Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[C:4]=1[NH2:5].[C:14](Cl)(Cl)=[O:15]>C1(C)C=CC=CC=1.CCOCC>[CH3:13][O:12][C:6]1[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=[C:3]([O:2][CH3:1])[C:4]=1[N:5]=[C:14]=[O:15]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: O=C(Cl)Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(N=C=O)c(OC)c1
Reaction time: 3 h

Procedure:
A suspension of 2,4,6-trimethoxyaniline (71.1 g, 0.324 mol) in a 12.5% wt/wt solution (540 mL) of phosgene in toluene was heated on a steam bath with periodic swirling for 3 hours. Additional phosgene in toluene solution (2×270 mL) was added after 1 and 2 hours. The suspension was allowed to cool, placed under house vacuum, and stirred for 2.5 days. The mixture was rotoevaporated to a dark purple solid. The residue was dissolved in ether (450 mL), filtered, rotoevaporated, and dried in vacuo to give a purple amorphous solid; yield 66.9 g (98.7%), mp 67°-70° C.
Reaction SMILES: FC(F)(F)C(O)=O.C([SiH](CC)CC)C.O[C:16]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33][C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1.C1(C)C=CC=CC=1>O>[C:37]1([CH3:40])[CH:38]=[CH:39][C:34]([S:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:35][CH:36]=1
Reactant: CCOC(=O)N1CCC(O)(c2ccccc2Sc2ccc(C)cc2)CC1
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)N1CCC(c2ccccc2Sc2ccc(C)cc2)CC1
Temperature: 60 °C

Procedure:
Trifluoroacetic acid (2.8 kg, 24.9 mol) and triethylsilane (362 g, 3.1 mol) was charged in a reactor with an efficient stirrer. Ethyl 4-hydroxy-4-(2-(4-tolylsulfanyl)phenyl)-piperidin-1-carboxylate (462 g, 1.24 mol) was added via a powder funnel in portions. The reaction was slightly exothermic. The temperature rose to 50° C. After the addition was finalised the reaction mixture was warmed to 60° C. for 18 hours. The reaction mixture was cooled down to room temperature. Toluene (750 mL) and water (750 mL) was added. The organic phase was isolated and the aqueous phase was extracted with another portion of toluene (750 mL). The organic phases were combined and washed with sodium chloride solution (15%, 500 mL) and dried over sodium sulphate. The sodium sulphate was filtered off, the filtrate evaporated at reduced pressure to a red oil, which was processed further in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(O)=O.CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccc(-c2ccnc(Cl)n2)s1
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: Clc1nccc(-c2ccc(CNc3ccccc3)s2)n1
Reaction time: 18 h
Yield: 59.4 %

Procedure:
[5-(2-Chloro-pyrimidin-4-yl)-thiophene-2-carbaldehyde (100 mg, 0.446 mmol) was dissolved in 25% HOAc in DMA (4 mL) and was treated with aniline (61 uL, 0.669 mmol) for 2 h. MP-CNBH3 resin was added the reaction was shaken for 18 h. The reaction was filtered and rinsed with DMA and the solution was concentrated in vacuo. The crude material was purified by SiO2 chromatography using a gradient 0-100% hexanes/EtOAc to afford title compound (80 mg, 59%).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10](=[O:20])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=1)[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:1]([N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10](=[O:20])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cccc1C(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCCCn1cccc1C(=O)c1cccc(N)c1
Yield: 85.6 %

Procedure:
A solution of 19 g (80 mmol) of 1-butyl-2-(3'-nitrobenzoyl)pyrrole in 250 ml of methanol was hydrogenated at 45 p.s.i. in the presence of 3 g of a 10% palladium-charcoal catalyst. After 45 minutes the catalyst was separated by filtration and the filtrate evaporated under reduced pressure. Purification of the residue by column chromatography on 750 g of silica gel, using hexane-ethyl acetate (75:25) as eluant, afforded 16.6 g (95%) of 1-butyl-2-(3'-aminobenzoyl)pyrrole, the title compound, as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:12](=[O:13])[C:11]2[CH2:14][CH2:15][CH2:16][C:10]=2[NH:9][C:8]1=[O:17].[H-].[Na+].Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)=[O:22].C1C(O)=CC=C(C)C=1.C(OC(C)C)(C)C>O.CN(P(N(C)C)(N(C)C)=O)C.O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:12](=[O:13])[C:11]2[CH2:14][CH2:15][CH2:16][C:10]=2[N:9]([C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[O:22])[C:8]1=[O:17]
Reactant: O=c1[nH]c2c(c(=O)n1C1CCCCO1)CCC2
Reactant: Cc1ccc(OC(=O)Cl)cc1
Agent: Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(OC(=O)n2c3c(c(=O)n(C4CCCCO4)c2=O)CCC3)cc1
Reaction time: 1.75 h
Yield: 65.9 %

