Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([CH2:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:15])([CH3:14])[CH2:4][CH2:3]1.C(Cl)(=[O:19])C.[Cl-].[Al+3].[Cl-].[Cl-].C(C[C:29]([CH3:32])(C)C)(C)C>>[CH3:14][C:5]1([CH3:15])[C:6]2[C:11](=[CH:10][C:9]([CH2:29][CH3:32])=[C:8]([C:12](=[O:19])[CH3:13])[CH:7]=2)[C:2]([CH3:16])([CH3:1])[CH2:3][CH2:4]1.[CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([CH2:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:15])([CH3:14])[CH2:4][CH2:3]1
Reactant: CC(C)CC(C)(C)C
Reactant: CC(=O)Cl
Agent: CCc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1cc2c(cc1C(C)=O)C(C)(C)CCC2(C)C
Yield: 89 %

Procedure:
A solution of 1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetrahydronaphthalene (528 grams) and acetyl chloride (234 grams) is added over a 31/2 hour period at 70° C. to a well stirred slurry of aluminum chloride (534 grams), 1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetrahydronaphthalene (1200 grams) and isooctane (432 grams). The reaction is worked up as in Example I to afford 689 grams of 1,1,4,4-tetramethyl-6-ethyl-7-acetyl-1,2,3,4-tetrahydronaphthalene (89% based on consumed 1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetrahydronaphthalene) and 1106 grams of recovered 1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetrahydronaphthalene.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:3]1.[C:17](OC=C)(=[O:19])[CH3:18]>CC(CC(C)C)=O>[C:17]([O:1][C@@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:3]1)(=[O:19])[CH3:18]
Reactant: C=COC(C)=O
Reactant: COc1cccc(CC2=CC(O)CC2=O)c1
Solvent: CC(=O)CC(C)C
Product: COc1cccc(CC2=C[C@H](OC(C)=O)CC2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Hydroxy-2-(3-methoxybenzyl)cyclopent-2-enone (9 g, 41.26 mmol) was dissolved in isobutyl methyl ketone (90 mL), and vinyl acetate (8.4 g, 97.57 mmol) and Lipase derived from Alcaligenese spp. (0.9 g) were added to the solution, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered to remove Lipase and the filtrate was evaporated. The resulting residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give (R)-3-(3-methoxybenzyl)-4-oxocyclopent-2-enyl acetate as yellow oil: 4.29 g (95% ee by HPLC using a chiral column) and (S)-4-hydroxy-2-(3-methoxybenzyl)cyclopent-2-enone as yellow oil: 4.05 g (100% ee by HPLC using a chiral column)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][C@@H:18]1[CH2:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[NH:20][C:19]1=[O:29]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([N:17]([CH3:16])[C@@H:18]1[CH2:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[NH:20][C:19]1=[O:29])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN[C@@H]1CCc2ccccc2NC1=O
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Product: CN(C(=O)CC(C)(C)NC(=O)OC(C)(C)C)[C@@H]1CCc2ccccc2NC1=O

