Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH:15][C:16]1[C:21](I)=[C:20]([CH3:23])[N:19]=[C:18]([NH2:24])[N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:25]([O:29][CH2:30][CH3:31])(=[O:28])[CH:26]=[CH2:27]>CN(C=O)C.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>[CH2:30]([O:29][C:25](=[O:28])/[CH:26]=[CH:27]/[C:21]1[C:16]([NH:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:17][C:18]([NH2:24])=[N:19][C:20]=1[CH3:23])[CH3:31]
Reactant: Cc1nc(N)nc(NCc2ccccc2)c1I
Reactant: C=CC(=O)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1c(C)nc(N)nc1NCc1ccccc1
Temperature: 95 °C
Reaction time: 24 h
Yield: 28 %

Procedure:
Triethylamine (7.60 mL, 54.5 mmol) was added to a suspension of N4-benzyl-5-iodo-6-methylpyrimidine-2,4-diamine (3.14 g, 10.9 mmol), ethyl acrylate (3.55 mL, 32.7 mmol) and Pd(PPh3)4 (629 mg, 0.545 mmol) in anhydrous DMF (20 mL). The reaction was heated to 95° C. under nitrogen. After 24 h, the reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was poured into a 10% solution of LiCl and washed with ethyl acetate (100 mL). The organic phase was separated and washed with brine, separated and dried over Na2SO4. The filtrate was concentrated in vacuo and purified on SiO2 (3:2 methylene chloride:ethyl acetate) to afford (E)-ethyl-3-(2-amino-4-(benzylamino)-6-methylpyrimidin-5-yl)acrylate (0.954 g, 28% yield) as a light yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=2)[CH3:2].[H-].[Na+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1>CN(C)C=O>[CH2:1]([C:3]1[N:4]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCOC(=O)c1ccc2[nH]c(CC)c(C)c2c1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)c(C)c(CC)n2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 500 mg portion of ethyl 2-ethyl-3-methyl-1H-indole-5-carboxylate was dissolved in 10 ml of N,N-dimethylformamide, and 113 mg of sodium hydride (55% dispersion in oil) was added under ice-cooling, followed by stirring at room temperature for 30 minutes. Then, 490 mg of 1-(bromomethyl)-4-fluorobenzene was added under ice-cooling, followed by stirring at room temperature for 2 hours. After evaporation of the solvent under a reduced pressure, the residue was diluted with ethyl acetate and washed with water and saturated brine. After drying the organic layer with anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:20 to 1:0) to obtain 587 mg of ethyl 2-ethyl-1-(4-fluorobenzyl)-3-methyl-1H-indole-5-carboxylate as a pale brown oily material.
Reaction SMILES: C([N:5]1[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:8][C:7]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[N:6]1)(C)(C)C>C(O)=O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C:7]2[CH:8]=[C:9]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17]([NH:20][C:21]4[S:22][CH:23]=[CH:24][N:25]=4)(=[O:18])=[O:19])=[CH:15][CH:16]=3)[NH:5][N:6]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)n1nc(Cc2ccc(Cl)cc2)cc1Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Solvent: O=CO
Product: O=S(=O)(Nc1nccs1)c1ccc(Nc2cc(Cc3ccc(Cl)cc3)n[nH]2)cc1
Reaction time: 16 h
Yield: 39.2 %

Procedure:
A solution of 4-[2-tert-butyl-5-(4-chloro-benzyl)-2H-pyrazol-3-ylamino]-N-thiazol-2-yl-benzenesulfonamide (20 mg, 0.04 mmol, 1.0 equiv) was heated in 1.0 mL of formic acid at 95° C. After 16 h, the reaction mixture was concentrated in vacuo. The residue was purified via automated flash chromatography (4 g SiO2, gradient from chloroform to 12% methanol in chloroform) to afford the product as an off-white solid (7 mg, 40%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.[ClH:23]>>[ClH:23].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: BrCCCCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: Cl
Product: BrCCCCCCOC1CCNCC1

Procedure:
In analogy to example 1.2a and 1.3, reaction of 4-Hydroxy-piperidine-1-carboxylic-acid tert-butyl ester and 1,6-dibromohexane followed by treatment with 4N HCl yielded 4-(6-Bromo-hexyloxy)-piperidine hydrochloride, MS: 264 (MH+, 1Br).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:35])[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:28]=[N:29][C:30]([CH2:33][CH3:34])=[CH:31][CH:32]=2)[CH:22]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:28]=[N:29][C:30]([CH2:33][CH3:34])=[CH:31][CH:32]=4)[CH:22]=3)[CH2:18][C:17](=[O:35])[NH:16][C:9]=2[CH:10]=1
Reactant: CCc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (4-chloro-2-{3-[3-(6-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example M171) (290 mg, 0.57 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (145 mg, 65%).
