Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([OH:20])[N:8]=[C:7]([CH:21]2[CH2:25][CH2:24][CH2:23][N:22]2C(OC(C)(C)C)=O)[N:6]=1)=[O:4].[C:33](O)(C(F)(F)F)=O.C(Cl)Cl>>[C:12]([O:11][C:10]1[C:9](=[O:20])[N:8]([CH3:33])[C:7]([CH:21]2[CH2:25][CH2:24][CH2:23][NH:22]2)=[N:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4])(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1nc(C2CCCN2C(=O)OC(C)(C)C)nc(O)c1OC(=O)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1nc(C2CCCN2)n(C)c(=O)c1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl-5-(benzoyloxy)-2-[1-(tert-butoxycarbonyl)pyrrolidin-2-yl]-6-hydroxypyrimidine-4-carboxylate was treated with TFA:CH2Cl2 (3:7) at 0° C. The solution was warmed to room temperature and the progress of the reaction was monitored by MS analysis. After 1 h the reaction was complete and the solvent was removed under reduced pressure using a rotatory evaporator. The title product was precipitated with Et2O and collected by filtration.
Reaction SMILES: O.CO.[SH:4][C:5]1[S:6][C:7]([SH:10])=[N:8][N:9]=1.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>[OH-].[Na+]>[SH:10][C:7]1[S:6][C:5]([S:4][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:9][N:8]=1
Reactant: CCOC(=O)CBr
Reactant: Sc1nnc(S)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(=O)CSc1nnc(S)s1
Reaction time: 8 h

Procedure:
In a mixture of 9.66 g of sodium hydroxide, 14.6 ml of water, and 122 ml of methanol was dissolved 36.3 g of 2,5-dimercapto-1,3,4-thiadiazole. After cooling the mixture, a solution of 24.1 ml of ethyl bromoacetate and 24 ml of methanol was added to the mixture below 10° C. The resultant mixture was stirred for 3 hours at room temperature and cooled below 10° C. 43.5 ml of water and 400 ml of 50% methanol were successively added to the reaction mixture, whereby crystals precipitated, and the mixture was allowed to stand overnight at 4° C. The crystals were collected by filtration, washed successively with water and then 50% methanol, and dried to provide 42.5 g of ethyl [(5-mercapto-1,3,4-thiadiazol-2-yl)thio]acetate.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([C:19](=[O:22])[CH2:20]Br)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:13]1([CH2:12][CH2:11][N:10]2[CH2:9][CH2:8][NH:7][CH2:20][C:19]2=[O:22])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCCN(CCc1ccccc1)C(=O)CBr
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CNCCN1CCc1ccccc1
Reaction time: 1 h
Yield: 256.4 %

Procedure:
To a solution of 2-[(bromoacetyl)(2-phenylethyl)amino]ethyl carbamic acid tert-butyl ester (0.81 g, 2.1 mmol) in CH2Cl2 (25 mL) was added trifluoroacetic acid (2.5 mL) and the mixture stirred for 1 h. The solvent was removed in vacuo and the residue azeotroped with toluene (10 mL) and CH2Cl2 (2×10 mL). The crude amine (1.1 g) was isolated as its trifluoroacetate salt, as a pale yellow oil and used crude in the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][O:41][CH3:42])=[CH:35][C:3]=1[CH2:4][N:5]([CH:32]1[CH2:34][CH2:33]1)[C:6](=[O:31])[CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][C:22]2[C:27]([Cl:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=2[Cl:30])=[CH:14][CH:13]=1)[C:8](=O)[CH3:9].C([O-])(=O)C.[NH4+:47].C([BH3-])#N.[Na+]>CO>[NH2:47][CH:8]([CH3:9])[CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][C:22]2[C:23]([Cl:30])=[CH:24][C:25]([CH3:29])=[CH:26][C:27]=2[Cl:28])=[CH:14][CH:13]=1)[C:6]([N:5]([CH2:4][C:3]1[CH:35]=[C:36]([CH2:39][CH2:40][O:41][CH3:42])[CH:37]=[CH:38][C:2]=1[Cl:1])[CH:32]1[CH2:34][CH2:33]1)=[O:31]
Reactant: [NH4+]
Reactant: COCCc1ccc(Cl)c(CN(C(=O)C(Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C(C)=O)C2CC2)c1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COCCc1ccc(Cl)c(CN(C(=O)C(Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C(C)N)C2CC2)c1

