Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:19]1[CH:33]=[CH:32][C:22]([CH2:23]P(=O)(OCC)OCC)=[CH:21][CH:20]=1.[CH2:34]([N:36]1[C:48]2[CH:47]=[CH:46][C:45]([CH:49]=O)=[CH:44][C:43]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH3:35].CC(C)([O-])C.[K+]>C1COCC1>[CH2:34]([N:36]1[C:48]2[CH:47]=[CH:46][C:45](/[CH:49]=[CH:23]/[C:22]3[CH:32]=[CH:33][C:19]([C:2]4[CH:3]=[CH:4][C:5]5[C:6]6[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=6)[C:12]6[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=6)[C:18]=5[CH:1]=4)=[CH:20][CH:21]=3)=[CH:44][C:43]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH3:35]
Reactant: CCOP(=O)(Cc1ccc(-c2ccc3c4ccccc4c4ccccc4c3c2)cc1)OCC
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCn1c2ccccc2c2cc(/C=C/c3ccc(-c4ccc5c6ccccc6c6ccccc6c5c4)cc3)ccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
Compound E (100 mg, 0.22 mmol) or E1 and N-ethylcarbazole-3-carboxaldehyde) (59 mg, 0.26 mmol) and dry THF (10 ml) were charged in two-necked bottle in an ice bath, potassium-tert-butoxide (49 mg, 0.44 mmol) in dry THF (10 ml) was added under nitrogen. The reaction mixture was stirred for 15 min at 0° C., followed by 1 h at room temperature. The solution mixture was extracted with ethyl acetate and washed with water. The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure to afford a crude product that was purified by sublimating at a temperature of 260° C. to obtain TSCz (90 mg, yield=78%) as yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([Cl:19])[C:10]=1[NH:20][C:21](=[O:48])[N:22]([C:24]1[N:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[CH:33][C:32]=2[NH:43][C:44](=[O:47])[CH:45]=[CH2:46])[CH:25]=1)[CH3:23].[C:49]([O:53][C:54](=[O:59])[NH:55][CH2:56][CH:57]=O)([CH3:52])([CH3:51])[CH3:50].C([BH3-])#N.[Na+]>C1COCC1.CO>[C:44]([NH:43][C:32]1[CH:33]=[C:34]([N:37]2[CH2:38][CH2:39][N:40]([CH2:57][CH2:56][NH:55][C:54](=[O:59])[O:53][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:41][CH2:42]2)[CH:35]=[CH:36][C:31]=1[NH:30][C:26]1[CH:25]=[C:24]([N:22]([CH3:23])[C:21]([NH:20][C:10]2[C:9]([Cl:8])=[C:14]([O:15][CH3:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[Cl:19])=[O:48])[N:29]=[CH:28][N:27]=1)(=[O:47])[CH:45]=[CH2:46]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: C=CC(=O)Nc1cc(N2CCNCC2)ccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: C=CC(=O)Nc1cc(N2CCN(CCNC(=O)OC(C)(C)C)CC2)ccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.4 %

Procedure:
To the solution of N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(piperazin-1-yl)phenyl)acrylamide 2,2,2-trifluoroacetate (Procedure 2L, Example 157) (30 g, 0.042 mmol) in THF (1.0 ml) and MeOH (1.0 ml) was added tert-butyl(2-oxoethyl)carbamate (13 g, 0.08 mmol). The reaction mixture was stirred at room temperature for 10 minutes. Sodium cyanoborohydride (7.0 g, 0.12 mmol) was added and the reaction mixture was stirred at room temperature over night. Solvent was evaporated and saturated NaHCO3 solution was added. The mixture was extracted three times with DCM. Combined organic layer was dried over Na2SO4 and evaporated. The remaining material was purified by flash chromatography on silica eluting with 0% to 15% MeOH in DCM to afford the title compound (17 mg, yield: 54%) ESI-MS: 744 [M+H]+.
Reaction SMILES: B(Cl)(Cl)Cl.C[O:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12](=[O:17])[CH:13]=[C:14]([CH3:16])[CH3:15].[K+].[Br-]>ClCCl>[OH:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12](=[O:17])[CH:13]=[C:14]([CH3:15])[CH3:16]
Reactant: COc1ccsc1C(=O)C=C(C)C
Agent: ClB(Cl)Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)=CC(=O)c1sccc1O
Temperature: 0 °C