Reaction SMILES: B(F)(F)F.CC[O:7][CH2:8][CH3:9].C[N:11]1[C:19]2C[CH2:17][CH2:16][C:15](=O)[C:14]=2[CH:13]=[N:12]1.[N+](=CC(OCC)=O)=[N-].C(=O)(O)[O-].[Na+].[OH-].[K+].Cl.COC(OC)N(C)C>ClCCl.O>[NH:11]1[C:19]2[CH2:14][CH2:15][CH2:16][CH2:17][C:8](=[O:7])[C:9]=2[CH:13]=[N:12]1
Reactant: Cn1ncc2c1CCCC2=O
Reactant: CCOCC
Agent: CCOC(=O)C=[N+]=[N-]
Agent: COC(OC)N(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C1CCCCc2[nH]ncc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 108 ml of boron trifluoride etherate in 300 ml of dichloromethane was added dropwise to a solution of 79.3 g of 1,5,6,7-tetrahydro-1-methyl-4H-indazol-4-one and 100 g of ethyl diazoacetate in 1500 ml of dichloromethane. The rate of the addition was adjusted so that the temperature of the reaction mixture did not exceed 25° C. and the evolution of gas did not become vigorous. The addition took 3.5 hours and the reaction mixture was then stirred at room temperature, cooled to 0° C., and treated dropwise with 1000 ml of saturated aqueous sodium bicarbonate solution. The resulting slurry was stirred briefly and the layers which formed on standing were separated. The organic layer was washed with brine and dried over magnesium sulfate and the solvent was removed under reduced pressure to leave an amber oil. The oil was dissolved in dichloromethane and washed with 2.5M sodium hydroxide (two 300-ml portions). The dichloromethane solution was dried over magnesium sulfate and concentrated under reduced pressure to leave an amber oil. This oil was flash chromatographed (10% acetone in dichloromethane) to provide a further amber oil. This oil was treated with 24 g of potassium hydroxide an 300 ml of water and the mixture was heated in a boiling-water bath for 30 minutes. 5N Hydrochloric acid was added slowly until the pH was 2. The mixture was then heated briefly in a boiling-water bath and poured over ice. It was then neutralized with saturated sodium bicarbonate and extracted exhaustively with dichloromethane The combined extracts were dried over magnesium su1fate and the solvent was removed under reduced pressure to provide a dark oil which was heated at reflux with 60 ml of N,N-dimethylformamide dimethyl acetal for 2 hours. The solvent was removed under reduced pressure and the residue was flash chromatographed (10% acetone in dichloromethane) to give 5,6,7,8-tetrahydro-4(1H)-cycloheptapyrazolone as a red crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.Cl[C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:3][CH:4]=2)=[O:9])=[CH:11][CH:12]=1
Reactant: Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A 5-L 4-neck flask equipped with a thermocouple controller, a mechanical stirrer, a condenser, and a nitrogen inlet/outlet adapter was charged with (4-aminophenyl)(4-chlorophenyl)methanone (86.6 g, 370.1 mmol), DCM (2.61 L), and Et3N (70.3 mL, 499.6 mmol). After the solution was cooled to 5° C. in an ice-bath, ethyl 3-chloro-3-oxopropanoate (64.5 mL, 407.1 mmol) was added dropwise over 60 min. The resulting mixture was stirred at 0° C. for 1 h. Additional ethyl 3-chloro-3-oxopropanoate (12.9 mL) was added dropwise and the mixture was stirred at 0° C. for an additional 2 h. The reaction was cooled to 0° C. and ice-water (2 L) was added, followed by solid K2CO3 (60 g) until the solution was basic (pH=9-10). After phase separation, the organic layer was concentrated at 40° C. (to remove DCM) and then at 60° C. (to remove ex Et3N) to yield ethyl 3-((4-(4-chlorobenzoyl)phenyl)amino)-3-oxopropanoate as a slightly yellowish solid, which was used in the next step without further purification. (ES, m/z) 346, 348 (M+H)+
