Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]12[C:19]([CH3:21])([CH3:20])[CH:16]([CH2:17][CH2:18]1)[CH2:15][C:14]2([CH2:23][C:24]([CH3:26])=[CH2:25])[OH:22].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:12][C:13]12[C:19]([CH3:20])([CH3:21])[CH:16]([CH2:17][CH2:18]1)[CH2:15][C:14]2([CH2:23][C:24]1([CH3:26])[CH2:25][O:9]1)[OH:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)CC1(O)CC2CCC1(C)C2(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(CC2(O)CC3CCC2(C)C3(C)C)CO1

Procedure:
38.0 g (0.22 mol) of m-chloroperbenzoic acid was added portionwise to a stirred and cooled (ice bath) suspension of 28.7 g (0.14 mol) of (1RS,2SR,4RS)-1,7,7-trimethyl-2-(2-methyl-2-propenyl)bicyclo[2.2.1]heptan-2-ol and 23.1 g (0.27 mol) of sodium bicarbonate in 500 ml of methylene chloride. The temperature was maintained below 20° C. The reaction mixture was stirred at room temperature for an additional 5 hours, filtered and washed with 300 ml of saturated aqueous sodium bicarbonate solution and 300 ml of brine. After drying with MgSO4 and evaporation of the solvent the crude epoxide (30.9 g) was used in the next step without further purification.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([N:23]3[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:29])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[O:31]1[CH2:34][C:33](=O)[CH2:32]1>>[O:30]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([N:23]3[CH2:27][CH2:26][CH:25]([NH:28][CH:33]4[CH2:34][O:31][CH2:32]4)[CH2:24]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:29])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCC(N)C3)c2c1
Reactant: O=C1COC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCC(NC4COC4)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 45-1 in Scheme 20 by using 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-amine and oxetan-3-one (prepared in analogy to Example 25) and oxetan-3-one. MS obsd. (ESI+) [(M+H)+] 479, 1H NMR (400 MHz, CD3OD) δ ppm 7.99-7.97 (m, J=2.2 Hz, 1 H), 7.83-7.80 (t, J=2.9 Hz, 2 H), 7.64-7.60 (m, J=4.1 Hz, 1 H), 7.47-7.43 (m, J=4.5 Hz, 2 H), 7.29-7.26 (m, J=2.5 Hz, 1 H), 6.12 (s, 1 H), 5.15 (s, 2 H), 4.85 (m, 2 H), 4.56 (m, 4 H), 4.14 (m, 1 H), 3.73 (m, 2 H), 3.60 (m, 3 H), 3.42 (m, 2 H), 2.40 (s, 3 H), 2.21 (m, 1 H), 1.87 (m, 1 H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([NH2:17])=[CH:6][C:7]([S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])=[CH:8][CH:9]=1)[CH3:2].[CH:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)=O>C(O)CCCC>[CH3:27][O:26][C:24](=[O:25])[C:23]1[CH:28]=[CH:29][C:20]([C:18]2[N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[CH:8][C:7]([S:10]([C:13]([F:16])([F:14])[F:15])(=[O:11])=[O:12])=[CH:6][C:5]=3[N:17]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CCNc1ccc(S(=O)(=O)C(F)(F)F)cc1N
Solvent: CCCCCO
Product: CCn1c(-c2ccc(C(=O)OC)cc2)nc2cc(S(=O)(=O)C(F)(F)F)ccc21

