Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(N(CC)CC)C.C1OC1C>CN(C)P(=O)(N(C)C)N(C)C>[CH2:17]([O:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCBr
Reactant: COc1cc([N+](=O)[O-])c2ncccc2c1O
Agent: CC1CO1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Product: CCCCCCOc1c(OC)cc([N+](=O)[O-])c2ncccc12
Reaction time: 8 h
Yield: 64.1 %

Procedure:
A stirred mixture of 5-hydroxy-6-methoxy-8-nitroquinoline (22 g, 0.1 mole), n-hexyl bromide (18.5 g, 0.11 mole), triethylamine (1 g) and hexamethylphosphoric triamide (16 ml) was maintained at a bath temperature of 120°-130° while 10 g of propylene oxide was added during 0.5 hr. The mixture was heated at a bath temperature of 130°-145° for 3 hr and 5 more grams of propylene oxide was added. After 8 hr at 110°-120°, a low-boiling fraction was distilled off at 100° (1 atm) and the residue was cooled and poured into 3 liters of ice water. The resulting dull red solid was filtered and extracted with diethyl ether (2.5 g of 5-hydroxy compound was recovered as a diethyl ether-insoluble red solid). The ether extract was washed with dilute sodium hydroxide and water, dried (sodium sulfate) and concentrated to leave a thick oil. Trituration with petroleum ether (bp 20°-40°) gave 19.5 g (65%) of the required 5-hexoxy-quinoline derivative as a tan solid, mp 46°-49°. Crystallization from aqueous methanol (carbon) provided an analytical sample as yellow needles, mp 53°-55°.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH:16][C:17](=[O:30])[C@@H:18]([N:23]3[CH2:27][CH2:26][CH2:25][S:24]3(=[O:29])=[O:28])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[O:29]=[S:24]1(=[O:28])[CH2:25][CH2:26][CH2:27][N:23]1[C@@H:18]([CH2:19][CH:20]([CH3:21])[CH3:22])[C:17]([NH:16][C@H:13]1[C@H:11]2[C@H:10]([CH2:9][NH:8][CH2:12]2)[CH2:15][CH2:14]1)=[O:30]
Reactant: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N1CCCS1(=O)=O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CNC[C@H]21)N1CCCS1(=O)=O

Procedure:
(25)-N-[(3aS,4R,6aR)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-yl]-2-(1,1-dioxidoisothiazolidin-2-yl)-4-methylpentanamide (265 mg, 0.611 mmol) from Example 220 Step D and ethanol (20 mL) were added to 20% Pd(OH)2 on carbon, wet (53.0 mg, 0.377 mmol) in a 50 mL pressure bottle and stirred for 48 hours under 30 psi hydrogen at 50° C. The mixture was filtered through a nylon membrane and the solvent removed in vacuo to give (2S)-2-(1,1-dioxidoisothiazolidin-2-yl)-4-methyl-N-[(3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]pentanamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.89 (dd, J=6.6, 18.9, 1H), 4.55-4.50 (m, 1H), 4.42-4.31 (m, 1H), 3.99-3.91 (m, 1H), 3.44-3.39 (m, 1H), 3.34 (dd, J=2.8, 11.4, 0.5H), 3.29-3.25 (m, 2H), 3.21 (dd, J=5.4, 13.2, 1H), 3.13 (dd, J=7.7, 11.2, 0.5H), 2.99 (td, J=7.5, 10.8, 1H), 2.79 (dd, J=3.3, 10.9, 0.5H), 2.73 (dd, J=3.3, 10.9, 0.5H), 2.69-2.55 (m, 2H), 2.31-2.16 (m, 2H), 2.12-2.00 (m, 1H), 1.94-1.78 (m, 4H), 1.69 (dddd, J=5.2, 11.0, 16.7, 19.8, 2H), 1.49-1.29 (m, 1H), 0.88 (t, J=6.5, 3H), 0.83 (t, J=6.4, 3H); MS (ESI+) m/z 344 (M+H)+
Reaction SMILES: C(O[C:6]1[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:7]=1)CCC.[Cl:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]=[CH:23][C:22]1=[O:27].O>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:20][N:21]1[CH2:26][CH2:25][C:24]2[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:7]=[C:6]([OH:10])[C:23]=2[C:22]1=[O:27]
Reactant: CCCCOc1cnc(C(=O)OCC)o1
Reactant: O=C1C=CCCN1Cc1ccc(F)c(Cl)c1
Solvent: O
Product: CCOC(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 130 °C
Reaction time: 72 h

