Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([C:14]([N:16]([CH2:21][C:22]2[CH:32]=[CH:31][C:25]3[O:26][CH2:27][CH2:28][CH2:29][O:30][C:24]=3[CH:23]=2)[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCO[C@@H](C(N(CC2C=CC3OCCCOC=3C=2)CC(C)C)=O)C1)C1C=CC=CC=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([N:16]([CH2:21][C:22]2[CH:32]=[CH:31][C:25]3[O:26][CH2:27][CH2:28][CH2:29][O:30][C:24]=3[CH:23]=2)[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CN(Cc1ccc2c(c1)OCCCO2)C(=O)[C@@H]1CN(Cc2ccccc2)CCO1
Agent: CC(C)CN(Cc1ccc2c(c1)OCCCO2)C(=O)[C@H]1CN(Cc2ccccc2)CCO1
Product: CC(C)CN(Cc1ccc2c(c1)OCCCO2)C(=O)C1CN(Cc2ccccc2)CCO1

Procedure:
(S)-(+)-4-benzyl-N-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylmorpholine-2-carboxamide and (R)-(−)-4-benzyl-N-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylmorpholine-2-carboxamide. Resolution into the pure enantiomers was performed by preparative HPLC using isocratic elution on ChiralPak AD at 1 mL/min, eluting with 100% ethanol. Under these conditions, the (R)-(−)-isomer elutes second after the (S)-(+)-isomer. (S)-(+)-4-benzyl-N-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylmorpholine-2-carboxamide: [α]D25° C.=+10° (c=1, MeOH), (R)-(−)-4-benzyl-N-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylmorpholine-2-carboxamide: [α]D25° C.=−10° (c=1, MeOH)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:12])[C:7]=1[CH2:8][C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:34][NH2:35])[CH:30]=[CH:31][CH:32]=1>C1COCC1>[Cl:12][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([NH:35][CH2:34][CH:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[CH:28]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:11]
Reactant: O=C(O)Cc1c(Cl)cncc1Cl
Reactant: COc1cccc(C(CN)c2ccccc2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cccc(C(CNC(=O)Cc2c(Cl)cncc2Cl)c2ccccc2)c1
Yield: 90.2 %

Procedure:
By working in a way similar to that described in example 4 but using (3.5-dichloro-pyridin-4-yl)-acetic acid (5.15 g, 25 mmoles), carbonyldiimidazole (4.24 g, 26.14 mmoles), THF (75 ml) and 2-(3-methoxy-phenyl)-2-phenyl-ethylamine (5.4 g, 23.76 mmoles), obtained as described in example 42, 8.9 g of the title compound were obtained (yield: 85.7%), m.p.: 142-143° C.
Reaction SMILES: CCOCC.[OH:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:10]=[CH:11][CH:12]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[CH2:27]([O:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:10]=[CH:11][CH:12]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCc2ccccc2)c1
Temperature: 70 °C

Procedure:
Instead of a Mitsunobu reaction, the ether was formed by alkylation as described. A suspension of phenol 58 (1 g, 3.5 mmol), benzyl bromide (0.3 mL, 3.5 mmol), cesium carbonate (1.158 g, 3.5 mmol) in NMP (3.5 mL) was heated at 70° C. for 24 h. The reaction mixture was quenched by the addition of water, extracted with DCM, washed with water, and dried over anhy. Na2SO4. Filtration and concentration under reduced pressure gave the crude product, which was purified by flash chromatography (hexane-ethyl acetate (0-30%) gradients) to give 2-(3-(3-(benzyloxy)phenyl)propyl)isoindoline-1,3-dione as a white solid. Yield (0.708 g, 55%): 1H NMR (400 MHz, DMSO-d6) δ 7.81-7.84 (m, 2H), 7.69-7.72 (m, 2H), 7.30-7.44 (m, 5H), 7.13-7.18 (m, 1H), 6.83-6.85 (m, 1H), 6.80 (d, J=7.6 Hz, 1H), 6.74 (dd, J=7.8, 2.0, 1H), 5.03 (s, 2H), 3.74 (t, J=7.2 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 2.0-2.08 (m, 2H).
Reaction SMILES: Cl.[CH2:2]([O:5][C:6](=[O:10])[C@@H:7]([CH3:9])[NH2:8])[CH2:3][CH3:4].[NH:11](C(OCC1C=CC=CC=1)=O)[C@H:12]([C:24](O)=[O:25])[CH2:13][C:14](=[O:23])[O:15]CC1C=CC=CC=1>>[CH2:2]([O:5][C:6](=[O:10])[C@@H:7]([CH3:9])[NH:8][C:24](=[O:25])[C@H:12]([CH2:13][C:14](=[O:15])[OH:23])[NH2:11])[CH2:3][CH3:4]
Reactant: CCCOC(=O)[C@@H](C)N
Reactant: O=C(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Agent: Cl
Product: CCCOC(=O)[C@@H](C)NC(=O)[C@@H](N)CC(=O)O

