Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH:7]1[CH2:36][CH2:35][N:10]2[C:11]3[C:16]([C:17]([C:18]4[C:19](=[O:34])[O:20][C:21](=O)[C:22]=4[C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH3:32])[CH:24]=4)=[C:9]2[CH2:8]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)(=O)C.[CH3:37][S:38]([O:41]S(C)(=O)=O)(=O)=[O:39].[N:46]1C=CC=CC=1>ClCCl>[CH3:37][S:38]([O:4][CH2:5][CH2:6][CH:7]1[CH2:36][CH2:35][N:10]2[C:11]3[C:16]([C:17]([C:18]4[C:19](=[O:34])[NH:46][C:21](=[O:20])[C:22]=4[C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH3:32])[CH:24]=4)=[C:9]2[CH2:8]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:41])=[O:39]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: c1ccncc1
Reactant: CC(=O)OCCC1CCn2c(c(C3=C(c4cn(C)c5ccccc45)C(=O)OC3=O)c3ccccc32)C1
Solvent: ClCCl
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(CCOS(C)(=O)=O)C4)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 500 mg of the pyrroledione product of Example 13 in 50 ml of dichloromethane was treated with 218 mg of methanesulfonic anhydride and 1 ml of pyridine. The resulting solution was stirred at room temperature under a nitrogen atmosphere for 1 hour. An additional 20 mg of methanesulfonic anhydride were then added and stirring was continued for 0.5 hour. The mixture was washed with water, dried and evaporated. Crystallization of the residue from ethyl acetate/petroleum ether gave 540 mg of 3-[6,7,8,9-tetrahydro-8-(2-methylsulfonyloxyethyl)pyrido-[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 244°-245° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.C([O-])(O)=O.[Na+].[CH3:22][CH2:23]O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([O:16][CH2:22][CH3:23])=[O:15])[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1
Reactant: O=C(O)Cc1cc(Cl)cc(OC(F)(F)F)c1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1cc(Cl)cc(OC(F)(F)F)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 3-chloro-5-trifluoromethoxyphenylacetic acid (5.2 g, 20.4 mmol; see step (iii) above) in EtOH (600 mL) was added sulfuric acid (several drops). The solution was refluxed for 18 h, cooled to room temperature, neutralized with solid NaHCO3 and the EtOH removed in vacuo. The residue was diluted with EtOAc then washed with H2O (1×), aqueous NaHCO3 (1×) and brine (1×). The organics were dried (Na2SO4), filtered and concentrated in vacuo to afford the sub-title compound (5.5 g, 96%) as an oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]([NH:12][C:13](=[O:33])[CH2:14][NH:15][C:16](=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31])=S)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[S]>C(O)C>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]([NH:12][C:13](=[O:33])[CH2:14][NH:15][C:16](=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]1[NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=1)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)C[C@H](NC(=O)CNC(=O)CCCCNC(=S)Nc1ccccc1N)c1cccnc1
Agent: [S]
Solvent: CCO
Product: COC(=O)C[C@H](NC(=O)CNC(=O)CCCCNc1nc2ccccc2[nH]1)c1cccnc1

Procedure:
An ethanol mixture (20 ml) of 24-7 (89 mg, 0.18 mmol), mercuric oxide (78.8 mg, 0.36 mmol) and sulfur (1.8 mg, 0.056 mmol) was refluxed for 2 hr. After cooling, the mixture was filtered and the filtrate concentrated to a semi-solid which was purified by flash chromatography (20% MeOH/CH2Cl2) to provide 24-8 as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25]C(=O)OC(C)(C)C)[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1>C(O)(C(F)(F)F)=O>[ClH:1].[NH2:25][C@@H:21]1[CH2:22][CH2:23][CH2:24][N:19]([C:3]2[C:2]([Cl:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([N:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)=[O:13])[C:4]=23)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(NC(=O)N4CCCC4)c23)C1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(NC(=O)N4CCCC4)c23)C1
Yield: 199.6 %

