Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([CH3:15])=[CH:9][CH:8]=3.[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([CH2:15][Br:23])=[CH:9][CH:8]=3
Reactant: Cc1ccc2c(c1)c1cc(Br)ccc1n2C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1c2ccc(Br)cc2c2cc(CBr)ccc21
Yield: 69.6 %

Procedure:
A suspension of 3-bromo-9-tert-butoxycarbonyl-6-methylcarbazole obtained from Example 25 (653 mg, 1.81 mmol) and recrystallised N-bromosuccinimide (355 mg, 2.00 mmol) in carbon tetrachloride was refluxed under nitrogen with irradiation from a 150 W halogen lamp for 2.5 h. The reaction mixture was cooled over an ice bath and filtered, and the filtrate evaporated. The crude product was chromatographed (PS with gradient elution to PS:DCM 1:1) to afford 3-bromo-6-bromomethyl-9-tert-butoxycarbonylcarbazole (551 mg, 1.26 mmol, 69%) as a colourless solid, mp 150° C. (dec).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH3:9])[C:5](N)=[N:6][CH:7]=1.[OH:11]S(O)(=O)=O.N([O-])=O.[Na+]>O>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH3:9])[C:5](=[O:11])[NH:6][CH:7]=1
Reactant: Cc1c(Br)cnc(N)c1C
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c(Br)c[nH]c(=O)c1C
Temperature: 31 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a mixture of 5-bromo-3,4-dimethylpyridin-2-amine (0.6 g, 3.0 mmol) and H2SO4 (98%, 1.62 mL) and H2O (18 mL) is added a solution of NaNO2 (243.6 mg, 4.2 mmol) in H2O (1.6 mL) drop-wise at 0° C. Then, it was stirred at 31° C. for 30 minutes and filtered. The resulting solid is washed with water to provide the title compound (375.0 mg, 62%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.48 (s, 1H), 2.32 (s, 3H), 2.19 (s, 3H). LCMS (M+H)+ 202.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[P:43](Cl)([O:48][CH2:49][CH3:50])([O:45][CH2:46][CH3:47])=[O:44]>ClCCl>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][P:43]([O:48][CH2:49][CH3:50])([O:45][CH2:46][CH3:47])=[O:44])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOP(=O)(Cl)OCC
Reactant: COc1ccc(-c2nn3c(NCCCCN)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(NCCCCNc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(OC)cc3)nn12)OCC
Yield: 81 %

Procedure:
To a cold (0° C.) solution of N-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine (21 mg, 0.04 mmol) in dichloromethane (3 mL) was added triethylamine (0.1 mL), and diethyl chlorophosphate (0.1 mL of a stock solution prepared from 0.1 mL of diethyl chlorophosphate in 3 mL of dichloromethane). The resultant solution was stirred for 3 hours at 0° C. and then quenched by the addition of saturated aqueous sodium bicarbonate. The organic layer was washed with brine. The aqueous layer was extracted with dichloromethane and the combined organics were dried over sodium sulfate. Filtration and concentration followed by flash chromatography (5% methanol in dichloromethane) provided diethyl 4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butylamidophosphate (22 mg, 81%) as a yellow solid. 1H NMR (CDCl3): δ 7.98 (d, 1 H), 7.76 (d, 1 H), 7.55 (d, 2 H), 7.28 (m, 1 H), 6.96 (d, 2 H), 6.31 (d, 1 H), 6.06 (m, 1 H), 5.97 (d, 1 H), 5.11 (d, 1 H), 4.34 (m, 1 H), 4.09–3.98 (m, 4 H), 3.86 (s, 3 H), 3.37 (m, 2 H), 2.95 (m, 2 H), 2.64 (m, 1 H), 2.11–1.48 (m, 12 H), 1.31–1.27 (m, 6 H); MS m/z 608 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.O1[CH2:10][CH2:9][CH2:8][CH2:7]1>>[Br:1][CH2:2][CH2:3][CH2:4][CH:7]=[CH:8][C:9]1[CH:10]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCCCBr
Reactant: C1CCOC1
Product: BrCCCC=Cc1ccccc1
Reaction time: 2 h

