Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][O:10][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:13].ClCCl.CO>C(O)C>[C:1]1([C@@H:7]([CH2:12][CH2:11][OH:10])[C:8]([NH2:13])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=C1OCC[C@@H]1c1ccccc1
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: NC(=O)[C@H](CCO)c1ccccc1
Yield: 63.3 %

Procedure:
(R)-2-phenylbutyrolactone (1 gram) was dissolved in 5 ml of absolute ethanol, followed by the addition of 0.5 gram of gaseous ammonia. The solution was kept in a stoppered flask, and the progress of the reaction was followed by thin layer chromatography (eluent dichloromethane/methanol 20:1). After the reaction was judged complete, the ethanol was evaporated and the resulting residue redissolved in ethyl acetate. Ammonia was removed by extraction with 1% HCl, and the ethyl acetate solution was dried over MgSO4, filtered, and rotary evaporated to leave 0.7 grams of (R)-2-phenyl-4hydroxybutyramide.
Reaction SMILES: CCCCCC.[F:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[CH3:14][O:15][C:16]([C@H:18]1[CH2:23][CH2:22][C@H:21]([C:24](Cl)=[O:25])[CH2:20][CH2:19]1)=[O:17]>C(OCC)C.[Cl-].[Zn+2].[Cl-].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>[CH3:14][O:15][C:16]([C@H:18]1[CH2:23][CH2:22][C@H:21]([C:24]([C:9]2[C:8]([F:7])=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:25])[CH2:20][CH2:19]1)=[O:17].[CH3:14][O:15][C:16]([C@H:18]1[CH2:23][CH2:22][C@H:21]([C:24]([C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[F:7])=[O:25])[CH2:20][CH2:19]1)=[O:17]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: Fc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CCCCCC
Product: COC(=O)[C@H]1CC[C@H](C(=O)c2ccncc2F)CC1
Product: COC(=O)[C@H]1CC[C@H](C(=O)c2ncccc2F)CC1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of N,N,N′N′-tetramethylethylenediamine (1.20 g, 10.3 mmol) in diethyl ether (50 ml) at −78° C. was added 1.6M N-butyl lithium solution in n-hexane (6.40 ml, 10.3 mmol). Stirring for 1 h at −20° C. was followed by addition of 3-fluoropyridine (1.00 g, 10.3 mmol) at −78° C. After stirring at −60 to −70° C. for 3 h a solution of zinc chloride (2.81 g, 20.6 mmol), which had previously been dried by melting in vacuo followed by cooling under argon, in diethyl ether (20 ml) was added dropwise at max. −60° C. The reaction mixture was allowed to warm to room temperature 45 minutes after completed addition. Addition of tetrakis(triphenylphosphine)palladium(0) (0.59 g, 0.51 mmol) and trans-4-chlorocarbonyl-cyclohexanecarboxylic acid methyl ester (2.10 g, 10.3 mmol) was followed by stirring for 16 h. The reaction was quenched with aqueous saturated ammonium chloride solution and the mixture was extracted with three 100-ml portions of tert-butyl methyl ether. The combined organic layers were washed with one 50-ml portion of 2 M aqueous sodium carbonate solution and one 50-ml portion of brine, dried over anhydrous sodium sulfate and concentrated to dryness. Separation by flash-chromatography with n-heptane/ethyl acetate as eluent gave trans-4-(3-fluoro-pyridine-2-carbonyl)-cyclohexanecarboxylic acid methyl ester (0.22 g, 7.9%) as yellow oil and trans-4-(3-fluoro-pyridine-4-carbonyl)-cyclohexanecarboxylic acid methyl ester (0.23 g, 8.4%) as yellow solid.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]2[CH:33]=[CH:32][C:14]3[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][C:21]=4[O:29][CH3:30])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:43]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]2[CH:33]=[CH:32][C:14]3[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:43])=[CH:22][C:21]=4[O:29][CH3:30])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccc1
Reactant: CCCCCCCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccc4)ccc3n2C)c(OC)c1
Yield: 68 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-heptyl chloroformate. Yield: 68% of theory, C37H46N6O6 (670.8) Rf value: 0.56 (silica gel; dichloromethane/ethanol=9:1) ##EQU141##
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:14]([OH:17])(=[O:16])=[O:15]>C(Cl)(Cl)Cl>[CH2:1]([C:8]1[S:9][C:10]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cc2cccs2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1ccc(Cc2ccccc2)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-benzylthiophene (0.875 g, 5 mmol) in chloroform (2 ml) at 0° C. was added chlorosulfonic acid dropwise and the reaction was stirred at 0° C. for 30 min. The reaction mixture was decomposed by pouring onto crushed ice (20 g). The mixture was extracted with ethyl acetate, dried over MgSO4 and filtered. The solvent was removed under reduced pressure to give 5-benzylthiophene-2-sulfonic acid.