Procedure:
N-[2-Chloro-5-(2-methoxyethyl)benzyl]-N-cyclopropyl-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxobutanamide from the previous step (1 eq.) and ammonium acetate (10 eq.) were combined in MeOH (0.06 M). After the addition of sodium cyanoborohydride (1.2 eq.), the resulting reaction mixture was heated at reflux for 2 h. The volatiles were then removed in vacuo and the resulting residue partitioned between EtOAc and 1 N aq. NaOH. The aqueous wash was separated and back extracted with EtOAc. The combined organic extracts were then washed further with water and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. The crude product thus obtained was purified further by way of flash chromatography (SiO2, 96:4 (v/v) CH2Cl2: 2.0 M NH3 in MeOH) to reveal the title compound as a white froth. MS (ESI+): 635.3.
Reaction SMILES: [NH2:1][C:2]1([C:12]#[N:13])[CH2:7][C:6](O)=[C:5]([F:9])[C:4](=[O:10])[N:3]1[CH3:11].P(Cl)(Cl)([Cl:16])=O>C(#N)C>[NH2:1][C:2]1([C:12]#[N:13])[CH2:7][C:6]([Cl:16])=[C:5]([F:9])[C:4](=[O:10])[N:3]1[CH3:11]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN1C(=O)C(F)=C(O)CC1(N)C#N
Solvent: CC#N
Product: CN1C(=O)C(F)=C(Cl)CC1(N)C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 2-amino-5-fluoro-4-hydroxy-1-methyl-6-oxo-1,6-dihydropyridine-carbonitrile (30.0 g, 0.164 mol) and anhydrous acetonitrile (150 mL). Slowly add phosphorous oxychloride (37 mL). After addition is complete heat to reflux. After 3 hours, cool to ambient temperature and then in an ice-bath. Add another portion of acetonitrile (150 mL). Slowly add to ice-water (300 mL, 10 volumes). Heat to about 50° C. After 5 hours, cool in an ice bath to give a solid, filter, rinse the solid with water, and dry in vacuo to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ7.73 (s, 2H). 3.33 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ153.3 (d, J=32.9 Hz), 139.2, 136.9, 128.5 (d, J=16.9 Hz), 115.3 (d, J=2.2 Hz), 68.1, 29.7 (d, J=1.4 Hz); 19F NMR (376 MHz, DMSO-d6) δ−152.0; MS (M+H)+m/z calcd 202.0. found 202.0. Combine the title compound (4.4 g) in 40 mL of dimethylacetamide (40 mL) and heat to 38° C. Add activated carbon (4.4 g). After 30 minutes filter through Celite®, rinse with dimethylacetamide, and add water to the filtrate, then cool in an ice bath to give a solid. Collect the solid by filtration, rinse with water (20 mL), and dry in vacuo at give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=O)[NH:9][CH:8]=[N:7][C:6]=2[N:12]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:10]1[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[N:12][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: O=c1[nH]cnc2nc(F)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc2c(Cl)ncnc2n1