Procedure:
This compound was prepared from 1.8 g D-alanine n-propyl ester hydrochloride and 3.6 g Z-Asp(OBzl) in a manner similar to Example 16 (A). Yield: 1.9 g.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH:27]([CH2:30][CH3:31])[CH2:26][NH:25][C:24](=[O:32])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1.C(O)(C(F)(F)F)=O>CN(C=O)C.CS(C)=O>[CH2:30]([CH:27]1[CH2:26][NH:25][C:24](=[O:32])[C:23]2[CH:22]=[C:21]([C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:13]=3[N:12]=[C:11]([O:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:20]=[CH:19]4)[NH:29][C:28]1=2)[CH3:31]
Reactant: Oc1ccccc1
Reactant: CCC1CNC(=O)c2cc(-c3cccc4ccc(Cl)nc34)[nH]c21
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CCC1CNC(=O)c2cc(-c3cccc4ccc(Oc5ccccc5)nc34)[nH]c21
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 39.6 %

Procedure:
To a slurry of NaH (60% in mineral oil; 0.064 g, 1.611 mmol) in 1 mL DMF was added phenol (0.152 g, 1.611 mmol). After 10 min, rac-2-(2-chloroquinolin-8-yl)-7-ethyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 22; 0.075 g, 0.230 mmol) was added, and the reaction was heated to 70° C. After 2 h, the reaction was cooled and treated with TFA (0.124 ml, 1.611 mmol) and 1 mL DMSO, and the solution was filtered and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 15-100% ACN/H2O with 0.1% TFA); product-containing fraction was treated with saturated aq. NaHCO3 and DCM. The organic layer was separated, and the aq. layer was extracted 3×DCM. The combined organic layers were then dried over Na2SO4, filtered, and concentrated in vacuo to give rac-7-ethyl-2-(2-phenoxyquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.035 g, 0.091 mmol, 40% yield) as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.12 (1H, br. s), 8.50 (1H, d, J=8.8 Hz), 8.14 (1H, dt, J=7.5, 0.7 Hz), 7.80 (1H, dt, J=8.0, 0.7 Hz), 7.35-7.64 (7H, m), 6.90-7.00 (1H, m), 6.82-6.91 (1H, m), 3.38-3.45 (1H, m), 3.12-3.20 (1H, m), 2.24-2.34 (1H, m), 1.13-1.34 (2H, m), 0.82 (3H, t, J=7.3 Hz). m/z (ESI, +ve) 384.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([F:13])[F:12].[CH3:14][S:15]([O-:17])=[O:16].[Na+].CNCCNC>CS(C)=O>[F:12][C:5]1([F:13])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([S:15]([CH3:14])(=[O:17])=[O:16])[CH:3]=2)[NH:7][C:6]1=[O:11]
Reactant: O=C1Nc2ccc(Br)cc2C1(F)F
Reactant: CS(=O)[O-]
Agent: CNCCNC
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc2c(c1)C(F)(F)C(=O)N2
Temperature: 120 °C
Reaction time: 14 h
Yield: 58.7 %