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:29])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[O:21])[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:30])[C:5]([C:31]([OH:33])=[O:32])=[CH:4]1)[CH3:2].Cl.[NH2:35]O>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:29])=[C:10]([N:13]3[CH2:14][CH2:15][N:16]([C:19](=[NH:35])[CH:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[OH:21])[CH2:17][CH2:18]3)[CH:11]=2)[C:6](=[O:30])[C:5]([C:31]([OH:33])=[O:32])=[CH:4]1)[CH3:2]
Reactant: NO
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=O)c4ccc(F)cc4)CC3)cc21
Agent: Cl
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C(=N)C(O)c4ccc(F)cc4)CC3)cc21

Procedure:
1-Ethyl-6-fluoro-7-{4-[2-(4-fluorophenyl)-2-hydroxy-iminoethyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid was prepared from 1-ethyl-6-fluoro-7-{4-[2-(4-fluorophenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (0.23 g, 0.5 mmole) and hydroxylamine hydrochloride (0.07 g, 1 mmol) by a method similar to that described for Example 3 (66% yield). 1H NMR (DMSO-d6): δ 1.39 (t, 3H, J=7.2), 2.62 and 3.25 (two m, 8H), 3.44 and 3.73 (two s, 2H), 4.57 (q, 2H, J=7.2), 7.15 (d, 1H, J=7.2), 7.42-7.83 (m, 4H),7.89 (d, 1H, J=13.3), 8.93 (s, 1H), 11.19 and 11.62 (two s, 1H), 15.23 (br s, 1H) Anal. Calcd. for C24H24F2N4O4•0.5 H2O: C, 60.12; H, 5.26; N, 11.68. Found: C, 60.01; H, 5.24; N, 11.60.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[CH2:8]=[O:9].[OH-].[Na+]>>[OH:9][CH2:8][C:2]1[C:1]([NH:5][C:4](=[O:6])[CH:3]=1)=[O:7]
Reactant: O=C1C=CC(=O)N1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Product: O=C1C=C(CO)C(=O)N1

Procedure:
24 Parts of maleimide (manufactured by Aldrich Corporation), 21 parts of 35% HCOH (manufactured by Wako Pure Chemical Industries, Ltd.) and 0.7 parts of a 5% aqueous NaOH solution are placed in a reactor and reacted at 40° C. for 2 hours. As a result, a white crystal of hydroxymethylmaleimide precipitates. This white crystal is filtered under reduced pressure and then dried at normal temperature under vacuum. The crude crystal of hydroxymethylmaleimide obtained in this manner is recrystallized from ethyl acetate to obtain 22 parts of hydroxymethylmaleimide.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.CS(C)(=O)=O>O1CCOCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([N:43]3[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]3)[N:13]=2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: CN1CCNCC1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CN1CCN(c2ncc(-c3cnc4[nH]ccc4n3)c(N[C@H]3CCCN(S(C)(=O)=O)C3)n2)CC1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, N-methylpiperazine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give ((S)-1-methanesulfonyl-piperidin-3-yl)-[2-(4-methyl-piperazin-1-yl)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-4-yl]-amine. MS (ES+): 472.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>ClCCl>[Br:1][C:2]1[CH:9]=[C:8]([O:10][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(O)cc(O)cc1Br