Procedure:
A solution of boron trichloride, (1.0 M in dichloromethane, 800 mL, 0.80 mol) was slowly added to a solution of 3-methoxy-2-(3-methyl-1-oxo-2-buten-1-yl)thiophene (52.3 g, 0.27 mol) in dichloromethane (400 mL) at -10° C. to 5° C. The resultant solution was stirred an additional 1.5 h at -5° C. Ice water was added slowly with rapid stirring. The organic layer was separated, dried over sodium sulfate, and eluted through a pad of silica gel. The solvent was evaporated in vacuo and the resultant oil was crystallized from hexanes at -70° C. to give the product, 40.0 g (82%), as a yellow solid: mp 32°-33° C.; IR (KBr): 1641, 1581 and 1541 cm-1 ; MS: m/z 183 (MH+); 1H NMR (CDCl3): δ2.00 (d, J=1.1 Hz, 3H), 2.30 (d, J=1.0 Hz, 3H), 6.25 (m, 1H), 6.75 (d, J=5.3 Hz, 1H), 7.37 (d, J=5.3 Hz, 1H) and 12.14 (s, exchanges with D2O, 1H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[N:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=4[C:10]3=[N:9][C:8]=2[C:22]([NH2:24])=[O:23])[CH:5]=[CH:4][CH:3]=[N:2]1.BrC1C=CC2OCCN3C(CN4C=CN=C4C)=C(C(N)=O)N=C3C=2C=1.N1C=CC=N1.[CH3:55][C:56]([OH:60])([C:58]#[CH:59])[CH3:57]>>[N:1]1([CH2:6][C:7]2[N:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:20]=[CH:19][C:18]([C:59]#[C:58][C:56]([OH:60])([CH3:57])[CH3:55])=[CH:17][C:16]=4[C:10]3=[N:9][C:8]=2[C:22]([NH2:24])=[O:23])[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: NC(=O)c1nc2n(c1Cn1cccn1)CCOc1ccc(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: Cc1nccn1Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Agent: c1cn[nH]c1
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(Cn3cccn3)n1CCO2
Yield: 14 %

Procedure:
Similar to as described in General Procedure G, 3((1H-pyrazol-1-yl)methyl)-10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-((2-methyl-1H-imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing 2-methylimidazole with pyrazole) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a colorless solid (14 mg, 14%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([CH2:17][CH2:18][CH2:19][CH3:20])[CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[H-].[Na+].[C:24]([O:28][C:29](=[O:39])[NH:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][N:32]=1)([CH3:27])([CH3:26])[CH3:25].C(O)C>CN(C=O)C.O>[CH2:10]([O:9][C:7](=[O:8])[C:6]([CH2:37][C:34]1[CH:33]=[N:32][C:31]([NH:30][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:39])=[CH:36][CH:35]=1)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]([CH2:17][CH2:18][CH2:19][CH3:20])[C:4]([O:3][CH2:1][CH3:2])=[O:21])[CH3:11]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Reactant: CCCCC(C(=O)OCC)C(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(C(=O)OCC)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 78.6 %

