Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)=O)[CH3:2].[CH3:15][NH:16][CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)[N:16]([CH3:17])[CH3:15])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)C(=O)c1cccc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)C(c1cccc(Br)c1)N(C)C
Temperature: 25 °C
Reaction time: 36 h
Yield: 15.7 %

Procedure:
A suspension of (3-bromo-phenyl)-oxo-acetic acid ethyl ester (2.0 g, 7.8 mmol), dimethylamine (19.5 mL, 2 N in THF, 39 mmol), and sodium triacetoxyborohydride (4.95 g, 23.4 mmol) in 1,2-dichloroethane (40 mL) was stirred at room temperature for 36 hours. Satuated sodium bicarbonate (50 mL) was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane to afford (3-bromo-phenyl)-dimethylamino-acetic acid ethyl ester (350 mg, 16%) as an oil. MS: m/z 286 (M+H+).
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:21][C:22]#[N:23]>CN(C)C=O>[S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:21][C:22]#[N:23])[CH2:4][CH2:3][CH2:2]1
Reactant: N#CCCl
Reactant: Oc1cccc2c1SCCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1cccc2c1SCCC2
Temperature: 60 °C
Yield: 98.8 %

Procedure:
Under argon, 2 g (12.03 mmol) of 8-thiochromanol are dissolved in 15 cm3 of DMF. 5 g (36.09 mmol) of potassium carbonate and a catalytic amount of potassium iodide are added. Then 5.45 g (72.18 mmol) of chloroacetonitrile dissolved in 5 cm3 of dimethylformamide (DMF) are added dropwise. The mixture is heated at 60° C. for 4 hours, and then the solvent is evaporated off. The residue is taken up in H2O and extracted with methylene chloride and then dried over MgSO4. After evaporation, the product is purified over a silica column. Eluant:methanol/CH2Cl2 1:99. 2.44 g of 2-(thiochroman-8-yl-oxy)acetonitrile are obtained (melting point: 66° C.).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([F:22])[CH:16]=2)=[CH:11][N:10]=[C:9]1[NH:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([NH2:38])[CH:33]=1.CCN(CC)CC>CN1C(=O)CCC1.CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH2:38][C:34]1[CH:33]=[C:32]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[C:13](=[O:14])[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:9]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)=[N:10][CH:11]=3)=[CH:16][C:17]=2[F:22])[CH:37]=[CH:36][N:35]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: O=c1c(-c2ccc(O)c(F)c2)cnc(Nc2ccc(F)cc2)n1Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1cc(Oc2ccc(-c3cnc(Nc4ccc(F)cc4)n(Cc4ccccc4)c3=O)cc2F)ccn1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
3-benzyl-5-(3-fluoro-4-hydroxyphenyl)-2-(4-fluorophenylamino)pyrimidin-4(3H)-one (731.4 mg, 1.804 mmol) and 4-chloropyridin-2-amine (473.7 mg, 3.685 mmol) were dissolved in NMP (8.0 ml) and Et3N (1.25 ml, 8.97 mmol) was added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (190 C) and stirred under nitrogen. After 19 hours, more 4-chloropyridin-2-amine (409 mg, 3.20 mmol), DMAP (286.5 mg, 2.345 mmol), Et3N (0.50 ml, 3.6 mmol) were added, followed by NMP (1.0 ml). Stirring was continued at 190 C. After 23 hours, the reaction was cooled to room temperature, diluted with DCM, and washed with water (2×50 ml). The aqueous extracts were combined and extracted with DCM. Some MeOH (˜10%) was also used to help solubilize the biphasic mixture. All the organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on silica gel (˜3 inches, DCM->50:1->20:1 DCM/MeOH) to afford the desired 5-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-3-benzyl-2-(4-fluorophenylamino)pyrimidin-4(3H)-one, which was taken on to the next step. MS (ESI pos. ion) m/z: 498 (MH+). Calc'd exact mass for C28H21F2N5O2: 497.
Reaction SMILES: F[C:2]1[C:7]2[C:8](=[N:11]O)[CH2:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.FC1C2C(=O)COC=2C=CC=1>CO.[Pd]>[O:10]1[C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:7]=2[CH:8]([NH2:11])[CH2:9]1
Reactant: ON=C1COc2cccc(F)c21
Agent: [Pd]
Agent: O=C1COc2cccc(F)c21
Solvent: CO
Product: NC1COc2ccccc21