Procedure:
N1-Ethyl-4-trifluoromethanesulfonyl-benzene-1,2-diamine (134 mg, 0.50 mmol) and methyl 4-formylbenzoate (82 mg, 1.1 equiv) were dissolved in 0.8 mL dry pentanol and heated to reflux for 18 h. The reaction mixture was then evaporated to one-third volume by blowing with a stream of nitrogen while heating. Upon cooling, the solids were collected and washed with ether to yield 155 mg upon drying. The solids may be recrystallized from EtOAc/ether to yield pure ester 35: 1HNMR (400 MHz, d6-DMSO) δ 8.48 (d, J=1.65 Hz, 1H), 8.19 (m, 3H), 8.01 (m, 3H), 4.45 (q, J=7.24 Hz, 2H), 3.92 (s, 3H), 1.36 (t, J=7.22 Hz, 3H); LCMS-APCI in/z 413 [M+1]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]1[CH:22]=[C:23]([CH2:29]O)[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1.[Br:31]N1C(=O)CCC1=O>ClCCl>[Br:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([CH2:29][Br:31])[CH:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(Br)cc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(Br)cc(CBr)c1
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
Triphenylphosphine (28 g; KANTO) was added to a dichloromethane (150 mL) solution of Intermediate 1 (22.05 g) with ice cooling, the resulting mixture was stirred for approx. 10 minutes followed by the addition of N-bromosuccinimide (20 g; TCI), and the resulting mixture was stirred at room temperature for 13 hours and 30 minutes. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (n-hexane/ethyl acetate) to give the title compound (23.94 g).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][C:32]1=[O:37]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:34]5[CH2:35][CH2:36][NH:31][C:32](=[O:37])[CH2:33]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:29])[F:30])[CH:3]=1
Reactant: O=C1CNCCN1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CCN1

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-2-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and piperazin-2-one following General Procedure C.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][C:12]2=[O:18])[CH2:5]1)=[N+:2]=[N-:3].[C:19](Cl)(=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>N1C=CC=CC=1>[N:1]([C@@H:4]1[C@@H:8]([CH2:9][O:10][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[O:7][C@@H:6]([N:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][C:12]2=[O:18])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: Cc1cnc(=O)n([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2cc(C)cnc2=O)C[C@@H]1N=[N+]=[N-]
Reaction time: 2 h
Yield: 29 %

Procedure:
1-(3-Azido-2,3-dideoxy-β-D-erythro-pentofuranosyl)-5-methyl-2(1H)-pyrimidinone (0.25 g, 1 mMol) was dissolved in 11 mL anhydrous pyridine at 0° C. under a nitrogen atmosphere. Freshly distilled palmitoyl chloride (2.5 mL) was added all at once and the reaction stirred for 2 hrs. The solvents were evaporated away and the residue applied to a silica gel column eluted with 1:6 EtOAc/hexane (v/v). Appropriate fractions were combined and evaporated to give the title compound 0.14 g (0.29 mMol; 29%); mp =65°-67° C.; UV (nm) EtOH: λmax =228 (ε=13400), λmin =212 (ε=10300); 1H NMR (DMSO-d6) δ7.03(d, J=1.37 Hz, 1H, H6), 5.90(dd, J=1.76 Hz, 6.45 Hz, 1H, H1 '), 5.34(s, 1H, H4), 4.50(s, 1H, H3 '), 4.30-4.24(m, 1H, H4 '), 3.93-3.70(m, 2H, H5 '), 2.91(t, J=12.7 Hz, 2H, --C(O)CH2 -- ), 2.57-2.26(m, 2H, H2 '), 1.73(s, 3H, 5-CH3), 1.54-0.80(m, 29 H, palmitoyl).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Li]CCCC.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C>C1COCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][C:2]([B:22]([OH:27])[OH:23])=[CH:3][C:4]=2[CH:9]=1
Reactant: c1ccc(Cc2ccc3occc3c2)nc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc2cc(Cc3ccccn3)ccc2o1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
A solution of 2-(benzofuran-5-ylmethyl)pyridine (66 mg, 315 mmol) in THF (2 mL) was cooled to −78° C. (under argon), treated with 2.5 M n-BuLi (in hexanes, 2.5 equiv, 0.315 mL) and stirred for 2 min, warmed to 0° C. for 30 min, cooled to −78° C., and treated with triisopropyl borate (178 μL, 946 μmol). After 5 min, cooling was removed, the mixture slowly warmed to room temperature and stirred for 2 h. The mixture was diluted with EtOAc, washed with 1× with brine, dried over MgSO4 and evaporated yielding yellow solids used without further purification. MS (ESI) m/z: Calculated: 253.1; Observed: 254.1 (M++1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20]([C:22]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[C:25]([CH:35]=O)[NH:24][CH:23]=1)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[C:25]([CH:35]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])[NH:24][CH:23]=1)=[O:21])[CH3:18]
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: CCOC(=O)c1c[nH]c(C=O)c1-c1ccc(OC)cc1
Product: CCOC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)c1-c1ccc(OC)cc1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 5-formyl-4-(4-methoxyphenyl)-1H-pyrrole-3-carboxylic acid ethyl ester to give the title compound.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:19][C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][N:21]=4)[S:16][C:17]=3[CH3:18])[CH:10]=[N:9]2)=CC=1.C([O-])([O-])=O.[Na+].[Na+].O>C(O)(C(F)(F)F)=O>[F:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([NH:19][C:15]2[S:16][C:17]([CH3:18])=[C:13]([C:11]3[CH:12]=[N:8][NH:9][CH:10]=3)[N:14]=2)[CH:25]=1
Reactant: COc1ccc(Cn2cc(-c3nc(Nc4cc(F)ccn4)sc3C)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1sc(Nc2cc(F)ccn2)nc1-c1cn[nH]c1
Yield: 51.5 %