Procedure:
A suspension of 2-amino-6-fluoronicotinamide (0.74 g, 4.77 mmol) in triethyl orthoformate (25 mL) is heated at reflux for 8 h. After cooling to room temperature the precipitate is filtered off and washed well with petroleum ether to give 7-fluoropyrido[2,3-d]pyrimid-4(3H)-one (0.76 g, 96s), 1H NMR (DMSO) δ 12.75 (1H, brs), 8.66 (1H, dd, J=10.4, 8.4 Hz), 8.38 (1H, s), 7.33 (1H, dd, J=8.4, 2.6 Hz) 4-(3-Bromoanilino)-7-fluoropyrido[2,3-d]pyrimidine. A suspension of 7-fluoropyrido[2,3-d]pyrimid-4(3H)-one (0.20 g, 1.21 mmol) in POCl3 (10 mL) is heated under reflux for 2 h. The volatiles are then removed under reduced pressure, and the residue is partitioned between aqueous NaHCO3 and EtOAc. The organic extract is worked up to give crude 4-chloro-7-fluoropyrido[2,3-d]pyrimidine, which is used directly in the next reaction. A solution of this product (0.20 g, 1.09 mm6l) and 3-bromoaniline (0.23 mL, 2.18 mmol) in propan-2-ol (1.0 mL) and THF (10 mL) containing a trace of conc. HCl is stirred at 20° C. for 1 h, and then concentrated to dryness. The residue is dissolved in EtOAc, washed with aqueous NaHCO3, and worked up to give an oil, which is chromatographed on silica gel. Elution with EtOAc/petroleum ether (1:5) gives 3-bromoaniline, while EtoAc/petroleum ether (1:1) elutes 4-(3-bromoanilino)-7-fluoropyrido[2,3-d]pyrimidine (0.18 g, 47%), mp (MeOH) 211-213° C. 1H NMR (DMSO) δ 10.18 (1H, brs), 9.17 (1H, t, J=8.6 Hz), 8.80 (1H, s), 8.17 (1H, t, J=1.8 Hz), 7.85 (1H, dt, Jd=7.6 Hz, J=1.8 Hz), 7.53 (1H, dd, J=8.6, 2.7 Hz), 7.41-7.34 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][CH2:11][CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[S:28]([O:13][CH2:12][CH2:11][CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:30])(=[O:29])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC(CCCO)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(CCCOS(C)(=O)=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. solution of 4-[(t-butoxycarbonyl)-amino]-4-phenylbutanol (133 mg, 0.5 mmol) in dichloromethane (8 mL) was added triethylamine (0.140 mL, 1.0 mmol), followed by methanesulfonylchloride (0.057 mL, 0.75 mmol). The solution was then stirred at 0° C. for 15 minutes before being quenched with an aqueous ammonium chloride solution (2 mL). The aqueous and organic layers were then separated, the aqueous layer extracted twice with dichloromethane, and the combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 4-[(t-butoxycarbonyl)-amino]-4-phenylbutanol mesylate as a yellow oil, which was used immediately in the next reaction without further purification. 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.67-2.00 (m, 4H), 2.95 (s, 3H), 4.18 (t, 2H, J=7.1 Hz), 4.20 (m, 1H), 4.92 (br s, 1H(NH)), 7.21-7.33 (m, 5H).
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH3:22])/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[CH2:7][C@H:8]([C:10]1[C@:11]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][CH:19]=1)[C:15](=[O:20])[CH2:14][CH2:13][CH2:12]2)[CH3:9].[Si:24](C1NC=CN=1)([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[CH3:9][C@@H:8]([C:10]1[C@:11]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][CH:19]=1)[C:15](=[O:20])[CH2:14][CH2:13][CH2:12]2)[CH2:7]/[CH:6]=[CH:5]/[CH:4]=[CH:3]/[C:2]([CH3:22])([O:1][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH3:23]
Reactant: C[C@H](C/C=C/C=C/C(C)(C)O)C1=CCC[C@H]2C(=O)CCC[C@]12C
Reactant: C[Si](C)(C)c1ncc[nH]1
Solvent: ClCCl
Product: C[C@H](C/C=C/C=C/C(C)(C)O[Si](C)(C)C)C1=CCC[C@H]2C(=O)CCC[C@]12C

Procedure:
420 mg of (4aS,8aR)-5-((3E,5E)-(R)-7-hydroxy-1,7-dimethyl-octa-3,5-dienyl)-4a-methyl-3,4,4a,7,8,8a-hexahydro-2H-naphthalen-1-one were reacted at RT with 0.389 ml of TMS-imidazole (2 equivalents) in 1.3 ml of CH2Cl2. After 20 hours the mixture was poured onto crushed ice, extracted with ether, washed with brine, dried over magnesium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=95/5) yielded 463 mg of (4aS,8aR)-5-[(3E,5E)-(R)-(1,7-dimethyl-7-trimethylsilanyloxy-octa-3,5-dienyl)]-4a-methyl-3,4,4a,7,8,8a-hexahydro-2H-naphthalen-1-one as colourless oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=1)(=[O:3])[CH3:2].[I:22](O)(=O)=O.II>C(O)C>[C:1]([NH:4][C:5]1[N:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=[C:7]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]=1[I:22])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cn1nc(-c2ccccc2)cc1NC(C)=O
Reactant: [O-][I+2]([O-])O
Agent: II
Solvent: CCO
Product: CCOC(=O)Cn1nc(-c2ccccc2)c(I)c1NC(C)=O
Temperature: 50 °C
Yield: 352.5 %

