Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][CH:6]([CH3:13])[CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22]>[N+](C1C=CC=CC=1)([O-])=O>[F:14][C:15]1[CH:20]=[C:19]([C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH:6]([CH3:13])[CH3:5])[CH:18]=[CH:17][C:16]=1[O:21][CH3:22]
Reactant: CC(C)CCCC(=O)Cl
Reactant: COc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)CCCC(C)C)cc1F
Temperature: 0 °C

Procedure:
14 ml of nitrobenzene are cooled in an ice-bath and then mixed in succession with 3.8 g of AlCl3 and 3.7 g of 5-methyl-hexanoyl chloride in 5 ml of nitrobenzene. The mixture is stirred and then treated with 2.7 ml of 2-fluoro-anisole. The solution is stirred overnight, then poured into ice-water and extracted with methylene chloride. The extracts are washed with water and 10% aqueous NaCl solution, and thereafter dried and concentrated and recrystallized using pentane. 5.31 g of 1-(3-fluoro-4-methoxy-phenyl)-5-methyl-hexan-1-one, MS: m/e 238 (M+), are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][C:23]([CH3:33])=[C:24]([CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[N:25]=2)=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][C:23]([CH3:33])=[C:24]([CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)[N:25]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Product: COc1ccc(-c2ccc(-c3nc(CCN4CCCC4)c(C)o3)cc2)c(OC)c1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 35 starting from 2,4-Dimethoxybenzene boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 393.2 (M+1)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[Br:28])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[C@@H:10]([CH3:31])[CH2:9]1)=O)(C)(C)C.[ClH:32]>>[ClH:32].[Br:28][C:27]1[CH:26]=[C:25]2[C:16]([N:17]3[C:22]([CH2:23][O:24]2)=[N:21][NH:20][C:19](=[O:29])[C@H:18]3[CH3:30])=[CH:15][C:14]=1[C@@H:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[CH3:31]
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(Br)c([C@@H]4CCN(C(=O)OC(C)(C)C)C[C@@H]4C)cc3N21
Agent: Cl
Product: C[C@@H]1C(=O)NN=C2COc3cc(Br)c([C@@H]4CCNC[C@@H]4C)cc3N21
Yield: 82 %

Procedure:
A solution of (3R,4R)-4-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (Example #199, Step D, 3 g, 6.08 mmol) in HCl (4M in EtOAc, 10 mL) was stirred at ambient temperature for 1 h. The organic solvent was removed in vacuo to give crude (R)-7-bromo-4-methyl-6-((3R,4R)-3-methyl-piperidin-4-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride (2.2 g, 82%) as a white solid, which was used directly in the next step. LC/MS (Table 1, Method 25) Rt=0.720 min.; MS m/z: 393 [M+H]+& 395 [M+H+2]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][S:12][C:13]2[C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:3][CH:2]=1.[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CN(C)C=O>[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:19]([C:18]2[C:13]([S:12][CH2:11][C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=[CH:2][CH:3]=3)=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:21])=[CH:25][CH:24]=1
Reactant: O=C(O)c1cccnc1SCc1ccnc2ccccc12
Reactant: Nc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)cc1)c1cccnc1SCc1ccnc2ccccc12
Yield: 75 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetrauroniumhexafluorophosphate (140 mg, 0.38 mmol) was added to a solution of 2-(quinolin-4-ylmethylthio)pyridine-3-carboxylic acid (Reference Compound No. 7-1.91 mg, 0.31 mmol), 4-chloroaniline (52 mg, 0.40 mmol) and N,N-diisopropylethylamine (0.13 mL, 0.74 mmol) in anhydrous N,N-dimethylformamide (2.0 mL) at room temperature, and the mixture was stirred for 24 hours. Ethyl acetate (50 mL) was added thereto, and the whole was washed with saturated aqueous sodium hydrogencarbonate solution (50 mL, twice) and brine (50 mL), The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the precipitated solid was filtered off and washed with a mixture of diethyl ether and ethyl acetate (1:1). The resulting solid was dried at 50° C. under reduced pressure to give 93 mg of the target compound as a reddish-brown solid (Yield: 75%)
Reaction SMILES: [OH:1][C@H:2]([C:13]1[CH:22]=[CH:21][C:16]2[C:17](=[O:20])[O:18][CH2:19][C:15]=2[C:14]=1[CH3:23])[CH2:3][N:4]1[CH:9]2[CH2:10][NH:11][CH2:12][CH:5]1[CH2:6][O:7][CH2:8]2.[CH3:24][C@H:25]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH:35]3[CH2:37][O:36]3)[CH:32]=2)[C:27](=[O:38])[O:26]1>>[OH:36][CH:35]([C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:38])[O:26][C@@H:25]([CH3:24])[CH2:34]2)[CH2:37][N:11]1[CH2:12][CH:5]2[N:4]([CH2:3][C@H:2]([OH:1])[C:13]3[C:14]([CH3:23])=[C:15]4[C:16](=[CH:21][CH:22]=3)[C:17](=[O:20])[O:18][CH2:19]4)[CH:9]([CH2:8][O:7][CH2:6]2)[CH2:10]1
Reactant: Cc1c([C@@H](O)CN2C3CNCC2COC3)ccc2c1COC2=O
Reactant: C[C@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Product: Cc1c([C@@H](O)CN2C3COCC2CN(CC(O)c2ccc4c(c2)C[C@H](C)OC4=O)C3)ccc2c1COC2=O