Procedure:
To a stirred solution of 5-bromo-3,3-difluoroindolin-2-one (5.0 g, 20 mmol) in DMSO (50 mL), sodium methanesulfinate (3.0 g, 30 mmol), copper(I) trifluoromethane-sulfonate benzene complex (1.52 g, 3.022 mmol) and N,N′-dimethylethylenediamine (0.33 mL, 3.022 mmol) were added and stirred at 120° C. for 14 h. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuo and resulting residue was purified by flash column chromatography to give the title product (2.9 g, 58.2%); MS: 247.9 (M+1).
Reaction SMILES: [C:1]1([C:7]23[CH2:16][CH2:15][CH2:14][CH:13]=[C:12]2[C:11](=[O:17])[NH:10][C:9](=[O:18])[CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.O1CCOCC1.[Pd]>[C:1]1([C@@:7]23[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:11](=[O:17])[NH:10][C:9](=[O:18])[CH2:8]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C1CC2(c3ccccc3)CCCC=C2C(=O)N1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C1C[C@]2(c3ccccc3)CCCC[C@H]2C(=O)N1

Procedure:
4a-Phenyl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline (3.0 g, 12.45 mmoles) from Ex. 1B was dissolved in 100 ml of glacial acetic acid and 50 ml of dioxane. The catalyst, 5% palladium on carbon (700 mg), was added and the mixture was hydrogenated under 40 psi of hydrogen for 24 hours in a Parr shaker. The catalyst was then filtered off and the filtrate evaporated. The white crystalline 4a-phenyl-1,3-diketo-trans-decahydroisoquinoline was recrystallized from ethanol, mp 180°-182.5°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1.[OH:11][C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:15]=[C:14]([CH3:23])[C:13]=1[N:24]=[N:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.CN(C)C1C=CC=CC=1.O>O1CCCC1>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([NH:1][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([N:25]=[N:24][C:13]4[C:14]([CH3:23])=[N:15][N:16]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[C:12]=4[OH:11])=[CH:27][CH:28]=3)=[CH:3][C:4]=2[N:8]=[N:7]1
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: Cc1nn(-c2ccccc2)c(O)c1N=Nc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)c1ccccc1
Product: Cc1nn(-c2ccccc2)c(O)c1N=Nc1ccc(C(=O)Nc2ccc3[nH]nnc3c2)cc1
Reaction time: 8 h

Procedure:
A mixture of 5-aminobenzotriazole (0.78 g), 4-(5-hydroxy-3-methyl-1-phenylpyrazol-4-ylazo)benzoyl chloride (2.0 g) and N,N-dimethylaniline (0.71 g) in dry tetrahydrofuran (15 ml) was stirred overnight and water (50 ml) was added. The precipitate was filtered and crystallized in aqueous pyridine (1.9 g), m.p. 285° decomp., λmax (methanol)=396 nm.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][C:12]2[CH:13]=[C:14]([NH2:19])[C:15]([NH2:18])=[CH:16][CH:17]=2)=[CH:3][CH:2]=1.[N:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[C:21]=S.C(Cl)CCl>CC#N>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]3[NH:18][C:21]([NH:20][C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=4)=[N:19][C:14]=3[CH:13]=2)=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Reactant: Nc1ccc(Oc2ccnc3ccccc23)cc1N
Solvent: ClCCCl
Solvent: CC#N
Product: FC(F)(F)c1ccc(Nc2nc3cc(Oc4ccnc5ccccc45)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-(quinolin-4-yloxy)-benzene-1,2-diamine (Step B, 227 mg) in CH3CN (60 mL) was added over 5 min, a solution of 1-isothiocyanato-4-trifluoromethyl-benzene (183 mg) in CH3CN 10 mL). The mixture was stirred for 12 h at RT and EDC (260 mg) was added, followed by CH3CN (30 mL). The resulting mixture was heated at 80° C. for 2 h, then cooled to RT. The solvent was evaporated and the residue was dissolved in EtOAc and washed with water. The organic phase was dried, filtered and evaporated. The residue was purified by flash chromatography in EtOAc to give an orange-brown solid. MS (MH+)=420.9, MW: 420.18 Calc'd for: C23H15F3N4O.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][C:16]([C:18]2[C:27]([NH:28]C(=O)OCC3C=CC=CC=3)=[CH:26][C:25]3[C:20](=[CH:21][C:22]([N:39]4[CH2:44][CH2:43][NH:42][C:41](=[O:45])[CH2:40]4)=[CH:23][CH:24]=3)[N:19]=2)=[O:17])[CH2:3]1.[H][H]>CO.[Pd]>[NH2:28][C:27]1[C:18]([C:16]([NH:15][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:9]=2[N:4]2[CH2:5][C@H:6]([CH3:8])[CH2:7][C@H:2]([NH2:1])[CH2:3]2)=[O:17])=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[C:22]([N:39]1[CH2:44][CH2:43][NH:42][C:41](=[O:45])[CH2:40]1)[CH:21]=2
Reactant: [H][H]
Reactant: C[C@@H]1C[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(N4CCNC(=O)C4)ccc3cc2NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1C[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(N4CCNC(=O)C4)ccc3cc2N)C1