Procedure:
A suspension of ethyl 2-(5-acetamido-3-phenyl-pyrazol-1-yl)acetate (34.81 g, 60.6 mmol), iodic acid (5.33 g, 30.3 mmol) and iodine (15.37 g, 60.6 mmol) in ethanol (250 mL) was heated at 50° C. for 1.5 h and cooled to room temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved in CH2Cl2 (250 mL). The solution was washed twice with 2 M Na2S2O3 followed by brine solution. The organic layer was dried (magnesium sulphate), filtered and concentrated in vacuo. The residue was triturated from diethyl ether, filtered and dried to provide the title compound as a solid (44.13 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[N:10]([CH3:11])[C:9]([CH3:12])=[C:8]([CH3:13])[C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:17].C(Cl)Cl.[OH-].[Na+]>O>[Cl:17][C:4]1[C:5]2[N:10]([CH3:11])[C:9]([CH3:12])=[C:8]([CH3:13])[C:6]=2[N:7]=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1nc2c(C)c(C)n(C)c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1nc(Cl)c2c(n1)c(C)c(C)n2C
Temperature: 100 °C
Reaction time: 17 h

Procedure:
A mixture of 2,5,6,7-tetramethyl-3H,4H,5H-pyrrolo[3,2-d]pyrimidin-4-one N9b (0.334 g, 1.75 mmol) and POCl3 (4 ml) is stirred at 100° C. for 17 hours. At 0° C. DCM (30 ml) and aqueous sodium hydroxide (1 mol/1, 20 ml) is added under vigorous stirring. The water phase is made basic with an aqueous solution of sodium hydroxide (1 mol/l) and extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is used without further purification. Yield: 330 mg (90%). HPLC-MS: M+H=210; tR=0.92 min (METHOD—1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:18]=3[CH3:19])[C:9]2=[O:12])=[CH:4][CH:3]=1.Br[CH2:21][CH:22]1[CH2:24][CH2:23]1.[H-].[Na+]>CN(C=O)C>[CH:22]1([CH2:21][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][N:8]([C:13]4[CH:14]=[N:15][CH:16]=[CH:17][C:18]=4[CH3:19])[C:9]3=[O:12])=[CH:4][CH:3]=2)[CH2:24][CH2:23]1
Reactant: Cc1ccncc1N1CCc2ccc(O)cc2C1=O
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccncc1N1CCc2ccc(OCC3CC3)cc2C1=O
Yield: 413.6 %

Procedure:
7-hydroxy-2-(4-methyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (27A: 50 mg, 0.196 mmol) was reacted with bromomethyl-cyclopropane (32 mg, 0.236 mmol) and 60% NaH (10 mg, 0.236 mmol) in DMF (2 mL) to afford the crude product. Purification by column chromatography on silica gel (15% ethylacetate in hexane) afforded 250 mg of the product (50% yield).
Reaction SMILES: [Na].[CH2:2]([O:9][C:10]([N:12]1[C@@H:17]([CH3:18])[C:16](=[O:19])[N:15]2[CH:20]([CH2:23][CH:24]=C)[CH2:21][CH2:22][C@H:14]2[CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(C)=[O:28]>O.[Os](=O)(=O)(=O)=O>[CH2:2]([O:9][C:10]([N:12]1[C@@H:17]([CH3:18])[C:16](=[O:19])[N:15]2[CH:20]([CH2:23][CH:24]=[O:28])[CH2:21][CH2:22][C@H:14]2[CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CCC1CC[C@H]2CN(C(=O)OCc3ccccc3)[C@@H](C)C(=O)N12
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na]
Solvent: O
Product: C[C@H]1C(=O)N2C(CC=O)CC[C@H]2CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium periodiate (206 mg, 0.96 mmol) and osmium tetroxide solution (2.5% in tert-butyl alcohol, 33 μL, 3.3 μmol) were added at 0° C. to a suspension of (3S,8aS)-6-allyl-3-methyl-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid benzyl ester (110 mg, 0.33 mmol) in acetone (1 mL) and water (1 mL). After removal of the ice bath the reaction mixture was stirred for 3 h at room temperature, then partitioned between EtOAc and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to furnish (3S,8aS)-3-methyl-4-oxo-6-(2-oxo-ethyl)-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid benzyl ester [MS: 331.2 (M+H)+]. This was dissolved in DCM (1 mL) and added at room temperature to a suspension of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (53 mg, 0.33 mmol), Et3N (33 mg, 0.33 mmol), HOAc (39 mg, 0.66 mmol), and sodium triacetoxyborohydride (77 mg, 0.36 mmol) in DCM (1 mL). After 16 h the reaction mixture was partitioned between EtOAc and 1 M aq. sodium carbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; DCM→DCM/MeOH/25% aq. ammonia solution 90:10:0.25) afforded the title compound (88 mg, 62%). Light yellow gum, MS: 442.4 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH3:8])[CH:7]=1.[Mg].II.[Br:14][C:15]1[CH:16]=[C:17]([C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][C:20]=1[Cl:21]>O1CCCC1>[Br:14][C:15]1[CH:16]=[C:17]([C:22]([C:2]2[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH3:8])[CH:7]=2)([OH:24])[CH3:23])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: CC(=O)c1ccc(Cl)c(Br)c1
Reactant: COc1ccc(Br)cc1C
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(O)c2ccc(Cl)c(Br)c2)cc1C
Temperature: 25 °C
Yield: 62.8 %