Procedure:
A mixture of ethyl 5-butoxy-1,3-oxazole-2-carboxylate (44.5 g, 208.6 mol), 1-(3-chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one (25 g, 104.3 mol), and water (2.82 mL, 156.7 mol) was heated in a sealed heavy walled vessel at 130° C. with stirring for 72 hours. Upon cooling, the product mixture solidified. The solid was triturated with diethyl ether and collected by filtration. The product was further purified by crystallization from boiling ethyl acetate.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH2:13][OH:14])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]>[O-2].[O-2].[Mn+4]>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][CH:13]=[O:14])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(/C=C/CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Product: CC(C)Oc1ccc(C=CC=O)cc1
Yield: 89 %

Procedure:
According to the same manner as that described in Reference Example 20, (E)-3-(4-isopropoxyphenyl)-2-propenol was oxidized with activated manganese dioxide to give 4-isopropoxycinnamaldehyde as an oil (yield: 89%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].[H-].[Na+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=1[Cl:30].[I-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:22][C:21]=2[Cl:30])[C:6]=1[CH3:14]
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2Cl)c2ncccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice cooled (0° C.) stirred solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((2.25 g, 1.1 mmol) in dry DMF (15 ml) is added sodium hydride (0.484 g of a 60% dispersion in mineral oil, 12.1 mmol). After stirring at room temperature for 3 hours, the reaction mixture is re-cooled to 0° C. and treated with 1-bromomethyl-2-chloro-4-methanesulfonyl-benzene (5.0 g, 17.6 mmol) and sodium iodide (2.64 g, 17.6 mmol). The resulting mixture is stirred and allowed to warm to room temperature overnight. The reaction mixture is poured onto water (300 ml) and extracted with 1:1 ethyl acetate/diethyl ether. The organic portions are washed with brine, dried (Na2SO4) and concentrated in vacuo and the resulting crude is purified by chromatography on silica eluting with ethyl acetate/iso-hexane (1:4 increasing to 1:2) to yield the titled product. (MH+ 407)
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[C:27]([O:31][C:32](=[O:52])[N:33]([CH2:42][C:43]1[C:44]([O:50][CH3:51])=[N:45][CH:46]=[C:47]([F:49])[CH:48]=1)[C:34]1[N:39]=[CH:38][C:37]([CH:40]=[O:41])=[CH:36][N:35]=1)([CH3:30])([CH3:29])[CH3:28].[Cl-].[NH4+]>O1CCCC1>[C:27]([O:31][C:32](=[O:52])[N:33]([C:34]1[N:39]=[CH:38][C:37]([CH:40]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=3)[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:11]=2)[OH:41])=[CH:36][N:35]=1)[CH2:42][C:43]1[C:44]([O:50][CH3:51])=[N:45][CH:46]=[C:47]([F:49])[CH:48]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1ncc(F)cc1CN(C(=O)OC(C)(C)C)c1ncc(C=O)cn1
Reactant: COc1cnc2c(c1)c(I)cn2S(=O)(=O)c1ccccc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cnc2c(c1)c(C(O)c1cnc(N(Cc3cc(F)cnc3OC)C(=O)OC(C)(C)C)nc1)cn2S(=O)(=O)c1ccccc1
Temperature: 5 °C

