Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:26]=[CH:25][C:12]([O:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([C:22]([O-:24])=[O:23])[CH2:18][CH2:17]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Na+].[F:28][CH:29]([F:46])[O:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[F:28][CH:29]([F:46])[O:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[N:4][C:5]([NH:8][C:9]3[CH:26]=[CH:25][C:12]([O:13][CH2:14][CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]4)=[CH:11][CH:10]=3)=[N:6][CH:7]=2)=[CH:33][CH:32]=1
Reactant: O=C([O-])C1CCN(CCOc2ccc(Nc3ncc(Br)cn3)cc2)CC1
Reactant: CC1(C)OB(c2ccc(OC(F)F)cc2)OC1(C)C
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: [Na+]
Solvent: C1COCCO1
Product: O=C(O)C1CCN(CCOc2ccc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)cc2)CC1
Temperature: 150 °C

Procedure:
To a solution of sodium 1-(2-(4-(5-bromopyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylate 13 (0.05 mmol) in 1,4-dioxane (1.0 mL) is added 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7 (0.05 mmol), 3M Na2CO3 (0.15 mmol) and Pd(PPh3)4 (0.0025 mmol). The reaction is evacuated and backfilled with nitrogen twice then heated at 150° C. for 10 min. Purification by prep-HPLC (ACN gradient 10-70%) affords 1-(2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylic acid A3. 1H NMR (400 MHz, d6-DMSO) δ 9.68 (s, 1H), 8.78 (s, 2H), 7.76 (d, J=8.8 Hz, 2H), 7.71 (d, J=9.2 Hz, 2H), 7.28 (t, J=74.0 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.8 Hz, 1H), 4.28 (t, J=4.8 Hz, 2H), 3.51 (m, 2H), 3.23 (m, 4H), 1.24 (t, J=7.2, 6H). MS (m/z) (M+1)+: 485.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:15]([C:20]3[CH:21]=[CH:22]C4[C:24]([CH:28]=3)=[N:25]SN=4)[CH2:16][C:17]([OH:19])=[O:18])=[CH:11][NH:12]2)=[CH:8][CH:7]=1.CS[C:31]1[NH:32][CH2:33][C:34](=[O:36])[N:35]=1>>[O:36]=[C:34]1[CH2:33][NH:32][C:31]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:14]=[C:13]3[C:9]([C:10]([CH:15]([C:20]4[CH:21]=[CH:22][N:25]=[CH:24][CH:28]=4)[CH2:16][C:17]([OH:19])=[O:18])=[CH:11][NH:12]3)=[CH:8][CH:7]=2)=[N:35]1
Reactant: NCCCOc1ccc2c(C(CC(=O)O)c3ccc4nsnc4c3)c[nH]c2c1
Reactant: CSC1=NC(=O)CN1
Product: O=C(O)CC(c1ccncc1)c1c[nH]c2cc(OCCCNC3=NC(=O)CN3)ccc12

Procedure:
Analogously to Example 16, the reaction of 3-[6-(3-aminopropoxy)-1H-indol-3-yl]-3-benzo-1,2,5-thiadiazol-5-ylpropionic acid (prepared analogously to Example 1.1-1.2 and 15) with 2-methylsulfanyl-1,5-dihydroimidazol-4-one and subsequent synthesis sequence gives
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])[CH3:10].Cl.C(OCC)(=O)C>C1COCC1>[OH:11][C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(O)c1ccccc1
Yield: 96 %

Procedure:
Under nitrogen atmosphere, 30 mL of THF was added to 3.96 g (6.50 mmol, 0.65 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 1.20 g (10 mmol) of acetophenone in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 0˜5° C. for 3 hours. 25 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 10 mL (×2) of hydrochloric acid, 20 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 20 mL of an aqueous saturated sodium chloride solution. The organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.99 g of the desired product (yield 96%).
Reaction SMILES: N[C:2]1[CH:7]=[C:6](OC)[CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([O:20][CH3:21])[C:14]([O:22][CH3:23])=[CH:13]2.Cl.[N:25]([O-:27])=[O:26].[Na+].O>C(O)(=O)C>[N+:25]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([O:20][CH3:21])[C:14]([O:22][CH3:23])=[CH:13]2)([O-:27])=[O:26]
Reactant: O=N[O-]
Reactant: COc1ccc(-c2ccc3cc(OC)c(OC)cc3c2)c(N)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2ccc(-c3ccccc3[N+](=O)[O-])cc2cc1OC
Reaction time: 8 h
Yield: 41.4 %

