Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH2:14][CH3:15])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:4]1=2)[CH3:2].C1C(=O)N([Br:23])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:13][C:10]1[CH:11]=[CH:12][C:4]2[C:3]([CH2:1][CH3:2])([CH2:14][CH3:15])[O:7][B:6]([OH:8])[C:5]=2[CH:9]=1
Reactant: CCC1(CC)OB(O)c2cc(C)ccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCC1(CC)OB(O)c2cc(CBr)ccc21
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a solution of 3,3-diethyl-6-methylbenzo[c][1,2]oxaborol-1(3H)-ol (0.8 g, 3.92 mmol) in CCl4 (10 mL) under nitrogen was added NBS (698 mg, 3.92 mmol) and BPO (94 mg, 0.39 mmol). The mixture was refluxed for 2 h under the light from Sun lamp and then it was cooled to rt, washed with aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography to provide the product (0.8 g, 72%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1.[F:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[CH:22][C:20]=1[NH2:21]>CC(O)CCC>[ClH:2].[F:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[CH:22][C:20]=1[NH:21][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: COCCOc1ccc2c(Cl)ncnc2c1
Reactant: Cc1cc(F)c(N)cc1O
Agent: Cl
Solvent: CCCC(C)O
Product: COCCOc1ccc2c(Nc3cc(O)c(C)cc3F)ncnc2c1
Yield: 77.7 %

Procedure:
A solution of 4-chloro-7-(2-methoxyethoxy)quinazoline hydrochloride (275 mg, 1 mmol) and 2-fluoro-5-hydroxy4-methylaniline (170 mg, 1.2 mmol), (prepared as described for the starting material in Example 8), in 2-pentanol (5 ml) was heated at reflux for 2 hours. The mixture was allowed to cool and the precipitate was collected by filtration, washed with isopropanol and ether, and dried under vacuum at 70° C. to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-methoxyethoxy)quinazoline hydrochloride(295 mg, 78%) as a cream solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7]([N+:14]([O-])=O)=[C:8]([CH:10]=[CH:11][C:12]=1[Cl:13])[NH2:9].O.O.[Sn](Cl)Cl.N#N>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:8]([NH2:9])[C:7]=1[NH2:14]
Reactant: Nc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: N#N
Solvent: CO
Solvent: O
Product: Nc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1N
Temperature: 75 °C
Reaction time: 10 h

Procedure:
3-(3-bromo-5-chlorophenoxy)-4-chloro-2-nitroaniline (5.7 g, 15 mmol) and tin(II) chloride dihydrate (17 g, 75 mmol) were suspended in MeOH (100 mL) and heated to 75° C. under a reflux condenser and N2. After 10 hours, the reaction was allowed to cool to room temperature. The reaction was concentrated under reduced pressure, diluted with ethyl acetate (150 mL) and 10% aqueous sodium carbonate (250 mL) was added with vigorous stirring until the pH was 10. The mixture was filtered through celite. The resulting biphasic filtrate was separated and the aqueous extracted again with ethyl acetate (150 mL). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to yield the title product. LRMS (M+1)=348.7.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([C:13]2([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.[B:21](OCCCC)([O:27]CCCC)[O:22]CCCC.Cl>C1COCC1.O>[C:18]([C:13]1([C:9]2[CH:8]=[C:7]([B:21]([OH:27])[OH:22])[CH:12]=[CH:11][CH:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1)([OH:20])=[O:19]
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: O=C(O)C1(c2cccc(Br)c2)CCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(c2cccc(B(O)O)c2)CCCC1
Reaction time: 0.75 h

Procedure:
A solution of n-butyl lithium (2.5 M in hexanes, 5 mL, 12.48 mmol) in THF (30 mL) is chilled to −78° C., and a solution of 1-(3-bromo-phenyl)-cyclopentanecarboxylic acid [1.05 g, 3.9 mmol] in THF (10 mL) is added dropwise via syringe. The solution is stirred at temperature for 45 minutes and treated with tributyl borate (3.2 mL, 11.7 mmol). The reaction mixture is allowed to stir for 2.5 hours and then diluted with water (60 mL), acidified with 3M HCl and extracted twice with EtOAc (50 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford 3-(1-carboxy-cyclopentyl)-phenylboronic acid as a solid, which is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[C:3]([CH3:12])[C:2]([Br:1])=[CH:7][CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(Br)ccc(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(Br)ccc(OCc2ccccc2)c1[N+](=O)[O-]

