Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[N:25][C:26]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:27][CH:28]=4)[CH:21]=3)[N:16]([S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:45][C@H:46]1[CH2:48][O:47]1.CCN(C(C)C)C(C)C>C(O)C>[CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][N:32]([CH2:45][C@@H:46]([OH:47])[CH3:48])[CH2:31][CH2:30]5)=[N:25][CH:24]=4)[CH:21]=3)[N:16]([S:35]([C:38]3[CH:39]=[CH:40][C:41]([CH3:42])=[CH:43][CH:44]=3)(=[O:36])=[O:37])[CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Yield: 86.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-phenethyl-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (product of step 2 of example 140) (85 mg, 0.14 mmol) was alkylated using (S)-2-methyloxirane (10 mg, 0.169 mmol), DIPEA (22 mg, 0.169 mmol) and ethanol (3 mL) to get 80 mg (86%) of the titled compound. MS: m/z=662.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:21][CH2:20][C:5]2[N:6]([CH2:14][C:15]([O:17]CC)=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2[N:6]([CH2:14][C:15]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:17])[C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=3[C:20]=2[CH2:21]1
Reactant: CCOC(=O)Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: C1CCNC1
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCCC2)CCN(C)C1
Temperature: 100 °C

Procedure:
A mixture of ethyl 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetate (100 mg) and pyrrolidine (1 ml) was heated at 100° C. for 15 h to obtain 60 mg of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyrrolidin-1-yl)ethanone as off white solid after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[C:10]([NH:13][C:14](=[O:26])[CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[CH2:27](C([Sn])=C(CCCC)CCCC)[CH2:28]CC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[Cl-].[Li+].[F-].[K+]>CN1CCCC1=O.C(Cl)(Cl)Cl>[CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[CH2:15][C:14]([NH:13][C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([CH:27]=[CH2:28])[CH:3]=2)[NH:12][N:11]=1)=[O:26]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: O=C(Cc1ccc2ccccc2c1)Nc1cc(-c2cncc(Br)c2)[nH]n1
Agent: [Cl-]
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Product: C=Cc1cncc(-c2cc(NC(=O)Cc3ccc4ccccc4c3)n[nH]2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
5-(5-Bromo-3-pyridyl)-3-(2-naphthylacetyl)aminopyrazole (509.8 mg), tributylvinyl tin (1.1 ml), a tris(dibenzylideneacetone)dipalladium—chloroform complex (74.2 mg), tri-2-furylphosphine (133.3 mg) and lithium chloride (311.3 mg) were dissolved in N-methylpyrrolidone (10 ml) with heating, and the mixture was stirred at 80° C. overnight. After the reaction solution was allowed to cool, it was poured into a saturated aqueous potassium fluoride solution (100 ml)—chloroform (100 ml) and vigrously stirred for 30 minutes. The mixture was filtered through Celite and the filtrate was separated. The aqueous layer was extracted with chloroform (50 ml×3). The organic layers were combined, dried over anhydrous magnesium sulfate and treated with an activated carbon. Then, the solvent was distilled away under a reduced pressure. The resultant residue was purified by column chromatography on silica gel (ethyl acetate:hexane=5: 1→chloroform:methanol=10:1) and then crystallized from chloroform to obtain the title compound (58.8 mg) as white crystals (melting point: 218-220° C.).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]1[C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9][N:8]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].Cl[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([N:14]2[CH2:13][CH2:12][C:11]3([CH2:7][N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:9][CH2:10]3)[CH2:16][CH2:15]2)=[CH:26][CH:27]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: N#Cc1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccc(C#N)cc3)CC2)C1
Yield: 49 %