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and the amine obtained in Step B by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CDCl3): 1.30 (br s,15H), 2.19 (m,1H), 2.42 (m,1H), 2.5-2.8 (m,3H), 2.91 (m,1H), 3.15 (s,3H), 5.32 (dd;6,8 Hz;1H), 5.52 (br s,1H), 6/97 (d,5 Hz,1H), 7.1-7.3 (m,3H), 7.35 (br s,1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2([F:12])[CH2:11][CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.[F:15][CH:16]([F:19])[CH2:17][OH:18].[H-].[Na+]>>[F:15][CH:16]([F:19])[CH2:17][O:18][C:2]1[C:7]([C:8]2([F:12])[CH2:11][CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1
Reactant: N#Cc1cc(Cl)c(C2(F)CCC2)cn1
Reactant: OCC(F)F
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cc(OCC(F)F)c(C2(F)CCC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 123c, using 4-chloro-5-(1-fluorocyclobutyl)-pyridine-2-carbonitrile (example 305c) and 2,2-Difluoro-ethanol (CAN 359-13-7) as starting materials and sodium hydride as reagent. The title was isolated (1 g, 83%) as a yellow oil; MS (ESI, m/z): 257.1 (M+H+).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].II.[CH:24]([O:26][CH2:27][CH3:28])=[O:25].OS(O)(=O)=O>CCOCC>[CH:24]([O:26][CH:27]([CH2:1][CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:28][CH2:19][CH2:18][CH2:17]/[CH:16]=[CH:15]\[CH2:14]/[CH:13]=[CH:12]\[CH2:11]/[CH:10]=[CH:9]\[CH2:8]/[CH:7]=[CH:6]\[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[O:25]
Reactant: CCOC=O
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCBr
Agent: II
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC(CCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC)OC=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of arachidonyl bromide (II, 1 g, 3 mmol) in anhydrous ether (30 mL) was added Mg turnings (78 mg, 3.2 mmol) followed by one crystal of iodine. The resulting mixture was refluxed under nitrogen for 10 hours. The mixture was cooled to room temperature. To the cloudy mixture under nitrogen was added ethyl formate (0.25 mL), and the resulting mixture was stirred at room temperature overnight. To the mixture was added 20 mL of 10% H2SO4 aqueous solution. The ether phase was separated and aqueous phase extracted with ether (30 mL). The combined organic phase was washed with water (2×25 mL), brine (25 mL), and then dried over anhydrous Na2SO4. Evaporation of the solvent gave 1.1 g of pale oil as a crude product (III). The crude product was purified by column chromatography on silica gel (230-400 mesh, 40 mL) eluted with 0-3% ethyl acetate gradient in hexanes. This afforded 0.43 g (40%) of diarachidonylmethyl formate (III) as pale oil.
Reaction SMILES: [Cl-].Cl[CH2:3][C:4]1[NH+:5]([CH2:9][CH3:10])[CH:6]=[CH:7][N:8]=1.[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:9]([N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[CH2:3][S:18][C:16]1[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=1)[CH3:10]
Reactant: CC[NH+]1C=CN=C1CCl
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1ccnc1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.2 %

Procedure:
A mixture of 2-(chloromethyl)-1-ethyl-1H-imidazol-1-ium chloride (1.0 g, 5.5 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (650 mg, 4.6 mmol), and potassium carbonate (2.0 g, 14.4 mmol) in anhydrous DMF (10 mL) was stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure. The solid residue was treated with dichloromethane (20 mL) and brine (60 mL). The aqueous layer was recovered and evaporated. The residue was purified by flash chromatography (0-20% MeOH/CH2Cl2), affording 2-{[(1-ethyl-1H-imidazol-2-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (244 mg, 21% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.27 (t, 3H, J=7.2 Hz), 2.17 (s, 3H), 4.00 (m, 2H), 4.50 (s, 2H), 6.00 (s, 1H), 6.81 (s, 1H), 7.15 (s, 1H); M+251. The product was used without further purification.
Reaction SMILES: C(O)(=O)C.[OH:5][C:6]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1.[H][H]>CO.[Rh]>[CH:17]1([C:6]2([OH:5])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:7]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccccc2)C1
Agent: [Rh]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(O)(C2CCCCC2)C1
Temperature: 85 °C
Yield: 100 %

Procedure:
0.5 ml of acetic acid and 40 mg of rhodium on alumina 5% are added to a solution containing 117 mg (0.470 mmol) of 3-hydroxy-3-phenyl-1-(tert-butoxy-carbonyl)azetidine (cf. procedure 1-2-1) dissolved in 4 ml of methanol. The reaction medium is placed at 4 bar of hydrogen and heated at 85° C. for 4 hours. The catalyst is filtered off and washed with methanol and the solvents are evaporated off. 120 mg in the form of a beige powder are obtained with a yield of 100%.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][C@H:7]([N:10]2[CH2:14][CH2:13][C@H:12]([NH:15]C(=O)OCC3C=CC=CC=3)[C:11]2=[O:26])[C@H:6]([CH2:27][CH2:28][CH3:29])[CH2:5]1)([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:15][C@H:12]1[CH2:13][CH2:14][N:10]([C@H:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][C@H:6]2[CH2:27][CH2:28][CH3:29])[C:11]1=[O:26]
Reactant: [H][H]
Reactant: CCC[C@@H]1CN(C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CCC[C@@H]1CN(C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reaction time: 8 h
Yield: 95 %