Procedure:
The reaction was carried out in a manner similar to Reference Example 12 a) except for using 5.11 g (29.9 mmol) of 4-bromo-3-methyl-2-nitrophenol, 6.30 g (27.2 mmol) of benzyl bromide, 8.26 g (59.7 mmol) of potassium carbonate and 150 ml of acetone. 3-Benzyloxy-6-bromo-2-nitrotoluene was thus obtained in the yield of 5.10 g (58.3%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Li+].C(O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:20][C:17]([O:16][C:14](=[O:15])[NH:13][C@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:4][CH2:3][OH:2])([CH3:18])[CH3:19]
Reactant: COC(=O)C[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.7 %

Procedure:
To a solution (R)-β-[[(1,1-Dimethylethoxy)carbonyl]amino]-benzenebutanoic acid methyl ester (1.5 g, 5.1 mmol, J. Med. Chem. 1985, 28, 434) in THF (10 mL), was added lithium borohydride (218 mg, 10 mmol), followed by ethanol (10 mL), dropwise. After stirring at rt for 18 hours, an additional lithium borohydride (218 mg 10 mmol) was added and stirring continued for 6 hours. The reaction mixture was ice cooled and adjusted to pH 4 by the addition of a 10% citric acid solution. Organic solvents were removed and the resulting cloudy aqueous solution was extracted with dichloromethane. The extracts were combined, dried (MgSO4) and concentrated in vacuo to afford a clear colorless oil residue which was purified by flash chromatography on silica gel eluting with 30% ethyl acetate in hexanes to yield (1.2 g, 89%) of the title compound as a clear colorless oil. MS; (M+H)+=266
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1-c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccccc2)c2ccccc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
To a stirred solution of 3-phenyl-1H-indole-2-carboxylic acid ethyl ester (3.99 g, 15.0 mmol) in DMF (25 mL) cooled to 0° C. and under a nitrogen atmosphere was added NaH (60% in mineral oil, 720 mg, 18.0 mmol). After stirring for 10 min at RT, the reaction mixture was cooled to 0° C. and 4-methylbenzenesulfonyl chloride (3.44 g, 18.0 mmol) in DMF (15 mL) added. Stirring was continued for 16 h at RT then the mixture was poured into 1.0M HCl and extracted with EtOAc (×2). The combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in pentane) affording the title compound as a colourless oil (3.25 g, 52%). 1H NMR (CDCl3, 400 MHz): δ 8.08 (1H, d, J=8.43 Hz), 7.92 (2H, d, J=8.37 Hz), 7.53-7.36 (7H, m), 7.28-7.21 (3H, m), 4.35 (2H, q, J=7.15 Hz), 2.36 (3H, s), 1.25 (3H, t, J=7.14 Hz)
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:52][C:53]1[CH:58]=[CH:57][C:56]([CH:59]([C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=2)[N:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)=[CH:55][CH:54]=1>CN(C=O)C.C(OCC)C>[F:72][C:69]1[CH:68]=[CH:67][C:66]([CH:59]([C:56]2[CH:57]=[CH:58][C:53]([F:52])=[CH:54][CH:55]=2)[N:60]2[CH2:61][CH2:62][N:63]([C:12]([C@@H:11]([NH:10][C:8]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:64][CH2:65]2)=[CH:71][CH:70]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (0.56 g, 2.2 mmol) was dissolved in dry DMF (7 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.76 mL, 4.4 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.82 g, 2.2 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.63 g, 2.2 mmol, Acros Organics, Pittsburgh, Pa.) was then added. After sequentially 30 minutes stirring at 0° C. and 2 hours at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (60% EtOAc in hexane) to provide 1.1 g (96%) of the pure titled compound as a white foam: mp 78-86° C. APCI-MS m/z 527.0 (MH+).
Reaction SMILES: [OH2:1].N(OS(=O)(=O)O)=O.[Br:9][C:10]1[CH:18]=C(C)[C:13]([C:14](N)=[O:15])=[C:12]([CH3:20])[CH:11]=1.Cl[CH2:22][Cl:23]>>[Br:9][C:10]1[CH:11]=[C:12]([CH3:20])[C:13]([C:14]([OH:1])=[O:15])=[C:22]([Cl:23])[CH:18]=1
Reactant: ClCCl
Reactant: O
Reactant: Cc1cc(Br)cc(C)c1C(N)=O
Agent: O=NOS(=O)(=O)O
Product: Cc1cc(Br)cc(Cl)c1C(=O)O
Yield: 88 %