Procedure:
Cesium carbonate (1.35 g, 4.16 mmol, 2.0 eq.) was added to a stirred solution of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (500 mg, 2.08 mmol, 1.0 eq.) and 4-chlorobenzonitrile (390 mg, 2.08 mmol, 1.0 eq.) in toluene (30 ml) and the reaction mixture was degassed with nitrogen for 15 min. BINAP (52 mg, 0.083 mmol, 0.04 eq.) and Pd(OAc)2 (10 mg, 0.0416 mmol, 0.02 eq.) were added and the resulting reaction mixture was heated at reflux for 16 h. The reaction mixture was filtered through celite and the filtrate was evaporated under reduced pressure to afford the crude product which was purified by column chromatography (silica gel; 15-20% EtOAdhexanes) to yield the pure product as an oil. Yield: 49% (350 mg, 1.026 mmol).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10].[OH:17][C:18]1[CH:27]=[CH:26][C:25]2[N:24]=[C:23]([NH2:28])[C:22]3[N:29]=[C:30]([CH2:35][O:36][CH3:37])[N:31]([CH2:32][CH2:33][CH3:34])[C:21]=3[C:20]=2[CH:19]=1.CN(C=O)C>ClCCl>[CH3:37][O:36][CH2:35][C:30]1[N:31]([CH2:32][CH2:33][CH3:34])[C:21]2[C:20]3[CH:19]=[C:18]([O:17][CH2:8][C:9]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[O:10])[CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:28])[C:22]=2[N:29]=1
Reactant: O=C(CBr)N1CCOCC1
Reactant: CCCn1c(COC)nc2c(N)nc3ccc(O)cc3c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCn1c(COC)nc2c(N)nc3ccc(OCC(=O)N4CCOCC4)cc3c21
Temperature: 70 °C
Yield: 49.2 %

Procedure:
Cesium carbonate (1.7 g, 5.25 mmol, 3 eq) was added to a mixture of 2-bromo-1-morpholin-4-yl-ethanone (400 mg, 1.92 mmol, 1.1 eq), 8-hydroxy-2-methoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (500 mg, 1.75 mmol, 1.0 eq), and anhydrous DMF. The reaction mixture was heated to 70° C. and maintained overnight. The reaction mixture was then cooled to ambient temperature, filtered, and concentrated under reduced pressure to yield a dark oil. The dark oil was dissolved in dichloromethane, filtered, purified by chromatography on a HORIZON HPFC system (eluting with a gradient of methanol/dichloromethane (20:80) in dichloromethane from 0:100 to 40:60), and crystallized from acetonitrile to afford 356 mg of 2-(methoxymethyl)-8-(2-morpholin-4-yl-2-oxoethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as an off white powder, mp 201-204° C.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[CH:17]=[C:18]([CH:32]=[C:33]([O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[C:34]=1[OH:35])[C:19]([NH:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=[O:20].[CH:43]1(O)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:15][C:16]1[CH:17]=[C:18]([CH:32]=[C:33]([O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[C:34]=1[O:35][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)[C:19]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=1)=[O:20]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(O)c(OC3CCCCC3)c2)cc1
Reactant: OC1CCCCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(OC3CCCCC3)c(OC3CCCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 102.2 %

Procedure:
Diisopropylazo dicarboxylate (63 μL, 0.32 mmol) was added dropwise to a stirring mixture of methyl 4-(3-chloro-5-(cyclohexyloxy)-4-hydroxybenzamido)benzoate (7) (65 mg, 161 μmol), cyclohexanol (34 μL, 0.32 mmol) and triphenylphosphine (84 mg, 0.32 mmol) in THF (2 mL) and the resulting yellow mixture was stirred at RT for 20 h. The reaction was quenched with MeOH (5 mL) and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (40 g, 0-15% EtOAc in iso-hexane) to give the desired methyl 4-(3-chloro-4,5-bis(cyclohexyloxy)benzamido)benzoate (8) (80 mg, 100%): m/z 486 [M+H]+ (ES+); 1H NMR (400-MHz, DMSO-d6) δ: 10.48 (1H, s), 7.97 (2H, d), 7.91 (2H, d), 7.67 (1H, d), 7.53 (1H, d), 4.53 (1H, m), 4.36 (1H, m), 3.84 (3H, m), 1.92 (4H, m), 1.80-1.70 (4H, m), 1.60-1.40 (6H, m), 1.30-1.05 (6H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[C:12]=23)=[CH:4][C:3]=1[F:22].[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30]>>[CH:18]1([C:10]2[N:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[C:12]3=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([O:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[CH3:23])=[C:3]([F:22])[CH:4]=3)[N:9]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: Cc1ccccc1O
Reactant: Nc1nccn2c(C3CCC3)nc(-c3ccc(Br)c(F)c3)c12
Product: Cc1ccccc1Oc1ccc(-c2nc(C3CCC3)n3ccnc(N)c23)cc1F

