Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[N:4]=1.[C-:27]#[N:28].[Na+].O>CS(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)[N:4]=[C:3]2[CH2:2][C:27]#[N:28]
Reactant: [C-]#N
Reactant: COc1ccc(Cn2nc(CCl)c3cc(OC)c(OC)cc32)cc1OC
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Cn2nc(CC#N)c3cc(OC)c(OC)cc32)cc1OC
Temperature: 25 °C
Yield: 60.9 %

Procedure:
3-Chloromethyl-5,6-dimethoxy-l-(3,4-dimethoxybenzyl)-1H-indazole (187.0 g) was dissolved in dimethyl sulfoxide (1000 ml) and a solution was stirred at room temperature. Then sodium cyanide (134.0 g) which had been ground in a mortar was added thereto. The reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was returned to room temperature, poured into water (15000 ml) and stirred for 1 hour. The solid thus precipitated was collected by filtration, washed with water (1000 ml×3), dissolved in chloroform (5000 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue thus obtained was purified by using silica gel columns (chloroform/ethanol =50/1, silica gel 2 kg, followed by silica gel 2 kg, ethyl acetate/hexane =3:1) to give 111.0 g of a pale brown solid product. This solid product was used in the subsequent reaction without purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13]Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[C:19]#N.Cl.CC[O:29]CC>O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:19](=[O:29])[C:18]2[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:17]=2[F:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: ClCC1CCN(Cc2ccccc2)C1
Reactant: N#Cc1ccc(F)cc1F
Agent: Cl
Agent: [Mg]
Solvent: O
Product: O=C(CC1CCN(Cc2ccccc2)C1)c1ccc(F)cc1F