Procedure:
5-Bromo-2-methoxytoluene (6.4 g, 0.032 mol) was dissolved in tetrahydrofuran (100 mL) and 5 mL of the solution was added to a stirred mixture of magnesium turnings (0.90 g, 0.037 mol) and iodine (a catalytic amount) in tetrahydrofuran (10 mL). The mixture was heated to vigorous reflux until some of the iodine colour was lost. The flask was removed from the heat and the remainder of the bromide was added so as to maintain a gentle reflux. The flask was then returned to the heat and stirred at reflux for 2 hours. The flask was removed from the heat and a solution of 1-(3-bromo-4-chlorophenyl)-ethanone (7.1 g, 0.030 mol) in tetrahydrofuran (100 mL) was added so as to maintain a gentle reflux. The reaction mixture was returned to the heat and stirred at reflux for 3 hours then cooled to room temperature and poured into ice-water (300 mL). The mixture was stirred for 5 minutes then concentrated to remove tetrahydrofuran. The aqueous residue was diluted with aqueous ammonium chloride (100 mL), extracted with ethyl acetate (3 200 mL) and the combined organic extracts were washed with water (100 mL) and brine (100 mL), dried (sodium sulfate) and concentrated to give the crude product as a red oil which was purified by flash chromatography (5 to 10% ethyl acetate/hexane) to give the desired alcohol as a bright yellow oil (6.7 g, 71%). 1H NMR (300 MHz; CDCl3) 7.72 (1H, d, J 2.1, Ar), 7.35 (1H, d, 8.5, Ar), 7.23-7.13 (3H, m, Ar), 6.76 (1H, d, J 8.5, Ar), 3.82 (3H, s, OMe), 2.19 (3H, s, Me), 2.11 (1H, s, OH), 1.88 (3H, s, Me).
Reaction SMILES: C(S[C:4](=[O:23])[CH:5]([C:19]([F:22])([F:21])[F:20])[CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)C.O.[NH2:25][NH2:26]>CCO>[F:20][C:19]([F:22])([F:21])[CH:5]1[CH2:6][C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:26][NH:25][C:4]1=[O:23]
Reactant: CCSC(=O)C(CC(=O)c1ccc(C(F)(F)F)cc1)C(F)(F)F
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1NN=C(c2ccc(C(F)(F)F)cc2)CC1C(F)(F)F
Temperature: 23 °C
Yield: 99.1 %