Procedure:
15 g of 3-(2-tetrahydropyranyl)-1,2,3,4,6,7-hexahydro-5H-cyclopentapyrimidine-2,4-dione [prepared according to the French Pat. No. 2,029,250] were introduced with stirring over 20 minutes at 20° C. into 130 ml of anhydrous tetrahydrofuran and 13 ml of hexamethylphosphotriamide and then 3.35 g of a 50% suspension of sodium hydride in oil were introduced in several portions at 0° C. with stirring for 105 minutes. Then 13 g of p-tolyl chloroformate prepared from p-cresol were introduced dropwise with stirring at 20° C. over 17 hours and the mixture was then poured into iced water. Isopropyl ether was added thereto and the mixture was vacuum filtered. The solid product was dried to obtain 15.5 g of 3-(2-tetrahydropyranyl)-1,2,3,4,6,7-hexahydro-1-(p-tolyloxycarbonyl)-5H-cyclopentapyrimidine-2,4-dione melting at 136° C.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:35]=[C:34]([CH3:36])[C:29]3[NH:30][C:31](=[O:33])[S:32][C:28]=3[CH:27]=2)[CH:20]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH3:36][C:34]1[C:29]2[NH:30][C:31](=[O:33])[S:32][C:28]=2[CH:27]=[C:26]([O:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:20]=2)[CH:35]=1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2sc(=O)[nH]c12
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2sc(=O)[nH]c12
Reaction time: 0.5 h

Procedure:
90 mg (0.35 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 105 mg (0.36 mmol) 6-(6-chloropyrimidin-4-yloxy)-4-methylbenzo[d]thiazol-2(3H)-one and 200 μL (1.16 mmol) DIPEA in 2.0 mL DMF were stirred for 14 h at 60° C. The reaction mixture was cooled, mixed with water and stirred for 30 min. The precipitate formed was suction filtered, stirred with methanol, suction filtered again and dried.
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH2:10][C:11]([O-:13])=O)=[N:4][C:3]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[Na+].[CH3:21][C@@H:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23]1>>[F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH2:10][C:11]([N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:30][C@H:22]2[CH3:21])=[O:13])=[N:4][C:3]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C[C@@H]1Cc2ccccc2N1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)c(F)c1=O
Agent: [Na+]
Product: C[C@@H]1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)c(F)c(=O)n1C
Yield: 53.5 %

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 88 mg of sodium (5-fluoro-1-methyl-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate obtained in step 2a of example 8a and 40 mg of (R)-2-methyl-2,3-dihydro-1H-indole (which can be prepared according to Krasnov, V. P. et al. (Mendeleev Commun. (2002), 12(1), 27-28)). After silica column purification: eluent 98/02 dichloromethane/methanol, 62 mg of 5-fluoro-3-methyl-2-[2-((R)-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])=[CH:4][C:3]=1[F:29].C([O-])(=O)C.[K+].[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>CN(C=O)C.ClCCl>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[CH2:12][N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:29])=[C:2]([C:40]3[CH:39]=[CH:38][CH:37]=[C:36]([F:35])[CH:41]=3)[N:11]=2)[C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8]1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(Cl)c(F)cc2c1=O
Reactant: OB(O)c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(-c3cccc(F)c3)c(F)cc2c1=O