Procedure:
A solution containing 238 mmol of 1-benzyl-3-chloromethylpyrrolidine in 400 ml of ether is added to a suspension containing 238 mmol of magnesium in 100 ml of ether. The combined mixture is brought to reflux until the metal has disappeared. After cooling, 238 mmol of 2,4-difluorobenzonitrile in 200 ml of ether are added to this solution. The mixture is brought to reflux for 24 hours, is then hydrolyzed with 78 ml of concentrated hydrochloric acid and 50 ml of water and again brought to boiling point for 2 hours. After cooling and separation by settling, the aqueous phase is brought to pH 10 and extracted with dichloromethane. The expected product is obtained in the form of an oil after drying, evaporation and purification by chromatography on a silica column, using a dichloromethane/methanol/aqueous ammonia (99/1/0.1) mixture as eluent.
Reaction SMILES: O[C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O>[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:14]([NH:13][C:8]1[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]2[O:4][C:3]([CH3:21])([CH3:22])[CH:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[C:6]=2[CH:7]=1)=[O:20]
Reactant: Cc1ccccc1C1(O)c2cc(NC(=O)CC(C)(C)C)c(C)c(C)c2OC1(C)C
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1C1c2cc(NC(=O)CC(C)(C)C)c(C)c(C)c2OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of N-(3-hydroxy-2,2,6,7-tetramethyl-3-(2-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (120 mg, 0.3 mmol) obtained in Example 242 in trifluoroacetic acid (2 mL) was added triethylsilane (71 mg, 0.6 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to water and the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 1 N sodium hydroxide solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) and recrystallized from ethyl acetate-hexane to obtain 93 mg (yield: 79%) of the title compound. Melting point: 161-162° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21](Br)([F:23])[F:22].[C:25]([O:29][C:30]([N:32]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([CH:41]=O)[CH:38]=2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C.[Zn]>[C:25]([O:29][C:30]([N:32]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([CH:41]=[C:21]([F:23])[F:22])[CH:38]=2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C=O)cc2C1
Reactant: FC(F)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2ccc(C=C(F)F)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To a stirred solution of 4.69 mmol triphenylphosphine in 5 ml DMF at 0° C. was added dropwise a solution of 4.69 mmol dibromodifluoromethane in 1 ml DMF and the mixture was stirred at RT for 30 min. 2.35 mmol 5-formyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester was then added at 0° C. and then 4.69 mmol zinc dust was added in small portions. The mixture was stirred at RT for 16 and then concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid (31% yield). MS (m/e): 226.1 ([M+H−Me2C═CH2]+, 100%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([C:11]([CH2:28]C)([CH3:27])[CH2:12][C:13]1[O:14][C:15]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:16]=2[N:17]=1)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:40])(=O)=O)=CC=1>O1CCCC1>[CH3:9][C:11]([CH3:28])([CH3:27])[CH2:12][C:13]1[O:14][C:15]2[CH:21]=[CH:20][C:19]([CH:22]([F:40])[C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:16]=2[N:17]=1
Reactant: CCC(C)(CC)Cc1nc2cc(CC(=O)OC)ccc2o1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(F)c1ccc2oc(CC(C)(C)C)nc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
A solution of lithium diisopropylamide (2.0M solution in tetrahydrofuran/ethylbenzene/heptane, 3.85 ml, 0.0077 mol) was added dropwise to a solution of methyl [2-(2,2-diethylpropyl)benzoxazol-5-yl]acetate (2.0 g, 0.0077 mol) in tetrahydrofuran (40 ml) at −78° C. under a nitrogen atmosphere and the mixture was stirred at −78° C. for 1 hour. A solution of N-fluorobenzenesulfonimide (2.42 g, 0.0077 mol) in tetrahydrofuran (10 ml) was added dropwise and the mixture was stirred at −70° C. for a further 1 hour. The cooling bath was removed and the mixture allowed to warm to room temperature over a period of 20 hours. The reaction mixture was diluted with water, acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic extracts were combined, washed with water, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate:dichloromethane 5:95, and was further purified by column chromatography on silica gel, eluting with ethyl acetate:hexane 1:3, to give methyl [2-(2,2-dimethylpropyl)benzoxazol-5-yl]fluoroacetate (1.4 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH:15]=2)[N:4]=1.Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:31][CH2:30][C:29]([O:28][CH2:26][CH3:27])=[O:32])[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH:15]=2)[N:4]=1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Oc2cccc(C(=O)N(C)C)c2)n1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)CNc1nc(SC)nc(Oc2cccc(C(=O)N(C)C)c2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-methylthio-4-chloro-5-nitro-6-(3-(dimethylaminocarbonyl)phenoxy)pyrimidine, a compound of formula (C), (3.0 g 8.14 mmol) in 80 mL of acetonitrile at 0° C. was added glycine ethyl ester hydrochloride, a compound of formula (D), (1.14 g, 8.14 mmol), followed by the addition of cesium carbonate (6.1 g, 18.7 mmol). The reaction mixture was allowed to warm to ambient temperature and then stirred for 2 hours. The volatiles were evaporated to yield 3.6 g of 2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-(dimethylaminocarbonyl)-phenoxy)pyrimidine, a compound of formula (E).
Reaction SMILES: [C:1](O)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(O)(=O)C>C(O)(C)(C)C>[CH3:3][C:2](=[CH2:1])[CH3:4].[O:5]=[CH:1][C:2](=[CH2:3])[CH3:4]
Reactant: C=C(C)C(=O)O
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: C=C(C)C
Product: C=C(C)C=O

Procedure:
In another aspect, the invention comprises a process for the recovery of methacrylic acid and acetic acid produced by the oxidation of isobutylene or tertiary butyl alcohol into methacrolein, followed by the recovery of methacrolein, and thereafter oxidation of the methacrolein to form methacrylic acid. The methacrylic acid and acetic acid are recovered by cooling and condensing the effluent from the second oxidation (of methacrolein) and then passing the condensed effluent directly, and without preliminary extraction, into an azeotropic distillation carried out in the presence of a solvent, preferably methyl n-propyl ketone. Substantially dry crude methacrylic acid is withdrawn as a bottoms product from the azeotropic distillation, along with impurities and acetic acid. Separation and recovery of methacrylic acid and acetic acid may be carried out in conventional distillation facilities.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[F:23][C:24]1[C:29]([CH:30]=[O:31])=[C:28]([F:32])[CH:27]=[CH:26][C:25]=1B(O)O.B(O)O>>[F:23][C:24]1[C:25]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)=[CH:26][CH:27]=[C:28]([F:32])[C:29]=1[CH:30]=[O:31]
Reactant: O=Cc1c(F)ccc(B(O)O)c1F
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Agent: OBO
Product: O=Cc1c(F)ccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)c1F