Procedure:
A mixture of 4-oxo-2-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-thiobutyric acid S-ethyl ester (example C.26 step 4) (16.0 g, 45 mmol) and hydrazine monohydrate (2.39 mL, 49 mmol) in EtOH (250 mL) was refluxed for 18 h under nitrogen atmosphere. Cooled to 23° C., the solvents were evaporated to leave the title compound as a brown solid (13.83 g, 100%), which was used without further purification [according to Synthesis 2003, (3), 436.]. MS (ISP) 311.1 [(M+H)+]; mp 135-136° C.
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:16]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>CN(C=O)C>[CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([N:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)=[O:21])=[C:17]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:16]=1
Reactant: C1COCCN1
Reactant: Cc1c(COc2ccc(C(=O)O)c(OCC3CCOCC3)c2)[nH]c2ccccc2c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(COc2ccc(C(=O)N3CCOCC3)c(OCC3CCOCC3)c2)[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.7 %

Procedure:
4-[(3-Methyl-4-oxo-1,4-dihydroquinolin-2-yl)methoxy]-2-(tetrahydro-2H-pyran-4-ylmethoxy)benzoic acid (67 mg) and 1-hydroxybenzotriazole hydrate (25 mg) were dissolved in DMF (1.3 mL). To this solution were sequentially added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (33 mg) and morpholine (15 mg), and the mixture was stirred at room temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution (5 mL) to the reaction mixture, followed by extraction with ethyl acetate (50 mL). The organic layer was washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=15/1) to obtain 3-methyl-2-{[4-(morpholin-4-ylcarbonyl)-3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinolin-4(1H)-one (73 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4](=[O:21])[CH:3]=1.P(Cl)(Cl)(Cl)=O.O.[OH-].[K+].CN(C)[CH:32]=[O:33]>>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6](=[O:14])[N:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:4](=[O:21])[C:3]=1[CH:32]=[O:33]
Reactant: Nc1cc(=O)n(-c2ccccc2)c(=O)n1-c1ccccc1
Reactant: CN(C)C=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1c(C=O)c(=O)n(-c2ccccc2)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A solution of 6-amino-1,3-diphenyluracil (10.0 g, 35.8 mmol) in dimethylformamide (100 mL) was cooled in an ice bath and phosphorus oxychloride (3.7 mL, 39.4 mmol) was dropped thereinto using a dropping funnel. The reaction mixture was stirred at room temperature for two hours and the reaction was stopped by adding 50 mL of water thereto. The pH was adjusted to 10 by a 1N solution of potassium hydroxide and stirring was carried out at room temperature for one additional hour. Crude crystals separated out therefrom were filtered and, after washing with 100 mL of water, the crude crystals were filtered. The resulting crude crystals were further recrystallized from hexane and ethyl acetate to give 6-amino-5-formyl-1,3-diphenyluracil (2.2 g) in a 40% yield.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC.[CH3:39][O:40][C:41]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]2[C:42]=1[C:43](=[O:65])[NH:44][C:45]([C:53]1[CH:58]=[CH:57][C:56]([N:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)=[CH:55][CH:54]=1)=[N:46]2>C1COCC1>[C:1]([N:62]1[CH2:63][CH2:64][N:59]([C:56]2[CH:57]=[CH:58][C:53]([C:45]3[NH:44][C:43](=[O:65])[C:42]4[C:47](=[CH:48][C:49]([O:51][CH3:52])=[CH:50][C:41]=4[O:40][CH3:39])[N:46]=3)=[CH:54][CH:55]=2)[CH2:60][CH2:61]1)(=[O:9])[C:2]1[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)c5ccncc5)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
To a solution of isonicotinic acid (0.083 g, 0.68 mmol) in THF (20 mL) was added HOBt (0.099 g, 0.74 mmol), EDCl (0.141 g, 0.74 mmol), Et3N (0.10 mL, 0.74 mmol) and 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.250 g, 0.68 mmol). The resulting solution was stirred overnight at room temperature. The solution was concentrated in vacuo and the resulting material was purified by flash chromatography on silica gel, eluting with 10% to 60% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, to afford the title compound (0.110 g, 34%). 1H NMR (300 MHz, DMSO-d6): δ 11.79 (s, 1H), 8.58-8.79 (m, 2H), 8.12 (d, J=9.0 Hz, 2H), 7.45 (d, J=6.0 Hz, 2H), 7.04 (d, J=9.0 Hz, 2H), 6.69 (s, 1H), 6.47 (s, 1H), 3.64-4.06 (m, 9H), 3.22-3.54 (m, 5H). APCI MS m/z 472 [M+H]+.