Procedure:
To a solution of 1-benzenesulfonyl-3-iodo-5-methoxy-1H-pyrrolo[2,3-b]pyridine (16, 1 equivalent) in 4.0 mL of tetrahydrofuran, isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 1 equivalent) is added slowly at −50° C. The reaction is allowed to warm to 5° C. over 70 minutes, then cooled to −45° C. and (5-fluoro-2-methoxy-pyridin-3-ylmethyl)-(5-formyl-pyrimidin-2-yl)-carbamic acid tert-butyl ester (123, 0.78 equivalent) in 2.0 mL of tetrahydrofuran is added. The reaction is allowed to warm to room temperature over 1 hour, then poured into aqueous ammonium chloride and extracted with ethyl ether. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound.
Reaction SMILES: [Li]CCCC.[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]1=2.[Cl:15][CH2:16][CH2:17][CH2:18]I.O>C1COCC1.[Cu]I>[Cl:15][CH2:16][CH2:17][CH2:18][C:10]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=1
Reactant: ClCCCI
Reactant: c1ccc2sccc2c1
Agent: [Cu]I
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: ClCCCc1cc2ccccc2s1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 44.1 %

Procedure:
n-BuLi in heptanes (0.75 ml, 1.2 mmol, 1.6M) was added drop wise to benzo[b]thiophene (134 mg, 1.0 mmol) in THF (4 ml) at −5° C. under argon. The reaction mixture was stirred at −5° C. for 15 min, then 1-chloro-3-iodopropane (151 μl, 1.2 mmol) and copper (1) iodide (19 mg, 0.1 mmol) were added. The reaction was stirred at −5° C. for 1 h, then at room temperature for 0.5 h. Water (5 ml) was added, the product was extracted with diethyl ether (2×10 ml) and the organic layer was dried (K2CO3), filtered and concentrated in vacuo. The product was purified by column chromatography (0-2% ethyl acetate in heptanes) to give 2-(3-chloro-propyl)-benzo[b]thiophene (93 mg, 44%). 1H NMR (CDCl3): δ2.22 (tt, 2H), 3.10 (dt, 2H), 3.61 (t, 2H), 7.06 (m, 1H), 7.30 (m, 2H), 7.69 (m, 1H), 7.78 (m, 1H). 2-(3-Chloro-propyl)-benzo[b]thiophene (53 mg, 0.25 mmol), 4-butylpiperidine (36 mg, 0.25 mmol), sodium iodide (75 mg, 0.5 mmol) and sodium carbonate (53 mg, 0.5 mmol) in acetonitrile (2 ml) were shaken at 80° C. for 18 h, then the reaction was cooled to room temperature. Water (5 ml) was added and the product was extracted with ethyl acetate (2×10 ml), dried (K2CO3), filtered and concentrated in vacuo. The product was purified by column chromatography (0-15% ethyl acetate in heptanes +0.1% Et3N) to yield the title compound 54. Yield 29 mg (37%). The hydrochloride salt was formed by addition of HCl (4M in dioxane) and recrystallised from methanol-diethyl ether to give a white precipitate that was filtered and dried. 1H NMR (CD3OD): δ0.91 (t, 3H), 1.32 (m, 6H), 1.39 (m, 2H), 1.55 (m, 1H), 1.96 (br. d, 2H), 2.19 (tt, 2H), 2.93 (m, 2H), 3.04 (t, 2H), 3.14 (m, 2H), 3.53 (m, 2H), 7.14 (br. s, 1H), 7.26 (m, 1H), 7.31 (m, 1H), 7.68 (m, 1H), 7.77 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]([CH2:25]Cl)=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.CC(C)([O-])C.[K+]>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[N:14]4[CH2:15][CH2:16][N:17]([C:18]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24])[CH2:25][C:13]4=[N:12][C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCn1c(CCl)nc2cnc3cc(Br)ccc3c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCn2c(nc3cnc4cc(Br)ccc4c32)C1
Reaction time: 8 h

