Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[C:15]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])[CH:14]=[CH:13][C:12]=1[Cl:30])(=[O:10])=[O:9].Cl[C:32]1C=CC(N2C(=O)C=C(C(F)(F)F)N(C)C2=O)=CC=1S(Cl)(=O)=O.COCCN.IC>CN(C)C=O>[CH3:3][O:4][CH2:5][CH2:6][N:7]([CH3:32])[S:8]([C:11]1[CH:16]=[C:15]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[N:19]([CH3:28])[C:18]2=[O:29])[CH:14]=[CH:13][C:12]=1[Cl:30])(=[O:10])=[O:9]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(S(=O)(=O)Cl)c2)c1=O
Reactant: COCCNS(=O)(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Agent: COCCN
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COCCN(C)S(=O)(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a stirred slurry of 0.2 g of a 60% dispersion of sodium hydride in mineral oil and 30 ml of N,N-dimethylformamide (DMF) cooled to 5° C. was added 1.95 g of N-(2-methoxyethyl)-2-chloro-5-(3,6-dihydro-3-methyl-4-trifluoromethyl-2,6-dioxo-1(2H)-pyrimidinyl)benzenesulfonamide (Compound #52) prepared according to the procedure set forth above Process B using 2-chloro-5-(3,6-dihydro-3-methyl-4-trifluoromethyl-2,6-dioxo-1(2H)pyrimidinyl)benzenesulfonyl chloride and 2-methoxyethylamine. After stirring for 1 hour at 5° C., 0.6 ml of iodomethane was added to the reaction mixture. After stirring at room temperature for 16 hours, the mixture was concentrated using a rotary evaporator. The resulting gummy residue was treated several times with water until a solid had formed. The solid was recrystallized from ethanol to give 1.3 g of the title compound as a white crystalline solid, m.p. 108°-110° C. Spectral data for this compound is found in Table I.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[C:16]([F:19])([F:18])[F:17])[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:29])[C:7](=[O:28])[N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:9]=1.C[C:31]1([NH2:42])[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32]1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C(O[Pd]OC(=O)C)(=O)C>[C:38]([O:37][C:35]([N:33]1[CH2:34][CH:31]([NH:42][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[C:16]([F:19])([F:18])[F:17])[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:29])[C:7](=[O:28])[N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:9]=2)[CH2:32]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(Br)cc3N21
Reactant: CC1(N)CN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 88.5 %

Procedure:
A mixture of 6-bromo-4-methyl-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (2.0 g, 4.05 mmol), tert-butyl 3-amino azetidine-1-carboxylate (1.39 g, 8.09 mmol), diacetoxypalladium (0.27 g, 1.21 mmol), Cs2CO3 (1.32 g, 4.05 mmol) and BINAP (1.0 g, 1.62 mmol) in toluene (10 mL) was heated at reflux for 2 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 20% EtOAc in petroleum ether) to give 3-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (2.1 g, 89%) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ 7.14 (s, 1H), 5.86 (s, 1H), 5.10 (q, J=9.2 Hz, 2H), 4.63 (m, 2H), 4.51 (m, 2H), 4.33 (m, 2H), 4.18 (m, 1H), 3.77 (m, 2H), 3.65 (t, J=8.4 Hz, 2H), 1.47 (d, J=6.4 Hz, 3H), 1.45 (s, 9H), 0.99 (t, J=8.4 Hz, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:11][CH:10]=1)[C:34]([NH:33][C:25]1[C:24]([CH:21]([CH3:22])[CH3:23])=[CH:29][CH:28]=[CH:27][C:26]=1[CH:30]([CH3:32])[CH3:31])=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: OCCCCOc1ccc(NCc2ccccc2)cc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(Cc1ccccc1)c1ccc(OCCCCO)cc1
Yield: 23.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using benzyl[4-(4-hydroxybutoxy)phenyl]amine (1.67 g) and 2,6-diisopropylphenyl isocyanate (1.37 g) as starting materials, 4-{4-[1-benzyl-3-(2,6-diisopropylphenyl)ureido]phenoxy}butanol (0.68 g) was obtained.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][O:13][C:14]1[CH:15]=[C:16](I)[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1.C(=O)=O.CO.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>O1CCCC1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([B:28]([OH:33])[OH:29])[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(I)cc(OC)c1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(OC)cc(B(O)O)c1
Reaction time: 0.33 h
Yield: 74.7 %