Procedure:
(3S)-6-(1-Hydroxy-2-(9-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)ethyl)-3-methylisochroman-1-one was prepared initially as a mixture of two diastereomers from 5-[(1R)-1-hydroxy-2-(3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one [INTERMEDIATE 17] and (3S)-3-methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one [INTERMEDIATE 24] in an analogous fashion to that described for the synthesis of EXAMPLE 1. The mixture of diastereomers was separated by preparative SFC-HPLC using a Chiralcel® OD column (30×250 mm) to afford the title single isomers.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][O-:12].[Na+].O.[Cl-].[NH4+].[OH-].[NH4+]>CN(C)C=O.CO.C(OCC)(=O)C.[Cu]I.[Cu]Br>[CH3:11][O:12][C:2]1[CH:3]=[C:4]2[CH:5]=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: C[O-]
Agent: [Cu]Br
Agent: [Cu]I
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cnc2[nH]ccc2c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To 5-bromo-7-azaindole (67, 500.0 mg, 2.53 mmol) in N,N-dimethylformamide (8 mL) were added copper(I) iodide (966 mg, 5.08 mmol) and sodium methoxide in methanol (3 M, 5 mL). The reaction was stirred overnight at 120° C. under an atmosphere of Argon. The reaction was poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated and purified with silica gel column chromatograph eluting with 20% ethyl acetate in hexane to give white solid (104, 140 mg, 28%). MS (ESI) [M+H+]+=149.1. In an alternative method, 2.3 g (11.7 mmol) 5-bromo-7-azaindole (67, 2.3 g, 11.7 mmol) was dissolved in 75 mL N,N-dimethylformamide and 50 mL methanol (50 mL), adding sodium methoxide (32 g, 0.6 mol) and copper-(I) bromide (3.2 g, 22.4 mmol) at room temperature. The reaction was stirred for three hours at 100° C. under an atmosphere of argon. The mixture was diluted with ethyl acetate and poured into a solution of ammonium chloride:ammonium hydroxide (4:1). The organic layer was extracted with ammonium chloride:ammonium hydroxide (4:1), washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The desired compound was isolated by silica gel column chromatography eluting with 30% to 70% ethyl acetate in hexanes to give a yellow solid (104, 0.27 g, 15.6%). MS (ESI) [M+H+]+=149.2.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6](N)=[CH:5][C:4]=1[C:10]([F:13])([F:12])[F:11])#[N:2].N([O-])=O.[Na+].[BrH:18]>>[Br:18][C:6]1[CH:8]=[CH:9][C:3]([C:1]#[N:2])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=1
Reactant: Br
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Product: N#Cc1ccc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
In a round bottom flask, 4-cyano-3-trifluoromethylaniline (20 g, 107.5 mmol) was solubilized in 300 mL of 47% aq HBr. This solution was cooled to 0° C. in an ice bath and NaNO2 (22.2 g, 322 mmol) was added slowly. Then CuBr (46.3 g, 322.5 mmol) was added slowly. After the addition, the ice bath was removed and the mixture was stirred at 20° C. for 3 hr. The mixture was cooled to 0° C. in an ice bath and 500 mL of water were added to get a yellow precipitate. Solid was filtered and washed successively with 10% aq. HCl (50 mL) and water (100 mL), and dried to give the product (23.5 g, 87%), 1H NMR (300 MHz, Acetone-d6)δ: 8.19 (s, 1H, C3—H), 8.16 (d, 1H, J=8 Hz, C6—H), 8.05 (d, 1H, J=8 Hz, C5—H).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[C:6]([C:24]([F:27])([F:26])[F:25])[CH:5]=1)([O-:3])=[O:2].Cl>C(Cl)Cl.O1CCOCC1.CCOC(C)=O>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[C:6]([C:24]([F:27])([F:25])[F:26])[CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(OC2CCNCC2)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A solution of tert-butyl 4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine-1-carboxylate (1.4 g, 1.0 eq, 3.6 mmol) in CH2Cl2 (25 mL) was cooled to 0° C. while stifling. 4N HCl in dioxane (15 mL) was added to the above solution and stirred at 0° C. for 30 minutes and brought to room temperature for 2 hours. The volatiles were removed under vacuum to leave a crude solid. The crude mixture was dissolved in EtOAc (100 mL) and partitioned with 1N aqueous NaOH solution (50 mL). Organic layers were separated and the aqueous layer was washed with EtOAc (50 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to give the desired product in 90% yield.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:21]([O:23]C)=[O:22])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2)#[N:2].[OH-].[Na+].O.Cl>CCO>[C:1]([C:3]1[N:4]=[C:5]([C:21]([OH:23])=[O:22])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2)#[N:2]
Reactant: COC(=O)c1nc(C#N)c(-c2ccccn2)c2cc(OC)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(C(=O)O)nc(C#N)c(-c3ccccn3)c2c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a suspension of methyl 3-cyano-6-methoxy-4-pyridin-2-ylisoquinoline-1-carboxylate (0.04 g, 0.125 mmol) in 3 mL EtOH, was added 0.251 mL 1(N) aqueous NaOH and 1.16 mL water. The reaction was stirred at 0° C. for 4 h and then 1(N) aqueous HCl (0.251 mL) was added. The reaction was warmed up to rt and concentrated to a tan solid (used without further purification).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[CH:27]=[N:28][NH:29][CH:30]=1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:28]3[CH:27]=[C:26]([CH3:25])[CH:30]=[N:29]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cn[nH]c1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: Cc1cnn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)c1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (371 mg, 1.0 mmol), 4-methyl-1H-pyrazole (164 mg, 2.0 mmol) and DMAP (366 mg, 3.0 mmol) in MeCN (10 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 165 mg (40% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.41-1.58 (m, 4 H), 1.61 (s, 9 H), 2.05 (s, 3 H), 2.22-2.47 (m, 1 H), 3.30-3.40 (m, 2 H), 3.91 (m, 2 H), 4.43 (d, J=7.62 Hz, 2 H), 7.60 (s, 1 H), 7.91 (d, J=8.2 Hz, 1 H), 7.95 (dd, J=8.8, 1.8 Hz, 1H), 8.05-8.14 (m, 1 H), 8.28 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=416.8.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:26])([F:25])[C:9]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])([OH:16])[CH2:10][N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[N:6][CH:7]=1.[CH2:27]([N:30]1[CH:34]=[N:33][N:32]=[N:31]1)[CH:28]=[CH2:29].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)C>CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:30]1([CH2:27]/[CH:28]=[CH:29]/[C:2]2[CH:3]=[CH:4][C:5]([C:8]([F:26])([F:25])[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])([OH:16])[CH2:10][N:11]3[CH:15]=[N:14][N:13]=[N:12]3)=[N:6][CH:7]=2)[CH:34]=[N:33][N:32]=[N:31]1
Reactant: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(Br)cn1
Reactant: C=CCn1cnnn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCN(CC)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(/C=C/Cn2cnnn2)cn1
Temperature: 110 °C
Yield: 13 %