Procedure:
83.16 g of p-chlorostyrene was reacted with metal magnesium at 35° C. for 5 hours under stirring in tetrahydrofuran flushed with nitrogen to obtain a magnesium composite. This composite was dropwise added to a solution mixture comprising tetrahydrofuran, 1,3-dibromopropane and Li2CuCl4 at 30° C. The reaction was continued at 30° C. for two hours. Then, the obtained product was fractionated by distillation. 3-bromopropylstyrene was obtained under 0.2 Torr at 110° C., and the yield based on the starting material pchlorostyrene was 47%. Identification of 3-bromopropylstyrene was conducted by the NMR method.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:17]\[C:13]1[NH:12][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: O=Cc1ccc[nH]1
Solvent: CC(C)O
Product: O=C1Nc2ccc(Br)cc2/C1=C/c1ccc[nH]1
Temperature: 23 °C

Procedure:
A mixture of 5-bromo-1,3-dihydro-2H-indol-2-one (3.10 g, 14.62 mmol) (Starting Material 6) and pyrrole-2-carboxaldehyde (1.46 g, 15.35 mmol) (Aldrich) in 2-propanol (73 mL) was treated with 10-12 drops of piperidne. The reaction mixture was heated at reflux for 20 h and then allowed to cool to 23° C., at which time, the reaction mixture was filtered. The resulting solid was washed well with hexanes, followed by petroleum ether, and then allowed to air dry to provide pure (Z)-5-bromo-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a yellow solid which was used without further purification. (Yield 4.01 g, 95%; mp 267-268° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([CH:15](OC)[O:16]C)=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+]>C1COCC1.Cl>[C:1]([O:5][C:6](=[O:20])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)c1ccc(/C=C/C(=O)OC(C)(C)C)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
A mixture of (E)-3-(5-dimethoxymethyl-pyridin-2-yl)-acrylic acid tert-butyl ester (1.76 mg, 6.30 mmol) in THF (30 ml) and 1 M HCl (25 ml) was stirred for 4 hours at room temperature, then brought to basic conditions with a 5% NaHCO3 solution and extracted twice with Et2O. The pooled organic phases were dried over Na2SO4 and evaporated in vacuo to dryness to give 1.45 g of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid tert-butyl ester as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CO.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[CH:26]=O.[BH3-]C#N.[Na+]>C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:26][C:25]2[CH:24]=[C:23]([Cl:22])[CH:30]=[C:29]([Cl:31])[CH:28]=2)[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cc(Cl)cc(CNCCNc2nc(Cl)nc3c2ncn3C2CCCC2)c1
Reaction time: 0.5 h

Procedure:
281 mg of the product obtained in Stage 1 of Example 7, 4 ml of methanol, 0.16 ml of 3,5-dichloro-benzaldehyde and 0.2 ml of acetic acid are mixed together, the reaction medium is agitated for 2 hours and 30 minutes, 0.1 g of NaBH3CN is added and agitation is carried out at ambient temperature for 1 hour. After evaporating the solvent, the residue is chromatographed on silica eluting with CH2Cl2/methanol/ammonium hydroxide (95/0.5/0.33) and 119 mg of expected product is obtained.
Reaction SMILES: Cl.[N:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([OH:29])[CH:27]=5)[N:22]=[CH:21][N:20]=4)=[CH:14][C:13]=3[CH3:30])=[CH:7][C:6]=12.[CH:31]12[O:36][CH:35]1[CH2:34][CH2:33][CH2:32]2.O.[OH-].[Cs+].CN(C=O)C>O>[N:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([O:29][C@@H:34]6[CH2:33][CH2:32][CH2:31][C@H:35]6[OH:36])[CH:27]=5)[N:22]=[CH:21][N:20]=4)=[CH:14][C:13]=3[CH3:30])=[CH:7][C:6]=12
Reactant: C1CC2OC2C1
Reactant: Cc1cc(Nc2ncnc3ccc(O)cc23)ccc1Oc1ccn2ncnc2c1
Agent: Cl
Agent: [Cs+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2ncnc3ccc(O[C@@H]4CCC[C@H]4O)cc23)ccc1Oc1ccn2ncnc2c1
Temperature: 92 °C
Reaction time: 24 h
Yield: 80.7 %