Reaction SMILES: IC.[C:3]1([C@@:9]2([CH2:21][NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:11][C@H:10]2[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:32](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:32][N:22]([CH2:21][C@:9]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:11][C@H:10]1[CH2:12][O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24]
Reactant: O=S(=O)(NC[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
Iodomethane (2.12 g, 14.9 mmol, 4 eq) was added portionwise to N-[((1R,2R)-1-phenyl-2-{[(phenylmethyl)oxy]methyl}cyclopropyl)methyl]benzenesulfonamide (1.71 g, 3.74 mmol, 1 eq), accessed via the method of preparation 5B, in 7 mL DMF with potassium carbonate (1.03 g, 7.48 mmol, 2 eq) over 6 h at 80° C. Following addition, the reaction mixture was stirred 16 h at 80° C. The reaction mixture was diluted with EtOAc, washed successively with saturated aqueous NaHCO3, water (4×) and brine, dried over MgSO4, filtered and concentrated to give a brown oil. The crude material was purified by flash chromatography (SiO2, eluted successively with hexanes and EtOAc/hexanes (1:4)) to give the title product (1.57 g, 100%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.58-7.21 (m, 15H), 4.26 (ABq, J=26.5, 11.7 Hz, 2H), 3.50 (d, J=14.0 Hz, 1H), 3.23-3.20 (m, 1H), 2.94-2.89 (m, 2H), 2.54 (s, 3H), 1.39 (m, 1H), 1.10 (m, 1H), 0.92 (m, 1H). ES-LCMS m/z 444.3 (M+Na).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[F:12][C:13]1[N:14]=[CH:15][C:16]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1cc(Br)oc1C
Reactant: OB(O)c1ccc(F)nc1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(F)nc2)oc1C
Yield: 89.5 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.6 g), 2-fluoropyridine-5-boronic acid (2.1 g), tetrakis(triphenylphosphine)palladium(0) (0.7 g), 2N aqueous sodium carbonate solution (15 mL) and 1,2-dimethoxyethane (20 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.5 g, 87%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[N:12][C:11]([NH2:14])=[CH:10][CH:9]=1.[Br:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]>C(#N)C>[BrH:15].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](=[NH:14])[N:12]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[N:13]=1
Reactant: Nc1ccc(-c2ccccc2F)nn1
Reactant: COC(=O)CBr
Solvent: CC#N
Product: Br
Product: COC(=O)Cn1nc(-c2ccccc2F)ccc1=N
Temperature: 0 °C
Yield: 76.7 %

Procedure:
A stirred solution of 6-(2-fluorophenyl)pyridazin-3-amine (0.500 g, 2.64 mmol) and methyl 2-bromoacetate (2.90 mmol) in acetonitrile (15 mL) is heated at 80° C. for 4 hours. The mixture is cooled to 0° C. and precipitate collected by filtration, washed with cold acetonitrile (2×10 mL) to afford the title compound (0.693 g, 76%) as a white solid: LCMS (m/z)=262.3 [M+H]+, tR=0.47 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>CN(C)C=O>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:14][CH:12]=[N:1]2)=[CH:7][CH:8]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: NC=O
Solvent: CN(C)C=O
Product: O=c1[nH]cnc2cc(F)ccc12
Temperature: 180 °C
Reaction time: 14 h
Yield: 81.9 %

Procedure:
2-amino-4-fluorobenzoic acid (100 g, 0.64 mol) and formamide (154 mL, 3.87 mol) were mixed with a catalytic amount (1 mL) of N,N-dimethylformamide. The mixture was heated to 180° C. and further stirred for 14 hours. The mixture was cooled to room temperature, and distilled water (1000 mL) was added thereto. The mixture was stirred for 30 min and filtered to obtain the title compound (86 g, 81.3%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[NH:10][C:9](=[O:11])[CH2:8]1)(=[O:3])[CH3:2].[C:12]([Si:16]([CH3:19])([CH3:18])Cl)([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C)C=O>[Si:16]([N:10]1[CH:7]([CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:8][C:9]1=[O:11])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:19])[CH3:18]
Reactant: CC(=O)OCCC1CC(=O)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OCCC1CC(=O)N1[Si](C)(C)C(C)(C)C
Reaction time: 0.08 h
Yield: 96.7 %

Procedure:
A solution of 4-(2'-acetoxyethyl)-2-azetidinone (50.2 g, 0.32 mole) and t-butyldimethylchlorosilane (50.6 g, 0.335 mole) in 250 ml anhydrous N,N-dimethylformamide is treated at 0° with triethylamine (35.6 g, 0.353 mole). A white precipitate appears immediately. The mixture is stirred for a period of five minutes. It is then partitioned between 1600 ml benzene and 600 ml water. The organic phase is washed an additional four times with water and finally with brine. The benzene solution is then dried over magnesium sulfate and filtered. Evaporation of the filtrate under reduced pressure gives 84.0 g of 1-(t-butyldimethylsilyl)-4-(2'-acetoxyethyl)-2-azetidinone. Recrystallization from pentane gives 68.9 g of product with m.p. 35°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13](=[O:27])[C@@H:14]1[CH2:18][CH:17]([OH:19])[CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:27])[C@@H:14]1[CH2:18][C:17](=[O:19])[CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21]
Reactant: COC(=O)[C@@H]1CC(O)CN1C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution of 9.63 mL (7.2 mmol) of oxalyl chloride in 10.6 mL of CH2Cl2 stirred at −78° C. was added a solution of 0.94 mL (13.2 mmol) of methyl sulfoxide in 15 mL of CH2Cl2. The solution was stirred at −78° C. for 30 min. A solution of 1.47 g (6 mmol) of N-Boc-4-hydroxyproline methyl ester in 19 mL of CH2Cl2 was then added dropwise. The mixture was stirred at −78° C. for 1.5 h, and 3.34 mL (24 mmol) of triethylamine was added. The solution was allowed to warm up to room temperature and stirred overnight. It was then diluted with 100 mL of CH2Cl2, washed successively with 100 mL of water, 100 mL of 1N HCl, and 100 mL of brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography over silica gel (eluted with ethyl acetate/hexanes, 1:3), to afford 1.294 g (89% yield) of N-Boc-4-oxo-proline methyl ester. 1H NMR (500 MHz, CDCl3) δ 1.45 (m, 9H), 2.60 (m, 1H), 2.95 (m, 1H), 3.75 (m, 3H), 3.90 (m, 2H), 4.80 (m, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6].[CH3:27][N:28]=[C:29]=[O:30]>>[CH3:27][NH:28][C:29]([NH:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6])=[O:30]
Reactant: NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CN=C=O
Agent: Cl
Product: CNC(=O)NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[[(methylamino)carbonyl]amino]-1-oxopropyl]hydrazide (12) was prepared from 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(3-amino-1-oxopropyl)hydrazide, monohydrochloride (9), prepared as described above in Example 9, and methylisocyanate, in the manner described in Example 10 above, on a one mmol scale to yield 0.17 g (40%) of product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([CH3:41])=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([CH3:41])=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN(C)S(C)(=O)=O
Reactant: Cc1ccnc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4c(C)ccnc4c3)ncnc2cc1OCCCN(C)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 41.4 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline (150 mg, 0.42 mmol), (prepared as described for the starting material in Example 152), potassium carbonate (90 mg, 0.63 mmol) and 7-hydroxy-4-methylquinoline (71 mg, 0.46 mmol), (Chem. Berich. 1967, 100, 2077), in DMF (5.0 ml) was stirred at 100° C. for 2 hours and allowed to cool to ambient temperature. The DMF solvent was removed by evaporation and the residue was taken up in 2N aqueous sodium hydroxide solution. The precipitate was filtered off, dried, taken up in dichloromethane and then filtered through phase separating paper. The solution was then evaporated to dryness. The resulting solid was recrystallised from acetonitrile, filtered and washed with diethyl ether to give 6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)-4-(4-methylquinolin-7-yloxy)quinazoline (84 mg, 42%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([CH2:14][O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[N:8]=1>CO.C(#N)C>[Cl:6][C:7]1[N:12]=[C:11]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[CH:10]=[C:9]([CH2:14][O:15][CH2:16][C:17]([F:20])([F:18])[F:19])[N:8]=1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Reactant: COCCN
Solvent: CC#N
Solvent: CO
Product: COCCNc1cc(COCC(F)(F)F)nc(Cl)n1
Temperature: 25 °C

Procedure:
A solution of 2-methoxyethanamine (59 μl, 0.69 mmol) in MeOH (2 mL) was added dropwise to an ice-cold solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (66 mg, 0.25 mmol) in acetonitrile (2 mL). The reaction was stirred at rt over night. The reaction mixture was concentrated in vacuo and the crude was purified by preparative HPLC to give the title compound as a solid, 43 mg (57%).