Reactant: C1=COCCC1
Solvent: ClCCl
Product: O=Cc1c(O)cc(OC2CCCCO2)cc1Br
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a mixture of 2-bromo-4,6-dihydroxybenzaldehyde (2.50 g, 11.5 mmol) in dichloromethane was added 3,4-dihydro-2H-pyran (1.45 g, 17.3 mol) and PPTs (0.58 g, 2.3 mmol) at room temperature. The resulting mixture was stirred for 2 h and quenched by saturated aqueous NaHCO3 (35 mL). The organic layer was washed with water (20 mL), brine (20 mL) and dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc=2:1) on silica gel to afford the title compound as a colorless oil (2.93 g, yield: 85%)
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[Br:11]N1C(=O)CCC1=O>CO>[Br:11][C:5]1[CH:6]=[CH:7][C:8]([NH2:10])=[N:9][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc(C2CC2)n1
Solvent: CO
Product: Nc1ccc(Br)c(C2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A solution of 6-cyclopropylpyridin-2-amine (2 g, 14.93 mmol), methanol (25 mL) was added N-bromosuccinimide (2.64 g, 14.93 mmol) portionwise. After stirring at room temperature for 30 minutes, mixture was evaporated and the residue obtained was purified on column (SiO2) using 10% ethyl acetate in hexanes as eluent. This afforded 2.1 gm (68.5% yield) of title compound. 1H NMR (CDCl3, 300 MHz): δ 7.45-7.43 (d, 1H), 6.16-6.13 (d, 1H), 4.30-4.20 (bs, 2H), 2.40-2.30 (m, 1H), 1.00-0.90 (m, 2H), 0.85-0.80 (m, 2H). MS: m/z=215.0 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:15]=[C:14]([O:16]C)[CH:13]=[C:12]2[C:4]=1[C@@:5]1([CH3:26])[C@H:10]([CH2:11]2)[C@@:9]2([CH3:25])[CH2:18][CH2:19][C:20](=[O:24])[C:21]([CH3:23])([CH3:22])[C@@H:8]2[CH2:7][CH2:6]1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]2[C:4]=1[C@@:5]1([CH3:26])[C@H:10]([CH2:11]2)[C@@:9]2([CH3:25])[CH2:18][CH2:19][C:20](=[O:24])[C:21]([CH3:22])([CH3:23])[C@@H:8]2[CH2:7][CH2:6]1
Reactant: COc1cc2c(c(OC)c1)[C@]1(C)CC[C@H]3C(C)(C)C(=O)CC[C@]3(C)[C@H]1C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)C(=O)CC[C@]2(C)[C@H]3Cc4cc(O)cc(O)c4[C@]3(C)CC[C@@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To ketone 6b (240 mg, 0.67 mmol) dissolved in 20 mL of methylene chloride stirring at 0° C. was added 2.7 mL of BBr3 (1.0 M in methylene chloride, 2.69 mmol). After stirring for one hour at 0° C., 6b was still present, and the reaction was allowed to reach room temperature over the next two hours. The reaction was then quenched with methanol, and water was added to the mixture. The aqueous phase was then extracted 3 times with methylene chloride (3×50 mL). The combined organic extracts were dried with MgSO4 and concentrated. The crude mixture was purified by flash chromatography to give 7b (190 mg, 0.578 mmol, 86%) as a white crystalline solid. 1H NMR (400 MHz, (CD3)2CO) δ 7.76 (s, 1H), 7.73 (s, 1H), 6.24 (t, J=0.96 Hz, 1H), 6.13 (d, J=1.6 Hz, 1H)), 2.66-2.61 (m, 1H), 2.59-2.52 (m, 2H), 2.49-2.46 (m, 1H), 2.44-2.37 (m, 1H), 1.86-1.82 (m, 1H), 1.81-1.77 (m, 1H), 1.76-1.71 (m, 1H), 1.67-1.55 (m, 4H), 1.15 (s, 3H), 1.13 (s, 3H), 1.07 (s, 3H), 1.09 (s, 3H); 13C NMR (100 MHz, (CD3)2CO) δ 216.9, 158.5, 154.8, 146.7, 131.9, 105.8, 102.8, 65.4, 57.2, 48.9, 47.3, 40.5, 39.6, 38.0, 35.4, 30.9, 27.9, 22.2, 22.1, 21.3, 16.9. ESIMS [M+Na]+ calcd for C21H28O3Na 351.1936, found 351.1929. [α]24D=+24.07°.