Procedure:
According to Scheme 3 Step 3: A solution of N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-methylthiazol-2-yl)-4-fluoropyridin-2-amine (0.33 mmol, 132 mg) in TFA (1.5 mL) was microwaved for 2 minutes at 150° C. A precipitate was formed after addition of a saturated solution of Na2CO3 and water. After filtration, the solid was washed with water and recrystallized in Et2O to yield N-(4-fluoropyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine (0.17 mmol, 47 mg, 51%) as a beige solid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:7]1[C:15]2[N:14]=[CH:13][NH:12][C:11]=2[C:10](=[O:16])[NH:9][C:8]1=[O:17])[CH2:4][CH2:5][CH3:6].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.CO>[CH2:18]([N:12]1[C:11]2[C:10](=[O:16])[NH:9][C:8](=[O:17])[N:7]([CH2:3][CH2:4][CH2:5][CH3:6])[C:15]=2[N:14]=[CH:13]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCCn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
10 g (0.25 mol) of sodium hydroxide dissolved in 100 ml of water were added to a suspension of 52 g (0.25 mol) of 3-butylxanthine in 300 ml of methanol and the reaction mixture was stirred at 70° C. for one hour, then treated dropwise at the same temperature with 42.8 g (0.25 mol) of benzyl bromide and kept between 70° and 80° C. for 5 hours. 1.0 g (0.025 mol) of sodium hydroxide and 4.28 g (0.025 mol) of benzyl bromide were then added. After a further 2 hours, the mixture was cooled, diluted with 1500 ml of water and filtered cold on a suction filter, the product was washed with water on the suction filter and dissolved in 1000 ml of 1 N sodium hydroxide solution, and the solution was filtered and slowly brought to pH 3 with stirring using concentrated hydrochloric acid. The crystallizate was filtered off from the solution, washed with water until chloride-free and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH:13]=[O:14])=[N:4][CH:5]=[CH:6][CH:7]=1.[I:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[C:11]([I:15])[CH:10]=[C:9]2[CH:13]=[O:14])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=Cc1cccn1-c1ncccc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(I)cn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.1 %

Procedure:
To a solution of 5.0 g of 3-chloro-2-(2-formyl-1H-pyrrol-1-yl)pyridine in 50 ml of N,N-dimethylformamide was added 5.4 g of N-iodosuccinimide. The resulting mixture was stirred at room temperature for 1 day. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.2 g of 1-(3-chloro-2-pyridinyl)-4-iodo-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:17]([F:18])=[CH:16][C:15]([OH:19])=[C:14]([N+:20]([O-:22])=[O:21])[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CC(C)=O.O>[Cl:1][C:2]1[C:3]([C:12]2[C:17]([F:18])=[CH:16][C:15]([O:19][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:14]([N+:20]([O-:22])=[O:21])[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:8])[F:9]
Reactant: CCOC(=O)CBr
Reactant: Cn1nc(-c2cc([N+](=O)[O-])c(O)cc2F)c(Cl)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(F)c(-c2nn(C)c(C(F)(F)F)c2Cl)cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
At 25° C., 6.11 g (0.018 mole) 4-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-fluoro-2-nitrophenol, 2.5 g (0,019 mole) K2CO3, and 2.0 mL (0.019 mole) ethyl bromoacetate were slurried in 100 mL acetone. The reaction mixture was stirred at 40° C. for 4 hours. The mixture was cooled, diluted with 100 mL cold water, and extracted four times with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4, and stripped in vacuo. The residue was recrystallized from methylcyclohexane to give 7.5 g (99%) of (4-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-fluoro-2-nitrophenoxy)acetic acid, ethyl ester as a light yellow solid, mp 95°-96° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11].[H-].[Na+].Cl[CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[N:16]1[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[N:28][C:29]([Cl:35])=[CH:30][CH:31]=2)[N:26]=1>O1CCCC1>[Cl:35][C:29]1[N:28]=[C:27]2[C:32]([CH:33]=[CH:34][C:25]([N:16]3[CH:15]([O:1][CH2:2][CH2:3][CH2:4][N:5]4[CH2:10][CH2:9][CH2:8][CH2:7][C:6]4=[O:11])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:24])=[N:26]2)=[CH:31][CH:30]=1
Reactant: O=C1CCCCN1CCCO
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCCCN1CCCOC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 14.6 %