Procedure:
6-(2-Amino-4-methoxyphenyl)-2,3-dimethoxynaphthalene (32) (12 mg, 0.039 mmol) was dissolved in acetic acid (0.6 mL) and concentrated hydrochloric acid (0.06 mL). The solution was cooled in an ice bath and diazotized by the dropwise addition of a solution of sodium nitrite (0.026 g in 0.5 mL water). The resulting diazonium solution was allowed to rise to room temperature slowly and left overnight. To the resulting red solution which contained some precipitate was added 30 mL water and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with diluted sodium hydroxide solution first, then with water and brine. The ethyl acetate extracts were dried with anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using 40:60 hexanes:ethyl acetate to give the pure 4 (5 mg) in 40% yield; mp 244-246° C.; IR (KBr) 2919, 1619, 1507, 1388, 1292, 1277, 1204 cm−1; UV (MeOH) 292, 266, 216 nm; 1H NMR (CDCl3) δ4.10 (6H, s), 4.22 (3H, s), 7.32 (1H, s), 7.54 (1H, dd, J1=9.1, J2=2.6), 8.04-8.08 (2H, m), 8.28 (1H, d, J=8.9), 8.49 (1H, d, J=9.1), 9.16 (1H, s); 13C NMR δ56.33, 56.52, 56.92, 104.36, 107.93, 108.92, 116.88, 117.08, 119.48, 123.51, 124.54, 127.14, 128.42, 132.46, 141.77, 148.52, 151.12, 151.40, 160.45; HRMS (EI) calcd for C19H16N2O3 m/z: 320.1161; found: 320.0384.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([NH:8][NH:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])=[O:7].Cl[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([N:8]=[N:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])=[O:7]
Reactant: COCCOC(=O)NNC(=O)OCCOC
Agent: [Na+]
Agent: [O-]Cl
Solvent: Cc1ccccc1
Product: COCCOC(=O)N=NC(=O)OCCOC
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a solution obtained by adding 1,2-hydrazinedicarboxylic acid bis(2-methoxyethyl) ester (200 mg, 0.85 mmol) and toluene (2 mL) to a 10 mL flask, followed by cooling with an ice bath, was added dropwise a 5% sodium hypochlorite solution (1.39 g, 0.85 mmol), and the reaction was allowed to proceed for one hour. After the reaction, the solution was washed with water (1 mL, ×2), and dehumidified with anhydrous magnesium sulfate, followed by concentration to dryness. The resulting solid was recrystallized with toluene (1 mL) and hexane (5 mL), to give azodicarboxylic acid bis(2-methoxyethyl) ester as a pale yellow crystal (73 mg, yield: 37%).
Reaction SMILES: [CH2:1]([N:8]([CH2:27][CH2:28][CH2:29][CH3:30])[C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH2:1]([N:8]([CH2:27][CH2:28][CH2:29][CH3:30])[C:9]1[C:14]2[N:15]=[C:16]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCN(Cc1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Reactant: C1CNCCN1
Product: CCCCN(Cc1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 118 from 8-(N-benzyl-butylamino)-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 153°-155° C.) and piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[NH:11][C:4]=2[CH:3]=1.[Cl:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]([C:21](=[O:22])[CH2:20][CH2:19][Cl:18])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)CCCl
Reactant: Clc1ccc2c(c1)Nc1ccccc1OCO2
Solvent: Cc1ccccc1
Product: O=C(CCCl)N1c2ccccc2OCOc2ccc(Cl)cc21
Temperature: 25 °C
Yield: 88.7 %