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.OS(O)(=O)=O>O>[O:15]=[C:14]1[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:4]2[N:3]=[C:2]([OH:1])[CH:11]=[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]1[C:5]=23
Reactant: O=C(O)c1ccccc1-c1nc(O)cc2ccccc12
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1c2ccccc2-c2nc(O)cc3cccc1c23
Temperature: 130 °C
Reaction time: 1 h

Procedure:
103 g. of o-(3-hydroxy-1-isoquinolinyl)-benzoic acid were dispersed in 310 ml. of 96% H2SO4. This dispersion was then heated to 130° C. and kept under stirring at that temperature for 1 hour. The reaction mass was then cooled to about 90° C. and was then carefully poured into about 20 liters of hot water at 90°-95° C. The reaction mass was then stirred for 1 hour while leaving it to cool down.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][C:17]=1[O:24][CH2:25][CH:26]1[CH2:28][CH2:27]1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][C:17]=1[O:24][CH2:25][CH:26]1[CH2:28][CH2:27]1
Reactant: OCc1ccc(Cl)c(OCC2CC2)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)c(OCC3CC3)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-3-(cyclopropylmethoxy)phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 0.36-0.40 (2H, m), 0.62-0.67 (2H, m), 1.25-1.32 (1H, m), 3.88 (2H, d, J=6.8 Hz), 5.18 (2H, s), 5.72 (1H, d, J=1.6 Hz), 6.92 (1H, dd, J=4.0 Hz, 8.0 Hz), 7.01 (1H, d, J=1.6 Hz), 7.37 (1H, d, J=8.0 Hz), 7.40 (1H, dd, J=1.2 Hz, 5.2 Hz), 7.56 (1H, d, J=2.0 Hz), 8.04 (1H, s), 8.68 (1H, d, J=5.2 Hz). [M+H] Calc'd for C20H17ClN4O2, 381. Found, 381.
Reaction SMILES: Br[C:2]1([Br:10])[CH:9]2[CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2.[CH2:11]([OH:15])[CH2:12][CH:13]=[CH2:14].CCOC(C)=O>C1(C)C=CC=CC=1.[Al]>[Br:10][C:2]1=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[O:15][CH2:11][CH2:12][CH:13]=[CH2:14]
Reactant: BrC1(Br)C2CCCCCC21
Reactant: C=CCCO
Agent: C=CCCOC1CCCCC/C=C\1Br
Agent: [Al]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCCOC1CCCCCC=C1Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The compound 1 (2.73 g, 10.18 mmol) and 3-buten-1-ol (8.75 ml, 100.7 mmol, 10 eq.) are placed in anhydrous toluene (50 ml) in a round-bottomed flask wrapped in aluminum. AgClO4 (6.33 g, 30.53 mmol, 3 eq.) is added and the suspension is stirred at ambient temperature for 48 h. After addition of 150 ml of AcOEt and filtering, the solution is washed with deionized water. The organic phase recovered is dried over MgSO4, filtered and purified by flash chromatography (cyclohexane/AcOEt 99:1). The product 2 obtained (1.45 g, 5.59 mmol, 55%) is in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:3]=1[O:4][CH2:5][C@H:6]([OH:36])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:17][C:18]2[C:26]([N:27]=1)=[CH:25][C:24]1[C:23](=[O:28])[N:22]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:21](=[O:35])[C:20]=1[CH:19]=2.[C:42](=[NH:47])(OCC)[CH3:43]>CCN(CC)CC>[CH3:1][C:2]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:3]=1[O:4][CH2:5][C@H:6]([OH:36])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:17][C:18]2[C:26]([N:27]=1)=[CH:25][C:24]1[C:23](=[O:28])[N:22]([CH:29]3[CH2:30][CH2:31][N:32]([C:42](=[NH:47])[CH3:43])[CH2:33][CH2:34]3)[C:21](=[O:35])[C:20]=1[CH:19]=2