Procedure:
To the solution of benzofuran-3(2H)-one oxime (1.0 g, obtained from commercially available benzofuran-3(2H)-one via the procedure outlined for the synthesis of 4-fluorobenzofuran-3(2H)-one oxime from 4-fluorobenzofuran-3(2H)-one) in 50 mL MeOH, 10% Palladium on active carbon (0.1 g) was added. The mixture was evacuated then filled with H2 three times. Finally the oxime was reduced under a H2 balloon for 24 hours. The mixture was filtered through a pad of celite, and the cake was washed with MeOH twice. After removing the solvents under vacuum, 0.99 g brown-yellow residue was obtained as the desired amine. 1H NMR (300 MHz, CDCl3): δ 7.32 (d, 1H), 7.19 (t, 1H), 6.94 (t, 1H), 6.82 (d, 1H), 4.5-4.7 (m, 1H), 4.64 (s, 1H), 4.1-4.2 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[C:8]2[CH3:15].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C=O>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[CH:31][C:32]([NH:35][C:12]([C:9]3[NH:10][C:11]4[C:7]([C:8]=3[CH3:15])=[CH:6][CH:5]=[CH:4][C:3]=4[O:2][CH3:1])=[O:14])=[CH:33][CH:34]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1cccc2c(C)c(C(=O)O)[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc2c(C)c(C(=O)Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.7 %

Procedure:
A mixture of 7-methoxy-3-methyl-1H-indole-2-carboxylic acid (61 mg, 0.3 mmol), 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (83 mg, 0.3 mmol), N-hydroxybenzotriazole (61 mg, 0.45 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg, 0.45 mmol) in 1:1 dichloromethane/dimethylformamide was stirred at room temperature for overnight. After the reaction, solvent was concentrated. The resulted mixture was mixed with water and extracted with ethyl acetate twice. The organic layers were collected, combined, washed with brine before being dried over sodium sulfate, and then concentrated to give a solid. The crude product was purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 0%-100% ethyl acetate in hexane) to give 40 mg of 4-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester as an off-white solid. LCMS calcd for C26H32N4O4 (m/e) 464, obsd 465 (M+H).
Reaction SMILES: [CH3:1][C:2]1([C:8](=[O:11])[CH2:9]Br)[CH2:7][O:6][CH2:5][O:4][CH2:3]1.[NH:12]1[CH:16]=[N:15][C-:14]=[N:13]1.[Na+]>O1CCCC1>[CH3:1][C:2]1([C:8](=[O:11])[CH2:9][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH2:7][O:6][CH2:5][O:4][CH2:3]1
Reactant: CC1(C(=O)CBr)COCOC1
Reactant: [c-]1nc[nH]n1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C(=O)Cn2cncn2)COCOC1
Reaction time: 8 h
Yield: 87.1 %