Procedure:
A suspension of 2-chloro-12H-dibenzo[d,g][1,3,6]dioxazocine (10.65 g, 43 mmol, prepared as described in Journal of Molecular Structures, 131, 1985, 131-140) and 3-chloropropionyl chloride (6.55 g, 51.6 mmol) in dry toluene (100 ml) was heated at reflux temperature for 5 h. After cooling to room temperature, the reaction mixture was washed with a saturated solution of sodium bicarbonate (50 ml). The organic layer was dried (MgSO4), and evaporated in vacuo, which afforded 2-chloro 12-(3-chloropropionyl)-12H-dibenzo[d,g][1,3,6]dioxazocine (12.9 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:31])[CH2:18][CH2:17][C:16]([CH2:29][NH2:30])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:30][CH2:29][C:16]1([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:31])[CH2:14][CH2:15]1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: NCC1(c2cnc(C(F)(F)F)nc2)CCC(F)(F)CC1
Product: O=C(NCC1(c2cnc(C(F)(F)F)nc2)CCC(F)(F)CC1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and [4,4-Difluoro-1-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexyl]methanamine. LCMS (MH+): m/z=452.1, tR (minutes, Method F)=3.08
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[CH:11]=[C:10]3[N:19]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:20](=O)[CH2:21][O:22][C:9]3=[CH:8][C:7]=2[N:6]=1)([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>C1(C)C=CC=CC=1>[CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[CH:11]=[C:10]3[N:19]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:20](=[S:38])[CH2:21][O:22][C:9]3=[CH:8][C:7]=2[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc3c(cc2n1)OCC(=O)N3CC(F)(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)Oc1cc(C(F)(F)F)c2cc3c(cc2n1)OCC(=S)N3CC(F)(F)F
Yield: 81.2 %

Procedure:
A mixture of 7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one (EXAMPLE 22) (48.4 mg, 0.119 mmol) and Lawesson's reagent (0.144 g, 0.356 mmol) in 2.4 mL toluene was heated at reflux for 6 h, whereupon the mixture was partitioned between EtOAc (40 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (20 mL), and the combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated. Flash chromatography (9:1 hexanes:EtOAc) afforded 41 mg of 7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-thione, a yellow oil. Data for 7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2 (3H)-thione: Rf 0.36 (9:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.72 (broad s, 1H), 7.48 (s, 1H), 7.13 (s, 1H), 5.54 (hept, 1H, J=6.2), 5.32-5.42 (m, 2H), 5.05 (s, 2H), 1.41 (d, 6H, J=6.2).
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[F:11][C:10]([F:13])([F:12])[C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:9]=1
Reactant: C1CCNCC1
Reactant: N#Cc1ccc(C(F)(F)F)cc1Cl
Product: N#Cc1ccc(C(F)(F)F)cc1N1CCCCC1
Temperature: 80 °C
Yield: 56 %

Procedure:
To commercially available 2-chloro-4-trifluoromethylbenzonitrile 13 (1 ml, 7.2 mmol) was added piperidine (4 equiv., 2.8 ml) and the solution was heated at 80° C. overnight. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The organic phase was evaporated obtaining 1 g of a yellow oil. Yield=56% 1HNMR (DMSO, 200 MHz) δ 1.60 (6H, m), 3.20 (4H, m), 7.34 (2H, m), 7.89 (1H, dd, J=8.6 Hz, J′=0.4 Hz)
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH:8]([CH3:12])[C:9](Cl)=[O:10])[N:3]=1.[O:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1>>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH:8]([CH3:12])[C:9]([CH:15]2[C:16](=[O:19])[CH2:17][CH2:18][O:13][CH2:14]2)=[O:10])[N:3]=1
Reactant: Cc1cc(C)n(C(C)C(=O)Cl)n1
Reactant: O=C1CCOCC1
Product: Cc1cc(C)n(C(C)C(=O)C2COCCC2=O)n1

Procedure:
3-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)propanoyl)dihydro-2H-pyran-4 (3H)-one was synthesised from 2-(3,5-dimethyl-1H-pyrazol-1-yl)propanoyl chloride (0.5 g, 2.97 mmol) and tetrahydro-4H-pyran-4-one (0.549 mL, 5.95 mmol) by the general procedure for the preparation of diketones. MS (ES+) m/z 251.1 (M+H)+
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[C:13](F)[CH:12]=[C:11](Br)[C:10]=1[Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23]>>[CH2:1]([S:8][C:9]1[C:10]([Cl:17])=[C:11]([N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(Br)c(Cl)c(SCc2ccccc2)c1
Reactant: O=C1CCCN1
Product: O=C1CCCN1c1cccc(SCc2ccccc2)c1Cl