Procedure:
A solution of 2-butyl-3-ethoxycarbonyl-succinic acid diethyl ester (1 g, 3 mmol) and NaH (119 mg, 5 mmol) in DMF (20 ml) was stirred for 60 minutes at 0° C. under argon. (5-Bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (1.425 g, 5 mmol) was added and the mixture was stirred at room temperature for one week. Ethanol (1 ml) was added and the reaction was poured into H2O and extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The product was purified by column chromatography (heptane/ethyl acetate, 4:1 to 1:1) to give 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-3-butyl-2-ethoxycarbonyl-succinic acid diethyl ester (1.2 g, 71.3%).
Reaction SMILES: C(O)C.B([O-])([O-])O[C:6]1[O:7][C:8]2[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][C:9]=2[CH:10]=1.Br[C:22]1[CH:23]=[CH:24][C:25]2[S:31](=[O:33])(=[O:32])[CH2:30][CH2:29][C:28]([C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([CH2:43][N:44]([CH3:51])[CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[CH:39][CH:38]=3)=[O:35])=[CH:27][C:26]=2[CH:52]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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.O>[CH3:51][N:44]([CH2:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]([C:28]2[CH2:29][CH2:30][S:31](=[O:33])(=[O:32])[C:25]3[CH:24]=[CH:23][C:22]([C:6]4[O:7][C:8]5[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][C:9]=5[CH:10]=4)=[CH:52][C:26]=3[CH:27]=2)=[O:35])=[CH:38][CH:39]=1)[CH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCOc1ccc2cc(OB([O-])[O-])oc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCOc1ccc2cc(-c3ccc4c(c3)C=C(C(=O)Nc3ccc(CN(C)C5CCOCC5)cc3)CCS4(=O)=O)oc2c1
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
In toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) were suspended 6-propoxy-benzofuran-2-yl borate (165 mg), 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) and potassium carbonate (208 mg), and the suspension was stirred under argon atmosphere for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (47 mg), and the mixture was stirred, under argon atmosphere, at 100° C. for 10 hours and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography and recrystallized from ethanol (40 ml) to give colorless crystals of N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-7-(6-propoxybenzofuran-2-yl)-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 141) (192 mg).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH2:4]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>O.C(Cl)Cl.[OH-].[Na+]>[C:15]([NH:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH2:4]1)(=[O:17])[CH3:16]
Reactant: COc1ccc2c(c1)CCC(N)C2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC(NC(C)=O)C2
Temperature: 15 °C

Procedure:
2-Amino-6-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride is dissolved in a mixture of water and methylene chloride, and 10 N sodium hydroxide solution is added thereto until the pH is 12. 1.5 equivalents of acetic anhydride are then added, the pH being kept between 10 and 12 with 10 N sodium hydroxide solution, and the mixture being cooled to about 15° C. The pH is then brought to between 7 and 8 and the organic phase is separated off, dried and evaporated. When recrystallised from petroleum ether, the residue melts at 175° C.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].ICI.Cl>O.CS(C)=O>[OH:9][C:8]1[CH:10]=[C:2]([CH:3]=[C:4]2[O:5][CH2:14][O:7][C:6]=12)[C:1]([O:12][CH3:13])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: ICI
Solvent: O
Product: COC(=O)c1cc(O)c2c(c1)OCO2
Temperature: 40 °C
Reaction time: 24 h
Yield: 40.4 %

Procedure:
A mixture comprising 34.4 g of commercially available methyl gallate, 25.8 g of anhydrous potassium carbonate, 400 ml of DMSO and 50.0 g of diiodomethane was stirred at 40° C. for 24 hours in a nitrogen current. After the reaction, the liquid mixture was poured into water and made acidic by 2N hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was washed with water. The solvent was removed from the extract and the residue was subjected to flash column chromatography [466 g of 230-400 mesh silica gel, solvent n-hexane/acetone (3/1), pressure 0.4 kg/cm2, 5th to 9th fractions when fractions of 100 ml were collected] to effect purification and obtain 14.8 g of methyl 3-hydroxy-4,5-(methylenedioxy)benzoate (the yield was 40.4%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].CN(CCN(CCN(C)C)C)C.C([Li])CCC.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=[O:34]>O1CCCC1.CCCCCC.O>[F:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([C:6]#[N:7])=[CH:8][C:9]=1[CH:33]([C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([F:29])[CH:31]=1)[OH:34]
Reactant: O=Cc1cccc(F)c1
Reactant: COc1cc(C#N)ccc1F
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COc1cc(C#N)cc(C(O)c2cccc(F)c2)c1F
Reaction time: 1 h

