Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8]Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[I-].[Na+].C(OCC)C.[NH2:17][C:18]1[S:19][CH:20]=[C:21](/[C:23](=[N:49]/[O:50][CH3:51])/[C:24]([NH:26][C@@H:27]2[C:47](=[O:48])[N:29]3[C:30]([C:44]([O-:46])=[O:45])=[C:31]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=4)[CH2:32][S:33][C@H:28]23)=[O:25])[N:22]=1.[Na+]>CC(C)=O.CN(C)C=O.C(OCC)(=O)C.O>[NH2:17][C:18]1[S:19][CH:20]=[C:21](/[C:23](=[N:49]/[O:50][CH3:51])/[C:24]([NH:26][C@@H:27]2[C:47](=[O:48])[N:29]3[C:30]([C:44]([O:46][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:45])=[C:31]([O:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]([C:42]#[N:43])=[CH:40][CH:41]=4)[CH2:32][S:33][C@H:28]23)=[O:25])[N:22]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(OCc3ccc(C#N)cc3)CS[C@H]12)c1csc(N)n1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(OCc3ccc(C#N)cc3)CS[C@H]12)c1csc(N)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
57.4 mg (0.38 mmol) of chloromethyl pivalate was dissolved in 2 ml of acetone, and 63 mg (0.42 mmol) of sodium iodide was added thereto. The mixture was heated for 30 minutes at 50° C., and 4 ml of ethyl ether was added thereto. Insolubles were filtered off and the solvent was distilled off. Then, the residue was dissolved in 1 ml of N,N-dimethylformamide. 100 mg (0.217 mmol) of sodium 7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(4-cyanobenzyloxy)-3-cephem-4-carboxylate prepared in the same manner as in Example 12 was dissolved in 1 ml of N,N-dimethylformamide. The above solution was added to this solution under cooling with ice and stirred for 30 minutes at room temperature. Water and ethyl acetate was added to the reaction solution, and the ethyl acetate layer was separated and washed sequentially with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off and the residue was triturated with ethyl ether to obtain 24.8 mg (yield: 21.2%) of the above-identified compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[N:31]1(CC#N)CCN[CH2:33][CH2:32]1.C(OC(N1CCN(CC#N)CC1)=O)(C)(C)C.Cl.C12NC(CC1)CN(C(=O)C)C2>>[O:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:11]3[CH2:12][CH2:13][N:8]([CH2:33][C:32]#[N:31])[CH2:9][CH2:10]3)=[CH:16][CH:17]=2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Reactant: N#CCN1CCNCC1
Agent: CC(=O)N1CC2CCC(C1)N2
Agent: CC(C)(C)OC(=O)N1CCN(CC#N)CC1
Agent: Cl
Product: N#CCN1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1

Procedure:
Compound 284 is synthesized from Intermediate C and piperazin-1-yl-acetonitrile (prepared from 4-Cyanomethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure used to synthesize Intermediate U from U-1) according to General Method F. (LC/MS method 16: ES+ m/z 351.3 [M+H]+, Rt=2.68 min)
Reaction SMILES: CC1NC(C)=CC=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:8]=1.C(O)C.Cl.[NH2:30]O.Cl>O>[NH:22]1[CH2:23][CH2:24][CH:19]([C:16]2[CH:17]=[CH:18][C:13]([C:9]3[N:8]=[C:7]([NH2:30])[CH:12]=[CH:11][CH:10]=3)=[CH:14][CH:15]=2)[CH2:20][CH2:21]1
Reactant: Cc1cc(-c2cccc(-c3ccc(C4CCNCC4)cc3)n2)c(C)[nH]1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cccc(-c2ccc(C3CCNCC3)cc2)n1

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 100 mg (0.302 mmol) 4-(4-(2-(2,5-dimethylpyrrolyl)pyrid-6-yl)phenyl)piperidine, 10 mL ethanol, 1 mL water, and 417 mg (6.04 mmol) hydroxylamine hydrochloride. The reaction was refluxed 20 hours cooled, and poured into dilute aqueous hydrochloric acid, then washed with ethyl acetate. The aqueous layer was adjusted to pH 10 with 6 N sodium hydroxide solution and extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and evaporated. The resulting oil (77 mg, 100%) was converted to the hydrochloride salt using HCl in, ether to afford a tan solid, 32 mg (32%), mp dec. above 150° C.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:14][O:13]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]([OH:13])[CH2:14][NH:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Oc1ccc([C@H]2CO2)cc1
Reactant: NCc1ccccc1
Product: CS(=O)(=O)Oc1ccc([C@H](O)CNCc2ccccc2)cc1
Temperature: 80 °C
Yield: 68.6 %