Procedure:
Prepared according to a procedure analogous to that described for synthesis of Example 171, except using 1-(4-bromo-3-fluoro-phenyl)-3-cyclobutyl-imidazo[1,5-a]pyrazin-8-ylamine and 2-methyl-phenol.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[C:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH:19]=[CH:18][C:17]4[CH:26]=[CH:27][CH:28]=[CH:29][C:16]3=4)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>>[CH:25]1[C:20]2[CH:19]=[CH:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[C:15](=[C:12]3[CH2:11][CH2:10][N:9]([CH2:8][CH:7]=[CH:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:31][CH:30]=4)[CH2:14][CH2:13]3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Product: CC(C)(C)C(=O)Nc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Yield: 92 %

Procedure:
This compound was prepared from 1-(4-Aminocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (compound 5) and pivaloyl chloride. Yield 92.0%
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]([CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28])=[O:23]>>[CH2:1]([N:8]([C:27](=[O:28])[CH2:26][CH2:25][CH2:24][C:22]([O:21][CH3:20])=[O:23])[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CNCCc2c[nH]c3ccccc23)cc1
Reactant: COC(=O)CCCC(=O)Cl
Product: COC(=O)CCCC(=O)N(CCc1c[nH]c2ccccc12)Cc1ccccc1
Yield: 64.9 %

Procedure:
42.8 g of N-benzyl-tryptamine (i.e., 3-(2-benzylaminoethyl)-indole) and 35.0 g of 4-methoxycarbonylbutyryl chloride were treated in the same manner as described in Example 1. 42.0 g of N-benzyl-N-(4-methoxycarbonylbutyryl)-tryptamine (i.e., 3-[2-(N-benzyl-4-methoxycarbonylbutanamido)ethyl]-indole) were thereby obtained. Yield: 75.0%
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[H-].[Na+].[CH3:12][Si:13]([CH2:16][CH2:17][O:18][CH2:19]Cl)([CH3:15])[CH3:14]>CN(C=O)C>[CH3:12][Si:13]([CH3:15])([CH3:14])[CH2:16][CH2:17][O:18][CH2:19][N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: c1cnc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ncc2cccnc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1H-pyrazolo[3,4-b]pyridine (380 mg, 3.2 mmol) in DMF (5 mL) was added NaH (60% dispersion in mineral oil, 153 mg, 3.8 mmol). After stirring for 20 min, the mixture was heated with a heat gun and then allowed to cool to rt. SEM-Cl (647 μL, 3.8 mmol) was added dropwise and stirring continued for 2 h. The resulting mixture was partitioned between water and ethyl acetate. The organic layer was separated and concentrated, and the residue was purified by flash column chromatography (silica gel, eluting with 0-50% ethyl acetate in hexanes) to provide 1-(2-trimethylsilanylethoxymethyl)-1H-pyrazolo[3,4-b]pyridine, which was dissolved in ethanol (30 mL) and flushed with a nitrogen stream. Palladium on charcoal (5% wet on carbon, ˜50 mg) was added and the mixture was placed under hydrogen (50 psi) for 2 days. The reaction mixture was filtered, and the filtrate was concentrated to provide the title compound: 1H NMR (500 MHz, CDCl3) δ 7.13 (s, 1H), 5.24 (s, 2H), 3.68 (br, 1H), 3.54 (t, J=8.2 Hz, 2H), 3.28 (m, 2H), 2.51 (t, J=6.1, 2H), 1.81 (m, 2H), 0.89 (t, J=8.2 Hz, 2H), −0.01 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I:28][C:29]1[N:30]=[C:31]([CH3:34])[NH:32][CH:33]=1>C(Cl)Cl>[I:28][C:29]1[N:30]=[C:31]([CH3:34])[N:32]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:33]=1
Reactant: Cc1nc(I)c[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(I)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Triethylamine (13.4 mL, 96.2 mmol) followed by trityl chloride (20.1 g, 72.1 mmol) were added to an ambient temperature solution of 4-iodo-2-methyl-1H-imidazole (ca. 10 g, 48.1 mmol) in methylene chloride (90 mL). After stirring at ambient temperature for 2 days, the reaction mixture was diluted with methylene chloride and washed with water and brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-15% acetone/methylene chloride afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1.C(C1C=CC([N+]([O-])=O)=CC=1N[S:25]([CH3:28])(=[O:27])=[O:26])C>>[Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH:6][S:25]([CH3:28])(=[O:27])=[O:26])=[C:4]([CH3:12])[CH:3]=1
Reactant: CCc1ccc([N+](=O)[O-])cc1NS(C)(=O)=O
Reactant: Cc1cc(Cl)c([N+](=O)[O-])cc1N
Product: Cc1cc(Cl)c([N+](=O)[O-])cc1NS(C)(=O)=O