Procedure:
Under argon, to anhydrous tetrahydrofuran (9.0 mL) stirred in a dry ice-methanol bath was gradually added a 1.57 M solution of n-butyllithium in hexane (3.9 mL, 5.9 mmol), followed by the dropwise addition of a solution of 3,5-dimethoxyiodobenzene (713.0 mg, 2.70 mmol) in anhydrous tetrahydrofuran (5.0 mL). After the mixture was stirred for 20 minutes in the dry ice-methanol bath, triisopropyl borate (0.75 mL, 3.2 mmol) was added and the mixture was additionally stirred for 20 minutes. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure, then a 1.0 M aqueous sodium hydroxide (7.0 mL) was added to the residue. The resulting aqueous solution was washed with chloroform, acidified by adding concentrated hydrochloric acid, and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from chloroform-hexane to yield the title compound as a colorless crystalline powder (melting point: 159.0-161.0° C.)(367.0 mg, yield: 91%).
Reaction SMILES: O=[C:2]1[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.[CH3:16][C@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.C(O)(=O)C.C1COCC1>[CH2:9]([O:8][C:6]([N:4]1[CH2:5][CH:2]([N:21]2[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:17]([CH3:16])[CH2:22]2)[CH2:3]1)=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CN(C2CN(C(=O)OCc3ccccc3)C2)CCN1C(=O)OC(C)(C)C
Yield: 64.5 %

Procedure:
To a mixed solution of benzyl 3-oxoazetidine-1-carboxylate (30.0 g, 146 mmol), which is a known and commercially available product, THF (100 mL) and acetic acid (60 mL) was added a commercially available product of tert-butyl(2S)-2-methylpiperazine-1-carboxylate (32.2 g, 161 mmol) at room temperature. The resultant mixture was stirred at room temperature for 1 hour. To the reaction mixture was added sodium triacetoxyborohydride (46.5 g, 219 mmol) at 0° C. The resultant mixture was stirred at room temperature for 1 hour and 30 minutes. To the reaction mixture were added sodium hydrogen carbonate and water at 0° C. The resultant solution was extracted with ethyl acetate. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=5:1) to give the title compound (36.7 g, yield: 64%).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:24]([O:23][C:21](=[O:22])[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=2)[CH:8]=1)[CH:25]=[CH2:26]
Reactant: C=CCOC(=O)Cl
Reactant: CC(C)(C)NCc1cccc(-c2ccnc(Cl)n2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N(Cc1cccc(-c2ccnc(Cl)n2)c1)C(C)(C)C
Yield: 61 %

Procedure:
tert-Butyl-[3-(2-chloro-pyrimidin-4-yl)-benzyl]-amine from the above reaction (1.33 g, 4.84 mmol) was treated with allyl chloroformate (0.77 mL) in methylene chloride (15 mL) with diisopropyl ethylamine (1.7 mL) at room temperature for 3 hours. The mixture was diluted with methylene chloride (50 mL), washed with water (2×), brine, dried over Na2SO4, filtered. Removal of the solvent followed by chromatography on silica gel (1:4 ethyl acetate:hexane eluent) afforded product in 61% yield. LC-MS showed the product had the expected M+H+ of 360. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) 8.6 (d, 1H) 7.9 (d, 2H) 7.6 (d, 1H) 7.4 (m, 2H) 5.9 (m, 1H) 5.2 (m, 2H) 4.7 (s, 2H) 4.6 (d, 2H) 1.4 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1/[CH:18]=[CH:19]/[C:20]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][N:21]=1)[C:5]2=[O:29].[CH:30](=O)[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1COCC1>[CH2:30]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1/[CH:18]=[CH:19]/[C:20]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][N:21]=1)[C:5]2=[O:29])[CH3:31]
Reactant: Nc1ccc2c(c1)C(=O)N(c1ccccc1/C=C/c1n[nH]c3ccccc13)C2=O
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNc1ccc2c(c1)C(=O)N(c1ccccc1/C=C/c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.6 %