Procedure:
A mixture of 4-((S)-oxiranyl)phenyl methanesulfonate (69 g, 322 mmol) and benzylamine (104 g, 971 mmol) was heated at 80° C. for 3 hours. An excess benzylamine was evaporated under reduced pressure and the residue was washed with diisopropyl ether to afford 4-((1S)-2-benzylamino-1-hydroxyethyl)phenyl methanesulfonate (71.0 g, 69%) as white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)#[N:13]>>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:12]#[N:13])[CH:19]=2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: N#Cc1cccc(B(O)O)c1
Product: CS(=O)(=O)c1ccc(-c2cccc(C#N)c2)cc1

Procedure:
By a method similar to that in Example 81 and using 1-bromo-4-(methylsulfonyl)benzene and (3-cyanophenyl)boronic acid, the title compound was obtained as a pale-yellow powder (10.4 g, 95%).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH2:21][CH3:22])[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([C:15]2[O:16][CH:17]=[CH:18][N:19]=2)[CH:14]=1)[C:9](O)=[O:10])=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:58][C@@H:59]([CH2:73][C:74]1[CH:79]=[C:78]([F:80])[CH:77]=[C:76]([F:81])[CH:75]=1)[C@H:60]([OH:72])[CH2:61][NH:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][CH3:71])[CH:65]=1>CN(C=O)C.C(Cl)(Cl)Cl>[F:81][C:76]1[CH:75]=[C:74]([CH:79]=[C:78]([F:80])[CH:77]=1)[CH2:73][C@H:59]([NH:58][C:9](=[O:10])[C:8]1[CH:12]=[C:13]([C:15]2[O:16][CH:17]=[CH:18][N:19]=2)[CH:14]=[C:6]([C:4]([N:3]([CH2:1][CH3:2])[CH2:20][CH2:21][CH3:22])=[O:5])[CH:7]=1)[C@H:60]([OH:72])[CH2:61][NH:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][CH3:71])[CH:65]=1
Reactant: CCCN(CC)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCCN(CC)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-{[Ethyl(propyl)amino]carbonyl}-5-(1,3-oxazol-2-yl)benzoic acid (290 mg, 0.96 mmol) is dissolved in DMF (5 mL), and diisopropylethylamine (668 μL, 3.8 mmol), HATU (438 mg, 1.15 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method of EXAMPLE SP-272 (391 mg, 0.96 mmol) are added. The reaction stirred at room temperature 5 h. The reaction mixture is diluted with chloroform, washed with water, 1N hydrochloric acid (aq), saturated sodium bicarbonate, saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 9% methanol/methylene chloride) provides the title compound. ESI MS m/z 619.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[C:12]([CH:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13].[BH4-].[Na+]>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:17][CH2:18]1)[CH2:6][CH2:5]2
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: O=C1CCc2cc(Br)ccc21
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](NC2CCc3cc(Br)ccc32)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 5-bromoindan-1-one (6.33 g, 30.0 mmol), titanium (IV) isopropoxide (17.8 mL, 60.0 mmol), 4-tert-butylcyclohexyl amine (9.32 g, 60.0 mmol) in absolute ethanol (200 mL) was stirred under nitrogen at room temperature for 12 h. Sodium borohydride (1.70 g, 45.0 mmol) was then added and the resulting mixture was stirred for an additional 8 h at room temperature. The reaction was quenched by pouring into aqueous ammonia (2N, 300 mL). The resulting inorganic precipitate was filtered off and washed with dichloromethane (150 mL). The organic layer was separated and the remaining aqueous layer was extracted once with dichloromethane (150 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. Chromatography (10% to 20% EtOAc in Hexane) afforded (5-Bromo-2,3-dihydro-1H-inden-1-yl)(trans-4-tert-butylcyclohexyl)amine and the corresponding cis product (less polar). HPLC/MS: m/z=350.1 (M+1), Rt=3.01 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:16]=[C:15]4[C:17]([C:20](O)=[O:21])=[CH:18][NH:19][C:14]4=[N:13][CH:12]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[NH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:16]=[C:15]4[C:17]([C:20]([NH:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])=[O:21])=[CH:18][NH:19][C:14]4=[N:13][CH:12]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1c[nH]c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(CO)NC(=O)c1c[nH]c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.5 %