Procedure:
The procedure is as in Example 22, but starting with N-(3-hydroxypropyl)-2-piperidone (7 g) in anhydrous tetrahydrofuran (150 cc), an oily suspension (50% by weight; 2.15 g) of sodium hydride and 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (10 g). The product obtained is purified by chromatography on silica (0.063-0.2 mm; 240 g) contained in a column 5 cm in diameter, collecting 50-cc fractions. Fractions 23 to 27, eluted with a mixture of methylene chloride and methanol (95:5 by volume), are concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue obtained is crystallized by stirring in acetonitrile and then recrystallized in carbon tetrachloride. 2-(7-Chloro-1,8-naphthyridin-2-yl)-3-[3-(2-oxopiperidino)propoxy]-1-isoindolinone (2 g), m.p. 140° C., is thereby obtained.
Reaction SMILES: N(C(C)C)(C(C)C)CC.[Cl:10][C:11]1[C:12]([CH:17]([NH2:34])[C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[CH:23][C:24](C4C=CC=CC=4)=[N:25]3)=[CH:20][CH:19]=2)=[N:13][CH:14]=[CH:15][N:16]=1.[CH:35]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:10][C:11]1[C:12]([CH:17]([NH:34][C:39]([CH:35]2[CH2:38][CH2:37][CH2:36]2)=[O:40])[C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[CH:23][CH:24]=[N:25]3)=[CH:20][CH:19]=2)=[N:13][CH:14]=[CH:15][N:16]=1
Reactant: O=C(Cl)C1CCC1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC(c1ccc2cccnc2c1)c1nccnc1Cl)C1CCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of NEt(iPr)2 (520 μL, 386 mg, 2.99 mmol), DMAP (12 mg, 0.098 mmol), and C-(3-chloropyrazin-2-yl)-C-quinolin-7-ylmethylamine (compound of Formula IV where Q1=quinolin-7-yl) (608 mg, 1.97 mmol) in dry CH2Cl2 (10 mL), cooled by ice/water, was added cyclobutanecarbonyl chloride (250 μL, 260 mg, 2.19 mmol), then the cooling bath was removed, and the reaction mixture was stirred at ambient temperature for 2.5 h. Water was added, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined CH2Cl2 layers were washed with dilute HCl (pH=2), water, saturated NaHCO3 solution, and brine and dried over MgSO4. The crude material is chromatographed on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with hexanes:EtOAc 1:1 (1-21)-1:3 (22-44)→EtOAc (45-56)], yielding the title compound as an orange foam; 1H NMR (CDCl3, 400 MHz) δ 1.81-1.91 (m, 1H), 1.91-2.03 (m, 1H), 2.11-2.23 (m, 2H), 2.23-2.35 (m, 2H), 3.12 (quint, J=8.6 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.39 (dd, J=4.0, 8.0 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.83 (s, 1H), 8.13 (d, J=8.4 Hz, 1H), 8.37 (d, J=2.2 Hz, 1H), 8.56 (d, J=2.2 Hz, 1H), 8.87 (dd, J=1.6, 4.0 Hz, 1H); MS (ES+): m/z 353.1/355.0 (100/39) [MH+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)O)([CH3:4])([CH3:3])[CH3:2].[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[N:23]1[C:19](=[O:29])[C:20]2[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:22]1=[O:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(O)c1cccc(Cl)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of [2-(3-chloro-phenyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester (20 g, 73.5 mmol), phthalimide (11.1 g, 73.5 mmol) and PPh3 (25.1 g, 95.5 mmol) in THF (500 mL) was added DEAD (11.4 mL, 95.5 mmol) dropwise at −5 to 0° C. The reaction mixture was stirred at room temperature for 3 hours. Then the mixture was concentrated to dryness. The residue was purified by column chromatography (ethyl acetate:petroleum ether, 1:10) to afford [2-(3-chloro-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-carbamic acid tert-butyl ester. (Yield 20 g, 69%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[O:45][N:44]=[C:43]([CH3:46])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[O:45][N:44]=[C:43]([CH3:46])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N4CCOCC4)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J1) (181 mg, 0.5 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K4) (151 mg, 0.5 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (117 mg).
Reaction SMILES: [CH:1]([CH:3]1[CH2:14][CH2:13][O:12][C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[O:5][CH2:4]1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][CH:3]1[CH2:14][CH2:13][O:12][C:6]2([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)[O:5][CH2:4]1
Reactant: O=CC1CCOC2(CCCCC2)OC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC1CCOC2(CCCCC2)OC1
Temperature: 10 °C