Procedure:
A solution of EXAMPLE 7F (210 mg), potassium acetate (176 mg), 3-fluorobenzeneboronic acid (84 mg), and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (II) (12 mg) in DMF (6 mL) was heated at 90° C. for 3 hours then cooled, diluted with dichloromethane, washed with water, and dried (Na2SO4), filtered, and concentrated; and the concentrate was flash chromatographed on silica gel with 0-2% methanol/dichloromethane.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[ClH:22]>CO>[ClH:22].[ClH:22].[N:19]1[CH:20]=[CH:21][C:16]([NH:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ccncc2)CC1
Agent: Cl
Solvent: CO
Product: c1cc(NCC2CCNCC2)ccn1
Reaction time: 8 h
Yield: 88 %

Procedure:
To a stirred solution of 1-Boc-4-[(pyrid-4-ylamino)methyl]piperidine (1.0 g, 3.43 mmol) in methanol (100 mL) was added HCl (1 M in ether, 34 mL), and the mixture stirred overnight. The solvent was removed in vacuo, and the resudue taken up in water and freeze dried to give the product as a yellow solid (800 mg, 88%).
Reaction SMILES: C[Si](Cl)(C)C.[I-].[K+].C[O:9][C:10]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=1>CC#N>[OH:9][C:10]1[C:18]([C:19]([F:21])([F:20])[F:22])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=1
Reactant: COc1ncc(C(=O)O)cc1C(F)(F)F
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)c1cnc(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31 %

Procedure:
To a solution of TMSCl (0.75 mL, 5.88 mmol) in dry MeCN is added potassium iodide (0.98 g, 5.88 mmol). The crude is stirred at room temperature for 10 mins. To this crude is added a solution of 6-methoxy-5-(trifluoromethyl)nicotinic acid (1.3 g, 5.88 mmol) in MeCN (2 mL). The crude is stirred at 80 deg C. for 4 hrs and room temperature for overnight. The crude is concentrated and diluted in ether and 1 N HCl. The organic layer is washed with water, brine, dried over MgSO4, filtered and concentrated. The crude is purified via RP-HPLC (SunFire C18, H2O(0.1% TFA)/CH3CN) to give 6-hydroxy-5-(trifluoromethyl)nicotinic acid (377 mg). HPLC retention time=0.85 minutes (condition B); MS 208.0 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm 8.34 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]2[C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][C:23]=3[CH:17]2[CH2:16]1)(=[O:14])=[O:13].[CH3:29]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:29][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]2[C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][C:23]=3[CH:17]2[CH2:16]1)(=[O:14])=[O:13]
Reactant: O=C1c2cccnc2C2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3Br)CCN12
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(C(F)(F)F)ccc1S(=O)(=O)N1CCN2C(=O)c3cccnc3C2C1
Temperature: 90 °C
Yield: 55.9 %

Procedure:
A mixture of 9-{[2-bromo-4-(trifluoromethyl)phenyl]sulfonyl}-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-a]pyrazin-5(7H)-one (265 mg; may be prepared as described in Intermediate 24), trimethylboroxin (182 mg), potassium carbonate (200 mg) and Pd(PPh3)4 (109 mg) was heated to 90° C. under argon for 6 hours. The reaction mixture was partitioned between EtOAc and saturated sodium bicarbonate solution, and then the aqueous was re-extracted with EtOAc. The combined organic phases were washed with brine, dried through a hydrophobic frit and evaporated to a brown oil (335 mg). The residue was purified by chromatography eluting with 0-90% ethyl acetate in iso-hexane over 12 column volumes. The desired fractions were combined and evaporated to give the title compound as a pale yellow crystalline solid (128 mg).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:28][CH3:29])=[C:21]([CH:23]=[CH:24][C:25](=[O:27])[CH3:26])[CH:22]=1>C(O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:28][CH3:29])=[C:21]([CH:23]2[CH2:3][C:2](=[O:1])[CH2:26][C:25](=[O:27])[CH2:24]2)[CH:22]=1
Reactant: CC[O-]
Reactant: COc1ccc(Cl)cc1C=CC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC(=O)OCC
Product: COc1ccc(Cl)cc1C1CC(=O)CC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20% sodium ethoxide in ethanol (2.3 g) was added at room temperature diethyl malonate (5.4 g) and then was added little by little 4-(5-chloro-2-methoxyphenyl)-3-buten-2-one (6.8 g), and the reaction mixture was stirred at room temperature for 30 minutes, refluxed for 2 hours and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated. To the residue was added 2M sodium hydroxide (18 ml), and the mixture was refluxed for 2 hours and cooled. To the mixture was added 2.5M sulfuric acid (18 ml) for 15 minutes, and the mixture was refluxed for 15 minutes, cooled and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 5-(5-chloro-2-methoxyphenyl)cyclohexane-1,3-dione (7.3 g) as amorphous.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]2[CH:12]=[CH:13][C:14]([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])=[CH:15][C:3]1=2.[BH4-].[Na+].C1(C)C=CC=CC=1.Cl>[OH-].[Na+].O>[N:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[CH2:2][C:3]3[CH:15]=[C:14]([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])[CH:13]=[CH:12][C:4]=3[O:5][C:6]=12
Reactant: CC(C(=O)O)c1ccc2oc3ncccc3c(=O)c2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C(=O)O)c1ccc2c(c1)Cc1cccnc1O2
Yield: 55.5 %