Procedure:
A mixture of 2-(6-chloro-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (140 mg, 0.446 mmol), 2-amino-2-methylpropan-1-ol (48 mg, 0.536 mmol), EDCI (256 mg, 1.338 mmol), HOBt (181 mg, 1.338 mmol) and DIPEA (173 mg, 1.338 mmol) in dry DMF (5 mL) was stirred for 16 hours at room temperature. Water (5 mL) was added and the formed precipitate was separated by filtration, then was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 35% acetonitrile/65% water (0.1% trifluoroacetic acid V/V) initially, and then proceed to 50% acetonitrile/50% water (0.1% trifluoroacetic acid V/V) in a linear fashion after just 9 min) to afford 2-(6-chloro-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (6 mg, 3%) as a white solid. LCMS: (M+H)+=385; 1H NMR (300 MHz, DMSO+D2O): δ 9.09 (s, 1H), 8.52 (d, 1H, J=8.4 Hz), 8.31 (s, 1H), 7.72 (s, 1H), 7.25 (d, 1H, J=9.0 Hz), 3.59 (s, 2H), 1.41 (s, 6H).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[C:19]2[NH:20][C:21]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:22][O:23][C:18]=2[CH:17]=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[O:4]=[C:2]1[N:20]2[C:21]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:22][O:23][C:18]3=[C:19]2[C:14](=[CH:15][CH:16]=[CH:17]3)[NH:13]1
Reactant: CC(=O)NCC1(c2ccccn2)COc2cccc(N)c2N1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCC1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Reaction time: 1 h
Yield: 176.2 %

Procedure:
Triphosgene (20 mg, 0.07 mmol) was added to a mixture of N-[(5-amino-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-3-yl)methyl]acetamide (50 mg, 0.2 mmol), tetrahydrofuran (5 mL) and N,N-diisopropylethylamine (60 μL) at room temperature. The reaction was stirred for 1 h then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude N-[(2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl)methyl]acetamide (0.040 g. 70%). LCMS calculated for C17H17N4O3 (M+H)+: m/z=325.1. found: 325.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[OH:11]>CC(O)=O>[C:3]([OH:12])(=[O:2])[CH3:4].[CH3:1][O:2][C:3]([CH:4]1[CH2:9][CH2:8][CH:7]([NH2:10])[CH2:6][CH:5]1[OH:11])=[O:12]
Reactant: COC(=O)c1ccc(N)cc1O
Solvent: CC(=O)O
Product: COC(=O)C1CCC(N)CC1O
Yield: 93.2 %

Procedure:
4-Amino-2-hydroxy-benzoic acid methyl ester (10 g) in 200 ml of HOAc was hydrogenated under 56 psi pressure at 60° C. for 42 h. The volatile was then removed. The residue was stirred in 50 ml of 4/1 of ether/EtOH and precipitate formed. Filtration gave 6.5 g of 4-amino-2-hydroxy-cyclohexanecarboxylic acid methyl ester acetic acid salt (m.p. 125.5–126.4° C.; M+: 173).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([OH:14])=O)=[CH:4][CH:3]=1.Cl.[CH2:24]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:25].C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C@H:11]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]([CH:27]2[CH:26]([CH2:24][CH3:25])[CH2:31][CH2:30][NH:29][CH2:28]2)=[O:14])=[CH:4][CH:3]=1
Reactant: CCC1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCc1ccc(N)nc1)C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC1CCNCC1C(=O)[C@H](CCCc1ccc(N)nc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.5 %

Procedure:
2.1 g (5.5 mmol) of O-(benzotriazol-1l-yl)-N,N,N′, N′-tetramethyluronium hexafluorophosphate (HBTU) are added portionwise with stirring, at 0° C. under nitrogen, to a mixture of 2.0 g of (S)-6-amino-α-[[(1,1-dimethylethoxy)carbonyl]amino]pyridine-3-pentanoic acid (5.5 mmol), 1.14 g (7.5 mmol) of 4-ethylpiperidine hydrochloride, N,N-diisopropylethylamine (DIEA) (25 ml; 14 mmol) in dichloromethane (30 ml) and 3 ml of anhydrous dimethylformamide (DMF). The mixture is allowed to warm to room temperature and stirring is continued for 18 hours. The reaction mixture is taken up in 250 ml of ethyl acetate and is washed with 50 ml of 0.1 N hydrochloric acid solution and with 50 ml of saturated sodium hydrogen carbonate solution and with 50 ml of saturated sodium chloride solution. The product obtained is then dried over sodium sulphate and then filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting under pressure with ethyl acetate. 1.48 g of 1,1-dimethylethyl (S)-[4-(6-aminopyrid-3-yl)-1-([4-ethylpiperid-3-yl)carbonyl]butyl]carbamate are obtained in the form of a viscous oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:32])([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:23]3[C:18](=[C:19]([CH3:24])[N:20]=[CH:21][CH:22]=3)[C:17](=[O:25])[N:16]([CH3:26])[C:15]=2[CH:27]=1)(C)(C)C.C1C(=O)N([Cl:41])C(=O)C1>C(#N)C>[NH2:7][C:8]([CH3:32])([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:9][O:10][C:11]1[C:12]([Cl:41])=[CH:13][C:14]2[C:23]3[C:18](=[C:19]([CH3:24])[N:20]=[CH:21][CH:22]=3)[C:17](=[O:25])[N:16]([CH3:26])[C:15]=2[CH:27]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OCC(C)(CC(C)C)NC(=O)OC(C)(C)C)ccc21
Solvent: CC#N
Product: Cc1nccc2c1c(=O)n(C)c1cc(OCC(C)(N)CC(C)C)c(Cl)cc21
Reaction time: 2 h
Yield: 13.3 %