Procedure:
To a solution of (E)-5-amino-2-{2-[2-(1H-indazol-3-yl)vinyl]phenyl}isoindole-1,3-dione (40 mg, 0.11 mmol) obtained in Example 193 in THF (1.0 mL), acetaldehyde (5.2 μL, 0.12 mmol) and sodium triacetoxyborohydride (33 mg, 0.16 mmol) were added and stirred at room temperature for 2.5 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform to chloroform/methanol=90/10) to obtain Compound 201 (16 mg, 38%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11]CC=C)=[CH:7][CH:6]=1.Cl[C:18]1[CH:23]=CC(Cl)=C[C:19]=1Cl>>[CH2:23]([C:7]1[CH:6]=[C:5]([O:4][CH2:3][C:2]([F:1])([F:15])[F:16])[CH:10]=[CH:9][C:8]=1[OH:11])[CH:18]=[CH2:19]
Reactant: Clc1ccc(Cl)c(Cl)c1
Reactant: C=CCOc1ccc(OCC(F)(F)F)cc1
Product: C=CCc1cc(OCC(F)(F)F)ccc1O

Procedure:
A solution of allyl 4-(2,2,2-trifluoroethoxy)phenyl ether (1.9 g, 8.2 mmol) in 1,2,4-trichlorobenzene 30 ml was heated to 180° C. for 24 hr. The solvent was removed under reduced pressure, and the crude product was chromatographed on silica gel eluting with 20% AcOEt/hexanes to give 0.9 g of 2-allyl-4-(2,2,2-trifluoroethoxy)phenol. This material was dissolved in 30 ml ethanol and was hydrogenated with 15 mg of 10% Pd/C in a Parr shaker under hydrogen atmosphere (50 psi) overnight. The catalyst was removed by suction-filtration through a pad of celite. The filtrate was concentrated to give the title compound 0.73 g as a clear oil.
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([C:18]4[N:19]=[N:20][N:21]([CH3:23])[N:22]=4)=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].C([Sn](CCCC)(CCCC)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)CCC>>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([S:25][C:11]2[C:12]3[C:13]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:14][C:15]([C:18]4[N:19]=[N:20][N:21]([CH3:23])[N:22]=4)=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:31][CH:30]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(-c3nnn(C)n3)cc12
Product: Cn1nnc(-c2cc(-c3ccccc3)c3c(Sc4ccc(Cl)cc4)c4n(c3c2)CCC4CC(=O)O)n1

