Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC#N.[C:4]([O:12][CH2:13][C@@:14]1([C:33]#[CH:34])[O:18][C@@H:17]([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:16][C@H:15]1OS(C)(=O)=O)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1CN2C(=NCCC2)C1>CC(O)=O>[C:4]([O:12][CH2:13][C@@:14]1([C:33]#[CH:34])[O:18][C@@H:17]([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH:16]=[CH:15]1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C#C[C@]1(COC(=O)c2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1OS(C)(=O)=O
Agent: C1CN=C2CCCN2C1
Solvent: CC(=O)O
Solvent: CC#N
Product: C#C[C@@]1(COC(=O)c2ccccc2)C=C[C@H](n2cc(C)c(=O)[nH]c2=O)O1
Temperature: 80 °C
Reaction time: 9 h
Yield: 94.6 %

Procedure:
To an CH3CN (4 mL) solution of 5 (101.9 mg, 0.18 mmol) was added DBN (67 μL, 0.54 mmol) at 0° C. under Ar atmosphere, and the mixture was stirred at 80° C. for 9 h. The reaction mixture was neutralized by adding AcOH, and partitioned between CHCl3/sat. aqueous NaHCO3. Silica gel column chromatography (1.5% MeOH in CH2Cl2) of the organic layer gave 6 (60 mg, 95%) as solid: 1H NMR (CDCl3) δ1.42 (3H, d, JMe,6=1.2 Hz, Me-5), 2.70 (1H, s, C□CH),), 4.59 (1H, d, J5′a,5′b=12.0 Hz, H-5′a), 4.76 (1H, d, J5′,5′b=12.0 Hz, H-5′b), 5.99 (1H, dd, J1′,2′=1.2, J2′,3′=5.9, H-2′), 6.38 (1H, dd, J1′,3′=2.0 and J2′,3′=5.9 Hz, H-3′), 6.98 (1H, d, JMe,6=1.2 Hz), 7.12 (1H, m, H-1′), 7.45-7.49, 7.60-7.63 and 8.00-8.03 (5H, each as m, Ph), 8.37 (1H, br); FAB-MS (m/z) 353 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:22]=[C:21]([C:23]([OH:25])=O)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl.[CH3:27][O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH2:32][NH:33][CH2:34]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:22]=[C:21]([C:23]([N:33]3[CH2:32][CH2:31][C:30]4[C:35](=[CH:36][CH:37]=[CH:38][C:29]=4[O:28][CH3:27])[CH2:34]3)=[O:25])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cccc2c1CCNC2
Reactant: COc1cc(-c2nc(C(=O)O)c3ccccc3n2)cc(OC)c1OC
Agent: Cl
Product: COc1cccc2c1CCN(C(=O)c1nc(-c3cc(OC)c(OC)c(OC)c3)nc3ccccc13)C2
Yield: 36.3 %

Procedure:
Reaction of 2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 90 (36.3% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.79 and 2.90 (2t, 2H), 3.56 and 4.08 (2t, 2H), 3.76-3.81 (m, 6H), 3.86 and 3.92 (2s, 6H), 4.50 and 4.99 (2s, 2H), 6.49-7.28 (m, 3H), 7.67-8.18 (m, 6H); MS (ESI) m/z 486 ([M+H]+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[C:31]=2[CH3:37])[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[C:31]=4[CH3:37])[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nccc(-c2cccc(C3=Nc4cc(Cl)c(C(F)(F)F)cc4NC(=O)C3)c2)c1C

Procedure:
The title compound was prepared from (5-chloro-2-{3-[3-(2,3-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M128) (0.31 g, 0.55 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (130 mg, 53%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cn2)CC1
Yield: 79.1 %