Procedure:
To the stirred solution of 8-((2-amino-2,4-dimethylpentyl)oxy)-4,6 dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (Prepared in Example 32, Part B) (0.08 g, 0.226 mmol) in acetonitrile (5 mL) was added NCS (0.030 g, 0.226 mmol)) at RT and the reaction mixture was stirred for 2 h. The mixture was then evaporated to dryness. The residue was purified by reverse phase HPLC (0.1% TFA in water/AcCN) to afford 8-((2-amino-2,4-dimethylpentyl)oxy)-9-chloro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (12 mg, 0.030 mmol, 13% yield). LC/MS (ESI) m/e 388.0 [(M+H)+, calcd for C21H27ClN3O2, 388.2] as an off-white solid. LC/MS retention time (method C): tR=2.13 min. HPLC retention time (method A): tR=8.97 min; HPLC retention time (method B): tR=10.16 min. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.99-1.02 (m, 6H), 1.30 (s, 3H), 1.54-1.66 (m, 2H), 1.84-1.90 (m, 1H), 3.05 (s, 1H), 3.73 (s, 1H), 4.04 (q, J=23.20 Hz, 2H), 7.03 (s, 1H), 8.06 (d, J=6.00 Hz, 1H), 8.39 (s, 1H), 8.54 (d, J=6.00 Hz, 1H).
Reaction SMILES: C(O)(=O)C[C:3]1[C:4](=CC=C(C=1)O)[OH:5].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(Cl)(=O)C.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:3][C:4]([C:19]1[CH:20]=[C:15]([O:14][CH3:13])[CH:16]=[CH:17][C:18]=1[O:21][CH3:22])=[O:5]
Reactant: O=C(O)Cc1cc(O)ccc1O
Reactant: COc1ccc(OC)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)Cl
Product: COc1ccc(OC)c(C(C)=O)c1

Procedure:
The best method known for preparing homogentisic acid appears to be that described in J. Biol. Chem. 179, 365 (1949), in which 1,4-dimethoxybenzene is reacted with acetyl chloride in the presence of aluminum chloride to give 2,5-dimethoxyacetophenone, the latter is reacted with sulphur in morpholine to give 2,5-dimethoxyphenylacetic acid, which on demethylation with hydrobromic acid gives homogentisic lactone, ring-opening of which gives the desired acid.
Reaction SMILES: [C:1]([N:11]1[CH2:18][C@@H:17]([OH:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:20]O.S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[C:1]([N:11]1[CH2:18][C@@H:17]([OH:19])[CH2:16][C@H:12]1[C:13]([O:15][CH3:20])=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CO
Reactant: O=C(O)[C@@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.5 g (0.024 mole) of N-carbobenzyloxy-cis-4-hydroxy-L-proline (J.A.C.S., 79, 189 (1957)] is dissolved in 65 ml. of methanol, stirred, and treated with 0.65 ml. of concentrated sulfuric acid. After stirring at room temperature for one-half hour, the solution is allowed to stand overnight. The bulk of solvent is removed on a rotary evaporator and the oily residue (13 g.) is taken up in 70 ml. of ether and washed with 35 ml. of 10% sodium bicarbonate solution. The wash is back extracted with 35 ml. of ether. The combined organic layers are dried (MgSO4), and the ether is evaporated to give 6.5 g. (96%) of product as a pale yellow viscous oil. [α]D25 -24° (c, 1% in chloroform).
Reaction SMILES: [Br:1][C:2]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:5]2[C:6]3[C:7](=[O:21])[NH:8][C:9]([NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.BrN1C(=O)CCC1=O.N1C=CC=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:5]2[C:6]3[C:7](=[O:21])[NH:8][C:9]([NH:14][C:15](=[O:20])[C:16]([CH3:18])([CH3:19])[CH3:17])=[N:10][C:11]=3[CH:12]=[CH:13][C:4]=2[CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1nc2c(c(=O)[nH]1)-c1cc([N+](=O)[O-])c(Br)cc1CC2
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)Nc1nc2ccc3cc(Br)c([N+](=O)[O-])cc3c2c(=O)[nH]1