Procedure:
The method described in Part D of Example 365 was used to treat tert-butyl 2-[7-bromo-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate (10.0 g, 22.7 mmol) with potassium tert-butoxide (27.29 mL of a 1 M solution in THF) with the modification that the reaction was stirred overnight to provide tert-butyl 3-bromo-10,11-dihydropyrazino [1′,2′:1,2]imidazo[4,5-c]quinohne-9(8H)-carboxylate in a crude mixture.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:11]3[S:12][CH2:13][CH2:14][N:10]3[N:9]=2)=[C:6]([F:22])[CH:5]=[CH:4][C:3]=1[NH2:23].[F:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[S:32](Cl)(=[O:34])=[O:33].[OH-].[K+]>N1C=CC=CC=1.C(OCC)(=O)C.C1COCC1>[F:1][C:2]1[C:7]([C:8]2[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:11]3[S:12][CH2:13][CH2:14][N:10]3[N:9]=2)=[C:6]([F:22])[CH:5]=[CH:4][C:3]=1[NH:23][S:32]([C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[F:24])(=[O:34])=[O:33]
Reactant: Nc1ccc(F)c(-c2nn3c(c2-c2ccncc2)SCC3)c1F
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1ccc(F)c(-c2nn3c(c2-c2ccncc2)SCC3)c1F)c1cc(F)ccc1F
Reaction time: 1 h
Yield: 23.4 %

Procedure:
To 2,4-difluoro-3-(7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazol-6-yl)phenylamine (115 mg, 0.54 mmol) in pyridine (3 mL) was added 2,5-difluoro-benzenesulfonyl chloride (88 μL, 0.81 mmol) and the mixture was stirred under nitrogen atmosphere for one hour. The mixture was diluted with ethyl acetate and washed with NaHCO3 saturated solution and with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and dried. The solvent was removed under reduce pressure to give a mixture of mono and bis-sulfonamide. The crude was dissolved in THF (4 mL). A 1 M KOH solution (4 mL) was added and the mixture was stirred at 70° C. overnight. The solvent was removed under reduced pressure and the crude was dissolved in ethyl acetate and washed with NaHCO3 saturated solution twice. The organic layer was dried over sodium sulphate, filtered and the solvent was removed under reduced pressure. N-[2,4-Difluoro-3-(7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazol-6-yl)-phenyl]-2,5-difluoro-benzenesulfonamide (64 mg, 37%) was isolated by silica gel chromatography column eluting with ethyl acetate 5% in hexane.
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[F:42][C:43]([F:54])([F:53])[O:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49][NH2:50])=[CH:47][CH:46]=1>C1COCC1>[F:42][C:43]([F:53])([F:54])[O:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49][NH:50][C:30]([C:28]2[CH:27]=[CH:26][C:12]3[N:13]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=4)[C:9]([CH2:8][O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:10][C:11]=3[CH:29]=2)=[O:31])=[CH:47][CH:46]=1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of 4-trifluormethoxy-benzylamine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 616.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[CH3:13].CO.[C:29]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C.CCCCCC>[CH3:29][O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH:12]([N:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]1)[CH3:13]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(c1c(O)ccc2c1OCC2=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1C(C)N1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 0 °C
Yield: 11.5 %

