Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1N.[BH3-][C:11]#[N:12].[Na+].O.[OH-].[K+].[CH3:17]C(O)=O>>[Br:9][C:7]1[CH:6]=[CH:5][C:3]([N:12]([CH3:11])[CH3:17])=[C:2]([F:1])[CH:8]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 2-fluoro-4-bromoaniline (1.0 g, 5.26 mmol) in AcOH (20 mL) at rt was added NaCNBH3 (1.654 g, 26.3 mmol). The mixture was stirred at rt overnight (˜17 h). The reaction was cooled in an ice bath. Water (10 mL) was added, followed by solid KOH until pH>11. The mixture was extracted with DCM. The combined extracts were dried (MgSO4) and concentrated to afford the title compound, which was used without further purification. LC-MS: calculated for C8H9BrFN 218.07, observed m/e 219.99 (M+H)+ (Rt 0.96 min).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([CH2:12][CH3:13])([O-:11])=[O:10].O>O1CCCC1.C(O)(C)(C)C.CC(C)([O-])C.[K+]>[N+:9]([CH:12]([CH3:13])[CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:8])([O-:11])=[O:10]
Reactant: O=Cc1ccccc1
Reactant: CC[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC(C(O)c1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
To a solution of benzaldehyde (20.0 g) and nitroethane (28.4 g) in tetrahydrofuran (50 mL) and tert-butanol (50 mL) was added potassium tert-butoxide (1.27 g) under ice-cooling, and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=10:1) to give the title compound as a blue oil (yield 32.0 g, 93%).
Reaction SMILES: N1C=CC=CC=1.[OH-].[K+].[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[CH3:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([CH3:38])[C:30]=1[S:31]([CH2:34][N+:35]([O-:37])=[O:36])(=[O:33])=[O:32])[NH2:27].Cl>O1CCCC1.O>[CH3:38][C:29]1[CH:28]=[C:26]([NH:27][S:19]([C:16]2[CH:17]=[CH:18][C:13]([S:10]([CH3:9])(=[O:12])=[O:11])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH:25]=[C:24]([CH3:23])[C:30]=1[S:31]([CH2:34][N+:35]([O-:37])=[O:36])(=[O:33])=[O:32]
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2ccc(S(C)(=O)=O)cc2)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.7 %

Procedure:
1.31 ml (16.2 mmol) of pyridine, dried over potassium hydroxide, and 2.5 g (9.82 mmol) of 4-(methylsulphonyl)benzenesulphonyl chloride are successively added to a solution, maintained under a nitrogen atmosphere, of 1.6 g (6.55 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline in 50 ml of anhydrous tetrahydrofuran. The reaction medium is stirred for 2 days at room temperature and then poured into 200 ml of water. The mixture obtained is brought to pH 3 by addition of 1N hydrochloric acid and is then extracted with 3 times 200 ml of ethyl acetate. The combined organic extracts are washed with water, dried over sodium sulphate and concentrated to dryness under reduced pressure. The residue is purified by chromatography on a column of silica (eluent: 2/1 methylene chloride/ethyl acetate) and recrystallization from a mixture of hexane and ethyl acetate, to give 0.78 g (26%) of N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-4-(methylsulphonyl)benzenesulphonamide.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][NH:12]C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)=[O:4].[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][NH2:12])[CH2:7][CH2:6]1)=[O:4].[F:22][C:23]([F:28])([F:27])[C:24]([O-:26])=[O:25]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NNC1CCN(C(=O)C(F)(F)F)CC1
Solvent: ClCCl
Product: NNC1CCN(C(=O)C(F)(F)F)CC1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5.0 g (16.1 mmol) tert-butyl N′-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-yl]-hydrazine-carboxylate are dissolved in 50 ml dichloromethane and combined with 6.0 ml (77.9 mmol) trifluoroacetic acid. The reaction mixture is stirred for 5 hours at ambient temperature, then concentrated by evaporation. Yield: 6.70 g
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:19]=[CH:18][C:11]([CH2:12][C@@H:13]([C:15]([OH:17])=[O:16])[NH2:14])=[CH:10][CH:9]=1)([O-:7])=[O:6].[CH3:20]O>>[ClH:3].[CH3:20][O:16][C:15](=[O:17])[C@H:13]([CH2:12][C:11]1[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:19][CH:18]=1)[NH2:14]
Reactant: O=S(Cl)Cl
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CO
Product: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Product: Cl
Reaction time: 24 h