Procedure:
4.75 g of 2-(5-oxo-5H-[1]benzopyrano[2,3-b]pyridin-7-yl)propionic acid is dissolved in a solution of 0.88 g of sodium hydroxide in 25 ml of water. To the solution are added 5 g of sodium borohydride and a small amount of toluene, and the mixture is heated under reflux for 3 hours. The reaction mixture is adjusted to pH 3 by adding concentrated hydrochloric acid under ice cooling. The resulting crystalline precipitate is filtered off, washed with water, and recrystallized from aqueous dioxane to give 2.5 g of 2-(5H-[1]benzopyrano[2,3-b]pyridin-7-yl)propionic acid as white needles melting at 182.5°-183.5°C.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[Li].O>O1CCOCC1.O>[C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(C)(C)C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)O)CC1
Yield: 90.7 %

Procedure:
To a stirring solution of methyl 4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoate (12.9 g, 33 mmol) in p-dioxane (150 mL) was added a solution of LiOH hydrate (2.8 g, 66 mmol) in water (75 mL). The next morning, the solvent was removed in vacuo, and the residue was diluted with water (200 mL) and washed with diethyl ether. The aqueous phase was then adjusted to pH 3 with citric acid and extracted twice with diethyl ether. The combined ether extracts were then washed twice with brine, dried with MgSO4, filtered and concentrated in vacuo to give 11.3 g (91%) of a white foam.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[C:12](=[O:27])[NH:13][C:14](=[O:26])[N:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)[C:5]=3[C:4]=2[N:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[NH2:42][C:39]1[N:40]=[CH:41][C:36]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[C:12](=[O:27])[NH:13][C:14](=[O:26])[N:15]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=5)[C:5]=4[C:4]=3[N:3]=2)=[CH:37][CH:38]=1
Reactant: O=c1[nH]c(=O)n(-c2cccc(C(F)(F)F)c2)c2c1cnc1ccc(Cl)nc12
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2ccc3ncc4c(=O)[nH]c(=O)n(-c5cccc(C(F)(F)F)c5)c4c3n2)cn1
Temperature: 25 °C
Yield: 12.4 %