Procedure:
A N,N-dimethylformamide solution (1 mL) of 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (106.4 mg, 0.323 mmol), and tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate (90 mg, 0.323 mmol) is heated at 90° C. for 40 min. After cooling in the refrigerator, the precipitate is collected, and washed with N,N-dimethylformamide and ether to give 147 mg (79%) of the title compound as a yellow solid. MS (ESI) m/z 576.1 (M+H)+1
Reaction SMILES: [N:1]1([CH:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8](=O)[C:7]2([CH3:18])[CH3:17])[CH:5]=[CH:4][N:3]=[CH:2]1.B.C1COCC1.Cl.[H][H].[OH-].[Na+]>C1COCC1>[N:1]1([CH:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8][C:7]2([CH3:18])[CH3:17])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: [H][H]
Reactant: CC1(C)C(=O)Nc2ccccc2C1n1ccnc1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CNc2ccccc2C1n1ccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-imidazol-1-yl-3,3-dimethyl-3,4-dihydro-1H-quinolin-2-one (80 mg, 0.332 mmol) in THF (3 mL) at room temperature is added BH3-THF (3.3 mL, 1.0 M solution) and the mixture is stirred at room temperature for 1 h. To the reaction mixture is added 6N HCl until no hydrogen gas evolves from the solution. The reaction mixture is stirred for 2 h at room temperature and is added aqueous 10% NaOH to adjust PH=12 and then the mixture is extracted into CH2Cl2 and washed by brine; dried with anhydrous sodium sulfate and concentrated to give the crude compound. Reverse phase HPLC (CH3CN:H2O=20 to 90% over 20 mins) purification gives the title compound: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.85 (s, 3 H), 1.06 (s, 3 H), 2.92-3.00 (m, 1 H), 3.12 (d, J=11.9 Hz, 1 H), 4.18 (br. s., 1 H), 4.78 (s, 1 H), 6.57-6.66 (m, 2 H), 6.80 (s, 1 H), 6.86 (d, J=7.1 Hz, 1 H), 7.02 (s, 1 H), 7.07-7.14 (m, 1 H), 7.47 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:8][CH2:7][C:6]2=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=[C:5]2[CH2:4][C:3]1=[O:14].[CH2:16]([CH:18]1[O:20][CH2:19]1)[Cl:17]>N1CCCCC1>[Cl:17][CH2:16][CH:18]([OH:20])[CH2:19][O:13][C:9]1[C:6]2[CH2:7][CH2:8][C:2]([CH3:15])([CH3:1])[C:3](=[O:14])[CH2:4][C:5]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CC1(C)CCc2c(O)cccc2CC1=O
Reactant: ClCC1CO1
Solvent: C1CCNCC1
Product: CC1(C)CCc2c(cccc2OCC(O)CCl)CC1=O
Reaction time: 4 h

Procedure:
Two drops of piperidine are added to 1.8 g 6,7,8,9-tetrahydro-7,7-dimethyl-6-oxo-5H-benzocyclohepten-1-ol in 8 ml epichlorohydrin. The mixture is stirred at 100° for 4 hours. The solution is evaporated, taken up in ether, filtered and concentrated to give crude 1-(3-chloro-2-hydroxypropoxy)-6,7,8,9-tetrahydro-7,7-dimethyl-5H-benzocyclohepten-6-one.
Reaction SMILES: C[O:2][C:3](=[O:22])[C@@H:4]([N:7]1[CH2:11][C:10]([O:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])=[CH:9][C:8]1=[O:21])[CH2:5][CH3:6].O.[OH-].[Li+].O>O1CCCC1.O>[F:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[O:12][C:10]1[CH2:11][N:7]([C@@H:4]([CH2:5][CH3:6])[C:3]([OH:22])=[O:2])[C:8](=[O:21])[CH:9]=1
Reactant: CC[C@@H](C(=O)OC)N1CC(Oc2c(F)cccc2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](C(=O)O)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution of (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-butyric acid methyl ester (0.119 g, 0.38 mol) in tetrahydrofuran:water (1:1, 8 mL) was added lithium hydroxide monohydrate (0.050 g 1.19 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water and washed with diethyl ether and the ether layer discarded. The aqueous phase was acidified with 1N aqueous hydrochloric acid (pH <2), and extracted with ethyl acetate (2×30 mL). The combined ethyl acetate layers were dried over magnesium sulfate, filtered and concentrated to afford (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-butyric acid (0.090 g, 83%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.87 (t, J=7.4 Hz, 3H), 1.60-2.06 (m, 2H), 4.23 (d, J=18.7 Hz, 1H), 4.31 (d, J=18.7 Hz, 1H), 4.43 (dd, J=10.7, 5.0 Hz, 1H), 5.05 (s, 1H), 7.21-7.54 (m, 3H), 12.94 (br. s., 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:23]([C:24]([NH2:26])=O)[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH:23]([C:24]#[N:26])[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C1Cc2c([nH]c3ccccc23)CN1C(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC1Cc2c([nH]c3ccccc23)CN1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 81.3 %