Procedure:
Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)thio]-6-(2-methyl-2H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate and tributyl(phenyl)stannane, the title compound was synthesized by following the procedures described in Example 42 and Step 10 of Example 7.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[N:13]=[N:14][C:15]([Cl:19])=[CH:16][C:17]=2Cl)=[C:7]([CH3:20])[CH:6]=1)(=O)C.[OH-].[Na+].CS(C)=[O:25].Cl>O1CCOCC1>[Cl:19][C:15]1[N:14]=[N:13][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][C:7]=2[CH3:20])=[C:17]([OH:25])[CH:16]=1
Reactant: CS(C)=O
Reactant: CC(=O)Oc1ccc(Oc2nnc(Cl)cc2Cl)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(O)ccc1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 1,4-dioxane(1.4 mL) was dissolved 173 mg (0.553 mmol) of 4-[(4,6-dichloro-3-pyridazinyl)oxy]-3-methylphenyl acetate obtained in Example 630(3), 0.7 mL (2.1 mmol) of 3 mol/L sodium hydroxide solution and dimethylsulfoxide (2.8 mL) were added to the solution and the resulting mixture was stirred at room temperature overnight. To the reaction mixture was added 4 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine. After drying over anhydrous magnesium sulfate, the solvent was removed. The obtained residue was purified by preparative thin-layer chromatography (developed by dichloromethane:methanol=36:1) to obtain 66.8 mg of 6-chloro-3-(4-hydroxy-2-methylphenoxy)-4-pyridazinol.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=4[CH:21]=3)[N:19]=2)[CH2:11][CH2:10]1)C.O.[OH-].[Li+].Cl>C1COCC1>[CH3:30][C:26]1([CH3:31])[CH2:25][CH2:24][C:23]([CH3:32])([CH3:33])[C:22]2[CH:21]=[C:20]([C:18]3[N:19]=[C:15]([N:12]4[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:34])=[O:3])[CH2:10][CH2:11]4)[S:16][CH:17]=3)[CH:29]=[CH:28][C:27]1=2
Reactant: CCOC(=O)CCCCN1CCN(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCN(CCCCC(=O)O)CC4)n3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60 mg of 5-{4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperazin-1-yl}pentanoic acid ethyl ester from step a was dissolved in 2.5 ml of THF, 250 μl of water and 11 mg (0.43 mmol) of lithium hydroxide were added, and the mixture was stirred at room temperature overnight. The reaction mixture was neutralised using a 1N hydrochloric acid solution, evaporated to dryness and purified by means of preparative HPLC. The product is in the form of the trifluoroacetate salt.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([C:16]3[C:17]4[CH2:18][CH2:19][N:20]([CH2:26][C:27]5[C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[N:30]=[CH:29][CH:28]=5)[CH2:21][C:22]=4[CH:23]=[CH:24][CH:25]=3)=[O:15])[CH:11]=2)[C:6]([CH3:38])([CH3:37])[CH2:5]1)(=O)C.Cl>C(O)C>[CH3:37][C:6]1([CH3:38])[C:7]2[C:12](=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]4[CH2:18][CH2:19][N:20]([CH2:26][C:27]5[C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[N:30]=[CH:29][CH:28]=5)[CH2:21][C:22]=4[CH:23]=[CH:24][CH:25]=3)=[O:15])=[CH:9][CH:8]=2)[NH:4][CH2:5]1
Reactant: CC(=O)N1CC(C)(C)c2ccc(NC(=O)c3cccc4c3CCN(Cc3ccnc5ccccc35)C4)cc21
Agent: Cl
Solvent: CCO
Product: CC1(C)CNc2cc(NC(=O)c3cccc4c3CCN(Cc3ccnc5ccccc35)C4)ccc21
Temperature: 60 °C
Yield: 69.4 %

Procedure:
N-(1-Acetyl-3,3-dimethylindolin-6-yl)-2-(quinolin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (55 mg, 0.109 mmol) was mostly dissolved in ethanol (1.25 mL) then added concentrated hydrochloric acid (0.745 mL). The reaction mixture was heated at 60° C. for 6 hours. The mixture was concentrated under vacuum and the remaining residue diluted with a small amount of water. The solution was brought to pH 9-10 with the addition of 6N aqueous sodium hydroxide. A precipitate formed which was collected on a glass frit, washing with minimal water then dichloromethane. The solid was dried under high vacuum to afford 35 mg of N-(3,3-dimethylindolin-6-yl)-2-(quinolin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide as a tan solid. MS (ESI, pos. ion) m/z: 463.2 (M+1)
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(OC)[C:11]([C@@H:13]1[CH2:17][C:16](=[O:18])[N:15]([C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[CH2:14]1)=[O:12].Cl>O1CCCC1>[C:1]1([C:11]([C@H:13]2[CH2:14][N:15]([C@@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[C:16](=[O:18])[CH2:17]2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CON(C)C(=O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@H](C(=O)c2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
In an atmosphere of nitrogen, phenylmagnesium bromide (3 N diethyl ether solution, 15 ml) was added dropwise to tetrahydrofuran solution (50 ml) of N-methyl-N-methoxy-1-[1-(R)-phenylethyl]-5-oxopyrrolidine-3-(R)-carboxamide (2.49 g, 9.0 mmol), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was mixed with 1 N hydrochloric acid (50 ml) under ice-cooling and extracted with ethyl acetate (8 ml×2). The organic layer was washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and the residue was subjected to a silica gel column chromatography. By eluting with n-hexane:ethyl acetate (1:1), 2.36 g (89%) of the title compound was obtained as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][O:13][CH3:14])[CH:3]=1.[OH-].[NH4+:16]>>[Br:1][C:2]1[C:10]2[C:9]([NH2:16])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][O:13][CH3:14])[CH:3]=1
Reactant: COCn1cc(Br)c2c(Cl)ncnc21
Reactant: [NH4+]
Agent: [OH-]
Product: COCn1cc(Br)c2c(N)ncnc21
Temperature: 100 °C
Yield: 71 %