Procedure:
In an adaptation of the method of Guttman and Boissonnas [Helv. Chem. Acta, 41, 1852-1867 (1958)], thionyl chloride (distilled, 0.69 ml, 9.5 mmol) was added dropwise to methanol (20 ml at -10° C.). p-Nitro-L-phenylalanine (compound 1, 1.00 g, 4.76 mmol) was added, and the solution was stirred 24 hours. After evaporating to dryness the residue was recrystallized from methanol/ether giving 1.00 g (81%) of a white solid melting at 218°-219° C.; [α]D25 =+11.5° (c=0.9, H2O).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.[Si]([O:39][CH2:40][CH2:41][C:42]#[C:43][B-](F)(F)F)(C(C)(C)C)(C)C.[K+].COC(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:3][C:2]=2[C:43]#[C:42][CH2:41][CH2:40][OH:39])[CH2:9][CH2:10]1)(=[O:16])=[O:15]
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCC#C[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2C#CCCO)CC1
Temperature: 135 °C
Yield: 23.9 %

Procedure:
2-(3-Bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (95 mg, 0.17 mmol, Example 69), potassium (4-(tert-butyldimethylsilyloxy)but-1-ynyl)trifluoroborate (75 mg, 0.26 mmol, ASDI, Newark, Del.), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (14 mg, 0.02 mmol, Strem Chemical Inc, Newburyport, Mass.), and cesium carbonate (182 mg, 0.56 mmol) were combined in toluene (1.5 mL) and water (0.2 mL). The reaction mixture was purged with nitrogen gas for several minutes and then stirred and heated in an Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 135° C. for 30 min. The reaction mixture was filtered through a pad of Celite® (diatomaceous earth) eluting with CH2Cl2 and the filtrate was concentrated in vacuo. The residue was suspended in 1N HCl (5 mL) and stirred at room temperature for 30 min. The mixture was partitioned between CH2Cl2 (5 mL) and saturated aqueous sodium bicarbonate (5 mL). The layers were separated, the organic material was dried (Na2SO4), filtered, and concentrated. This crude material was subjected to reverse-phase preparative HPLC using a Phenomenex Gemini C18 column (150×30 mm, 10 μm) eluting with 0.1% TFA in CH3CN/H2O (30% to 100% over 10 min) to provide 4-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-3-butyn-1-ol (22 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.11 (dd, J=1.27, 4.99 Hz, 1H), 7.71 (dd, J=1.37, 3.72 Hz, 1H), 7.55 (s, 1H), 7.52 (d, J=8.61 Hz, 1H), 7.35 (dd, J=3.81, 4.99 Hz, 1H), 7.08 (d, J=8.80 Hz, 1H), 4.88 (t, J=5.38 Hz, 1H), 3.50-3.59 (m, 2H), 3.27-3.32 (m, 4H), 3.08-3.15 (m, 4H) 2.56 (t, J=6.70 Hz, 2H); m/z (ESI, +ve ion) 543.1 (M+H)+. GK-GKRP IC50 (Binding)=0.656 μM. GK-GKRP EC50 (LC MS/MS-2)=0.895 μM.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:13][CH2:12][C:11](=O)[CH2:10][S:9]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+]>CO>[NH2:21][CH:11]1[CH2:12][S:13][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[S:9][CH2:10]1
Reactant: Cc1ccc(C2SCC(=O)CS2)cc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(C2SCC(N)CS2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
22.4 g (0.1 mol) of 2-(4-methylphenyl)-1,3-dithian-5-one and 77.1 g (1.0 mol) of ammonium acetate were stirred in 250 ml of methanol with the addition of 37.5 g of molecular sieve (3 Å) for 30 minutes and 6.30 g (0.1 mol) of sodium cyanoborohydride were then added in portions at 20° C. The mixture was stirred at room temperature for 48 hours, diluted with methanol and filtered. The filtrate was concentrated and the residue was taken up in dilute hydrochloric acid/toluene. The hydrochloric acid phase was rendered basic with concentrated sodium hydroxide solution and extracted with ether. This gave 2.2 g of product as a colorless oil (9.8% of theory), which was reacted without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.CCN(CC)CC.Cl.[CH3:38][NH:39][O:40][CH3:41]>C1COCC1>[CH3:41][O:40][N:39]([CH3:38])[C:12]([CH:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:11]1)=[O:14]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 127.9 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (5.15 g, 25.6 mmol) in THF (100 mL) was added DCC (7.11 g, 34.5 mmol), Et3N (5.18 g, 51.2 mmol) and N,O-dimethylhydroxylamine hydrochloride (3.44 g, 35.3 mmol), the reaction was stirred at RT for about 16 hr. Concentrated under reduced pressure to remove solvent, the residue was portioned between EA (100 mL) and water (50 mL), the aqueous was further extracted with EA (50 mL×3). The combined organic phases were washed with brine (20 mL), concentrated under reduced pressure to remove solvent, then purified by column chromatography on silica gel (200-300 mesh, CH2Cl2/MeOH=20/1) to give the crude product (˜8.0 g) as a colorless oil. MS (ESI) m/e [M+23]+ 266.9, [M−55]+ 189.