Procedure:
A mixture of benzyl (S)-1-((3R,4S)-1-isopropyl-3-propylpiperidin-4-yl)-2-oxopyrrolidin-3-ylcarbamate (faster) (0.262 g) and Pd/C (0.056 g) in MeOH were stirred at rt under 50 psi hydrogen. After overnight stirring, the reaction was filtered through Celite. Concentrated and dried in vacuo to get the desired product, (3S)-3-amino-1-((3R,4S)-1-isopropyl-3-propylpiperidin-4-yl)pyrrolidin-2-one (faster) (0.166 g, yield=95%) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:18]([F:21])([F:20])[F:19])[C:5]([N:8]2[C:12]([OH:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]2)=[N:6][CH:7]=1.Br[CH2:23][N:24]1[C:28](=[O:29])[C:27]2[C:30]([CH:36]([CH3:38])[CH3:37])=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:26]=2[S:25]1(=[O:40])=[O:39]>CN(C=O)C>[C:36](=[C:30]1[CH:27]2[C:28](=[O:29])[N:24]([CH2:23][O:13][C:12]3[N:8]([C:5]4[C:4]([C:18]([F:19])([F:21])[F:20])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=4)[N:9]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:11]=3)[S:25](=[O:40])(=[O:39])[C:26]2=[CH:33][C:32]([O:34][CH3:35])=[CH:31]1)([CH3:38])[CH3:37]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Reactant: Oc1cc(C(F)(F)F)nn1-c1ncc(Cl)cc1C(F)(F)F
Solvent: CN(C)C=O
Product: COC1=CC(=C(C)C)C2C(=O)N(COc3cc(C(F)(F)F)nn3-c3ncc(Cl)cc3C(F)(F)F)S(=O)(=O)C2=C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
To a mixture 1-(5-chloro-3-trifluoromethyl-2-pyridyl)-3-trifluoromethyl-5-hydroxypyrazole (440 mg; 1.30 mmol) in 8 ml of DMF was added under nitrogen KF (132 mg, 2.28 mmol) and the mixture was stirred at room temperature for 10 minutes. To the above mixture was added 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (400 mg, 1.14 mmol) and the resulting mixture was stirred at room temperature for one hour. The mixture was quenched with cold saturated ammonium chloride solution, diluted with water, and extracted with ether (3×). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue (an oil) was purified by flash chromatography (silica gel; 20% ethyl acetate in hexane) and recrystallized from ether/hexane to afford 343 mg (50%) of 4-isopropyyl-6-methoxy-2-[1-(5-chloro-3-trifluoromethyl-2-pyridyl)-3-trifluoromethylpyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =3-CF3 -5-Cl-2-pyridyl; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 141°-142° C.
Reaction SMILES: CS(O)(=O)=O.C(OC([N:13]1[CH2:18][CH2:17][C:16]2=[N:19][N:20]([CH2:23][C:24]([F:27])([F:26])[F:25])[C:21](=[O:22])[C:15]2([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:14]1)=O)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][C:15]12[C:21](=[O:22])[N:20]([CH2:23][C:24]([F:26])([F:27])[F:25])[N:19]=[C:16]1[CH2:17][CH2:18][NH:13][CH2:14]2
Reactant: CC(C)(C)OC(=O)N1CCC2=NN(CC(F)(F)F)C(=O)C2(Cc2ccccn2)C1
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1N(CC(F)(F)F)N=C2CCNCC12Cc1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
Methanesulfonic acid (11.6 g, 121 mmol) was added dropwise to a solution of the product from step B (10 g, 24.2 mmol) in CH2Cl2 (100 mL) over about 30 minutes. The reaction mixture was stirred for about 1 hour, then cooled to about 0° C., and then triethylamine (18.6 mL, 133.1 mmol) was added through an addition funnel. The mixture was allowed to warm to room temperature over about 1 hour, diluted with additional CH2Cl2 and washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated in vacuo to afford the product as a white solid (7.2 g). 1H-NMR (CDCl3) δ: 2.51-2.72 (m, 4H), 3.35 (m, 2H), 3.49 (m, 2H), 4.03 (m, 1H), 4.25 (m, 1H), 7.08 (d, 2H), 7.51 (t, 1H), 8.37 (d, 1H).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4].[C:8]1([CH:18]=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1>>[C:8]1([CH2:18][N:1]2[CH2:7][CH2:6][CH2:5][C@H:2]2[CH2:3][OH:4])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: OC[C@@H]1CCCN1
Reactant: O=Cc1cccc2ccccc12
Product: OC[C@@H]1CCCN1Cc1cccc2ccccc12