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 2,4-difluoro-3-formylphenylboronic acid as a boronic acid, 2,6-difluoro-3-(2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-benzaldehyde was obtained. Methanol and sodium borohydride were added, which was stirred at room temperature for 1 hour, followed by elution with 2M ammonia methanol solution through SCX resin and then concentration. Purification by preparative TLC afforded the desired compound as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[C:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:14]=[CH:13][C:12]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31](=O)([O-])[O-].[K+].[K+].C=O.C(N(CCOCCOC)CCOCCOC)COCCOC>C1(C)C=CC=CC=1.CCOC(C)=O.O>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[C:15]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH:14]=[CH:13][C:12]=1[C:25](=[CH2:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Cc1ccc(NC(=O)OC(C)(C)C)cc1CN(C)C(=O)OC(C)(C)C
Agent: C=O
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C(=O)OCC)c1ccc(NC(=O)OC(C)(C)C)cc1CN(C)C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 10 h
Yield: 31.7 %

Procedure:
15D (0.573 g, 1.356 mmol) was dissolved in toluene (5 mL), and to the resulting solution were sequentially added potassium carbonate (0.375 g, 2.71 mmol), paraformaldehyde (0.407 g, 13.56 mmol) and tris(3,6-dioxaheptyl)amine (tda-1) (0.043 mL, 0.136 mmol). The reaction mixture was stirred at 85° C. for 10 h. The reaction mixture was diluted with EtOAc (20 mL) and water (10 mL) and stirred for 15 min. The organic phase was separated, washed with water (3×10 mL), brine (1×10 mL) and dried (Na2SO4). EtOAc was removed under reduced pressure and the residue was purified flash chromatography (0-35% EtOAc/hexanes). Fractions were combined and concentrated under reduced pressure to give 15E (0.187 g, 31.7% yield) as a colorless syrup. MS (ESI) m/z: 435.1 [M+1]+. 1H NMR: (400 MHz, CDCl3) δ ppm 7.40 (1H, d, J=5.77 Hz), 7.06 (2H, d, J=8.28 Hz), 6.50 (1H, s), 5.67 (1H, d, J=1.76 Hz), 4.27-4.39 (2H, m), 4.21 (2H, q, J=7.03 Hz), 2.61-2.77 (3H, m), 1.38-1.55 (18H, m), 1.26 (3H, t, J=7.03 Hz).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]([NH2:7])=[S:6])=S.CI.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:13]=1[CH2:14][NH2:15]>CO.C(O)C>[CH3:21][O:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:12]([O:11][CH3:10])[C:13]=1[CH2:14][NH:15][C:2](=[NH:1])[NH:4][C:5]([NH2:7])=[S:6]
Reactant: COc1cccc(OC)c1CN
Reactant: NC(=S)NC(N)=S
Solvent: CO
Solvent: CCO
Solvent: CI
Product: COc1cccc(OC)c1CNC(=N)NC(N)=S
Temperature: 5 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
2.00 g (14.8 mmol) dithiobiuret were placed in 25 ml methanol and 2.10 g (14.8 mmol) methyliodide were added at room temperature. The mixture was heated for 3 hours at reflux, then the solution was concentrated, was diluted with 25 ml of ethanol and 2.47 g (14.8 mmol) 2,6-dimethoxybenzylamine were added. The mixture was subsequently stirred again for 2 hours at reflux and subsequently for 30 minutes at 5° C. Filtration of the precipitate formed yielded 970 mg N-[[(2,6-dimethoxybenzyl)amino](imino)methyl]thiourea.
Reaction SMILES: I/[CH:2]=[CH:3]/[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]I>[C:8]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:10][C:5]([O:4]/[CH:3]=[CH:2]/[N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)=[CH:6][CH:7]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: I/C=C/Oc1ccc(-c2ccccc2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C(=C/n1ccc2ccccc21)\Oc1ccc(-c2ccccc2)cc1
Yield: 86.7 %