Procedure:
A mixture of benzyl [2-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(3-oxopiperazin-1-yl)quinolin-3-yl]carbamate (0.0086 g, 0.014 mmol) in 3.0 mL of MeOH was hydrogenated in the presence of 8 mg of 10% Pd on carbon under a balloon of hydrogen at room temperature for 1 h. The mixture was filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C25H31N8O2 [M+H]+: m/z=475.3. found: 475.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH2:15][CH:16]2[CH2:21][CH2:20][C:19]([CH:23]([OH:25])[CH3:24])([OH:22])[CH2:18][CH:17]2[C:26]([O:28]CC2C=CC=CC=2)=O)[CH:4]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C>CN(C)C1C=CN=CC=1.[Pd].N1C=CC=CC=1>[OH:25][CH:23]([C:19]1([OH:22])[CH2:20][CH2:21][CH:16]2[CH:17]([C:26](=[O:28])[C:4]3[C:5]([CH2:15]2)=[C:6]([O:13][CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=3[O:2][CH3:1])[CH2:18]1)[CH3:24]
Reactant: COc1cc(CC2CCC(O)(C(C)O)CC2C(=O)OCc2ccccc2)c(OC)c2ccccc12
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1c2c(c(OC)c3ccccc13)C(=O)C1CC(O)(C(C)O)CCC1C2
Yield: 66.1 %