Procedure:
Intermediate 35 (35 g, 313.6 mmol) was coupled with pyrrolidin-2-one (11.396 g, 133.91 mmol) in close analogy to the procedure described in step 1.6). After workup the crude product was used without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:13]([CH3:22])[N:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[Br:34]Br.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:13]([CH3:22])[N:12]=[C:11]1[Br:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncn(COCc2ccccc2)c1Sc1ccccc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1nc(Br)n(COCc2ccccc2)c1Sc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 92.5 %

Procedure:
In 5 ml of dry tetrahydrofuran is dissolved 300 mg of 1-benzyloxymethyl-4-methyl-5-phenylthioimidazole (I-3) (1 mmol) obtained in Example 3, and the resulting solution is chilled at -78° C. To the solution is added dropwise 1.64M solution of n-butyl lithium in 0.71 ml of hexane (1.16 mmol) and the mixture allowed to stand for 10 minutes, when 185 mg of bromine (1.16 mmol) is added thereto. Fifteen minutes later, the mixture is poured onto ice water. The mixture is neutralized with sodium bicarbonate and extracted with ethyl ether. The extract is washed with water, dried over sodium sulfate, filtered and the filtrate is concentrated. The crude product is chromatographed on a column of silica gel, eluting with ethyl acetate/n-hexane (1:2) to give 360 mg of the product (I-20; mp. 55° C.). Yield, 96%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=2[CH2:25][CH2:26][CH3:27])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:30][N:31]([CH3:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1>>[CH3:30][N:31]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]3[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=3[CH2:25][CH2:26][CH3:27])=[O:16])[C:5]3[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)=[CH:35][CH:34]=1)[CH3:48]
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C
Reactant: CN(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(CN(C)C)cc2)cc2c1c(C)nn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for example 67 from 6-bromo-3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (0.090 g, 0.196 mmol) and N,N-dimethyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (0.070 g, 0.235 mmol). The product was collected as a white solid (72 mg, 70%); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.33 Hz, 3H), 1.45 (d, J=6.57 Hz, 6H), 1.56 (sxt, J=7.53 Hz, 2H), 2.07-2.23 (m, 9H), 2.44 (s, 3H), 2.52-2.59 (m, 2H), 3.43 (s, 2H), 4.38 (d, J=5.05 Hz, 2H), 5.06 (quin J=6.63 Hz, 1H), 5.90 (s, 1H), 7.33-7.45 (m, 3H), 7.75 (d, J=8.08 Hz, 2H), 7.93 (d, J=1.26 Hz, 1H), 8.45 (t, J=4.93 Hz, 1H), 11.50 (s, 1H); LCMS (ES+) m/z: 514.5.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:11]([O:22][CH:23]([CH3:25])[CH3:24])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:11]([O:22][CH:23]([CH3:24])[CH3:25])[CH:10]=1
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)cc1OC(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(O)cc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (E)-ethyl 3-(4-(benzyloxy)-2-isopropoxyphenyl)acrylate (699) (530 mg, 1.56 mmol) in ethanol (12 mL) was added Pd/C (0.5 eq, 10% Degussa type). A balloon of hydrogen gas was added and the reaction was evacuated and back-filled with hydrogen three times. The reaction was stirred overnight at room temperature, filtered through a pad of celite and concentrated in vacuo to give ethyl 3-(4-hydroxy-2 isopropoxyphenyl)propanoate (700).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]2[S:10][C:9]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][NH:35]3)O1>>[NH:35]1[C:36]2[C:32](=[C:31]([C:2]3[N:3]=[C:4]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:5]4[S:10][C:9]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])=[CH:8][C:6]=4[N:7]=3)[CH:39]=[CH:38][CH:37]=2)[CH:33]=[N:34]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: COCC(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: COCC(=O)Nc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
70 mg of crude N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-2-methoxyacetamide was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 28.1 mg of 119. MS (Q1) 425 (M)+
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[C:21](Cl)=[O:22]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:21](=[O:22])[C:20]4[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=[C:18]([O:17][CH3:16])[CH:19]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Product: COc1cc(OC)cc(C(=O)Nc2nc3cccc(-c4ccoc4)n3n2)c1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 3,5-dimethoxybenzoyl chloride (60 mg; 0.30 mmol; 1.2 eq.) as a white powder (42.9 mg; 47%). HPLC, Rt: 3.51 min. (purity 95.3%). LC/MS, M+(ESI): 365.3, M−(ESI): 363.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([F:34])=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([F:34])=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCc1cn(C)c2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)c(F)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1ncc(-c2nc(-c3c(F)ccc4c(CCC(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
To a solution of ethyl 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1-methyl-1H-indol-3-yl]propanoate (D150) (270 mg) in isopropanol (7 mL) and water (7 mL) was added NaOH (5.6 mL, 0.5 M aq) at room temperature. The reaction suspension was stirred at 90° C. for 2 hours until the solution turned clear. Isopropanol was removed in vacuo and water (8 mL) was added to the residue. The aqueous solution was acidified to pH=1 and extracted with ethyl acetate (3×10 mL). The combined organic phase was dried over sodium sulphate. The organic solution was concentrated and the residue was purified by MDAP to afford 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1-methyl-1H-indol-3-yl]propanoic acid (E108) (72 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.32 (6H, d), 2.53 (2H, t), 2.88 (2H, t), 3.28 (3H, s), 5.39 (1H, m), 7.02 (1H, m), 7.11 (1H, s), 7.75 (1H, m), 8.53 (1H, d), 8.90 (1H, d), 12.07 (1H, s). MS (ES): C22H20ClFN4O4 requires 458; found 459.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([NH:15][CH3:16])[CH:7]=[C:6]2[OH:17].[NH2:18][C:19]1[CH:40]=[CH:39][C:22](OC2C3C(=CC(OC)=C(OC)C=3)N=C(N)C=2)=[C:21]([F:41])[CH:20]=1>>[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([O:17][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[C:8]([NH:15][CH3:16])[CH:7]=2)=[C:21]([F:41])[CH:20]=1
Reactant: COc1cc2nc(N)cc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: CNc1cc(O)c2cc(OC)c(OC)cc2n1
Product: CNc1cc(Oc2ccc(N)cc2F)c2cc(OC)c(OC)cc2n1