Procedure:
A 50 mL flask was charged with 4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenylamino)quinazolin-6-ol hydrochloride (3.117 g, 7.406 mmol), 6-oxa-bicyclo[3.1.0]hexane (0.6924 ml, 7.777 mmol), cesium hydroxide monohydrate (2.736 g, 16.29 mmol), DMF (20 mL). The reaction was heated to 92° C. for 12 hours, then cooled to room temperature and dilute with 200 mL of water. The mixture was stirred for 24 hours. The resulting precipitate was collected by filtration, washed with water and air dried to provide 2.80 g of the title compound as a racemic mixture. MS APCI (+) m/z 469.3 (M+1) detected.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](O)=[O:8])[CH:2]=1.C(Cl)(=O)C([Cl:14])=O>C1C=CC=CC=1.CN(C=O)C>[CH3:10][C:1]1[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=1)[C:7]([Cl:14])=[O:8]
Reactant: Cc1cccc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: Cc1cccc(C(=O)Cl)c1

Procedure:
Meanwhile, the 3-methylbenzoyl chloride acylating agent was prepared by suspending 3.016 g (22.0 mmol) of m-toluic acid in 100 ml benzene. To this solution was added 2.0 equiv. (3.84 ml) of oxalyl chloride, dropwise via a pressure-equalizing dropping funnel at O° C. DMF (2-3 drops) was added to the reaction mixture catalytically and the ice bath was removed. The progress of the reaction was monitored via infrared spectroscopy. The solvent was removed by rotary vacuum evaporation and the residual oil was pumped down under high vacuum overnight.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:5][C:4]=1[CH3:13])=[O:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:13][C:4]1[CH:5]=[C:6]([CH2:8][CH2:9][C:10]([N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)=[O:12])[NH:7][C:3]=1[CH:1]=[O:2]
Reactant: Cc1cc(CCC(=O)O)[nH]c1C=O
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(CCC(=O)N2CCN(C)CC2)[nH]c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of 3-(5-formyl-4-methyl-1H-pyrrol-2-yl)-propionic acid (271.8 mg, 1.5 mmol) in DMF (4mL) was added HOBt (243.2 mg, 1.8 mmol), EDC (345.1 mg, 1.8 mmol) and then 1-methylpiperazine (0.2 mL, 1.8 mmol). The mixture was stirred at room temperature under nitrogen for overnight. The reaction was poured into sat. sodium bicarbonate (50 mL) and extracted with ethyl acetate. The combined organic layer was dried, concentrated and column chromatographed (MeOH/DCM) to give 325.2 mg (82%) of 3-methyl-5-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrole-2-carbaldehyde as a white solid.
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[C:5]([N+:24]([O-:26])=[O:25])=[C:6]([CH:21]=[CH:22][CH:23]=1)[O:7][CH2:8][CH:9]([OH:20])[CH2:10][NH:11][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13].[C:27](Cl)(=[O:29])[CH3:28].C(N(CC)CC)C>ClCCl>[CH3:2][O:3][C:4]1[C:5]([N+:24]([O-:26])=[O:25])=[C:6]([CH:21]=[CH:22][CH:23]=1)[O:7][CH2:8][C:9](=[O:20])[CH2:10][N:11]([C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[C:27](=[O:29])[CH3:28]
Reactant: COc1cccc(OCC(O)CN[C@H](C)c2ccccc2)c1[N+](=O)[O-]
Reactant: CC(=O)Cl
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(OCC(=O)CN(C(C)=O)[C@H](C)c2ccccc2)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product from Example 7B (33.0 g, 77.6 mmol) in dichloromethane (600 mL) at 0 ° C. was treated sequentially with acetyl chloride (6.4 g, 81.0 mmol) and triethylamine (23.6 g,233 mmol) in dichloromethane (50 mL), stirred for 1 hour at 0° C., and quenched with 1M NaOH. The organic layer was washed with brine, dried (MgSO4), and concentrated to provide the title compound. 1H NMR (300 MHz, CDCl3) δ1.60 (d, 3H), 2.29 (s, 3H), 3.70 (d, 1H),3.86 (s, 3H), 4.14 (d, 1H), 4.55 (d, 1H), 4.73 (d, 1H), 5.15 (q, 1H), 6.55 (d, 1H), 6.65 (d, 1H), 7.20-7.42 (m, 6H).
Reaction SMILES: C(OC([NH:8][CH:9]([C:27]([F:30])([F:29])[F:28])[CH2:10][N:11]1[C:15]([C:16](OCC)=[O:17])=[C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]([I:26])=[N:12]1)=O)(C)(C)C>Cl.O1CCOCC1>[I:26][C:13]1[C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:15]2[C:16](=[O:17])[NH:8][CH:9]([C:27]([F:30])([F:29])[F:28])[CH2:10][N:11]2[N:12]=1
Reactant: CCOC(=O)c1c(I)nn(CC(NC(=O)OC(C)(C)C)C(F)(F)F)c1C(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1c(I)nn2c1C(=O)NC(C(F)(F)F)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
Intermediate 346A (3 g, 5.46 mmol) was dissolved in 4 M HCl in 1,4-dioxane (50 mL) and stirred at RT for 2 h. The volatiles were removed under reduced pressure, and the crude residue was dissolved in EtOAc (250 mL) and washed with an aq. solution of NaHCO3, then dried over Na2SO4 and concentrated under reduced pressure. The crude was dissolved in EtOH (25 mL) and stirred at 60° C. for 16 h. Ethanol was removed under reduced pressure and the resulting residue was stirred with hexanes for 15 min. The triturated solid was filtered and dried to afford Intermediate 346B (0.96 g, 41.4%) as an off-white solid. MS(ES): −m/z=404.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.34 (d, J=4.5 Hz, 1H), 4.84-4.73 (m, 2H), 4.71-4.60 (m, 1H), 4.34-4.20 (m, 2H), 1.32-1.23 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.[H][H]>C(O)(=O)C.[Pt]>[Br:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH3:13])[NH:7]2
Reactant: Cc1ccc2c(Br)c(F)ccc2n1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Product: CC1CCc2c(ccc(F)c2Br)N1