Procedure:
Operating as described in Example 6, 0.44 g of 1-(1,4-dimethoxy-3-naphthylmethyl)-2-benzyloxycarbonyl-4-(1-hydroxyethyl)-4-hydroxy-cyclohexane, prepared as described in Example 11, was treated with acetic anhydride in presence of 4-dimethylamino-pyridine and pyridine. The corresponding acetate was treated with cyclohexone in the presence of 10% by weight palladium-on-carbon in order to remove the benzyl group. The acid was cyclized by treatment with a mixture of trifluoroacetic anhydride and trifluoroacetic acid at 0° C. Finally the removal of the acetyl 0-protecting groups by treatment with sodium methylate afforded, after purification by chromatography on a silica gel column, 0.225 g of the title compound (overall yield 66%); IR (film): 3450 cm-1 (OH), 1675 cm-1 (C=O, benzylic ketone). PMR (CDCl3): inter alia δ1.3 (d, J=4 Hz, CH3 --CH), 1.6-3.5 (m, 3H), 3.85 (s, OCH3), 3.90 (s, OCH3), 7.2-8.4 (m, four aromatic H).
Reaction SMILES: [Br:1]Br.[CH3:3][C@@H:4]1[NH:10][C:9]2[N:11]=[CH:12][CH:13]=[CH:14][C:8]=2[CH2:7][NH:6][C:5]1=[O:15]>C(O)(=O)C>[Br:1][C:13]1[CH:12]=[N:11][C:9]2[NH:10][C@@H:4]([CH3:3])[C:5](=[O:15])[NH:6][CH2:7][C:8]=2[CH:14]=1
Reactant: C[C@@H]1Nc2ncccc2CNC1=O
Reactant: BrBr
Solvent: CC(=O)O
Product: C[C@@H]1Nc2ncc(Br)cc2CNC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
Bromine (43 ul, 0.84 mmol) was added drop wise to a solution of (S)-2-methyl-1,2,4,5-tetrahydropyrido[2,3-e][1,4]diazepin-3-one (136 mg, 0.77 mmol) in acetic acid (10 mL). The reaction was stirred at room temperature for 3 h. The reaction was quenched with sat. NaHCO3 (10 mL) and extracted with ethyl acetate (3×15 mL), dried over sodium sulfate and concentrated to give the title compound (140 mg, 71%): 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.31 (s, 1H), 7.20 (b, 1H), 5.95 (bs, 1H), 4.97-4.91 (m, 1H), 4.72-4.70 (m, 1H), 3.85-3.79 (m, 1H), 1.47 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](N)=[C:4]([O:10][CH3:11])[CH:3]=1.Cl.N([O-])=O.[Na+].[PH2](O)=O>O.C(OCC)(=O)C.C(O)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Br)cc(C)c1N
Agent: Cl
Agent: O=N[O-]
Agent: O=[PH2]O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(C)cc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
In a 250 mL round bottom flask, 4-bromo-2-methoxy-6-methyl-phenylamine (5.8 g, 26.84 mmol) was charged with acetic acid (49 mL) and concentrated HCl (5.6 mL). Sodium nitrite (2.19 g, 31.78 mmol) in 7 mL water was added to the mixture dropwise at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes. 50% Hypophosphorous acid (56.5 mL) was added at 0° C. The reaction mixture was stirred at 0° C., and warmed up to room temperature overnight. Ethyl acetate was then added, followed by washing with saturated NaHCO3 solution. The organic layer was concentrated and purified (silica gel, 100% hexane) to give a pale liquid (5.12 g, 95%). 1H NMR (300 MHz, CDCl3): δ 6.97 (s, 1H), 6.87 (s, 1H), 6.64 (s, 1H), 3.80 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:23])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.C(OCC)(=O)C>[F:22][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:23])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2ccc(F)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(F)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-tert-Butoxycarbonyl-4-(4-fluorophenylcarbamoyl)-piperazine (0.30 g) was dissolved in a solution of hydrogen chloride in ethyl acetate (4N, 2 ml), and the solution was stirred at ambient temperature for 1 hour. The solvent was removed by evaporation under reduced pressure to give 1-(4-fluorophenylcarbamoyl)piperazine as a white powder, which was taken up into dichloromethane (3 ml), and to the mixture were added in turn pyridine (0.25 ml), 4-trifluoromethoxybenzoyl chloride (0.146 ml), and catalytic amount of N,N-dimethylaminopyridine. After stirring at ambient temperature for 12 hours, the mixture was washed in turn with hydrochloric acid (0.5N), aqueous sodium hydrogen carbonate, and brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was chromatographed on silica gel (50 ml) eluting with 0%-3% methanol in dichloromethane to give 1-(4-fluorophenylcarbamoyl)-4-(4-trifluoromethoxybenzoyl)-piperazine (0.19 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]1.Cl[C:10]1[N:15]2[N:16]=[C:17]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=3)[N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C.C>CC(O)(C)C>[OH:8][CH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][C:10]2[N:15]3[N:16]=[C:17]([NH:19][C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=4)[N:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)[CH2:3]1
Reactant: NC1CCCC(O)C1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: O=C(Nc1nc2cccc(NC3CCCC(O)C3)n2n1)c1cccnc1
Temperature: 200 °C
Reaction time: 0.08 h

