and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and n-hexane was added to the residue. Precipitates were filtered, and thus the title compound (8.69 g) was obtained.