Procedure:
(3RS)-2-Benzyloxycarbonyl-1,2,3,4-tetrahydro-β-carboline-3-carboxamide (1.05 g) is dissolved in pyridine (6 ml) and thereto is added dropwise POCl3 (0.37 ml) at -5° C. The mixture is stirred at the same temperature for 2 hours, and the reaction mixture is poured onto ice-water and extracted with ethyl acetate. The ethyl acetate layer is washed with 10% HCl and water and dried, and then the solvent is distilled off to give the title compound (0.81 g, 82%) as white powder.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]([O:32]CC)=[O:31])[CH2:26][CH2:25]2)[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO.O>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]([N:24]2[CH2:25][CH2:26][CH:27]([C:30]([OH:32])=[O:31])[CH2:28][CH2:29]2)[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C1CCN(C(C)c2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)N1CCC(C(=O)O)CC1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Ethyl 1-(1-(6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)piperidine-4-carboxylate (100 mg, 0.22 mmol) was dissolved in EtOH (5 mL). Then sodium hydroxide (44 mg, 1.1 mmol, 5.0 eq) in water (0.5 mL) was added. The mixture was stirred at 85° C. for 2 h. Solvent was removed and the residue was dissolved in H2O (3 mL). 1M aqueous HCl was added to adjust pH=7. The mixture was filtrated to give 1-(1-(6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)piperidine-4-carboxylic acid as white solid (50 mg, 50%). ESI-MS (M+H+): 438.3. HPLC: 100%. 1H NMR (400 MHz, CD3OD) δ: 7.80-7.78 (m, 2H), 7.34 (d, J=8.8 Hz, 1H), 7.42 (dd, J=8.4, 1.6 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H), 7.11 (dd, J=8.8, 2.0 Hz, 1H), 4.37-4.28 (m, 2H), 3.24-3.17 (m, 2H), 2.82-2.76 (m, 2H), 2.23-2.19 (m, 3H), 1.97-1.84 (m, 5H), 1.71 (d, J=6.8 Hz, 3H), 1.41-1.32 (m, 2H), 1.26-1.16 (m, 3H), 1.10-1.04 (m, 1H), 0.86 (s, 9H).
Reaction SMILES: [CH2:1]([C@:3]([OH:31])([C:15]1[CH:23]=[C:22]2[N:18]([CH2:19][CH2:20][C:21]32OCC[O:24]3)[C:17](=[O:28])[C:16]=1[CH2:29][OH:30])[C:4](N[C@@H](C1C=CC=CC=1)C)=[O:5])[CH3:2].OS(O)(=O)=O.ClCCl>C(COC)OC>[CH2:1]([C@:3]1([OH:31])[C:15]2[CH:23]=[C:22]3[N:18]([CH2:19][CH2:20][C:21]3=[O:24])[C:17](=[O:28])[C:16]=2[CH2:29][O:30][C:4]1=[O:5])[CH3:2]
Reactant: CC[C@@](O)(C(=O)N[C@H](C)c1ccccc1)c1cc2n(c(=O)c1CO)CCC21OCCO1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: COCCOC
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)CCC1=O
Reaction time: 20 h
Yield: 62.9 %

Procedure:
Dissolved in 15 ml of dimethoxyethane was 815 mg of the compound (VI) obtained in the above procedure (1), followed by an addition of 5 ml of 2N H2SO4. The thus-prepared solution was heated with stirring for 20 hours under a nitrogen gas stream. After completion of the reaction, 150 ml of dichloromethane was added and the resultant mixture was washed with water. The organic layer was then dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was recrystallized from a mixed solvent of ethanol and petroleum ether to obtain 315 mg of the title compound as colorless needle-like crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[CH:5]=[CH:6][C:7]=1[NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.N12CCCN=C1CCCCC2.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCCl.C(Cl)(Cl)Cl>[CH:9]1([N:8]2[C:7]3[CH:6]=[CH:5][C:4]([N+:14]([O-:16])=[O:15])=[CH:3][C:2]=3[NH:1][C:29]2=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1NC1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.7 %