Reaction SMILES: O.[Cl:2][C:3]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:6]([N+:19]([O-])=O)=[C:5]([F:22])[CH:4]=1>C(O)(=O)C.[Fe]>[Cl:2][C:3]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:6]([NH2:19])=[C:5]([F:22])[CH:4]=1
Reactant: CCCCCOC(=O)COc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCOC(=O)COc1cc(N)c(F)cc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
A mixture of iron powder (115 g), acetic acid (29 g) and water (551 g) was heated at 80° C., and a solution of the compound (III) (132 g) in acetic acid (200 g) was dropwise added thereto in 1 hour, followed by heating under reflux for 5 hours. The reaction mixture was filtered to remove insoluble materials, and the filtrate was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was distilled off under reduced pressure to give 4-chloro-2-fluoro-5-(pentyloxycarbonylmethyloxy)aniline (Compound (II)) (90 g). Yield, 75 b.p., 145°-149° C./0.4 mmHg. m.p., 32°-3420 C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:6].[NH3:24]>CO>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH:15]=[CH:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:24])=[O:2])=[CH:9][CH:10]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)CC(=O)Nc1ccc(C=Cc2ccc(F)cc2)cc1
Reactant: N
Solvent: CO
Product: NC(=O)CC(=O)Nc1ccc(C=Cc2ccc(F)cc2)cc1
Yield: 89 %

Procedure:
Prepared in analogy to example 3 from N-{4-[2-(4-fluoro-phenyl)-vinyl]-phenyl}-malonamic acid methyl ester and 7M ammonia in methanol. Yield=89%. Colorless solid. MS: m/e=299.2 (M++H).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C:7]2=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:31])C=CC=CC=1.C(OCC)C>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:31])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C:7]2=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1ncc2cc(COC(C)=O)c(=O)n(C3CCCC3)c2n1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Acetic acid 8-cyclopentyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-ylmethyl ester (0.85 g, 2.55 mmol), prepared as in Example 26, and 2-benzenesulfonyl-3-phenyl-oxaziridine (0.8 g, 3.06 mmol) were mixed in dichloromethane (20 ml) and stirred at room temperature for 5 hours. To this mixture was added diethyl ether giving a solid precipitate which was filtered and dried in vacuo to provide acetic acid 8-cyclopentyl-2-methanesulfinyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-ylmethyl ester as a solid (0.81 g, (91%). MS (APCI) M++1; Calc'd 350.41. Found 350.2.
Reaction SMILES: [CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[O:3][CH2:2]1.Cl[CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:14]=1>>[CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][N:7]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=4)[CH:14]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCC4(CC3)OCCO4)ccn2)cc(OC)c1OC

Procedure:
4-Piperidone ethylene ketal (12.0 g) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (12.3 g) was condensed in the same manner as described in Example 2 to give the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:20][CH3:21])=[C:8]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=2)[CH2:4][NH:3]1.CCN(C(C)C)C(C)C.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:34]=1[CH2:35]Cl.[Cl-].[NH4+]>CN(C=O)C.O>[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:34]=1[CH2:35][N:3]1[CH:2]([CH3:1])[CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:20][CH3:21])=[C:8]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=2)[CH2:4]1
Reactant: COc1cc2c(cc1OCc1ccccc1)CC(C)NC2
Reactant: COc1ccc(OC)c(CCl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(OC)c(CN2Cc3cc(OC)c(OCc4ccccc4)cc3CC2C)c1
Temperature: 80 °C
Yield: 75.9 %

Procedure:
3-Methyl-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline (338 mg, 1.2 mmol) was dissolved in anhydrous DMF (3.6 mL), DIPEA (314 mg, 2.4 mmol) and 2,5-dimethoxybenzyl chloride (279 mg, 1.5 mmol) were added. The mixture was heated to 80° C. for 20 h, cooled to room temperature and poured into water (50 mL) and ammonium chloride (saturated, 2 mL). The mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography using Flashmaster (SiO2: 20 g, hexane 100% to hexane/ethyl acetate 50/50). W8 was obtained as sticky orange oil (395 mg, 76%). 1H NMR (270 MHz, CDCl3) δ 1.14 (3H, d, J 6.3, CHCH3), 2.48 (1H, dd, J 16.3, 6.0, one of ArCH2CH), 2.86 (1H, dd, J 16.1, 4.8, one of ArCH2CH), 3.11 (1H, sext, J 6.1, CHCH3), 3.58-3.77 (4H, m, 2×ArCH2N), 3.76 (3H, s, OCH3), 3.77 (3H, s, OCH3), 3.81 (3H, s, OCH3), 5.11 (2H, s, OCH2Ph), 6.50 (1H, s, CH), 6.61 (1H, s, CH), 6.74 (1H, dd, J 8.8, 3.0, CH), 6.80 (1H, d, J 8.8, CH), 7.07 (1H, d, J 2.8, CH), 7.24-7.47 (5H, m, OCH2C6H5). 13C NMR (67.5 MHz, CDCl3): δ 15.5, 34.5, 50.0, 51.4, 52.4, 55.7, 56.0, 56.0, 71.0, 109.9, 111.3, 111.9, 114.4, 116.0, 125.8, 127.0, 127.2, 127.7, 128.4, 128.9, 137.3, 146.5, 147.7, 151.9, 153.6.