Reactant: CCOC(C)=N
Reactant: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCNCC2)C4=O)c(C)c1
Solvent: CCN(CC)CC
Product: CC(=N)N1CCC(N2C(=O)c3cc4nc(-c5c(NC[C@@H](O)COc6ccc(C)cc6C)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Temperature: 25 °C
Reaction time: 110 h

Procedure:
A mixture of 2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-1H-1,3,6-triaza-s-indacene-5,7-dione (109 mg, 0.2 mmol) and ethyl acetimidate (3 g) in Et3N (8 mL) was stirred at the room temperature for 110 h. After it was concentrated at 35° C. (the bath temperature) under reduced pressure, the mixture was subjected to chromatography [CH2Cl2/MeOH/28% aqueous NH4OH (90:10:1)] to furnish a fluorescent product which was purified again with HPLC to afford the title compound in TFA salt form (5.06 mg, 3.6%). 1H NMR (DMSO-d6) δ 1.93 (m, 2H), 2.19 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.35 (s, 3H, CH3), 3.26 (m, 1H), 3.40 (m, 1H), 3.58 (m, 1H), 3.86 (m, 1H), 3.91-4.26 (7H), 4.43 (m, 1H), 6.23 (d, J=7 Hz, 1H), 6.86 (d, J=7 Hz, 1H), 6.92 (d, J=7 Hz, 1H), 7.00 (s, 1H), 7.41 (d, J=7 Hz, 1H), 7.71 (s, 1H), 8.10 (s, 1H), 8.68 (br s, 1H, NH), 9.21 (br s, 1H, NH), 10.97 (br s, 1H, NH), 11.30 (br s, 1H, NH); ESI-MS m/z 598.7 (MH+).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:9]C[N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[CH3:11])[C:6](=O)[CH2:5]1.I[C:37]1[CH:42]=[CH:41][N:40]([CH3:43])[C:39](=[O:44])[CH:38]=1.[C:45]([O-:48])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:5][CH2:6][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([C:37]3[CH:42]=[CH:41][N:40]([CH3:43])[C:39](=[O:44])[CH:38]=3)=[CH:14][CH:13]=2)[CH3:11])[C:45](=[O:48])[CH2:9]1
Reactant: Cn1ccc(I)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)CC1=O
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)CC1=O
Temperature: 110 °C
Yield: 13.7 %

Procedure:
To a solution of (R)-4-(2-hydroxy-2-methylpropyl)-4-phenyl-1-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)piperidin-2-one (20 mg, 0.042 mmol) and 4-iodo-1-methylpyridin-2(1H)-one (7.8 mg, 0.084 mmol) in dry 1,4-dioxane (5 mL) was added Cs2CO3 (0.042 mL, 0.084 mmol) and Pd(PPh3)2Cl2 (10 mg). After addition, the mixture was warmed at 110° C. for 2 h under nitrogen. After TLC showed the starting material had disappeared, the solid was filtered off. Water (20 mL) and EtOAc (10 mL) were added, the organic layer was separated, and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give 4-(4-((S)-1-((R)-4-(2-hydroxy-2-methylpropyl)-2-oxo-4-phenylpiperidin-1-yl)ethyl)phenyl)-1-methylpyridin-2(1H)-one (2.63 mg, 14%), which was purified by preparative HPLC. LC-MS Method 2, tR=1.163 min, m/z=459.2. 1H NMR (CDCl3): δ 0.81 (s, 3H), 0.98 (s, 3H), 1.41 (d, 3H), 1.80 (m, 1H), 1.96 (m, 1H), 1.99-2.18 (m, 4H), 2.58 (m, 1H), 2.87 (m, 1H), 3.47 (m, 1H), 3.57 (s, 3H), 5.95 (m, 1H), 6.41 (m, 1H), 6.80 (s, 1H), 6.91 (m, 2H), 7.18 (m, 1H), 7.24 (m, 6H), 7.32 (d, 1H).