Procedure:
To a solution of 20 g of 5-bromo-6-fluoroquinaldine in 150 ml of glacial acetic acid was added 2.0 g of platinum on charcoal. The mixture was hydrogenated on a Paar apparatus at a temperature of about 20° C. until the theoretical amount of hydrogen was taken up. The mixture was then filtered through celite to provide a solution of 5-bromo-6-fluoro-1,2,3,4-tetrahydroquinaldine. Evaporation of the solvent provides the desired intermediate. This intermediate could be used directly in Part C below without purification.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.[NH:14]1[CH2:18][CH2:17][C:16]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20](=[O:27])[O:19]2)[CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:14]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: O=C1OC2(CCNC2)c2ccccc21
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(-c2ccc(N3CCC4(C3)OC(=O)c3ccccc34)nn2)n1

Procedure:
The object product (10 mg, 6%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (100 mg) obtained in Example 43(2), 3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (110 mg) and potassium carbonate (150 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]2[C:18]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][O:25][CH3:26])=[CH:22][C:17]=3[O:16][CH2:15][C:14]2([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=2)[CH3:27])[CH:10]=[CH:11][CH:12]=1.[I-:38].[Na+].O>C(C(C)=O)C>[I:38][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]2[C:18]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][O:25][CH3:26])=[CH:22][C:17]=3[O:16][CH2:15][C:14]2([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=2)[CH3:27])[CH:10]=[CH:11][CH:12]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2cccc(OCCCCCl)c2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2cccc(OCCCCI)c2)cc1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
(3RS,4RS)-4-[3-(4-Chlorobutyloxy)phenyl]-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-2,3-dihydro-4H-benzopyran (300 mg, 0.57 mmol) and sodium iodide (260 mg, 1.73 mmol) were dissolved in methyl ethyl ketone (30 ml) and then refluxed for 12 hours. The reaction mixture was cooled to room temperature and then water was added thereto. The reaction solution was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to remove the organic solvent. The concentrate was separated by column chromatography (n-hexane:ethyl acetate=4:1) to obtain 340 mg (yield: 97%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[CH:11]([C:14]1[N:15]=[C:16]([CH3:19])[S:17][CH:18]=1)([CH3:13])[CH3:12].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:19][C:16]2[S:17][CH:18]=[C:14]([CH:11]([CH3:13])[CH3:12])[N:15]=2)[CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: Cc1nc(C(C)C)cs1
Reactant: N#Cc1cccc(C=O)c1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(C)c1csc(C=Cc2cccc(C#N)c2)n1
Temperature: 170 °C
Reaction time: 24 h
Yield: 53.7 %