Procedure:
Water (5 mL) was chilled in an ice bath and nitrososulfuric acid was added dropwise. A suspension of 4-Bromo-2,6-dimethyl-benzamide (1.30 g, 5.23 mmol) in dichloromethane (10 mL) was added. The organic phase was dried over magnesium sulfate and concentrated. It was taken up in ethyl acetate and extracted three times with saturated sodium bicarbonate. The combined aqueous extracts were acidified with 6M hydrochloric acid and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated to provide the title compound as a colourless solid (1.14 g, 88%). 1H NMR CDCl3: δ 7.48 (s, 1H), 7.35 (s, 1H), 2.45 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[CH2:17]([O:19][C:20](=[O:25])[C:21](Br)([CH3:23])[CH3:22])[CH3:18]>CN(C=O)C>[CH2:17]([O:19][C:20](=[O:25])[C:21]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:23])[CH3:22])[CH3:18]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(Br)cc1C=O
Temperature: 140 °C
Yield: 68 %

Procedure:
To a mixture of 5-bromo-2-hydroxy-benzaldehyde (14 g, 70 mmol), KI (5 g) and K2CO3 (19 g, 140 mmol) in DMF (100 mL) was added 2-bromo-2-methyl-propionic acid ethyl ester (17.6 g, 90 mmol). The mixture was heated at 140° C. for 2 h, and then cooled to room temperature, partitioned between water and ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound (15 g).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][NH:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:27](I)[CH3:28]>CN(C)C=O>[CH2:27]([N:7]1[C:8]2[C:3](=[C:2]([F:1])[C:11]([F:12])=[C:10]([F:13])[C:9]=2[F:14])[C:4](=[O:20])[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6]1)[CH3:28]
Reactant: CCOC(=O)c1c[nH]c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2c(F)c(F)c(F)c(F)c2c1=O
Reaction time: 8 h

Procedure:
To 38.5 g (134 mmol) of 5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester in 700 ml of N,N-dimethylformamide was added 37.15 g (two equivalents) of potassium carbonate and 50 ml (five equivalents) of ethyl iodide. The mixture was brought to 50° C. and stirred vigorously overnight. The solvents were removed and the residue partioned between water and dichloromethane. The dichloromethane was dried (magnesium sulfate) and concentrated. The residue was triturated with diethyl ether to give 30.5 g of material which was recrystallized from ethanol. Filtration gave 23.5 g of the title compound, mp 217°-220° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:20]=[CH:19][C:12]3[CH2:13][CH2:14][CH:15]([CH:17]=O)[O:16][C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:28][CH:29]=[CH:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:34]([O:33][C:31](=[O:32])[CH:30]=[CH:29][CH:28]=[CH:17][CH:15]1[CH2:14][CH2:13][C:12]2[CH:19]=[CH:20][C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:10][C:11]=2[O:16]1)[CH3:35]
Reactant: CCOC(=O)C=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1CCc2ccc(OCc3ccccc3)cc2O1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=CC=CC1CCc2ccc(OCc3ccccc3)cc2O1
Yield: 30.2 %