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]([CH3:15])[CH2:7][C:6]2=[O:16].N1C=CC=CC=1.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].C(Cl)(Cl)Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH:8]([CH3:15])[CH2:7][C:6]2=[O:16]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1cc2c(cc1OC)C(=O)CC(C)N2
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)N(C(=O)OCc1ccccc1)C(C)CC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a stirred solution of 10.0 g. (0.45 mol.) of 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline in 76 ml. of pyridine, at 0° C., was added, dropwise, during a 30 minute period, 45 ml. of benzyl chloroformate. Stirring was continued for 15 minutes, and then an additional 10 ml. of benzyl chloroformate was added. After a further 10 minutes, a further 10 ml. of benzyl chloroformate was added. The reaction mixture was heated on a steam bath for 30 minutes, cooled to room temperature and then poured into a mixture of 950 ml. of chloroform and 300 ml. of water. The separated chloroform layer was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate, and water, and then it was dried (MgSO4) and concentrated to dryness in vacuo. The residue was an oil which solidified after trituration with ehtyl acetate-hexane. The resulting solid was then recrystallized from the same solvent system, giving 11.4 g. of the title compound, m.p. 127.5°-129.5° C. (71% yield). Further recrystallization of a small portion of the product from ethyl acetate-hexane raised the melting point to 128.5°-130° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][CH:17]=[N:18][C:11]=2[N:10]=[C:9]1[CH2:19][CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]([O-:26])=O.[Na+].[Br:28]Br>C(O)(=O)C>[NH2:8][CH2:13][CH2:12][CH2:11][N:10]([CH:19]([C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][CH:17]=[N:18][C:11]=2[N:10]=1)[CH:20]([CH3:22])[CH3:21])[C:24](=[O:26])[C:23]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1.[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][CH:17]=[N:18][C:11]=2[N:10]=[C:9]1[CH:19]([Br:28])[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Cc1nc2ncccc2c(=O)n1Cc1ccccc1
Reactant: BrBr
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)C(Br)c1nc2ncccc2c(=O)n1Cc1ccccc1
Product: Cc1ccc(C(=O)N(CCCN)C(c2nc3ncccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Preparation of Formula 105 where R1 to R3 are H; R5 is Benzyl; R6 is i-Propyl; R6′ is H; W, X and Y are —C═; and Z is —N═: To a stirred, 40° C. mixture of 3-benzyl-2-isobutyl-3-H-pyrido[2,3-d]pyrimidin-4-one (2.82 g, 9.603 mmol), NaOAc (1.18 g, 14.41 mmol) and acetic acid (40 mL) was added bromine (2.31 g, 14.41 mmol) dropwise. The reaction mixture was stirred at 40° C. for 1 h until complete consumption of the starting material was observed by TLC. The reaction mixture was poured into ice water (500 mL) and stirred at room temperature for 2 h. The precipitated product was isolated by filtration, washed with warm water to remove traces of acetic acid, and rinsed with a small amount of isopropanol. Drying under vacuum yielded the desired product, 3-benzyl-2-(1-bromo-2-methyl-propyl)-3-H-pyrido[2,3-d]pyrimidin-4-one, as a white solid which was taken on without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:11][C:12]1[C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=[CH:14][C:13]=1[NH:27][C:28]([C:30]1[S:34][C:33]2[CH2:35][CH2:36][CH2:37][CH2:38][C:32]=2[CH:31]=1)=[O:29].BrC1C(=O)N(C)C=C(Br)C=1>COCCOC.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>[NH2:10][C:4]1[CH:3]=[C:2]([C:17]2[C:12]([CH3:11])=[C:13]([NH:27][C:28]([C:30]3[S:34][C:33]4[CH2:35][CH2:36][CH2:37][CH2:38][C:32]=4[CH:31]=3)=[O:29])[CH:14]=[CH:15][CH:16]=2)[CH:7]=[N:6][C:5]=1[O:8][CH3:9]
Reactant: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ncc(Br)cc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cn1cc(Br)cc(Br)c1=O
Solvent: COCCOC
Product: COc1ncc(-c2cccc(NC(=O)c3cc4c(s3)CCCC4)c2C)cc1N
Temperature: 95 °C
Yield: 65 %