Procedure:
3-Cyanobenzaldehyde (3.93 g, 30.0 mmol) was mixed with 4-isopropyl-2-methylthiazole (4.19 g, 30.0 mmol), and acetic anhydride (1.53 g, 15.0 mmol) was added. The mixture was heated under stirring at 170° C for 24 hours. After the reaction, acetic acid was distilled out under reduced pressure and the residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate=3/l) to afford the indicated compound (4.10 g) with a yield of 54%.
Reaction SMILES: [CH3:1][C:2]([O:6][C@@H:7]([C:12]1[C:41]([CH3:42])=[N:40][C:39]2=[CH:43][C:36]3=[N:37][N:38]2[C:13]=1[N:14]1[CH2:48][CH2:47][C:17]([CH3:49])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([CH3:46])[O:24][C:25]2[CH:26]=[CH:27][C:28]([CH3:45])=[CH:29][C:30]=2[C:31]2[CH:44]=[C:35]3[CH:34]=[CH:33][CH:32]=2)[CH2:16][CH2:15]1)[C:8]([O:10]C)=[O:9])([CH2:4][CH3:5])[CH3:3].[OH-].[Na+]>CO>[CH3:1][C:2]([O:6][C@@H:7]([C:12]1[C:41]([CH3:42])=[N:40][C:39]2=[CH:43][C:36]3=[N:37][N:38]2[C:13]=1[N:14]1[CH2:15][CH2:16][C:17]([CH3:49])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([CH3:46])[O:24][C:25]2[CH:26]=[CH:27][C:28]([CH3:45])=[CH:29][C:30]=2[C:31]2[CH:44]=[C:35]3[CH:34]=[CH:33][CH:32]=2)[CH2:47][CH2:48]1)[C:8]([OH:10])=[O:9])([CH2:4][CH3:5])[CH3:3]
Reactant: CCC(C)(C)O[C@H](C(=O)OC)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(C)cc1-c1cccc-3c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(C)(C)O[C@H](C(=O)O)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(C)cc1-c1cccc-3c1
Temperature: 75 °C
Yield: 65.1 %