Procedure:
To a stirred solution of compound 1 (200 mg, 0.46 mmol) in DMF (2 mL) were added compound T (161 mg, 1.47 mmol), tri-o-tolylphosphine (447 mg, 0.14 mmol), Pd(OAc)2 (22.7 mg, 0.10 mmol) and N,N-diethylisopropylamine (DIEA; 179 mg, 1.38 mmol) at RT, and the mixture was purged with inert gas for 15 min. The resulting reaction mixture was stirred at 110° C. under microwave heating for 15 min; progress of the reaction was monitored by TLC. The reaction mixture was cooled to RT, diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 75% EtOAc/hexanes) afforded 42 (30 mg, 0.06 mmol, 14.3%). 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.67 (s, 1H), 8.49 (s, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.37-7.31 (m, 2H), 6.78-6.68 (m, 1H), 6.67-6.64 (m, 1H), 6.61 (s, OH), 6.53-6.48 (m, 1H), 5.52 (d, J=14.5 Hz, 1H), 5.27 (d, J=6.0 Hz, 2H), 5.16 (d, J=14.5 Hz, 1H). MS (ESI): m/z 462 [M+H]+. HPLC: 94.2%.
Reaction SMILES: CN(C=O)C.O.Br[C:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:14][CH:15]=2)[N:10]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(OCC)(=O)C>[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:14][CH:15]=3)[N:10]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[CH:9]=2)=[CH:46][CH:45]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(Br)cn(-c4ccncc4)c3c2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cn(-c3ccncc3)c3cc(N4CCN(C(=O)OC(C)(C)C)CC4)ccc23)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100.6 %