Procedure:
N-(8-Bromo-1,2,5,6-tetrahydro-9-nitro-1-oxobenzo[f]quinazolin-3-yl)- pivalamide (0.23 g, 0.5 mmole) was reacted with N-bromosuccinimide (0.12 g, 0.7 mmole) and pyridine (0.06 ml, 0.8 mmole) in dry benzene (150 ml) in the same manner as in example 2. The crude product was purified by trituration with methanol:water (1:9), followed by filtration and washing (water and methanol) to give, after drying, N-(8-bromo-1,2-dihydro-9-nitro-1-oxobenzo[f]quinazolin-3-yl)pivala- mide as a pale yellow solid. (0.20 g, 94%) 1H NMR(DMSO-d61 200MHz) δ: 1.27(s, 9H, t-butyl); 7.76(d, J=9.0 Hz, 1H, Ar); 8.32(d, J=9.0 Hz, 1H, Ar); 8.65(s, 1H, Ar); 10.21(s, 1H, Ar); 11.40(s, 1H, NH:I; 12.45(br s, 1H, NH).
Reaction SMILES: [C:1]([C:4]1[NH:9][C:8](=[O:10])[NH:7][C:6](=[O:11])[CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[F:17][C:18](I)([F:20])[F:19].OO>[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2].CS(C)=O>[C:1]([C:4]1[NH:9][C:8](=[O:10])[NH:7][C:6](=[O:11])[C:5]=1[C:18]([F:20])([F:19])[F:17])([OH:3])=[O:2]
Reactant: FC(F)(F)I
Reactant: O=C(O)c1cc(=O)[nH]c(=O)[nH]1
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CS(C)=O
Product: O=C(O)c1[nH]c(=O)[nH]c(=O)c1C(F)(F)F
Temperature: 65 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
0.17 g (1.0 mmol) of 6-carboxyuracil and 0.058 g (0.3 mmol) of ferrocene were weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 1.8 ml of dimethyl sulfoxide, 2.0 ml of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide and 0.2 ml of a 30% hydrogen peroxide aqueous solution. The mixture was stirred at 60 to 70° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 6-carboxy-5-trifluoromethyluracil (19F-NMR yield: 95%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 6-Carboxy-5-trifluoromethyluracil was obtained (0.076 g, yield: 34%) by column chromatography.
Reaction SMILES: [OH-].[Na+].C([O:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)=[N:16][C:15](=[O:25])[N:14]([CH2:26][CH3:27])[C:13]=2[N:28]=1)[CH3:8])(=O)C.Cl>CO>[Cl:24][C:20]1[CH:19]=[C:18]([C:17]2[C:12]3[CH:11]=[CH:10][C:9]([CH:7]([OH:6])[CH3:8])=[N:28][C:13]=3[N:14]([CH2:26][CH3:27])[C:15](=[O:25])[N:16]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C(C)OC(C)=O)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C(C)O)nc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
Methanol (30 ml) and 30 ml of 1 N sodium hydroxide aqueous solution were added to 6.78 g (18.2 mmol) of 7-(1-acetoxyethyl)-4-(3-chlorophenyl)-1-ethylpyrido[2,3-d]pyrimidin-2(1H)-one, followed by stirring for 20 minutes at room temperature. The reaction solution was neutralized by adding 1 N hydrochloric acid and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and the resulting filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (chloroform) to give 4.50 g of 4-(3-chlorophenyl)-1-ethyl-7-(1-hydroxyethyl)pyrido[2,3-d]pyrimidin-2(1H)-one in the form of crystals. The yield was 75%.
Reaction SMILES: [NH:1]([C:3](=[S:6])OC)[NH2:2].[NH:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1.C(OCC)(=O)C>C(O)C>[NH:1]([C:3]([N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)=[S:6])[NH2:2]
Reactant: COC(=S)NN
Reactant: OC1CCNCC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: NNC(=S)N1CCC(O)CC1
Temperature: 90 °C

Procedure:
A solution of methyl hydrazinecarbothioate (1.0 g, 8.2 mmol) and piperidin-4-ol (1.24 g, 12.3 mmol) in ethanol (7 mL) was refluxed with heating at 90° C. for 2 days. After addition of ethyl acetate, the reaction solution was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the crude desired product. The crude product was used directly for the next reaction.