Procedure:
Intermediate 79A was prepared from 4-chloro-2-methyl-5-nitroaniline following the procedure employed in the preparation of Intermediate 78A. HPLC: Rt=1.618 min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min., monitoring at 220 nm). MS (ES): m/z=265 [M+H]+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>>[C:10]1([CH:8]([OH:9])[CH:7]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Reactant: NCC1CCCCO1
Product: OC(c1ccccc1)C(NCC1CCCCO1)c1ccccc1
Temperature: 140 °C
Reaction time: 14 h
Yield: 83.2 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mol) and 2-aminomethyltetrahydropyran (3.45 g, 0.030 mol) was heated in an oil bath at 140° C. for 6 hours. After standing at ambient temperature for 14 hours, the solidified reaction mixture was triturated with isooctane, and the tan solid collected by filtration to obtain 2.59 g (83% yield) of the product. The material was recrystallized from toluene-isooctane; mp 159°-163° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([CH:23]=O)[C:20]([O:25][CH3:26])=[CH:19][C:18]=1[O:27][CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=1)(=[O:31])[CH3:30]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21](/[CH:23]=[CH:30]/[C:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=2)=[O:31])[C:20]([O:25][CH3:26])=[CH:19][C:18]=1[O:27][CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C(=O)OC(C)(C)C)cc1C=O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1cc(OC)c(-c2cc3ccccc3n2C(=O)OC(C)(C)C)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 8 %

Procedure:
The title compound was prepared by condensing 2-(5-formyl-2,4-dimethoxy-phenyl)-indole-1-carboxylic acid tert-butyl ester (Ex-36A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, 8% yield, mp 182–183° C. 1H-NMR (CDCl3) δ 8.21 (d, J=8 Hz, 2H), 8.19 (d, J=13 Hz, 1H), 8.16 (d, J=7 Hz, 1H), 8.07 (d, J=8 Hz, 2H), 7.69 (s, 1H), 7.54 (d, J=7 Hz, 1H), 7.52 (d, J=13 Hz, 1H), 7.29–7.35 (m, 1H), 7.23 (d, J=7 Hz, 1H), 6.55 (s, 1H), 6.50 (s, 1H), 4.00 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H). MS m/z=528 ([M+H]+, 100%). Anal. calc. for C31H29NO7H2O: C, 68.25; H, 5.73; N, 2.56; found: C, 68.63; H, 5.62; N, 2.45.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3=[N:27][CH:28]=[C:29]([CH3:31])[CH:30]=[C:25]3[N:24]([CH:32]([CH3:34])[CH3:33])[C:23]2=[O:35])=[CH:18][CH:17]=1.[H-].[Na+].O>CN(C=O)C>[CH3:31][C:29]1[CH:30]=[C:25]2[N:24]([CH:32]([CH3:33])[CH3:34])[C:23](=[O:35])[N:22]([C:19]3[CH:18]=[CH:17][C:16]([O:15][C:3]4[N:2]([CH3:1])[C:6]5=[N:7][CH:8]=[CH:9][CH:10]=[C:5]5[N:4]=4)=[CH:21][CH:20]=3)[C:26]2=[N:27][CH:28]=1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: Cc1cnc2c(c1)n(C(C)C)c(=O)n2-c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc2c(c1)n(C(C)C)c(=O)n2-c1ccc(Oc2nc3cccnc3n2C)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
To a mixture of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (198 mg) and 3-(4-hydroxyphenyl)-6-methyl-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (177 mg) in DMF (1.5 mL) was added NaH (40.0 mg), and the mixture was stirred at 100° C. for 1 h. The mixture was heated at 180° C. for 30 min under microwave irradiation. The mixture was poured into water, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (125 mg) as white crystals.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH:20]4[CH2:24][CH2:23][CH2:22][O:21]4)=[O:19])[CH2:14][CH2:13]3)[CH2:9]2)C=CC=CC=1.CO>[OH-].[OH-].[Pd+2].C(O)(=O)C>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([CH:20]3[CH2:24][CH2:23][CH2:22][O:21]3)=[O:19])[CH2:16][CH2:17]2)[CH2:9]1
Reactant: O=C(C1CCCO1)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(C1CCCO1)N1CCN(C2CNC2)CC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Palladium hydroxide on carbon (0.15 g) was placed in a 5 mL tube and then a solution of 1-[1-(diphenylmethyl)azetidin-3-yl]-4-(tetrahydrofuran-2-ylcarbonyl)piperazine (0.66 g, 1.6 mmol), methanol (4 mL) and acetic acid (0.3 mL) was added. The mixture was stirred under hydrogen (1.6 bar) at RT for 60 h and then the catalyst was filtered off by means of Celite®. The solvent was removed by evaporation and the crude product was used in the next step without quantification. LCMS: m/z 240 (M+1)+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][N:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][N:41]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: Cc1ccc(CCl)nc1
Agent: Cl
Product: Cc1ccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)nc1
Yield: 80.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 2-(chloromethyl)-5-methylpyridine (0.43 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.71 g) was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[CH:26][S:27][CH:28]=3)=[C:18]([Cl:29])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[OH:30][C@H:31]1[CH2:36][CH2:35][O:34][C:32]1=[O:33]>>[Cl:29][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][CH2:3][CH2:2][NH:1][C:32](=[O:33])[C@@H:31]([OH:30])[CH2:36][CH2:35][OH:34])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[N:25]=[CH:26][S:27][CH:28]=1
Reactant: O=C1OCC[C@@H]1O
Reactant: NCCOc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12
Product: O=C(NCCOc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12)[C@@H](O)CCO
Yield: 66 %