Procedure:
Using (S)-prolinol ((S)-VII1) and α-naphthoaldehyde as the starting materials, a similar operation was carried out to obtain (S)-N-(α-naphthyl)methyl-2-pyrrolidine methanol ((S)-II-2). ##STR316##
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:13][CH2:14]O>>[CH2:13]([O:10][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH3:12])[CH3:14]
Reactant: CCO
Reactant: CC(C(=O)O)c1ccc(O)cc1
Product: CCOC(=O)C(C)c1ccc(O)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a mixture of 13.0 g (78.2 mmol) of 2-(4-hydroxyphenyl)propionic acid in 250 ml EtOH 5.82 ml (78.2 mmol) thionyl chloride are added slowly at 0° C. The reaction mixture is stirred at 70° C. for 2 h. After cooling to r.t. the solvent is removed in vacuo. The residue is mixed with toluene and the solvent is removed again.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12](I)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1.[Cu](I)I>[C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([C:26]#[C:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(N)c(I)c1
Reactant: C#Cc1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)c1ccc(N)c(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
[1-(4-Amino-3-iodophenyl)ethyl]carbamic acid tert-butyl ester (500 mg, 1.380 mmol, 1 eq.), dichloro(bistriphenylphosphine) palladium (48.4 mg, 0.069 mmol, 0.05 eq.) and copper iodide 13.1 mg (0.069 mmol, 0.05 eq.) were added in THF. After stirring for 30 min at room temperature, TEA (577.0 μl, 4.140 mmol, 3 eq) and phenylacetylene (197.0 μl, 1.794 mmol, 1.3 eq) were added into the reaction mixture. The reaction mixture was stirred overnight with reflux. A reaction solvent was removed in vacuo. The residue was purified with column chromatography (n-Hx:EA=5:1) to yield title compound (452.7 mg) as a yellow liquid.
Reaction SMILES: [CH2:1]([C:4]([C:18]#[N:19])([CH:15]([CH3:17])[CH3:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[CH:2]=[CH2:3].N(C(C)(C)C#N)=NC(C)(C)C#N.[BrH:32].C(=O)([O-])[O-].[K+].[K+]>C1CCCCC1.CCCCCC>[Br:32][CH2:3][CH2:2][CH2:1][C:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)([CH:15]([CH3:17])[CH3:16])[C:18]#[N:19]
Reactant: Br
Reactant: C=CCC(C#N)(c1ccc(OC)c(OC)c1)C(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Yield: 94 %

Procedure:
To a solution of 50 g of α-allyl-α-isopropyl-3,4-dimethoxy- benzyl cyanide and 2 g of azobisisobutyronitrile in 400 ml of cyclohexane (or n-hexane) gaseous hydrogen bromide was introduced for 70 minutes, when, according to GLC, the reaction mixture did not contain the starting allyl derivative. During the introduction of the hydrogen bromide, the reaction temperature raised to 40° C. The reaction mixture was neutralized with 200 ml of 30% solution of potassium carbonate. The separated cyclohexane solution of the product was washed with water until neutral pH. After drying and evaporating the solvent under diminished pressure, the crude product (61.7 g, 94%) was obtained, which could be used without purification in further reaction step.
Reaction SMILES: CO.[Cl:3][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:7][NH:8][C:9]1[C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][N:12]=[C:11]([N:20]2[CH2:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)[N:10]=1.O.[Na]>O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:7][NH:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]([N:20]2[CH2:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)[N:10]=1
Reactant: CCOC(=O)c1cnc(N2Cc3cccnc3C2)nc1NCc1ccc(OC)c(Cl)c1
Agent: [Na]
Solvent: O
Solvent: CO
Product: COc1ccc(CNc2nc(N3Cc4cccnc4C3)ncc2C(=O)O)cc1Cl
Reaction time: 8 h
Yield: 36 %

Procedure:
Methanol (30 mL) was added in ethyl 4-((3-chloro-4-methoxybenzyl)amino)-2-(5H-pyrrolo[3,4-b]pyridin-6 (7H)yl)-5-pyrimidine carboxylate (3.0 g, 6.82 mmol). Sodium hydrate (0.55 g, 13.6 mmol) was dissolved in water (10 mL) and added into the solution. The reaction was conducted in an oil bath of 50 to 60° C. overnight. LC-MS was used to monitor the reaction. The organic solvent was removed by rotary evaporation. The residual aqueous phase was adjusted to a pH of 3 to 4. Solid was precipitated, filtrated, and dried (1.0 g, 36.0% yield).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C@H:20]1[CH2:22][O:21]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH3:34])=[O:32])=[C:26]([Cl:35])[CH:25]=1)#[N:7]>O1CCCC1>[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C@H:20]([OH:21])[CH2:22][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH3:34])=[O:32])=[C:26]([Cl:35])[CH:25]=1)#[N:7]
Reactant: C1CCNC1
Reactant: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC[C@H]4CO4)c(C#N)cc23)cc1Cl
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC[C@H](O)CN4CCCC4)c(C#N)cc23)cc1Cl
Temperature: 60 °C