Procedure:
The compound 9 was prepared following the procedure described for 5 with 4 (0.32 g, 1 mmol, 1 eq), indole (0.14 g, 1.2 mmol, 1.2 eq), Cs2CO3 (0.81 g, 2.5 mmol, 2.5 eq), CuI (0.095 g, 0.5 mmol, 0.5 eq) and L2 (0.097 g, 0.5 mmol, 0.5 eq) at 70° C. for 12 h to give crude product which were purified by silica gel column chromatography using ethyl acetate-hexane (9:95) to afford compound 9 as white crystals (0.27 g, 87%): mp 140-142° C. 1H NMR (300 MHz, CDCl3): 7.58-7.46 (m, 6H, HAr), 7.40-7.32 (m, 3H, HAr), 7.25-7.21 (m, 1H, HAr), 7.20-7.14 (m, 2H, HAr), 7.12-7.02 (m, 4H, HAr and H(O)C═(N)CH), 6.55 (d, H, J=3.1 Hz, HAr). 13C NMR (75 MHz, CDCl3): 156.8, 140.4, 136.5, 136.4, 128.9, 128.8, 128.5, 127.1, 126.9, 125.7, 125.6, 121.2, 120.5, 116.5, 115.2, 109.8, 104.0 ppm; IR (cm−1): 3034, 2358, 2338, 1682, 1606, 1515, 1485, 1475, 1462, 1358, 1333, 1322, 1301, 1232, 1202, 1186, 1174, 1134, 1115, 1088, 1031, 1007, 907, 865, 834; HRMS (ESI), Calculated for C22H17NO [M+H]+ 312.1388. Found 312.1381; Elemental analysis Calculated for C22H17NO.0.25H2O: C, 83.65; H, 5.58; N, 4.43. found: C, 83.61; H, 5.65; N, 4.01.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]=[O:10])=[C:4]([NH2:11])[N:3]=1.[CH:12]([O-])=[O:13].[NH4+].C(O)=O>O.[Pd]>[OH2:10].[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH:9][CH:12]=[O:13])=[C:4]([NH2:11])[N:3]=1
Reactant: O=C[O-]
Reactant: Nc1nc(N)c(N=O)c(N)n1
Agent: [Pd]
Agent: [NH4+]
Solvent: O=CO
Solvent: O
Product: Nc1nc(N)c(NC=O)c(N)n1

Procedure:
A suspension of 7.9 g (0.05 mol) of 2,4,6-triamino-5-nitrosopyrimidine in 50 ml of water was mixed with 3.25 g (0.05 mol) of ammonium formate, 13.9 g (0.3 mol) of formic acid and 0.5 g of the palladium catalyst according to Example 1. This mixture was heated for 4 hours to 100° C. After cooling, the catalyst was filtered off, the filtrate concentrated to about 25 ml and neutralised with about 10 ml of 25% aqueous sodium hydroxide solution to pH 7.5. A crystal slurry thereby resulted which was filtered off with suction. In this way, there were obtained 8.1 g (87% of theory) of pale beige crystals of 2,4,6-triamino-5-formylaminopyrimidine hydrate.
Reaction SMILES: C[N:2]1[N:6](CCCCC2C=CC(OCC3C=CC4C(=CC=CC=4)N=3)=CC=2)C=N[NH:3]1.[CH3:29][CH:30]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH2:51][C:52]3[CH:61]=[CH:60][C:59]4[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=4)[N:53]=3)=[CH:46][CH:45]=2)=[CH:38][CH:37]=1)[CH2:31][CH2:32][C:33]#[N:34].[Na].[Cl-].[NH4+]>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:29][CH:30]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH2:51][C:52]3[CH:61]=[CH:60][C:59]4[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=4)[N:53]=3)=[CH:46][CH:45]=2)=[CH:40][CH:41]=1)[CH2:31][CH2:32][C:33]1[NH:6][N:2]=[N:3][N:34]=1
Reactant: CN1NN=CN1CCCCc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CC(CCC#N)Cc1ccc(OCc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(CCc1nnn[nH]1)Cc1ccc(OCc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Temperature: 135 °C

Procedure:
5-(3-methyl-4-(4-(4-(2-quinolinylmethyloxy)phenyl)butyl)tetrazole. A mixture of 4-methyl-5-(4-(4-(2-quinolinylmethyloxy)benzyloxy)phenyl) valeronitrile (1.5 g.), sodium aside (3 g), ammonium chloride (1.9 g) in dimethylformamide (20 ml) is stirred and heated at 135° C. for 18 hours. After cooling, the reaction mixture is poured into ice water and the insoluble material is taken up by chloroform. The residue from the evaporation of chloroform is purified by silica gel dry column (5% methanol in chloroform as eluant) to yield 5-(3-methyl-4-(4-(4-(2-quinolinylmethyloxy)benzyloxy)-phenyl)butyl)tetrazole.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:15][CH:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:17]1[C:25]([F:26])=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][C:18]=1[F:27])[CH3:14].[CH2:33]([NH2:37])[CH:34]([CH3:36])[CH3:35].CCOC(C)=O>C1COCC1>[CH2:31]([O:30][C:28](=[O:29])[CH:16]([C:17]1[C:18]([F:27])=[CH:19][C:20]([C:21](=[O:23])[NH:37][CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:24][C:25]=1[F:26])[O:15][CH2:13][CH3:14])[CH3:32]
Reactant: CC(C)CN
Reactant: CCOC(=O)C(OCC)c1c(F)cc(C(=O)O)cc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(OCC)c1c(F)cc(C(=O)NCC(C)C)cc1F
Reaction time: 3 h
Yield: 67.3 %