Procedure:
A solution of (R)-tert-butyl 1-(5-chloro-3-(pyrrolidine-1-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (130 mg, 0.281 mmol) in neat TFA (4 mL) was stirred at room temperature for 10 minutes, and then the TFA was removed in vacuo. The resulting oily residue was dissolved in CH3OH (5 mL) and evaporated from CH3CN (2×5 mL) to provide (R)-N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolidine-1-carboxamide hydrochloride (112 mg, 91% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 1.68 (br s, 1H), 8.25 (s, 3H), 8.10 (s, 1H), 7.85 (s, 1H), 7.42 (d, 1H), 3.51-3.45 (m, 1H), 3.44-3.36 (m, 4H), 3.34-3.22 (m, 3H), 3.16-3.07 (m, 1H), 2.09-2.01 (m, 1H), 1.90-1.87 (m, 4H), 1.80-1.72 (m, 1H), 1.67-1.41 (m, 2H). LCMS (APCI+) m/z 363 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][C@@H:36]([CH2:48][OH:49])[C@H:37]([C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)[OH:38]>>[OH:38][C@@H:37]([C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)[C@@H:36]([NH:35][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:28]=[CH:27][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:31][CH:30]=1)=[O:7])=[O:18])[CH2:48][OH:49]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: N[C@@H](CO)[C@@H](O)c1ccc([N+](=O)[O-])cc1
Product: CON=C1C[C@@H](C(=O)N[C@@H](CO)[C@@H](O)c2ccc([N+](=O)[O-])cc2)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, the title compound was obtained in 74% purity by HPLC. MS(ESI+): m/z=547.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[CH:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[C:4]([O:25][CH3:26])[N:3]=1.[O:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1>>[O:27]1[CH:31]=[CH:30][C:29]([C:2]2[CH:7]=[C:6]([C:8]3[N:12]4[CH:13]=[C:14]([NH:17][CH:18]5[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19]5)[CH:15]=[CH:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[C:4]([O:25][CH3:26])[N:3]=2)=[CH:28]1
Reactant: COc1cc(-c2cnc3ccc(NC4CCCC(O)C4)cn23)cc(Cl)n1
Reactant: OB(O)c1ccoc1
Product: COc1cc(-c2cnc3ccc(NC4CCCC(O)C4)cn23)cc(-c2ccoc2)n1

Procedure:
The title compound is prepared from (1SR,3SR)-3-[3-(2-Chloro-6-methoxy-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol (Intermediate O) and 3-furyl boronic acid using a procedure analogous to that described in Example 2.3.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[N:24]1[C:29]2[NH:30][CH:31]=[CH:32][C:28]=2[CH:27]=[N:26][CH:25]=1.[OH-].[K+].O>CO>[F:1][C:2]1[C:7]([CH:8]([OH:9])[C:32]2[C:28]3[CH:27]=[N:26][CH:25]=[N:24][C:29]=3[NH:30][CH:31]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: c1ncc2cc[nH]c2n1
Reactant: O=Cc1cccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=S(=O)(Nc1cccc(C(O)c2c[nH]c3ncncc23)c1F)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.3 %

Procedure:
To N-(2-fluoro-3-formyl-phenyl)-4-trifluoromethyl-benzenesulfonamide (34, 172 mg, 0.50 mmol) in 1 mL of methanol, 7H-pyrrolo[2,3-d]pyrimidine (6, 71 mg, 0.60 mmol) and potassium hydroxide (84 mg, 1.5 mmol) were added under an atmosphere of nitrogen. The reaction was stirred at room temperature for 24 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography eluting with 5% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a solid (P-0034, 101 mg, 44%). MS(ESI) [M+H+]−=467.8.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:27]([C:24]1[CH:23]=[CH:22][C:21]([S:18]([CH3:17])(=[O:20])=[O:19])=[CH:26][CH:25]=1)(=[O:29])=[O:28])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: CS(=O)(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 127 mg of 4-Methanesulfonyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 2.92 (s, 3H), 7.34 (m, 3H), 7.434 (m, 2H), 7.51 (dd, 1H, J=8.8 Hz, 2.4 Hz), 7.60 (m, 1H), 7.75 (d, 1H, J=8.8 Hz), 7.80-7.86 (m, 4H), 9.86 (b, 1H). MS: m/z 450.9 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][CH:11]([CH2:26]O)[CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:29]C(Br)(Br)Br>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:28])[NH:10][CH:11]([CH2:26][Br:29])[CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(CO)CCCN1C(=O)c2ccccc2C1=O)OCc1ccccc1
Reactant: BrC(Br)(Br)Br
Solvent: Cc1ccccc1
Product: O=C(NC(CBr)CCCN1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At −20° C. under N2 to the suspension of 6-2 (253 mg, 0.66 mmol) and TPP (260 mg, 1.5 equivalents) in toluene was added tetrabromocarbon (242 mg, 1.1 equivalents) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography eluted with hexanes and EtOAc (2:1). The purified product [1-Bromomethyl-4-phthalimido-butyl]-carbamic acid benzyl ester (6-3) was obtained as a white solid, 263 mg (99%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][N:5]=[C:4]([S:18][CH3:19])[N:3]=1.ClC1C=CC=C(C(OO)=[O:28])C=1.O>CCOC(C)=O>[CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][N:5]=[C:4]([S:18]([CH3:19])=[O:28])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc(C(=O)OCc2ccccc2)c(C)n1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(S(C)=O)ncc1C(=O)OCc1ccccc1
Yield: 84 %