Procedure:
After adding tetrahydrofuran (1.0 ml) and pyrrolidine (0.10 ml) to N-(4-{6-cyano-7-[(2R)-oxiran-2-yl]methoxyquinolin-4-yloxy}-2-chlorophenyl)-N′-methylurea (110 mg), the mixture was heated at 60° C. for 2 hours. The reaction solution was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to obtain the title compound (65 mg) as light yellow crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1>>[CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:14][CH2:15][N:16]([C:22]4[CH:23]=[CH:24][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=4)[CH2:17][CH2:18]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Product: Cc1c(C)c(N2CCN(c3ccc(OC(F)(F)F)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 50.9 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (311 mg, 1.0 mmol) synthesized in Reference example 61 and 1-bromo-4-(trifluoromethoxy)benzene (0.223 mL, 1.5 mmol), the reaction was carried out in the same manner as Example 1 to synthesize the title compound 221 mg (yield 51%). Melting point was 216 to 219° C. (hexane).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[N:7]([C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:24](=[O:29])[NH:25][CH2:26][C:27]=2[N:28]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:41].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:37])[N:7]([C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:24](=[O:29])[N:25]([CH3:41])[CH2:26][C:27]=2[N:28]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CNC(=O)N3c2ccc(Cl)cc2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CN(C)C(=O)N3c2ccc(Cl)cc2)c(OC)c1
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To a solution of [1-(4-chloro-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl]-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (Example 21, low RF compound from Step 1) (120 mg, 0.23 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 14 mg, 0.34 mmol, 1.5 equiv) and the reaction mixture was stirred for 1 h. Iodomethane (30 μL, 0.46 mmol, 2 equiv) was added and stirring was continued overnight. Water was added and the product was extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered and the solvent evaporated. The crude material was purified by column chromatography (SiO2, eluted with petrol—EtOAc 0-100%) to afford [1-(4-chloro-phenyl)-3-methyl-2-oxo-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl]-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (49 mg). MS: [M+H]+=539.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]1[C:17](=[O:18])[CH2:16][NH:15][C:14](=O)[CH:13]=[C:8]12.O=P(Cl)(Cl)Cl.[CH:25]([C:28]1[N:29]=[CH:30][NH:31][CH:32]=1)([CH3:27])[CH3:26].C([O-])(O)=O.[Na+]>ClCCCl>[CH:25]([C:28]1[N:29]=[CH:30][N:31]([C:14]2[CH:13]=[C:8]3[C:9]4[C:4]([CH2:5][CH2:6][N:7]3[C:17](=[O:18])[CH2:16][N:15]=2)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=4)[CH:32]=1)([CH3:27])[CH3:26]
Reactant: COc1cccc2c1CCN1C(=O)CNC(=O)C=C21
Reactant: CC(C)c1c[nH]cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc2c1CCN1C(=O)CN=C(n3cnc(C(C)C)c3)C=C21
Temperature: 100 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
To a stirred solution of 9-methoxy-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (80 mg, 0.31 mmol) in 1,2-dichloroethane (8 mL) was added POCl3 (0.058 mL, 0.62 mmol) and the resulting yellow suspension was stirred at 100° C. for 1 h. The reaction mixture was cooled to RT and concentrated under reduced pressure to dryness. The resulting crude chloro compound was dissolved in 1,2-dichloroethane (8 mL), 4-isopropyl-1H-imidazole (102 mg, 0.93 mmol) was added and the mixture was stirred at 100° C. for 2 h. The reaction mixture was allowed to warm to RT. Saturated aqueous NaHCO3 solution was added and the mixture was extracted twice with DCM. The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (eluent: gradient 0% to 100% ethyl acetate/cyclohexane in 30 min) to yield 15 mg of a brown solid. Further purification by SFC (column: Diol 5 μm, 250×30 mm, 60A, Princeton; eluent: 13% MeOH/CO2 for 0.5 min, then from 13% MeOH/CO2 to 18% MeOH/CO2 in 6 min; then from 18% MeOH/CO2 to 50% MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) yielded the title compound (9 mg). UPLC-MS: MS 351.3 (M+H+); UPLC rt 0.90 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.35 (d, J=6.8 Hz, 6 H), 2.95 (t, J=6.2 Hz, 2 H), 3.03-3.19 (m, 1 H), 3.88 (s, 3 H), 3.92-4.05 (m, 2 H), 4.40 (s, 2 H), 6.87-7.05 (m, 2 H), 7.19-7.58 (m, 4 H).