Procedure:
DMF/water (4:1, 2 mL) was added to a mixture of tert-butyl 4-(3-bromo-1-(pyridin-4-yl)-1H-indol-6-yl)piperazine-1-carboxylate (29 mg, 0.0636 mmol), potassium carbonate (18 mg, 0.13 mmol) and 4-methoxyphenylboronic acid (11 mg, 0.070 mmol) and the dissolved gas was removed. After adding Pd(dppf)Cl2 (10.4 mg, 0.013 mmol), the mixture was stirred at room temperature for 14 hours. After adding ethyl acetate and water, the mixture was filtered using a diatomite pad. After separation of the organic layer, the aqueous layer was extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The residue was purified by chromatography (silica gel, EA:Hx=1:4 1:1). The target compound (31 mg) was obtained as white solid.
Reaction SMILES: [CH:1]([Si:4]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]1[S:11][CH:12]=[CH:13][N:14]=1)([CH3:3])[CH3:2].[CH2:21]([Li])CCC.IC.O>O1CCCC1>[CH3:21][C:12]1[S:11][C:10]([C:6]2[N:5]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:15]([CH3:17])[CH3:16])[CH:18]([CH3:20])[CH3:19])[CH:9]=[CH:8][CH:7]=2)=[N:14][CH:13]=1
Reactant: [Li]CCCC
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cccc1-c1nccs1
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cnc(-c2cccn2[Si](C(C)C)(C(C)C)C(C)C)s1
Reaction time: 0.67 h
Yield: 65.1 %