Procedure:
A solution of benzyl 4-methyl-2-(methylthio)-5-pyrimidinecarboxylate (3.6 g) and m-chloroperbenzoic acid (P=75%) (2.72 g) in AcOEt (30 ml) was stirred at ambient temperature for 2 hours. The reaction mixture was poured into a mixture of AcOEt and H2O and the organic layer was washed with saturated NaHCO3 solution, brine and dried over MgSO4. The solvent was evaporated in vacuo to give benzyl 4-methyl-2-(methylsulfinyl)-5-pyrimidinecarboxylate (3.2 g)
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([C:18](I)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.[C:22]([C:24]1[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=1)#[CH:23]>>[F:1][C:2]1[C:3]2[N:4]([C:18]([C:23]#[C:22][C:24]3[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: C#Cc1cnc(N)nc1
Reactant: Fc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(I)cnc12
Product: Nc1ncc(C#Cc2cnc3c(F)cc(-c4ccc(C(F)(F)F)cc4)cn23)cn1

Procedure:
The title compound was prepared from 8-fluoro-3-iodo-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.29 step 6) (350 mg, 0.85 mmol) and 5-ethynyl-pyrimidin-2-ylamine (example D.2) (122 mg, 0.85 mmol) according to general procedure II. Obtained as an off-white solid (116 mg, 29%). MS (ISP) 398.2 [(M+H)+]; mp 286° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[NH:11]([CH2:13][C:14](O)=[O:15])[CH3:12].C(N(CC)CC)C>CS(C)=O>[CH3:12][N:11]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:8][C:14](=[O:15])[CH2:13]1
Reactant: CNCC(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1CC(=O)Nc2ccccc21

Procedure:
5.2 g of o-fluoro-nitrobenzene, 3.2 g of sarcosine and 5.2 ml triethylamine was stirred in 25 ml DMSO at 70° C. for 4 days. The mixture was then evaporated in vacuo and the residue was partitioned between water and methylene chloride. The organic phase was evaporated in vacuo. The residue was dissolved in 100 ml 96% ethanol and was hydrogenated at normal pressure using 0.5 g Pd/C. After completion of hydrogen uptake, the mixture was filtered and evaporated in vacuo. The residue was washed with water with disodium carbonate, ether and water. yield of title compound: 1.3 g M.p. 132° C.
Reaction SMILES: C(OCCC[N:7]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:19]=3)=[CH:17][C:12]=2[CH:11]=[C:10]([C:31](O)=[O:32])[CH2:9][CH2:8]1)C.S(Cl)(Cl)=O.C[N:39](C=O)C>C1COCC1>[CH2:28]([O:27][CH2:26][CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[CH:15]=[CH:14][C:13]3[NH:7][CH2:8][CH2:9][C:10]([C:31]([NH2:39])=[O:32])=[CH:11][C:12]=3[CH:17]=2)=[CH:19][CH:20]=1)[CH2:29][CH3:30]
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCCOCC)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(N)=O)CCN3)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 1-(3-ethoxypropyl)-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (250 mg) in THF (10 ml) were added thionyl chloride (0.080 ml) and DMF (one droplet) at room temperature, and the mixture was stirred for 1.5 hours. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in THF (20 ml), which was added dropwise to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (133 mg) and triethylamine (0.46 ml) in THF (3 ml) at 0° C. The mixture was stirred at room temperature for 2.5 hours, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. After concentration under reduced pressure, the residue was purified with column chromatography (ethanol:ethyl acetate=1:9→1:3), and the resulting crystals were purified by recrystallization (hexane-ethyl acetate) to give 1-(3-ethoxypropyl)-N-[4-[[N-methyl-N-tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 105) (242 mg) as yellow crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:20]=[C:19]3[C:13]([CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18]3)=[N:12]2)=[CH:7][CH:6]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl.CO>[CH3:1][N:2]([CH3:28])[C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:20]=[C:19]3[C:13]([CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[N:12]2)=[CH:7][CH:6]=1
Reactant: CN(C)C(=O)c1ccc(-n2cc3c(n2)CCN(C(=O)OC(C)(C)C)CC3)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(-n2cc3c(n2)CCNCC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl 2-{4-[(dimethylamino)carbonyl]phenyl}-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 41) (194 mg, 0.50 mmol) in dichloromethane (14 ml) was added trifluoroacetic acid (7 ml). The resulting mixture was stirred at room temperature, under argon, for 2 hours and then diluted with methanol. Reaction was purified by SCX, eluting with methanol and then 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo. Resulting crude product was purified further by column chromatography on silica gel, eluting with a mixture of 2M ammonia in methanol/dichloromethane (0-3%) to afford the title compound (D42). MS (ES+) m/e 285 [M+H]+.
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH:10]([O:12][C:13]1[C:14]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:19][C:15]=2[N:16]=[CH:17][N:18]=1)[CH3:11])C1C=CC=CC=1.C(O)(=O)C>[Pd].CO>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]2[C:14]3[C:13]([O:12][CH:10]([CH3:11])[CH2:9][NH:8][CH3:1])=[N:18][CH:17]=[N:16][C:15]=3[O:19][C:20]=2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OC(C)CN(C)Cc4ccccc4)c23)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CNCC(C)Oc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12