Procedure:
A solution of tert-butyl 4-[1-(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)ethyl]piperazine-1-carboxylate (0.75 g, 2.1 mmol) synthesized in Example B7, Step 2 in tetrahydrofuran (20 mL) was added with methanol (0.20 g, 6.3 mmol), and triphenylphosphine (0.65 g, 2.5 mmol). The reaction mixture was stirred at 0° C. under an argon atmosphere, and added dropwise with a 40% solution of diethyl azodicarboxylate in toluene (1.91 g, 4.4 mmol). After completion of the addition, the mixture was stirred at 40° C. for 20 hours. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluted with hexane/ethyl acetate (85:15→0:100)) to obtain a solid containing the objective substance. The solid was suspended in a mixed solvent of hexane and ethyl acetate and thereby washed, and the insoluble matter was removed by filtration. The filtrate was concentrated, the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with hexane/ethyl acetate (2:1→1:3)) to obtain tert-butyl 4-[1-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)ethyl]piperazine-1-carboxylate (0.091 g, 12%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br/[CH:41]=[CH:42]/[CH2:43][C:44]([O:47][Si:48]([CH2:53][CH3:54])([CH2:51][CH3:52])[CH2:49][CH3:50])([CH3:46])[CH3:45].[H-].[Na+].C1OCCOCCOCCOCCOC1>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24]/[CH:41]=[CH:42]/[CH2:43][C:44]([O:47][Si:48]([CH2:49][CH3:50])([CH2:51][CH3:52])[CH2:53][CH3:54])([CH3:45])[CH3:46])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[Si](CC)(CC)OC(C)(C)C/C=C/Br
Reactant: CC(C)(O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)C/C=C/OC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 99 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene (103 mg, 0.180 mmol), 1-bromo-4-triethylsilyloxy-4-methyl-(2E)-pentene (211 mg, 0.719 mmol), sodium hydride (60% in oil, 43 mg, 1.08 mmol), 15-crown-5 (40 mg, 0.182 mmol) and tetrahydrofuran (3 ml) were subjected to reaction using a procedure similar to that of Example 5(1) (reflux under heating for 6 hours), worked up and purified by column chromatography (hexane:toluene=2:1) to give the titled compound (140 mg, 99%) as a colorless solid.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:22]=1[CH2:23][NH2:24].CCN(C(C)C)C(C)C>>[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:22]=1[CH2:23][NH:24][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: COc1cccc(F)c1CN
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(F)c1CNC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-fluoro-6-methoxy-benzylamine and DIEA to give 2-(2-fluoro-6-methoxy-benzylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 394 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:28]([NH2:29])=[N:27][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:15]=[CH:16][C:11]=2[CH:10]=1.[H-].[Na+].[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:28]([NH:29][C:39]([NH:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:40])=[N:27][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCN(CC)CCCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)Nc3ccccc3)nc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
To a solution of 6-(2,6-dichlorophenyl)-N2 -(4-diethylamino-butyl)-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 53 in DMF (15 mL) was added one equivalent of 60% sodium hydride suspension (0.93 g). After stirring for approximately 1 hour at room temperature, one equivalent of phenyl isocyanate (0.275 g) was added, and the reaction was monitored by thin layer chromatography. After approximately 24 hours, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, and this solution was washed several times, first with water and then a saturated solution of sodium chloride. The ethyl acetate layer was dried with magnesium sulfate and concentrated in vacuo. Chromatography of the residue over silica gel using ethyl acetate:methanol: triethylamine (90:10:1) followed by ethyl acetate: ethanol:triethylamine (9:2:1) gave 0.8461 g of the title compound 1-[6-(2,6-dichlorophenyl)-2-(4-diethylamino-butylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-phenyl-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=552 (Base), 433; mp 81°-87.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[O:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:5]=[C:4]([NH:13]C(=O)C(F)(F)F)[CH:3]=1.[OH-].[Na+]>>[NH2:13][C:4]1[CH:3]=[C:2]([Cl:1])[C:11]2[O:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:5]=1
Reactant: O=C1COc2c(Cl)cc(NC(=O)C(F)(F)F)cc2N1
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(Cl)c2c(c1)NC(=O)CO2

Procedure:
N-(8-Chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2,2,2-trifluoroacetamide was hydrolyzed with sodium hydroxide to obtain 6-amino-8-chloro-2H-1,4-benzoxazin-3(4H)-one.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:20]([CH2:19][C:18]1[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=1)[CH2:11]2
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)c1c(Cl)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C1c2c(Cl)cccc2CN1Cc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A mixture of 2-bromomethyl-6-chloro-benzoic acid methyl ester (0.132 g, 0.5 mmol), 4-chloro-benzylamine (0.073 g, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-chloro-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.116 g, 79%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.24 (s, 2H), 4.74 (s, 2H) 7.24-7.46 (m, 7H). GC-MS: m/z 291 (M)+.