Procedure:
A solution of 223 g (1 mole) of 1-(5-methyl-1,3-dioxan-5-yl)-2-bromoethan-1-one in 200 ml of tetrahydrofuran is added dropwise in the course of 2 hours to a suspension, stirred under pure nitrogen, of 100 g (1.1 moles) of sodium 1,2,4-triazolide in 300 ml of dry tetrahydrofuran, at 25° C. The mixture is refluxed for 8 hours, the inorganic precipitate is then filtered off, and the filtrate is concentrated to half its volume. It is then seeded and left to stand overnight at +3° C. The precipitate is filtered off, washed with 30 ml of cold (+5° C.) tetrahydrofuran, then with 80 ml of ether and thereafter with 100 ml of n-pentane, and dried. 184 g (87.2%) of 1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-ethan-1-one are obtained as white crystals of melting point 95°-97° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CS(Cl)(=O)=O.[C:14]([N:18]([C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1)[NH2:19])([CH3:17])([CH3:16])[CH3:15].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CC(C)=O.C(N(CC)CC)C>[C:14]([N:18]([C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1)[NH:19][C:6]([C:4]1[N:3]=[N:2][NH:1][CH:5]=1)=[O:8])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1cccc(C(=O)N(N)C(C)(C)C)c1
Reactant: O=C(O)c1c[nH]nn1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C(=O)N(NC(=O)c2c[nH]nn2)C(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
1,2,3-triazole-4-carboxylic acid (1.0 g) and triethylamine (0.9 g) were dissolved in 40 ml methylene chloride and cooled in an ice bath. Methanesulfonylchloride (1.0 g) was added dropwise. After addition was complete, the reaction mixture was stirred for 0.5 hours. N'-t-butyl-N'-(3methylbenzoyl)hydrazine (1.84 g) in 10 ml CH2Cl2 was added dropwise. The resulting mixture was allowed to stand for 14 hours. Aqueous sodium bicarbonate was added. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to give a yellow oil. Chromatography on silica gel using acetone as eluant afforded N'-t-butyl-N-1,2,3-triazole-4-carbonyl-N'-(3-methylbenzoyl)hydrazine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=2)[CH:18]=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:23])[N:21]=2)[CH:18]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: Nc1ccccc1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)c1cn2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a solution of 3 g of aniline in 366 mL of toluene cooled to 0° C. are added dropwise 22.5 mL of a 2M solution of trimethylaluminium in toluene, followed by addition, at 20° C., of 5.6 g of ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate. The reaction mixture is stirred for 2 hours at room temperature. The resulting mixture is cooled to 4° C. and 150 mL of saturated ammonium chloride solution are then added. The reaction mixture is concentrated to dryness and is then taken up in 400 mL of water and 400 mL of dichloromethane. The organic phase is dried over magnesium sulfate, filtered through Celite and evaporated to dryness under reduced pressure to give 4.6 g of 6-bromo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of an off-white powder.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][C:3]=1[F:14].[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1>O1CCCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][O:15]3)=[CH:23][CH:24]=2)=[O:7])=[CH:4][C:3]=1[F:14]
Reactant: CON(C)C(=O)c1ccc(Br)c(F)c1
Reactant: Br[Mg]c1ccc(OC2CCCCO2)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a solution of 4-bromo-3-fluoro-N-methoxy-N-methylbenzamide (1.00 g, 3.8 mmol) in dry tetrahydrofuran at 0° C. under nitrogen was added dropwise (4-(tetrahydro-2H-pyran-2-yloxy)phenyl)magnesium bromide (7.6 mmol). After addition, the reaction mixture was let warm to room temperature, stirred for 2 h., quenched with saturated ammonium chloride, and extracted with ethyl acetate. The extract was dried over sodium sulfate, concentrated, and purified by column chromatography to give the desired product as a colorless oil (1.10 g, 76% yield).
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[N:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:2]=[CH2:3].[N:13]#[C:14][NH2:15]>>[CH2:1]([NH:4][C:5]([NH:15][C:14]#[N:13])=[N:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:2]=[CH2:3]
Reactant: N#CN
Reactant: C=CCN=C=Nc1ccccc1
Product: C=CCNC(=Nc1ccccc1)NC#N

Procedure:
0.6 g of N-allyl-N'-phenylcarbodiimide in 8 ml of 1,2-dichloromethane is reacted with 0.17 g cyanamide and the reaction mixture is worked up as described in Example 4. Recrystallisation from diethyl ether yields a colourless crystalline product which melts at 99.5°-100.5° C.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17](S(C)(=O)=O)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:35]#[N:36].[K+].O>CN(C)C=O>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:35]#[N:36])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A solution of N-(2,2-diphenylethyl)-2-(methylsulfonyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (Preparation 4) (20.1 g, 42.1 mmol) in dry N,N-dimethylformamide (100 ml) was treated with potassium cyanide (5.5 g, 84.6 mmol) and the mixture heated at 120° C. for 24 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, poured into water (1000 ml) and stirring continued for a further 1 hour. The resultant solid was filtered and washed several times with water. The solid was then dissolved in dichloromethane and the solution washed with water, dried with anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was azeotroped with diethyl ether (twice) to afford the title compound as an oil (17 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[N:11]=[C:10]([C:12]3[N:16]([CH:17]([CH3:19])[CH3:18])[N:15]=[CH:14][N:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:33]1[C:41]2[C:36](=[C:37](B3OC(C)(C)C(C)(C)O3)[C:38]([F:42])=[CH:39][CH:40]=2)[CH:35]=[CH:34]1)(C(C)(C)C)(C)C>>[F:42][C:38]1[C:37]([C:2]2[N:3]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:5]3[N:11]=[C:10]([C:12]4[N:16]([CH:17]([CH3:19])[CH3:18])[N:15]=[CH:14][N:13]=4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:36]2[C:41](=[CH:40][CH:39]=1)[NH:33][CH:34]=[CH:35]2
Reactant: CC(C)n1ncnc1-c1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Product: CC(C)n1ncnc1-c1ccc2nc(-c3c(F)ccc4[nH]ccc34)nc(N3CCOCC3)c2n1