Procedure:
2-[1-(Triisopropylsilyl)-1H-pyrrol-2-yl]-1,3-thiazole (317 mg, 1.03 mmol) synthesized in Example (3a) was dissolved in tetrahydrofuran (10 mL), and cooled to −78° C. n-Butyl lithium (2.64M hexane solution, 0.51 mL, 1.35 mmol) was added dropwise, followed by stirring for 40 minutes, and subsequently iodomethane (0.13 mL, 2.09 mmol) was added and stirring was carried out for 3 hours with the temperature being gradually raised from −78° C. to room temperature. Water (10 mL) was added, and extraction was carried out with diethyl ether (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: hexane) to afford the desired compound (215 mg, yield 65%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH2:30]([C:32]1[O:33][CH:34]=[C:35]([CH2:37][N:38]2[C:43]3[CH:44]=[C:45]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[S:46][C:42]=3[C:41](=[O:53])[N:40]([CH:54]3[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)[C:39]2=[O:60])[N:36]=1)[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:57]4[CH2:58][CH2:59][CH:54]([N:40]5[C:41](=[O:53])[C:42]6[S:46][C:45]([C:47]7[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=7)=[CH:44][C:43]=6[N:38]([CH2:37][C:35]6[N:36]=[C:32]([CH2:30][CH3:31])[O:33][CH:34]=6)[C:39]5=[O:60])[CH2:55][CH2:56]4)=[O:21])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCc1nc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)co1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5coc(CC)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
The title compound is prepared analogously as described for example 11 using 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C10), 1-[(2-ethyl-1,3-oxazol-4-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (190 mg; compound B41), HBTU (167 mg), DIPEA (207 mg) and DCM (8 ml). After 3 h additional HBTU (91 mg) and 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (20 mg; compound C10) are added and the mixture is stirred for 22 h at RT. Saturated aqueous sodium bicarbonate solution (2.5 ml) is added and the mixture is extracted twice with DCM (2×5 ml). The combined organic layers are applied to a phase separator and the solvent is removed under vacuo. The resulting residue is purified by flash column chromatography for three times [amino phase silica gel, eluation gradient: cyclohexane/EtOAc, 100/0 to 0/100 (v/v)] to yield the title compound as a solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH2:28])[C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:15]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:14]=2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[N:32]=[CH:33][N:34]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:28][C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[N:32]=[CH:33][NH:34]2)[C:12]1[N:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:15]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:14]=2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](CCOCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc2nc([C@H](CCOCc3ccccc3)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c2c1
Temperature: 100 °C
Yield: 83.8 %

Procedure:
A mixture of (S)-3-benzyloxy-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propylamine (639 mg, 1.7 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (410 mg, 1.7 mmol) and DIPEA (1.5 mL, 8.5 mmol) in n-butanol (6 mL) was heated at 100° C. for 18 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford the title compound as a white solid (703 mg, 84%). LCMS (Method C): RT 3.10 min [M+H]+ 494.3.
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25]>CN(C=O)C>[CH3:25][C:24]([CH3:26])=[CH:23][CH2:22][N:3]1[CH2:2][CH2:1][C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4]1
Reactant: c1ccc2c(c1)CC[C@@H]1CNCC[C@@H]21
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)=CCN1CC[C@H]2c3ccccc3CC[C@@H]2C1
Yield: 16.2 %

Procedure:
Following the procedure of Example 3, step 4, 0.163 g (0.872 mmol) of crude trans-1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline in 10 ml of anhydrous DMF was reacted with 0.133 g (0.962 mmol) of anhydrous potassium carbonate and 0.106 ml (0.917 mmol) of 4-bromo-2-methyl-2-butene. Chromatography on flash silica, eluting with 3-10% methanol/dichloromethane gave 0.036 g (16%) of the title product as a white solid. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent and recrystallisation from ethanol/ethyl acetate, the title product hydrochloride was obtained as a white solid, m.p. 222°-225° C. NMR δ(D2O/CD3CN) 1.56 (1H, m), 1.67 (1H, m), 1.78 (3H, s), 1.86 (3H, s), 1.76-1.92 (2H, m), 2.62-2.73 (2H, m), 2.84 (1H, t, J=12.0 Hz), 2.92-2.94 ( 2H, m), 3.11 (1H, m), 3.53 (1H, m), 3.69 (1H, m), 3.75 (2H, d, J=7.9 Hz), 5.34 (1H, t), 7.22-7.26 (3H, m), 7.32-7.34 (1H, m). m/z (CI+, NH3) 256 (M+H)+, 188 (M-CH2CH=CMe2 +2H)+, 159, 130, 108, 94, 84, 70.
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][C:4]([NH:6][C@H:7]([C:18]([O:20]C)=[O:19])[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:5].[OH-].[Na+]>CO>[CH3:1][C:2]([CH3:22])=[CH:3][C:4]([NH:6][C@H:7]([C:18]([OH:20])=[O:19])[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:5]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)=CC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Yield: 79.7 %

Procedure:
The same procedures as in Example 171 were carried out from the compound obtained in Example 162 (2.5 g), 1 mol/L of an aqueous sodium hydroxide solution (13 mL), and methanol (130 mL), to give the captioned compound (1.9 g, 78%) as an amorphous solid product.