Procedure:
Using the procedure of example 30, 2.7 g (10 mmoles) of the aldehyde product from example 83 was condensed with 4.4 g (12 mmoles) of ethyl 4-(triphenylphosphoranylidene)-2-butenoate in 30 ml of toluene (3.5 hr at 100° C.). Chromatography of the crude product on 100 g of silica gel gave 1.1 g (30%) of racemic-5-[3,4-dihydro-7-(phenylmethoxy)-2H-1-benzopyran-2-yl]-2,4-pentadienoic acid ethyl ester (mixture of E- and Z-isomers) as a yellow oil eluted with toluene and 19:1 toluene-ethyl acetate.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:13]=[C:14]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[CH:15]=1)(C(C)(C)C)(C)C.[C:31](Cl)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:40]1[CH:47]=[CH:46][C:43]([O:44][CH3:45])=[CH:42][CH:41]=1)[C:32]1[CH:39]=[CH:38][C:35]([O:36][CH3:37])=[CH:34][CH:33]=1.C(Cl)(Cl)Cl>CO>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:13]=[C:14]([CH2:16][O:17][C:31]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:40]2[CH:47]=[CH:46][C:43]([O:44][CH3:45])=[CH:42][CH:41]=2)[C:32]2[CH:39]=[CH:38][C:35]([O:36][CH3:37])=[CH:34][CH:33]=2)[CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CO[Si](C)(C)C(C)(C)C)cc(-c2ccccc2)c1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(OCc2cc(CO)cc(-c3ccccc3)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 96 h
Yield: 79 %

Procedure:
10.7 ml of pyrizine was added to dissolve 0.4596 g of Compound (2) in an Ar atmosphere, and 0.9547 g (2.80 mmol, 1.3 eq) of DMTrCl was added. This was agitated for 96 hours in an Ar atmosphere. After extraction with chloroform the organic layer was washed with H2O, sat. NaHCO3 aq and sat. NaCl aq, and dried by addition of anhydrous NaSO4. The solvent was distilled off under reduced pressure, and 0.4231 g (0.82 mmol, 38%) of Compound (3) was isolated by silica gel chromatography (chloroform:methanol=100:1).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[S:15][C:14]=1[NH2:22].[SH:23][C:24]1[N:28]=[C:27]([CH3:29])[NH:26][N:25]=1>>[CH3:29][C:27]1[NH:28][C:24]([S:23][C:10]2[CH:9]=[CH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:22][C:14]4[S:15][C:16]5[C:21]([N:13]=4)=[CH:20][CH:19]=[CH:18][N:17]=5)[C:3]=3[N:11]=2)=[N:25][N:26]=1
Reactant: Nc1nc2cccnc2s1
Reactant: Cc1nc(S)n[nH]1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Product: Cc1nnc(Sc2ccc3ncnc(Nc4nc5cccnc5s4)c3n2)[nH]1

Procedure:
The compound of Example 35 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 4,6-dichloro-pyrido[3,2-d]pyrimidine, thiazolo[5,4-b]-pyridin-2-yl-amine and 3-mercapto-5-methyl-1,2,4-triazole.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18](C)([C:24](OCC)=O)[C:19]([O:21]CC)=[O:20])=[CH:10][C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>C(O)C>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]([CH3:24])[C:19]([OH:21])=[O:20])=[CH:10][C:9]1=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1cc(=O)n(Cc2ccccc2)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1cc(=O)n(Cc2ccccc2)c2ccccc12
Yield: 66.3 %

Procedure:
A solution of diethyl α-(1-benzyl-1,2-dihydro-2-oxoquinol-4-yl)-α-methylmalonate (3.0g.) in ethanol (20ml.) containing sodium hydroxide (3.0g.) and water (3.0ml.) was heated under reflux for 1 hour. The solution was then cooled and poured into water (200ml.). The resultant solution was acidified to pH 3 by addition of concentrated hydrochloric acid to give α-(1-benzyl-1,2-dihydro-2-oxoquinol-4-yl)propionic acid 1.5g., m.p. 179°-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[C:15]([N+:24]([O-])=O)=[C:16]([OH:23])[C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:12]=2[N:11]=1.C(O)(=O)C>C1C=CC=CC=1.[Fe]>[NH2:24][C:15]1[C:13]2[NH:14][C:10]([NH:9][C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:11][C:12]=2[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[C:16]=1[OH:23]
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c([N+](=O)[O-])c1O
Agent: [Fe]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c(N)c1O
Yield: 95.5 %