Procedure:
1,1′-Carbonyldiimidazole (88 mg) was dissolved in THF (1 ml) and a solution of (RS)-4-(ethoxy-ethoxycarbonyl-methyl)-3,5-difluoro-benzoic acid (156 mg) in THF (1 ml) was added. After 30 min stirring at rt isobutylamine (41 mg) was added and the mixture was stirred 3 h. AcOEt (20 ml) was added and the solution was washed with 1 N HCl (20 ml). The aqueous layer was extracted with two more portions AcOEt (20 ml), the the combined organic layers were dried (Na2SO4) and the solvent was evaporated. CC (Hept/AcOET 3:1) afforded 125 mg (67%) of (RS)-(2,6-difluoro-4-isobutylcarbamoyl-phenyl)-ethoxy-acetic acid ethyl ester. White solid.
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:13]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:12]2[C:11]3[CH2:10][CH2:9][O:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[C:14]([CH:15]([CH2:38][CH2:37][CH3:41])[C:16]([O:18][CH3:19])=[O:17])=[C:13]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[C:12]2[C:11]3[CH2:10][CH2:9][O:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCOC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCOC3
Yield: 29.8 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,8-dihydro-6H-7-oxa-9-thia-1-aza-fluoren-3-yl]acetate (0.270 g; 0.73 mmol), LHMDS 1N in THF (0.8 mL; 0.8 mmol), 1-iodopropane (0.122 mL; 1.09 mmol) in DMF (3 mL) for 19 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.089 g (30%) of the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11](=O)[CH:12]=[CH2:13].[NH2:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[N:25]([C:22]3[CH:23]=[CH:24][C:19]([S:16]([NH2:15])(=[O:17])=[O:18])=[CH:20][CH:21]=3)[C:11]([CH3:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C=CC(C)=O
Product: Cc1ccc(-c2ccc(Br)cc2)n1-c1ccc(S(N)(=O)=O)cc1

Procedure:
4-Bromobenzaldehyde and but-3-en-2-one were treated according to the procedure outlined in General Procedure C followed by subjecting the resulting product to conditions outlined in General Procedure D along with p-aminosulfonyl phenylamine to obtain the titled compound. 1H NMR (CDCl3) δ ppm 2.15 (3H), 4.81 (2H), 6.15 (1H), 6.29 (1H), 6.95-7.85 (8H); MS (ESI) m/z 391/393 (M+H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: OCCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)OCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15.2 %

Procedure:
To a solution of 2-(4-bromophenyl)ethanol (1 g, 5 mmol) in THF (15 ml) was added sodium hydride (60% in parafin liquid) (220 mg, 5.5 mmol) at 0° C., and the mixture was stirred at room temperature for 15 minutes. To the mixture was added ethyl 2-bromoisobutyrate (1.08 g, 5.5 mmol), and the mixture was stirred at room temperature for 12 hours. To this reaction solution were added ethyl acetate and a saturated aqueous ammonium chloride solution, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate, and the extracts were combined with the organic layer. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resultant was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the title compound (240 mg, 15%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.O=S(Cl)[Cl:15]>CN(C=O)C>[Cl:15][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: O=c1[nH]cnc2ccc(I)cc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1ncnc2ccc(I)cc12
Temperature: 90 °C
Yield: 70 %

Procedure:
To a mixture of 6-iodoquinazolin-4(3H)-one (1.70 g, 6.25 mmol) in SOCl2 (10 mL) was dropped a few drops of DMF, and then it was heated at 90° C. for 5 hours. After excess SOCl2 was removed under reduced pressure, to it was added CH2Cl2 and water, and neutralized with saturated NaHCO3 solution. The aqueous was extracted with CH2Cl2 three times. Extracts were dried over MgSO4 and concentrated under reduced pressure to afford 4-chloro-6-iodoquinazoline as solid (1.266 g, 70%). 1H NMR (300 MHz, CDCl3) δ 9.07 (s, 1H), 8.67 (d, 1H), 8.22 (dd, 1H), 7.81 (d, 1H).