Procedure:
To a solution of 15.0 g of 4-fluoro-3-methoxybenzonitrile and 21.8 ml of N,N,N′,N′,N″-pentamethyldiethylenetriamine in 300 ml tetrahydrofuran was added 65.5 ml of a 1.59 M solution of n-butyllithium in hexane at −78° C. in an atmosphere of nitrogen gas, followed by stirring at the same temperature for 1 hour. At the same temperature, 10.5 ml of 3-fluorobenzaldehyde was added dropwise, followed by stirring at the same temperature for 1 hour. Then, water was added and the mixture was extracted with diethyl ether. The organic layer was washed with saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10 to 1:3), to give 7.1 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1.[C:40](Cl)(=[O:42])[CH3:41].N1C=CC=CC=1>C(Cl)Cl>[C:40]([N:27]1[CH2:28][CH2:29][CH:24]([O:23][C:17]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[CH:15]2[CH2:14][C:13](=[O:30])[NH:12][CH:11]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:10]32[C:5]2[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:9]3=[O:39])[CH2:25][CH2:26]1)(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC2CCNCC2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCC(Oc2ccc(Cl)cc2C2CC(=O)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)CC1
Reaction time: 4 h
Yield: 8.2 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(4-piperidinyloxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (110 mg, 0.2 mmol), acetyl chloride (0.017 mL, 0.24 mmol) in DCM (5 mL) was added pyridine (23 mg, 0.3 mmol) at r.t. The reaction mixture was stirred for 4 h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep-HPLC to give the title compound as a white solid (Yield: 10 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:18]=[CH:17][N:16]=[CH:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:7]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([NH2:28])=[N:20]1>>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([NH:28][C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][N:20]=2)[C:3]2[CH:18]=[CH:17][N:16]=[CH:15][C:4]=2[N:5]=1
Reactant: Nc1n[nH]c2ccccc12
Reactant: Clc1ccccc1-c1nc(Cl)c2ccncc2n1
Product: Clc1ccccc1-c1nc(Nc2n[nH]c3ccccc23)c2ccncc2n1

Procedure:
Prepared from 4-Chloro-2-(2-chloro-phenyl)-pyrido[3,4-d]pyrimidine (100 mg, 0.36 mmol) and 1H-indazol-3-ylamine (88 mg, 0.66 mmol)+. Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (72 mg, 33% yield). HPLC-Method A, Rt 3.21 min; 1H NMR (DMSO, 500 MHz): δ 12.95 (1H, s), 10.90 (1H, bs), 9.25 (1H, s), 8.75 (1H, m), 8.55 (1H, m), 7.65 (1H, m), 7.55 (1H, m), 7.50-7.30 (5H, m), 7.00 (1H, m); MS (m/z), MH+ 373.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:28][O:27]C(C)(C)[O:25]3)=[CH:20][N:19]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:43].Cl>C(O)(=O)C.C(OCC)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:13]2[NH:43][C:16]([C:18]3[N:19]=[CH:20][C:21]([CH:24]([OH:25])[CH2:28][OH:27])=[CH:22][CH:23]=3)=[CH:15][CH:14]=2)[CH2:32][CH:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CC1(C)OCC(c2ccc(C(=O)CCC(=O)C(CC3CCOCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)nc2)O1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(C(O)CO)cn3)[nH]2)cc1Cl
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 90.1 %

Procedure:
To a solution of 5-[3-chloro-4-(methylsulfonyl)phenyl]-1-[5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (620 mg) in acetic acid (5 mL) was added ammonium acetate (1.36 g), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated to give a crude product (660 mg). To a solution of the obtained crude product (660 mg) in tetrahydrofuran (5 mL) was added 1M hydrochloric acid (5 mL), and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (500 mg, yield 90%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-methanol (9:1, volume ratio). MS: 507 (MH+). 1H NMR (300 MHz, CDCl3) δ1.24-1.48 (3H, m), 1.51-1.62 (3 H, m), 1.74-1.89 (1 H, m), 1.95-2.09 (1H, m), 2.38 (1 H, brs), 3.01 (1 H, s), 3.19-3.34 (5 H, m), 3.55-3.66 (1 H, m), 3.69-3.80 (1 H, m), 3.85-3.97 (2H, m), 4.02-4.14 (1 H, m), 4.78 (1 H, dd, J=7.8, 3.6 Hz), 6.61-6.68 (1 H, m), 7.24 (1 H, dd, J=8.1, 1.7 Hz), 7.32 (1 H, d, J=1.5 Hz), 7.50 (1 H, d, J=8.3 Hz), 7.59-7.67 (1 H, m), 7.97-8.05 (1 H, m), 8.30 (1 H, s), 9.71 (1 H, brs).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:13][O:12][C:10](=[O:11])[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[CH:16][N:17]([CH3:19])[CH3:18]
Reactant: COC(=O)Cc1ccc(OC)cc1
Reactant: COC(OC)N(C)C
Product: COC(=O)C(=CN(C)C)c1ccc(OC)cc1
Temperature: 100 °C