Procedure:
To a solution of methyl 2-[(2-chloro-6-fluorophenyl)amino]-6-hydroxy-7-nitro-1H-benzimidazole-5-carboxylate (Step-2 of Intermediate-56, 0.500 g) in benzene (2.0 mL), were added iron powder (0.500 g) and acetic acid (4.0 mL). The reaction mass was refluxed for 3 h. Decant the reaction mass removed the solvent under vacuum. The obtained solid mass was washed with water. The reaction mass was extracted with MeOH:DCM (5%). The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.440 g of the desired product.
Reaction SMILES: [C:1]([OH:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.S(Cl)([Cl:14])=O>CN(C)C=O>[C:1]([Cl:14])(=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: COc1cccc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)Cl)c1

Procedure:
This intermediate was prepared by either of two methods. In the first, a mixture of 100 g of m-anisic acid (0.658 mole), 250 g thionyl chloride (2.10 mole), and 5 mL of dimethylformamide was heated under reflux in a round-bottom flask with desiccant in the top of the condenser for exclusion of atmospheric moisture. Excess thionyl chloride was distilled from the product using a rotary film-evaporator at about 26.6 kPa pressure. The m-anisoyl chloride was then isolated by fractional distillation through a 25 cm Vigreux column at 109° C. and 1.6 kPa pressure.
Reaction SMILES: [F:1][C:2]1[C:3]([C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:4]([NH:9][C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].F[C:28]1C(F)=CC=C2[C:29]=1C(C1C=CC(F)=CC=1)(O)N(CC(F)(F)F)C(=O)N2.C(N(CC)CC)C.S(Cl)(Cl)=O.C([Mg]Br)C>C1COCC1>[CH2:28]([C:18]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:3]2[C:4](=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[NH:9][C:10](=[O:11])[N:12]1[CH2:13][C:14]([F:17])([F:16])[F:15])[CH3:29]
Reactant: O=C(NCC(F)(F)F)Nc1ccc(F)c(F)c1C(=O)c1ccc(F)cc1
Reactant: O=C1Nc2ccc(F)c(F)c2C(O)(c2ccc(F)cc2)N1CC(F)(F)F
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCC1(c2ccc(F)cc2)c2c(ccc(F)c2F)NC(=O)N1CC(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1.5 g (3.987 mmol) N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (open form) and 5,6-difluoro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (closed form) in 8 ml THF was added 2.0 mL (19.933 mmol) triethylamine. After 1 h at 80° C., the reaction mixture was cooled to −78° C. To this solution was added 0.498 mL (4.186 mmol) thionyl chloride. After 30 minutes at −78° C., 5 mL (12.358 mmol) ethylmagnesium bromide (3.0M solution in diethyl ether) was added dropwise. After 1 h at −78° C., the reaction mixture was quenched with saturated NH4Cl and warmed to room temperature. The reaction mixture was extracted three times with EtOAc and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (1×14 cm silica gel, linear gradient 0-50% EtOAc:hexane) afforded 4-ethyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one. Chiral Separation (ChiralPak AD column, 5 cm×50 cm, 20μ, 10-40% ethanol/hexane, modifier: DEA 1 mL/L, 60 mins) afforded 350 mg of the second isomer.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[C:25](O)(=[O:29])[CH:26]([CH3:28])[CH3:27]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H]3CCCN3)c2c1N
Reactant: CC(C)C(=O)O
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H]3CCCN3C(=O)C(C)C)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)-quinoline-3-carboxylate (Example 89b) and isobutyric acid as brown solid (46%). MS 400 (MH+).