Procedure:
To a solution of 3-amino-4-cyclopentylamino-1-nitrobenzene (445 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mL) in 1,2-dichloroethane (5 mL) was added triphosgene (358 mg) at 0° C., and the mixture was stirred at room temperature under nitrogen atmosphere for 20 minutes. The resulting mixture was diluted with chloroform and washed successively with water(twice) and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of n-hexane and ethyl acetate (3:1). The obtained substance was triturated with diisopropyl ether to give 1-cyclopentyl-5-nitro-2,3-dihydro-1H-benzimidazol-2-one (249.8 mg) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:37][CH:36]([C:38]([NH:40][CH3:41])=[O:39])[CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:35][CH:36]([C:38]([NH:40][CH3:41])=[O:39])[CH2:37]3)(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: CNC(=O)C1CN(S(=O)(=O)c2ccccc2Br)C1
Product: CNC(=O)C1CN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)C1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 1-((2-bromophenyl)sulfonyl)-N-methylazetidine-3-carboxamide. MS (ESI): mass calcd. for C21H20FN5O3S, 441.13; m/z found, 441.9 [M+H]+. 1H NMR (500 MHz, DMSO-δ6) δ 8.52 (s, 2H), 8.02 (d, J=7.9, 1H), 7.84 (d, J=4.8, 1H), 7.79-7.72 (m, 1H), 7.69-7.63 (m, 1H), 7.61-7.55 (m, 1H), 7.45 (d, J=7.5, 1H), 7.33 (d, J=11.7, 1H), 7.27 (d, J=7.8, 1H), 6.89 (s, 2H), 3.70 (t, J=7.0, 2H), 3.63 (t, J=8.0, 2H), 3.19-3.08 (m, 1H), 2.56 (d, J=4.4, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]([CH2:18][OH:19])[CH2:5]2.[H-].[Na+].[CH3:22]I.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH:6]([CH2:18][O:19][CH3:22])[CH2:5]2
Reactant: CC(C)(C)OC(=O)N1c2ccc(Cl)cc2CC1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC1Cc2cc(Cl)ccc2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, to a solution of 700 mg of tert-butyl 5-chloro-2-(hydroxymethyl)-2,3-dihydro-1H-indole-1-carboxylate in 14 mL of tetrahydrofuran was added portionwise 197 mg of 60% sodium hydride under ice-cooling, followed by warming to room temperature and stirring for 4 hours. After ice-cooling again, 462 μL of methyl iodide was added dropwise thereto, followed by warming to room temperature and stirring for 2 hours. Water was added thereto, followed by extraction with chloroform, and then the obtained organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 230 mg of tert-butyl 5-chloro-2-(methoxymethyl)-2,3-dihydro-1H-indole-1-carboxylate as a brown oil.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:18][CH2:19]O)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1)(=[O:7])=[O:6].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:19][CH2:18][N:4]([CH2:3][CH2:2][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][O:21]1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1)(=[O:6])=[O:7]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)N(CCO)CCO)ccc1Cl
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(S(=O)(=O)N(CCC2CCCCO2)CCC2CCCCO2)ccc1Cl
Yield: 89.2 %