Procedure:
Methyl 4-methoxyphenylacetate (3.3 g) was diss olved in N,N-5 dimethylformamide (3 cm3) treated with N,N-dimethylformamide dimethyl acetal (6 cm3) and heated at 100° C. for 18 h. The reaction was then cooled and evaporated under high vacuum to afford crude methyl-3-dimethylamino-2-(4-methoxyphenyl)propenoate (3.6 g) which was used without further purification. δH (250 MHz; CDCl3); 2.68 (6H, s), 3.62 (3H, s), 3.8 (3H, s), 6.82 (2H, d, J8.7 Hz), 71 (2H, d, J8.7 Hz) and 7.54 (1H, s).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[C:11][CH3:12])[CH2:8][CH2:7][C@H:6]1[C:13]#[N:14])=[O:4].[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>C(#N)C>[CH:15]1([NH:20][CH2:2][C:3]([N:5]2[C@@H:9]([C:10]#[C:11][CH3:12])[CH2:8][CH2:7][C@H:6]2[C:13]#[N:14])=[O:4])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: NC1CCCC1
Solvent: CC#N
Product: CC#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-propynylpyrrolidine-2-carbonitrile (0.018 g, 0.086 mmol ) in acetonitrile (1 mL) at room temperature was added cyclopentyl amine (0.017 mL, 0.17 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol/97% dichloromethane to provide the titled compound. MS (ESI) m/z 260 (M+H)+; 1H NMR (DMSO) δ ppm 4.89 (m, 1H), 4.84 (m, 1H), 4.07-4.13 (m, 2H), 3.52 (m, 1H), 2.05-2.42 (m, 4H), 1.96 (m, 2H), 1.87 (d, 3H), 1.70 (m, 4H), 1.52 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[N:19]=[C:18]([O:20][CH2:21][CH2:22][N:23]5C(=O)C6C(=CC=CC=6)C5=O)[CH:17]=[CH:16][N:15]4[C:34]=3[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.O.NN>C(O)C.C(OC(C)C)(C)C>[NH2:23][CH2:22][CH2:21][O:20][C:18]1[CH:17]=[CH:16][N:15]2[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([C:2]4([NH2:1])[CH2:5][CH2:4][CH2:3]4)=[CH:7][CH:8]=3)[N:13]=[C:14]2[N:19]=1
Reactant: NC1(c2ccc(-c3nc4nc(OCCN5C(=O)c6ccccc6C5=O)ccn4c3-c3ccccc3)cc2)CCC1
Agent: NN
Solvent: CCO
Solvent: CC(C)OC(C)C
Solvent: O
Product: NCCOc1ccn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2n1
Temperature: 80 °C
Yield: 87.7 %

Procedure:
2-(2-{2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyrimidin-7-yloxy}-ethyl)-isoindole-1,3-dione (340 mg from Step 1) was dissolved in ethanol (6.8 mL), treated with hydrazine hydrate (98%, 0.045 mL) and heated at 80° C. for 22 h. On cooling, the reaction mixture was diluted with diisopropyl ether and filtered. The filtrate was concentrated in vacuo to give the title compound (225 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[F:23][C:24]([F:28])([F:27])[CH2:25]O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:25][C:24]([F:28])([F:27])[F:23])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: OCC(F)(F)F
Product: FC(F)(F)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound IIk was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and 2,2,2-trifluoroethanol following the general procedure for the Mitsunobu reaction as described above.