Procedure:
4-(2-chloro-6-(1-isopropyl-1H-1,2,4-triazol-5-yl)pyrido[3,2-d]pyrimidin-4-yl)morpholine (0.11 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 57.7 mg of 141 following reverse phase HPLC purification. MS (Q1) 459.2 (M)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:29])=[C:6]([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11]=[C:10]3[N:16]([C:21]4[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=4[F:28])[C:17](=[O:20])[NH:18][CH2:19][C:9]=23)[CH:7]=1.[S:30]1[CH:34]=[CH:33][C:32]([C:35](O)=[O:36])=[CH:31]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[F:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([F:28])[C:21]=1[N:16]1[C:10]2[N:11]=[C:12]([S:14][CH3:15])[N:13]=[C:8]([C:6]3[CH:7]=[C:2]([NH:1][C:35]([C:32]4[CH:33]=[CH:34][S:30][CH:31]=4)=[O:36])[CH:3]=[CH:4][C:5]=3[CH3:29])[C:9]=2[CH2:19][NH:18][C:17]1=[O:20]
Reactant: O=C(O)c1ccsc1
Reactant: CSc1nc(-c2cc(N)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CSc1nc(-c2cc(NC(=O)c3ccsc3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compounds 5-(5-amino-2-methylphenyl)-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.205 g, 0.5 mmol), 3-thiophenecarboxylic acid (0.0647 g, 0.5 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.107 g, 0.55 mmol), 4-(dimethylamino)pyridine (0.002 g, 0.016 mmol), and triethylamine (0.14 mL, 1 mmol), were dissolved in chloroform (10 mL) and stirred under argon at room temperature for 16 h. The reaction was not complete. An additional 3-thiophenecarboxylic acid (0.13 g, 1.0 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.107 g, 0.55 mmol) were dded and heated to 40° C. for 17 h. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water (3×), brine (1×), dried over anhydrous Na2SO4, filtered and evaporated. The crude product was flash chromatographed on silica gel (10 g) eluted with 0-5% MeOH/CH2Cl2 to give the title compound as a solid. LC-MS m/z 524 (M+H)+, 2.2 min (ret. time).
Reaction SMILES: [C:1]([O:5]/[N:6]=[C:7](\[C:17]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][N:18]=1)/[C:8]1[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[CH:10][C:9]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:32])C=1.S([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5]/[N:6]=[C:7](\[C:17]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][N+:18]=1[O-:32])/[C:8]1[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[CH:10][C:9]=1[OH:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)O/N=C(/c1cc(F)c(Cl)cc1O)c1ncccc1O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)O/N=C(/c1cc(F)c(Cl)cc1O)c1c(O)ccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
To a solution of (Z)-2-(4-chloro-5-fluoro-2-hydroxybenzoyl)-3-hydroxypyridine O-t-butyloxime (0.82 g) in chloroform (30 ml) was added 70% m-chloroperbenzoic acid (1.01 g) at 0° C. The mixture was warmed up to room temperature and stirred for 5 hours. To the reaction mixture was added an aqueous solution of sodium hydrogensulfite to quench the reaction. The reaction mixture was subjected to extraction with chloroform. The organic layer was dried (anhydrous magnesium sulfate). The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give (Z)-2-(4-chloro-5-fluoro-2-hydroxybenzoyl)-3-hydroxypyridine N-oxide O-t-butyloxime (0.79 g) (Compound 56).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][C:4]=1[F:11])#[N:2].[CH:12]([C:14]1[N:15]=[C:16]([CH3:19])[NH:17][CH:18]=1)=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:15]2[C:14]([CH:12]=[O:13])=[CH:18][N:17]=[C:16]2[CH3:19])=[CH:5][C:4]=1[F:11])#[N:2]
Reactant: Cc1nc(C=O)c[nH]1
Reactant: N#Cc1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ncc(C=O)n1Cc1ccc(C#N)c(F)c1
Reaction time: 2 h

Procedure:
To a solution of 4-cyano-3-fluorobenzyl bromide, as described in Example 1, Step D, (1.26 g, 5.9 mmol) in DMF (10 mL), at 0° C., was added 4-formyl-2-methylimidazole (0.650 g, 5.9 mmol) and cesium carbonate (2.9 g, 8.9 mmol). After 2 hours, the reaction mixture was poured into EtOAc—30% hexane, washed with H2O, then brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the crude product. The crude material was purified by silica gel chromatography, eluting with a gradient of CHCl3—2% to 5% MeOH, to obtain the above-titled product.
Reaction SMILES: [CH3:1][C:2](OC(C)=O)=[O:3].CCN(CC)CC.[CH3:15][O:16][C:17]([C:19]1[S:20][C:21]([CH2:24][CH2:25][CH2:26][C@@H:27]2[C@@H:31]([C:32]3[CH:37]=[CH:36][C:35]([CH:38]([O:44][CH2:45][C:46]4[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=4)[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:34][CH:33]=3)[C:30](=[O:54])[CH:29]([OH:55])[CH:28]2[OH:56])=[CH:22][CH:23]=1)=[O:18].[C:57](OCC)(=[O:59])[CH3:58]>CN(C1C=CN=CC=1)C.C(Cl)CCl>[CH3:15][O:16][C:17]([C:19]1[S:20][C:21]([CH2:24][CH2:25][CH2:26][C@@H:27]2[C@@H:31]([C:32]3[CH:37]=[CH:36][C:35]([CH:38]([O:44][CH2:45][C:46]4[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=4)[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:34][CH:33]=3)[C:30](=[O:54])[CH:29]([O:55][C:2](=[O:3])[CH3:1])[CH:28]2[O:56][C:57](=[O:59])[CH3:58])=[CH:22][CH:23]=1)=[O:18]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(C)=O
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc([C@H]2C(=O)C(O)C(O)[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCCCCC(OCc1ccc(OC)cc1)c1ccc([C@H]2C(=O)C(OC(C)=O)C(OC(C)=O)[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Reaction time: 8 h
Yield: 51 %