Procedure:
A solution of N,N-di(2-hydroxyethyl)-4-chloro-3-nitrobenzenesulfonamide (7.1 g, 21.9 mmol), 3,4-dihydro-2H-pyran (4.4 mL, 48 mmol) and p-toluenesulfonic acid hydrate (0.10 g) in methylene chloride (200 mL) was stirred at 20°-25° for 3 days. After washing with a saturated solution of sodium bicarbonate the organic layer was dried (Na2SO4), filtered and concentrated. Flash chromatography of the residue over silica gel with chloroform gave 9.0 g of product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)[CH3:21]>>[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[N:3]=2)=[CH:25][CH:24]=1)[CH3:21]
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: CCOc1ccc(B(O)O)cc1
Product: CCOc1ccc(-c2nc(Nc3cc[nH]n3)cc3cc(OC)ccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-ethoxy-phenylboronic acid to give [1-(4-ethoxy-phenyl)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 361(MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[NH:10][C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.C.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]([OH:29])([C:27]#[CH:28])[CH3:26].N1CCCCC1>CCOC(C)=O.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.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:28]#[C:27][C:25]([OH:29])([C:21]4[S:20][CH:24]=[CH:23][N:22]=4)[CH3:26])[CH:15]=[CH:16][C:11]=3[NH:10][C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-n2c(=O)[nH]c3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1nccs1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: CC(O)(C#Cc1ccc2[nH]c(=O)n(-c3ccnc(N)n3)c2c1)c1nccs1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-bromo-2,3-dihydro-1H-1,3-benzodiazol-2-one (230 mg, 0.751 mmol) in EtOAc was added charcoal (5 mol %). The mixture was stirred at RT for 20 min then filtered and concentrated in vacuo. To the residue in a sealed tube was added 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (230 mg, 1.50 mmol), piperidine (2 mL), tetrakis(triphenylphosphine)palladium (43.4 mg, 0.038 mmol) and copper(I) iodide (14.3 mg, 0.075 mmol). The reaction mixture was then heated at 75° C. for 18 hr then partitioned between EtOAc (15 mL) and water (2 mL). The organic layer was concentrated in vacuo and the residue purified by reverse phase preparative HPLC to afford the title compound: 1H NMR (500 MHz, DMSO) δ 1.90 (3 H, s), 6.92 (2H, s), 6.95 (1H, s), 7.04 (1H, d, J=8.04 Hz), 7.21 (1H, dd, J=8.04, 1.42 Hz), 7.40 (1H, d, J=5.52 Hz), 7.68 (1H, d, J=3.31 Hz), 7.77 (1H, d, J=3.15 Hz), 8.26-8.36 (2H, m), 11.57 (1H, br. s.); LC-MS: m/z=+379.0 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].[H-].[Na+].[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH:17](Br)[CH3:18])[CH:16]=1.[NH4+].[Cl-]>CN(C=O)C.O.CCOC(C)=O>[Br:10][C:11]1[CH:16]=[C:15]([CH:17]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][C:2]2=[O:7])[CH3:18])[CH:14]=[N:13][CH:12]=1
Reactant: CC(Br)c1cncc(Br)c1
Reactant: O=C1COCCN1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(c1cncc(Br)c1)N1CCOCC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
Morpholin-3-one (650 mg, 6.4 mmol) is dissolved in DMF (20 mL) and 60% sodium hydride in mineral oil (190 mg, 4.8 mmol) is added at 0° C. The mixture is stirred for 15 min and 3-bromo-5-(1-bromo-ethyl)-pyridine (850 mg, 3.2 mmol) is added at 0° C. The mixture is warmed up to room temperature for 2 hrs. Then saturated NH4Cl aqueous solution (25 mL) is added along with EtOAc (50 mL) and water (50 mL). The mixture is stirred for 10 min and the aqueous layer is separated and extracted with EtOAc (2×50 mL). The organic layers are combined, washed with water (3×30 mL) and concentrated to give the crude product. Purification by flash column chromatography affords 750 mg of 4-[1-(5-bromo-pyridin-3-yl)-ethyl]-morpholin-3-one. 4-[1-(5-Bromo-pyridin-3-yl)-ethyl]-morpholin-3-one (750 mg, 2.6 mmol) is coupled with Intermediate H (3.1 mmol, using crude) to give 850 mg of the titled product using Suzuki Coupling Method VI.
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:3]=1.[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>CN(C)C=O>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][N:8]1[C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:3]=[C:2]1[CH3:1]
Reactant: CC1=COc2ccccc2C(=O)N1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=COc2ccccc2C(=O)N1CCCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.0 g of 4,5-dihydro-3-methyl-1,4-benzoxazepin-5-one was dissolved in 120 ml of dimethylformamide, then 548 mg (1.2 equivalents) of 60% sodium hydride was added under ice cooling. This was agitated at room temperature for 1 hour, then 4.1 ml (3 equivalents) of 1,4-dibromobutane was added and the resultant mixture was agitated for 3 hours.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]3[N-:34][C:33]([C:4]2=[CH:3][CH:2]=1)=[N:32][C:30]1=[N:31][C:23]([C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:22][C:20]1[N-:21][C:13](=[C:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]2)[N:12]=[C:11]1[C:35]2[C:40]([C:9](=[N:10]1)[N:8]=3)=[CH:39][CH:38]=[CH:37][CH:36]=2.[Cu:41]>OCC1CC2CC1C1C2CCC1.O>[CH:38]1[CH:39]=[C:40]2[C:9]3[N:10]=[C:11]([C:35]2=[CH:36][CH:37]=1)[N:12]=[C:13]1[C:14]2[C:19]([C:20](=[N:21]1)[N:22]=[C:23]1[C:24]4[C:29]([C:30](=[N:31]1)[N:32]=[C:33]1[C:4]5[C:5]([C:7](=[N:34]1)[N:8]=3)=[CH:6][CH:1]=[CH:2][CH:3]=5)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:18][CH:17]=[CH:16][CH:15]=2.[Cu:41]
Reactant: c1ccc2c(c1)-c1nc-2nc2[n-]c(nc3nc(nc4[n-]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Agent: [Cu]
Agent: OCC1CC2CC1C1CCCC21
Solvent: O
Product: c1ccc2c(c1)C1=NC2=NC2=NC(=NC3=NC(=NC4=NC(=N1)c1ccccc14)c1ccccc13)c1ccccc12
Yield: 91.2 %

Procedure:
14.8 g of crude β-copper phthalocyanine, 0.2 g of 8-hydroxymethyltricyclo[5.2.1.02,6 ]decane [TCD alcohol M®, ex Hoechst], 125 g of water and 400 g of glass beads with a diameter of 3.5-4.0 mm are ground for 15 hours at 320 rpm, with water cooling, in a 500 ml glass bead mill of 8 cm diameter. The pigment suspension is separated from the glass beads, which are washed with water. The suspension is then filtered and the filter cake is dried at 70°-80° C. in a vacuum drying cabinet, affording 13.5 g of blue copper phthalocyanine pigment which, when incorporated in powder form into varnishes, gives strong finishes.