Procedure:
To a solution of methyl (25)-2-[(2-methylbutan-2-yl)oxy]-2-[(22S)-4,17,22,28-tetramethyl-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (10 mg, 0.015 mmol) in MeOH (1 mL) was added 1N NaOH (0.150 mL, 0.150 mmol) solution and the resulting mixture was heated at 75° C. for 3 h. Then, the mixture was cooled and purified by prep HPLC to afford (2S)-2-[(2-methylbutan-2-yl)oxy]-2-[(22S)-4,17,22,28-tetramethyl-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid (6.4 mg, 9.77 μmol, 65.4% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.33 (d, J=7.0 Hz, 1H), 7.17-7.08 (m, 3H), 7.05 (d, J=8.5 Hz, 1H), 5.65 (br. s., 1H), 4.62 (d, J=6.1 Hz, 1H), 4.49 (t, J=12.5 Hz, 1H), 3.64-3.54 (m, 1H), 3.48-3.42 (m, 2H), 2.80 (d, J=10.4 Hz, 1H), 2.29 (s, 3H), 2.03-1.86 (m, 3H), 1.72-1.62 (m, 4H), 1.60-1.41 (m, 5H), 1.19 (s, 3H), 1.15 (s, 3H), 1.11-1.03 (m, 6H), 0.72 (t, J=7.3 Hz, 3H). 4 missing piperidine hydrogens. LCMS (M+H)=655.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:39]=[CH:38][S:37][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:26][C:27]4[CH:28]=[CH:29][C:30]([C:33]([O:35]C)=[O:34])=[N:31][CH:32]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:39]=[CH:38][S:37][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:26][C:27]4[CH:28]=[CH:29][C:30]([C:33]([OH:35])=[O:34])=[N:31][CH:32]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(NC(=O)C2CCCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)Nc4ccc(C(=O)O)nc4)C3)nc3scnc23)cc1OC
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a solution of methyl 5-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxamido)picolinate (130 mg, 0.24 mmol) in dioxane/H2O (8 mL/8 mL) was added NaOH (70 mg, 1.75 mmol), the reaction mixture was heated to 35° C. with stirring for 30 minutes, the dioxane was removed in vacuo, and the aqueous layer was adjusted to pH=4-5 with conc. HCl, the precipitate was collected by filtration and washed with methanol (5 mL) to afford 5-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxamido)picolinic acid (98 mg, 76.2%) as an orange solid. 1H NMR (300 MHz, DMSO): δ 10.58 (s, 1H), 9.68 (s, 1H), 8.87 (s, 2H), 8.24 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 8.03 (d, 1H, J=8.7 Hz), 7.67 (d, 1H, J=2.1 Hz), 7.35 (dd, 1H, J1=8.7 Hz, J2=2.1 Hz), 6.82 (brs, 1H), 4.84-4.65 (m, 2H), 3.77-3.65 (m, 6H), 3.18-3.00 (m, 2H), 2.67-2.64 (m, 1H), 2.05-1.75 (m, 4H). LC-MS: 536 [M+H]+, tR=1.50 min. HPLC: 97.47% at 214 nm, 97.48% at 254 nm, tR=4.096 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:16][C:9]2[NH:10][C:11](=[O:15])[C:12](=[O:14])[NH:13][C:8]=2[C:7]=1[CH3:17])=[O:5])C>[OH-].[Na+]>[C:4]([C:6]1[S:16][C:9]2[NH:10][C:11](=[O:15])[C:12](=[O:14])[NH:13][C:8]=2[C:7]=1[CH3:17])([OH:5])=[O:3]
Reactant: CCOC(=O)c1sc2[nH]c(=O)c(=O)[nH]c2c1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(C(=O)O)sc2[nH]c(=O)c(=O)[nH]c12
Reaction time: 8 h
Yield: 54.3 %

Procedure:
6-Ethoxycarbonyl-7-methylthieno[2,3-b]pyrazine-2,3-(1H,4H)-dione (60 mg, 0.236 mmol) was warmed in 1 M NaOH (0.944 ml) at 50° C. under stirring for 8 hours. The mixture was filtrated and acidified with 2 M HCl (1.0 ml) under cooling in an ice bath. The precipitate was filtered off, washed with water and dried to afford 29 mg (54%) of the title compound. M.p. 289°-294° C. 1H-NMR (DMSO-D6, δ): 2.45 (s, 3H), 11.96 (s, 1H), 12.45 (s, 1H), 12.96 (s, 1H).
Reaction SMILES: [CH2:1]([NH:5][C:6]([C@@H:8]1[C@H:16]([CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]1[C:18](=[O:23])[C@@H:19]([NH2:22])[CH2:20][CH3:21])=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:24](NC([C@H]1[C@@H](C)C2C(=CC=CC=2)N1C(=O)[C@@H](N)CC)=O)CCC>>[CH2:1]([NH:5][C:6]([CH:8]1[C:16]([CH3:24])([CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]1[C:18](=[O:23])[C@@H:19]([NH2:22])[CH2:20][CH3:21])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@H]1[C@@H](C)c2ccccc2N1C(=O)[C@@H](N)CC
Reactant: CCCCNC(=O)[C@@H]1[C@H](C)c2ccccc2N1C(=O)[C@@H](N)CC
Product: CCCCNC(=O)C1N(C(=O)[C@@H](N)CC)c2ccccc2C1(C)C

Procedure:
1-(2(S)-aminobutyryl)-3(R)-methylindoline-2(S)-carboxylic acid butylamide and 1-(2(S)-aminobutyryl)-3(S)-methylindoline-2(R)-carboxylic acid butylamide;