Procedure:
5-bromo-4-chloro-7-[(methyloxy)methyl]-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.723 mmol) was transferred to a 5 mL microwave vial and then ammonium hydroxide (1.5 mL, 38.5 mmol) was added. The mixture was heated in microwave reactor at 100° C. for 30 minutes. The solid was isolated by filtration and dried to give 5-bromo-7-[(methyloxy)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (132 mg, 71.0% yield) as a white solid. LC-MS (ES) m/z=257.0, 259.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.56 (s, 1H), 6.81 (br. s., 2H), 5.43 (s, 2H), 3.21 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[CH2:7][N:6](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:5]2.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[CH2:7][NH:6][CH2:5]2
Reactant: Fc1cc2c(cc1Cl)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc2c(cc1Cl)CNC2

Procedure:
Prepared in analogy to Example A2 (c) from 5-chloro-6-fluoro-2-trityl-2,3-dihydro-1H-isoindole and trifluoroacetic acid. Light brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])=[CH:6][CH:5]=1)([O-])=O.C1COCC1.[NH4+].[Cl-].C([O-])(O)=O.[Na+]>[Fe].O>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])=[CH:6][CH:5]=1
Reactant: N#Cc1cccc(OCn2ccc3ccc([N+](=O)[O-])cc32)c1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cccc(OCn2ccc3ccc(N)cc32)c1
Temperature: 64 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
To a mixture of 3-((6-nitro-1H-indol-1-yl)methoxy)benzonitrile (3.0 g, 10.2 mmol), THF (80 mL) and water (40 mL) were added iron powder (2.86 g, 51.2 mmol) and NH4Cl (1.09 g, 20.4 mmol) and the mixture was stirred at 64° C. overnight. The mixture was then cooled to rt and to the resulting mixture was added saturated NaHCO3 aqueous solution. The mixture was filtered and the filtrate was extracted with EtOAc (30 mL×4). The combined organic layers were washed with brine (40 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as a yellow solid (1.76 g, 65%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:14][C:15]([F:24])([F:23])[C:16]1[N:21]=[CH:20][N:19]=[C:18](O)[CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:18]1[CH:17]=[C:16]([C:15]([F:24])([F:23])[F:14])[N:21]=[CH:20][N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCOCc1ccccc1
Reactant: Oc1cc(C(F)(F)F)ncn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(OCCCCOCc2ccccc2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a solution of 4-(benzyloxy)butan-1-ol (3.00 g), 6-(trifluoromethyl)pyrimidin-4-ol (3.00 g), and triphenylphosphine (5.25 g) in THF (30 mL) was added diisopropyl azodicarboxylate (4.05 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to obtain 4-[4-(benzyloxy)butoxy]-6-(trifluoromethyl)pyrimidine (2.83 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[C:10]([C:18]([OH:20])=O)[CH:9]=2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O.[F:44][C:45]1[CH:50]=[CH:49][C:48]([CH2:51][NH2:52])=[CH:47][CH:46]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([C:18](=[O:20])[NH:52][CH2:51][C:48]3[CH:49]=[CH:50][C:45]([F:44])=[CH:46][CH:47]=3)[CH:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1cc(C(=O)O)cc(-c2ccc(F)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)NCc2ccc(F)cc2)cc(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 105.1 %

Procedure:
To a solution of 4′-fluoro-5-(methoxycarbonyl)biphenyl-3-carboxylic acid (400 mg, 1.459 mmol) in DMF/CH2Cl2 at rt was added EDCI.HCl (363 mg, 1.896 mmol) followed by HOBt.H2O (197 mg, 1.459 mmol). After one minute, (4-fluorophenyl)methanamine (183 mg, 1.459 mmol) was added to the mixture and the reaction mixture was stirred at rt for 4 h. To the reaction mixture were added EtOAc and aq. NaHCO3. The EtOAc layer was separated, washed with water, dried over MgSO4 and concentrated in vacuo to obtain a crude product as a light yellow solid (585 mg, >100% yield), MS: M+H=382.21. The crude product was used directly in the next step without further purification. 1H NMR (CDCl3): δ 8.39 (s, 1H), 8.32 (s, 1H), 7.58˜7.02 (m, 9H), 4.63 (d, J=6.0 Hz, 2H), 3.95 (s, 3H).