Procedure:
Ac2O (100 μL, 1.06 mmol), Et3N (160 μL, 1.15 mmol) and DMAP (26 mg, 0.21 mmol) were added to a solution of the diol (27, 55 mg, 0.093 mmol) in ClCH2CH2Cl (0.5 mL). The reaction was stirred overnight, diluted with ethyl acetate and then washed with 1 M HCl, saturated NaHCO3, and brine. The ethyl acetate solution was then dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/hexanes) provided the title compound (32 mg, 51%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([NH2:14])=[C:5]([NH2:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:17]([CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1)=[C:18]=S>>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:8]=[C:3]([C:2]([F:15])([F:16])[F:1])[C:4]2[N:14]=[C:18]([NH:17][CH:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22][CH2:21]3)[NH:13][C:5]=2[CH:6]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1N
Reactant: S=C=NC1CCCc2ccccc21
Product: FC(F)(F)c1cc(C(F)(F)F)c2nc(NC3CCCc4ccccc43)[nH]c2c1

Procedure:
The title compound was prepared from 3,5-bis(trifluoromethyl)-1,2-diaminobenzene and 1-isothiocyanato-1,2,3,4-tetrahydronaphthalene by Procedure D. The title compound was isolated by column chromatography as the free base and as a mixture of enantiomers (solid, dec. >240° C.). MS(ES+) m/z 400 ([M+1]+, 100).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1([C@@H:11]2[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1.Cl[C:19]1[C:24]([Cl:25])=[C:23]([CH2:26][CH3:27])[N:22]=[CH:21][N:20]=1>CN(C)C=O.O>[CH3:7][C:8]1([C@@H:11]2[CH2:16][CH2:15][C@H:14]([NH:17][C:19]3[C:24]([Cl:25])=[C:23]([CH2:26][CH3:27])[N:22]=[CH:21][N:20]=3)[CH2:13][CH2:12]2)[CH2:9][CH2:10]1
Reactant: CCc1ncnc(Cl)c1Cl
Reactant: CC1([C@H]2CC[C@@H](N)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ncnc(N[C@H]2CC[C@@H](C3(C)CC3)CC2)c1Cl
Temperature: 80 °C
Reaction time: 4 h

Procedure:
1.8 g (13.0 mmol) of K2CO3 were placed in 10 ml of dimethylformamide, 1.3 g (8.5 mmol) of cis-4-(1-methylcyclopropyl)cyclohexylamine and 1.5 g (8.5 mmol) of 4,5-dichloro-6-ethylpyrimidine were added, and the mixture was stirred at 80° C. for 4 hours. For working up, the cooled reaction solution was taken up in water. Extraction was carried out with ether, and the combined organic phases were washed with water, dried and concentrated. For purification, the mixture was chromatographed on silica gel with petroleum ether/ethyl acetate 3:1. 1.8 g (71.1% of theory) were obtained of a colorless oil.
Reaction SMILES: [OH:1]O.C([C:5]1[C:14](=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1CCCCCCC)=O>CCO.[OH-].[Na+]>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:5][C:6]1=[O:1]
Reactant: OO
Reactant: CCCCCCCc1[nH]c2ccccc2c(=O)c1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=c1ccc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
Aqueous hydrogen peroxide (27.5 wt % solution in water, 145 μl) was added to a solution of 3-formyl-2-heptyl-4(1H)-quinolone (1 mmol) in EtOH (3 ml) and 1M NaOH solution (1.0 ml) under nitrogen, and the mixture was stirred at room temperature for 6 hours. The precipitate was removed by filtration, air dried and crystallised from EtOAc to give 2-heptyl-3-hydroxy-4(1M-quinolone in 70% yield as off-white needles, mp 195-197° C.