Procedure:
To a solution of 9-formyl-7,12-dioxaspiro[5,6]dodecane of formula IV (5 g) in methanol (15 ml) was added in small portions NaBH4 (0.5 g) while stirring the solution and maintaining the temperature at 10° C. After complete addition, the reaction mixture was stirred for 3 hr at 20° C. The product residue obtained after evaporation of methanol was treated with water (20 ml), extracted into ether and dried over K2CO3. Evaporation of ether gave 9-hydroxymethyl-7, 12-dioxaspiro[5,6]dodecane of formula V (5 g) of the drawings as colorless viscous liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C@H:12]1[CH2:21][N:16]3[CH2:17][CH2:18][NH:19][CH2:20][C@@H:15]3[CH2:14][CH2:13]1)[CH:6]=[CH:5]2.Cl[C:23]1[N:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C@H:12]1[CH2:21][N:16]3[CH2:17][CH2:18][N:19]([C:23]4[N:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=4)[CH2:20][C@@H:15]3[CH2:14][CH2:13]1)[CH:6]=[CH:5]2
Reactant: Fc1ccc2c(ccn2C[C@@H]2CC[C@H]3CNCCN3C2)c1
Reactant: Fc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Fc1cnc(N2CCN3C[C@H](Cn4ccc5cc(F)ccc54)CC[C@H]3C2)nc1
Temperature: 95 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
A mixture of 2.20 g (7.67 mmol) of (7R,9aS)-7-(5-fluoroindol-1-yl)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine, 1.02 9 (7.67 mmol) of 2-chloro-5-fluoropyrimidine and 1.95 g (18.4 mmol) of sodium carbonate in 100 mL of water was stirred at 95° C. for 72 h. The mixture was cooled to room temperature, extracted with chloroform (3×), the combined organic phase was washed with brine, dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 50:50 ethyl acetate:hexane gave 1.17 g (40%) of the title compound. mp (—HCl) 180-182° C. HRMS calc for HRMS calcd for C21H23F2N5: 383.1922, found: 383.1924.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:31])[C:7]=1[NH:8][C:9](=[O:30])[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([OH:21])[CH:19]=2)[N:14]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:13]=1)=[O:11].[BH4-].[Na+]>CO.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:31])[C:7]=1[NH:8][C:9](=[O:30])[CH:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([OH:21])[CH:19]=2)[N:14]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:13]=1)[OH:11]
Reactant: O=C(Nc1c(Cl)cncc1Cl)C(=O)c1cn(Cc2ccc(F)cc2)c2ccc(O)cc12
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1c(Cl)cncc1Cl)C(O)c1cn(Cc2ccc(F)cc2)c2ccc(O)cc12
Temperature: 20 °C
Reaction time: 6 h

Procedure:
1 g of N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide (1; 2 mmol) are suspended in 75 ml methanol. After addition of a solution of 0.2 g of sodium borohydride in 3 ml dilute sodium hydroxide solution, the reaction mixture is stirred at 20° C. for 6 hours. After the solvent has been removed by distillation, the residue is recrystallized from 40 ml ethanol.