Procedure:
In a 48 mL sealed tube equipped with a magnetic stirring bar was placed 5-bromo-2-methoxypyridin-3-amine (16) (1.0 g, 4.0 mmol), N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide (1(2.4 g, 6.7 mmol), and Pd(PPh3)4 (0.30 g, 0.20 mmol) in DME/1N Na2CO3 (10 mL, 1/1). After the reaction mixture was degassed for 15 min., it was heated at 95° C. for 16 h. Then, the mixture was cooled to room temperature and diluted with dichloromethane (10 mL) and H2O (10 mL), and the layers were separated. The aqueous phase was extracted with dichloromethane (3×10 mL), and the combined organic extracts were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude mixture was purified by column chromatography, gradient 0-25% MeOH in dichloromethane, to afford 1.0 g (65%) of N-(3-(5-amino-6-methoxypyridin-3-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide (17) as a solid.
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30](O)([CH3:32])[CH3:31])=[CH:29][C:24]=2[O:23][CH2:22]1>C1C=CC=CC=1>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]([S:1][CH2:2][C:3]([OH:5])=[O:4])([CH3:32])[CH3:31])=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: CC(C)(O)c1ccc2c(c1)OCO2
Reactant: O=C(O)CS
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: c1ccccc1
Product: CC(C)(SCC(=O)O)c1ccc2c(c1)OCO2
Yield: 45.8 %

Procedure:
600 ml of benzene, 59.5 g of mercaptoacetic acid and a catalytic amount of D-10-camphorsulfonic acid were added to 97 g of 2-(1,3-benzodioxol-5-yl)-2-propanol and the mixture was heated under reflux for 4 h. The solvent was distilled off and the pH of the residue was adjusted to 10 with 1N aqueous sodium hydroxide solution. After washing with ethyl acetate, 4N hydrochloric acid was added thereto under cooling with ice to acidity the aqueous layer. After extraction with chloroform, the extract was washed with water and dried over anhydrous magnesium sulfate. It was filtered and the filtrate was concentrated. The crystals thus formed were recrystallized form diisopropyl ether to obtain 62.70 g of the intended compound in the form of colorless crystals.
Reaction SMILES: CC1C=CC(S(O[C:12]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][C:14]#[N:15])(=O)=O)=CC=1.Cl.[NH2:22][CH:23](C(OCC)=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25].[O-]CC.[Na+].Cl>C(O)C.O1CCCC1>[NH2:15][C:14]1[CH:13]=[C:12]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[NH:22][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OC(=CC#N)c2ccco2)cc1
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1[nH]c(-c2ccco2)cc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 33.3 %

Procedure:
To a solution of 2-cyano-1-(2-furyl)vinyl 4-methylbenzenesulfonate (10.48 g) and diethyl aminomalonate hydrochloride (7.67 g) in a mixed solvent of ethanol (120 mL)-tetrahydrofuran (64 mL) was added dropwise a solution (36.9 mL) of 20% sodium ethoxide in ethanol under ice-cooling. After stirring at room temperature for 12 hrs, the reaction mixture was poured into ice water (350 mL) and adjusted to pH 7 with 1N hydrochloric acid. The organic solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (150 mL×3). The organic layers were combined, washed with saturated brine (100 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane:methyl acetate=3:1→1:1) and the obtained solid was recrystallized from ethyl acetate-hexane to give the title compound (2.66 g).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][C:2]1=O.O=S(Cl)Cl>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1
Reactant: O=c1ncc2ccccc2[nH]1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: c1ccc2ncncc2c1
Temperature: 80 °C