Procedure:
9-chloro-1-(3-(trifluoromethyl)phenyl)pyrimidino[5,4-c][1,5]naphthyridine-2,4(1H,3H)-dione (400 mg, 1 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (440 mg, 2.0 mmol), potassium carbonate (414 mg, 3.0 mmol) and tetrakis(triphenylphosphine)palladium(58 mg, 0.05 mmol) were added to 40 mL dioxane and 2 mL water. The resulting mixture was reacted under reflux in the nitrogen protection for 18 hrs, cooled to room temperature, filtered with Celite, concentrated, and separated by silicagel column chromatography (EtOAc/PE=0-10/1) to obtain a crude product, which was washed with methanol to obtain a yellow solid of 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)pyrimidino[5,4-c][1,5]naphthyridine-2,4(1H,3H)-dione (56 mg).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH2:8][CH2:9][CH2:10][N:11]([C:14]1[N:23]=[C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:35]#[N:36])[CH:20]=2)[N:15]=1)OC)=[O:7])C.Cl.[CH2:38](O)C>>[C:6]([CH2:8][CH2:9][CH2:10][N:11]([C:14]1[N:23]=[C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:35]#[N:36])[CH:20]=2)[N:15]=1)[CH3:38])([OH:5])=[O:7]
Reactant: CCO
Reactant: CCOC(=O)CCCN(OC)c1nc(NCc2ccc3c(c2)OCO3)c2cc(C#N)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(CCCC(=O)O)c1nc(NCc2ccc3c(c2)OCO3)c2cc(C#N)ccc2n1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
20 ml of ethanol and 2.61 ml of a 1N aqueous solution of sodium hydroxide were added to 389 mg of 2-(N-(3-ethoxycarbonylpropyl)-N-methoxyamino]-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline. The obtained mixture was stirred at room temperature for 4 hours and at 50° C. for 10 minutes and neutralized with 1N hydrochloric acid. The crystals precipitated were recovered by filtration, purified by silica gel column chromatography (chloroform/methanol) and recrystallized from ethanol/acetone/water to give 305 mg of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:16])[CH:14]=O)=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2.Cl.[NH2:22][OH:23].[OH-].[Na+].Cl>O.C(O)C>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:16])[CH:14]=[N:22][OH:23])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2
Reactant: NO
Reactant: CC(C=O)c1ccc2c(=O)c3ccccc3ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C=NO)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
To a solution of 0.288 g. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propanal in 4 ml. of ethanol is added a solution of 0.12 g. of hydroxylamine hydrochloride and 0.11 g. of sodium hydroxide in 0.4 ml. of water. The mixture is refluxed briefly, then acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract is washed, dried and evaporated to yield a crude product which is chromatographed on silica gel, eluting with chloroform:methanol (19:1) to afford 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propanal oxime.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:15]([NH2:18])(=[O:17])=[O:16])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1.[H][H].C(N(CC)CC)C>O1CCCC1.[Pd]>[O:12]=[S:9]1(=[O:11])[C:8]([CH3:13])=[CH:7][C:6]2[CH:14]=[CH:2][CH:3]=[C:4]([S:15]([NH2:18])(=[O:16])=[O:17])[C:5]=2[O:10]1
Reactant: [H][H]
Reactant: CC1=Cc2cc(Br)cc(S(N)(=O)=O)c2OS1(=O)=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1=Cc2cccc(S(N)(=O)=O)c2OS1(=O)=O
Temperature: 0 °C
Yield: 75.1 %

Procedure:
120 g of 6-bromo-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide are dissolved in 2.4 liters of tetrahydrofuran and the solution is hydrogenated with hydrogen for 40 minutes, in the presence of 41.3 g of triethylamine and 12.0 g of 5% palladium on carbon catalyst, under normal pressure and in the temperature range from 20° to 25° C. The mixture is filtered, the filtrate is concentrated, and the residue is taken up in 1300 ml of hot 90% aqueous ethanol. The insoluble constituents are separated and the solution is cooled to 0° C. The precipitate is separated and dried, affording 70 g of 2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide of m.p. 204°-205° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13](I)[C:14]=1[OH:15])[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1C1C=CC=CN=1.[CH3:29][S:30]SC>CN(C)C=O.[Zn].[Ni](Br)Br>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([S:30][CH3:29])[C:14]=1[OH:15])[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSSC
Reactant: COC(=O)c1cc(I)c(O)c(C(C)(C)C)c1
Agent: Br[Ni]Br
Agent: [Zn]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(SC)c(O)c(C(C)(C)C)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Methyl 3-t-butyl-4-hydroxy-5-iodobenzoate (1.00 g) was dissolved in N,N-dimethylformamide (10 mL), and 2,2′-bipyridine (47 mg), zinc powder (391 mg), nickel bromide (66 mg) and dimethyl disulfide (142 mg) were added to the solution, and then the mixture was stirred at 130° C. for 1 hour. After the reaction solution was filtered, 1N hydrochloric acid was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=12:1) to obtain the title compound (382 mg) as a pale yellow oily substance.