Procedure:
The procedure described in Example 63 was repeated using 5-(2-aminoethoxy)-N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 71, preparation of starting materials) and (S)-(−)-α-hydroxy-γ-butyrolactone to give the title compound in 66% yield; NMR spectrum (DMSO-d6 400 MHz) 1.44-1.55 (m, 1H), 1.73-1.85 (m, 1H), 3.41-3.52 (m, 2H), 3.65-3.77 (m, 2H), 3.93-4.02 (m, 1H), 4.31-4.48 (m, 3H), 5.38 (s, 2H), 5.50 (d, 1H), 7.17 (d, 1H), 7.33 (t, 2H), (7.60 (dd, 1H), 7.74 (t, 1H), 7.83 (s, 1H), 8.02 (s, 1H), 8.20 (t, 1H), 8.48 (s, 1H), 9.17 (s, 1H), 9.85 (s, 1H); Mass spectrum MH+ 529.9.
Reaction SMILES: [Cl:1][C:2]1[C:20]([O:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[O:27][CH2:28][CH3:29]>O1CCOCC1>[Cl:1][C:2]1[C:20]([O:21][CH:22]([CH2:23][CH3:24])[CH2:25][CH3:26])=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)=[O:7])=[CH:4][C:3]=1[O:27][CH2:28][CH3:29]
Reactant: CCOc1cc(C(=O)Nc2ccc(C(=O)OC)cc2)cc(OC(CC)CC)c1Cl
Solvent: C1COCCO1
Product: CCOc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(OC(CC)CC)c1Cl
Temperature: 50 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
4-(4-Chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)benzoic acid (AAA-114) (50 mg, 65%) was prepared from methyl 4-(4-chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)benzoate (11) (76 mg, 0.18 mmol) using a procedure essentially the same as in step (ii) for AAA-001 except that dioxane (2 mL) was used instead of THF and the mixture was stirred at 50° C. for 2 h: m/z 406 [M+H]+ (ES+), 404 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.79 (1H, br s), 10.46 (1H, s), 7.99-7.93 (2H, m), 7.91-7.82 (2H, m), 7.27 (2H, dd), 4.46 (1H, quin), 4.20 (2H, q), 1.71-1.64 (4H, m), 1.39 (3H, t), 0.93 (6H, t).