Procedure:
Put 500 mg palladium on charcoal (10%) under argon in 100 ml methanol. Add 1.7 g (3.55 mmol) (+/−)-N-Benzyl-2-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-N-methylpropane-1-amine and 2.5 ml acetic acid, and hydrogenate at RT and normal pressure. After 2 h filter with a diatomite filter and concentrate by evaporation. Dissolve the residue in water and wash twice with ethyl acetate. Discard the ethyl acetate phases. Make the aqueous phase basic with solid sodium hydrogencarbonate and extract twice with ethyl acetate. Wash the combined ethyl acetate phases once with satd. sodium chloride solution, dry over magnesium sulphate and concentrate by evaporation. 900 mg (65.2% of theor.) of the target compound is obtained.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[CH2:3][NH:2]1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32]>ClCCl>[CH3:40][O:39][C:35]1[CH:34]=[C:30]([CH:29]=[C:28]([O:27][CH3:26])[C:36]=1[O:37][CH3:38])[C:31]([N:2]1[CH2:3][C:4]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:32]
Reactant: c1ccc2c(c1)CC1(CNCc3ccccc31)O2
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)N2Cc3ccccc3C3(Cc4ccccc4O3)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.7 %

Procedure:
To a cold solution of spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (8.0 g) and triethylamine (4.0 g) in dry dichloromethane (100 ml) is added dropwise a solution of 3,4,5-trimethoxybenzoyl chloride (9.5 g) in dry dichloromethane (50 ml). After stirring at ambient temperature for 24 hours, the mixture is washed with water (2x), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the solvent is evaporated to an oil, which solidifies upon trituration with hexanes. The solid is recrystallized twice from hexane/methanol to yield 10.0 g (66%) of product, mp 122° (dec.).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=[O:12])[N:3]1[CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:56]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)(=[O:58])[CH3:57]>CN(C)C(=O)C>[C:56]([N:59]1[CH2:64][CH2:63][N:62]([C:20]([C@H:17]2[CH2:18][CH2:19][C@H:14]([CH2:13][N:3]3[C:4](=[O:12])[CH2:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2]3=[O:1])[CH2:15][CH2:16]2)=[O:22])[CH2:61][CH2:60]1)(=[O:58])[CH3:57]
Reactant: O=C1Cc2ccccc2C(=O)N1C[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(C(=O)[C@H]2CC[C@H](CN3C(=O)Cc4ccccc4C3=O)CC2)CC1
Reaction time: 1 h

Procedure:
trans-4-(1,3-Dioxo-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-cyclo hexanecarboxylic acid (100 mg, 0.33 mmol) was dissolved in N,N-dimethyl acetamide (3 mL), HATU (125 mg, 0.33 mmol) and diisopropyl ethylamine (0.06 mL, 0.33 mmol) were added and the mixture was left stirring for 1 h. Then 1-acetylpiperazine (128 mg, 0.3 mmol) was added and the reaction stirred for 18 hours. The solvent was removed under reduced pressure and the residue was dissolved in 2 mL of DCM and washed with 2 mL of 0.4M Na2CO3 solution. The organic phase was collected and the solvent removed under reduced pressure. The crude was purified by SiO2 column, eluting with DCM-MeOH (97:3) and the fractions containing the desired product collected and further purified by prep HPLC. 42 mg of the title product were obtained (31% yield).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>ClCCl>[Cl:17][CH2:18][CH2:19][C:20]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:8]=1)=[O:21]
Reactant: COC(=O)COc1ccccc1
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)COc1ccc(C(=O)CCCl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Aluminium chloride (33.35 g) was added portionwise to a stirred cooled (<0° C.) solution of methyl phenoxyacetate (14.46 ml) and 3-chloropropionyl chloride (9.55 ml) in dichloromethane (500 ml). After the addition the ice-bath was removed and the mixture stirred for 1 hour when it was poured into ice-water (500 ml). The organic phase was separated and the aqueous portion extracted two times with dichloromethane. The combined dichloromethane extracts were washed with water, then brine and dried (MgSO4). The residue, after removal of the solvent in vacuo and trituration with ether gave methyl 4-[3-chloropropanoyl]phenoxyacetate, 22.3 g, as a solid: m.p. 89°-90° C.; NMR (d6DMSO) δ7.95(2H,d), 7.05(2H,d), 4.92(2H,s), 3.91(2H,t), 3.71(3H,s), 3.49(2H t); m/e 257(M+H)+ ; calculated for C12H13ClO4 : C, 56.1; H, 5.0. found: C, 55.8; H, 5.1%.