Procedure:
[4-(4-Amino-2-fluoro-phenoxy)-6,7-dimethoxy-quinolin-2-yl]-methyl-amine was synthesized from 6,7-dimethoxy-2-methylamino-quinolin-4-ol in a similar manner as 4-(4-Amino-2-fluoro-phenoxy)-6,7-dimethoxy-quinolin-2-ylamine, and isolated as a yellow oil (58% yield). LCMS: m/z 330 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([CH2:13][CH3:14])=[CH:11][C:10](Br)=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].C(N(CC)CC)C>CO.[Pd]>[C:1]([C:4]1[O:5][C:6]2[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CCc1cc(Br)cc2cc(C(C)=O)oc12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCc1cccc2cc(C(C)=O)oc12
Yield: 86.3 %

Procedure:
A mixture of 80.1 g of 2-acetyl-5-bromo-7-ethylbenzofuran, 37.5 g of triethylamine and 5 g of 5% palladium-on-carbon in 1300 ml of methanol was hydrogenated at room temperature and atmospheric pressure until 1 molar equivalent of hydrogen had been absorbed. The catalyst was filtered off and the filtrate evaporated to dryness. The residual solid was dissolved in ethyl acetate, the resulting solution washed with water and with brine and dried over anhydrous sodium sulphate. The sodium sulphate was then filtered off and the filtrate evaporated under reduced pressure. The residual solid was crystallized from petroleum ether (boiling range 60°-80°C) to give 48.7 g of 2-acetyl-7-ethylbenzofuran as a white crystalline solid of melting point 59°-60°C.