Procedure:
3-amino-cyclohexanol (Betapharma, 67.33 mg; 0.58 mmol; 2.0 eq.) was added to a mixture of N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B4), 80 mg; 0.29 mmol; 1.0 eq.), DIEA (76 mg; 0.58 mmol; 2.0 eq.) and activated Charcoal (8 mg) in tBuOH (0.8 mL). The reaction mixture was heated at 200° C. for 2×30 min under microwave irradiation. After this time, it was filtered on a celite pad and the cake was washed with ACN. The filtrate was directly purified by RP-HPLC (Starting with 15% ACN in water for 5 min, then up to 30% in 10 min.). The title compound was isolated after lyophilisation as a white powder (51 mg, 49%). HPLC, Rt: 2.14 min. (purity 98.0%). LC/MS, M+(ESI): 353.0, M−(ESI): 351.0.
Reaction SMILES: [CH2:1]([C:5]1([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][C:9](=[O:11])[O:8][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[F:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][C:23]([CH2:27][O:28][C:29]3[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=3)[NH2:32])=[N:24]2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][C:23]([CH2:27][O:28][C:29]3[CH:30]=[C:31]([NH:32][C:9](=[O:11])[CH2:10][C:5]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([OH:8])=[O:7])[CH:33]=[CH:34][CH:35]=3)=[N:24]2)=[CH:19][CH:18]=1
Reactant: CCCCC1(CCCC)CC(=O)OC1=O
Reactant: Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1
Product: CCCCC(CCCC)(CC(=O)Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1)C(=O)O

Procedure:
The title compound is prepared analogously to the compound described in Example 20 from 2,2-dibutylsuccinic acid anhydride (prepared analogously to the instructions of H. Le Moal et al. Bull. Soc. Chim. 1964, 579 and 828) and 3-(7-fluoro-2-quinolinylmethoxy)aniline; beige crystals of m.p. 156°-157°.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([CH:9]2[CH2:12][CH:11]([C:13]#[N:14])[CH2:10]2)[C:7]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:6]=2[N:5]=1)[CH3:3].Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:19][C:16]1[CH:17]=[CH:18][C:6]2[N:5]=[C:4]([C@@H:2]([NH:1][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:3])[N:8]([CH:9]3[CH2:12][CH:11]([C:13]#[N:14])[CH2:10]3)[C:7]=2[CH:15]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1C1CC(C#N)C1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CC(C#N)C1
Yield: 32.1 %

Procedure:
3-[2-((S)-1-Aminoethyl)-6-fluorobenzoimidazol-1-yl]cyclobutanecarbonitrile (0.075 g, 0.29 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.070 g, 0.29 mmol) and DIPEA (0.26 mL, 1.45 mmol) in 2-propanol (5 mL) was stirred at 90° C. in a sealed microwave tube for 16 hours. After cooling, the reaction mixture was concentrated in vacuo and the residue loaded onto an Isolute® SCX-2 cartridge which was washed with DCM and MeOH, then the product eluted with 2M NH3/MeOH then concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 100% DCM—10% methanol in DCM to give 399 as a solid (0.035 g, 32%). LCMS (Method K): RT 2.76 min [M+H]+ 376.0. 1H NMR (MeOD-d4) δ: 8.33 (1H, br s), 8.05 (1H, br s), 7.53-7.61 (2H, m), 6.97-7.04 (1H, m), 6.02 (1H, br s), 5.76-5.87 (1H, m), 3.38-3.49 (2H, m), 3.21-3.30 (2H, m), 2.76-2.88 (1H, m), 2.37-2.47 (1H, m), 1.76 (3H, d, J=6.1 Hz)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.BrC1[C:28](=[O:43])[C:29]2[C:34]([C:35]=1[C:36]1C=CC=CC=1)=[CH:33][CH:32]=C(O)C=2.O1CCC(CCO)CC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:32][CH2:33][CH:34]4[CH2:29][CH2:28][O:43][CH2:36][CH2:35]4)=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: OCCC1CCOCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCC3CCOCC3)cc21
Reaction time: 17 h
Yield: 33 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 64 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 2-(tetrahydro-2H-pyran-4-yl)ethanol (2.0 eq) instead of 4-(2-hydroxyethyl)morpholine, using 2 equivalents of PPh3 and DIAD, being stirred for 17 h, and being purified by prep. HPLC (20% H2O/CH3CN) to provide the title compound (33%).