Procedure:
Quinazolone Z.8 (817 mg, 3.36 mmol) is combined with SOCl2 (20 mL) and DMF (0.05 mL) and heated to 80° C. for 2 h. The solvent is removed and quinazoline D*.3 (879 mg, 100%) is obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C.[NH2:25][C@@H:26]([CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:25][C@H:26]([CH2:27][N:28]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]2=[O:38])[CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1
Reactant: Cn1nccc1-c1cc(C(=O)O)sc1Cl
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To a solution of 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (150 mg, 0.62 mmol) [Prepared in Example 95], N,N-diisopropylethylamine (0.54 ml, 3.10 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (200 mg, 0.62 mmol) [Prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (347 mg, 0.74 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 45% EtOAc in hexanes) yielding 5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (168 mg, 0.33 mmol, 53% yield) as a clear oil: LCMS (ES) m/e 511, 513 (M, M+2)+.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][CH2:5][NH:6][CH:7]=[O:8].[N+:10]([C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[C:18]2[CH2:23][Cl:24])([O-:12])=[O:11]>O>[Cl-:24].[CH3:1][N+:2]([CH3:9])([CH2:23][C:18]1[C:19]2[C:14](=[C:13]([N+:10]([O-:12])=[O:11])[CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1)[CH2:3][CH2:4][CH2:5][NH:6][CH:7]=[O:8]
Reactant: O=[N+]([O-])c1cccc2c(CCl)cccc12
Reactant: CN(C)CCCNC=O
Solvent: O
Product: C[N+](C)(CCCNC=O)Cc1cccc2c([N+](=O)[O-])cccc12
Product: [Cl-]

Procedure:
Proceeding in a manner similar to that described above in B-8a, 29.9 parts of N-(3-dimethylaminopropyl)formamide and 44.3 parts of 5-nitro-1-chloromethylnaphthalene were interacted in 30 parts of water to obtain N,N-dimethyl-N-(5-nitro-1-naphthylmethyl)-N-3-formamidopropylammonium chloride. The product was not isolated but was used directly in solution for reduction of the nitro group.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][C:23]=1F)[CH2:7][N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:11](=[O:19])[NH:10][C:9]1=[O:20])([OH:3])=O.CC1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)N[C:31](=O)[NH:30][C:29]2=[O:37].BrCC1C=CC(F)=C(C=1)C(OC)=O.COC(C1C=[C:57](C=CC=1)[CH2:58][N:59]1C2C(=CC=CC=2)C(=O)N[C:60]1=O)=O>>[CH:28]1([C:29]([N:30]2[CH2:31][CH2:60][N:59]([C:1]([C:4]3[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=3)[CH2:7][N:8]3[C:17]4[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=4)[C:11](=[O:19])[NH:10][C:9]3=[O:20])=[O:3])[CH2:58][CH2:57]2)=[O:37])[CH2:27][CH2:35][CH2:34][CH2:33]1
Reactant: Cc1ccc2[nH]c(=O)[nH]c(=O)c2c1
Reactant: Cc1ccc2c(c1)c(=O)[nH]c(=O)n2Cc1ccc(F)c(C(=O)O)c1
Reactant: COC(=O)c1cccc(Cn2c(=O)[nH]c(=O)c3ccccc32)c1
Agent: COC(=O)c1cc(CBr)ccc1F
Product: Cc1ccc2c(c1)c(=O)[nH]c(=O)n2Cc1cccc(C(=O)N2CCN(C(=O)C3CCCC3)CC2)c1

Procedure:
The following compounds were prepared from 1-(3-carboxy-4-fluorobenzyl)-6-methylquinazoline-2,4(1H,3H)-dione (prepared from 6-methylquinazoline-2,4(1H,3H)-dione and methyl 5-(bromomethyl)-2-fluorobenzoate using a procedure similar to those for compounds of Example 1 and 2), and the corresponding substituted piperazine using a procedure similar to those described for the synthesis of compound of Example 3.