Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25]([OH:27])=O)=[CH:5][C:4]=2[N:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:15][C:16]([CH3:18])([OH:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[O:27])=[CH:5][C:4]=2[N:3]=1
Reactant: COCc1nc2c(N)nc3cc(CCC(=O)O)ccc3c2n1CC(C)(C)O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: COCc1nc2c(N)nc3cc(CCC(=O)N4CCOCC4)ccc3c2n1CC(C)(C)O
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
3-[4-Amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanoic acid (1.25 g, 3.30 mmol), anhydrous pyridine (75 mL) and 1-hydroxybenzotriazole (892 mg, 6.60 mmol) were combined and the reaction was stirred for 30 minutes. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (1.27 g, 6.60 mmol) was added and the reaction mixture was stirred for an additional 15 minutes. Morpholine (581 mg, 6.60 mmol) was added in one portion. After stirring for 18 hours the solution was concentrated under reduced pressure. The resulting foam was dissolved in chloroform (50 mL) and washed with 1% aqueous sodium carbonate (2×15 mL). The combined aqueous washes were extracted with chloroform. The combined organic fractions were concentrated under reduced pressure and then purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient; 0-20% CMA over 1500 mL, followed by 20-25% CMA over 500 mL, and finally 25-30% CMA over 500 mL). A final recrystallization from acetonitrile provided 913 mg of 3-[4-amino-2-(methoxymethyl)-7-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as an off-white solid, mp 215-217° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][N:19]([CH2:27][CH2:28][OH:29])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:16][CH:15]=1.CCN(CC)CC>[Cl-].[Zn+2].[Cl-].ClCCCl.CC(O)(C)C>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][N:19]([CH2:27][CH2:28][OH:29])[C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[CH:30][CH:31]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1ccc(N)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCO)Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Zinc(II) chloride (1.0 M in Et2O; 3.30 mL, 3.30 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.658 g, 3.03 mmol) in 1:1 DCE/t-BuOH (20 mL) at 0° C. under nitrogen. After stirring for 1 hour at 0° C., a solution of tert-butyl 4-aminobenzyl(2-hydroxyethyl)carbamate (A70) (0.734 g, 2.75 mmol) in 1:1 DCE/t-BuOH (20 mL) was added followed by a solution of Et3N (0.423 mL, 3.03 mmol) in 1:1 DCE/t-BuOH (5 mL) at 0° C. The resulting mixture was vigorously stirred at 0° C. for 30 minutes, then at room temperature for 20 hours. The volatiles were evaporated in vacuo and the residue adsorbed onto silica gel then purified by column chromatography (CombiFlash Rf, 80 g SiO2 cartridge, 10-40% EtOAc in cyclohexane) to give the title compound A71 as a white solid (1.06 g, 85%); 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 7.59-7.52 (m, 3H), 7.28 (m, 2H), 4.49 (s, 2H), 3.74 (s, 2H), 3.43-3.20 (m, 3H), 1.50 (s, 9H). LCMS-B: rt 7.856 min; m/z 447 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][CH:17]=[C:16]2[C:20]1([CH2:30][CH3:31])[C:28]2[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:30]([C:20]1([C:16]2[C:15]3[C:19](=[C:11]([NH2:10])[CH:12]=[CH:13][CH:14]=3)[NH:18][CH:17]=2)[C:28]2[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)[CH3:31]
Reactant: CCC1(c2c[nH]c3c(NC(=O)OCc4ccccc4)cccc23)CCc2cc(F)ccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCC1(c2c[nH]c3c(N)cccc23)CCc2cc(F)ccc21
Reaction time: 18 h
Yield: 94.1 %

Procedure:
A mixture of [3-(1-ethyl-5-fluoro-indan-1-yl)-1H-indol-7-yl]-carbamic acid benzyl ester (7.78 g, 18.2 mmol) and 20% palladium hydroxide on carbon (1.6 g) in ethanol is hydrogenated at 50° C. at 60 psi for 18 hours. After filtration of the catalyst the solution is concentrated in vacuo to furnish the title compound as a black solid (5.04 g, 94%). LC-MS m/z 295.1 (M++1).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.Br[C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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]>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: Cn1cnc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: Oc1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cnc2ccc(-c3cccc(O)c3)cc21
Temperature: 100 °C
Yield: 92 %

Procedure:
To a solution of 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (6 g, 23.1 mmol) in dioxane/water (50 mL) was added 3-bromophenol (4.8 g, 27.7 mmol), Pd(dppf)Cl2 (0.3 g) and Cs2CO3 (15 g, 46.2 mmol). The reaction mixture was heated at 100° C. for 3 h, cooled and concentrated. The crude reaction mixture was purified by column chromatography. (4.8 g, yield 92%) MS (ESI+) e/z: 225.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][CH2:24][F:25])=[O:10])[C:2]1C=CC=C[CH:3]=1.Cl.[H][H].ClC(OCC=C)=O.[OH-].[Na+]>[Pd].O.O1CCCC1.CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][CH2:24][F:25])=[O:10])[CH:2]=[CH2:3]
Reactant: [H][H]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCCF)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: C=CCOC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COCCF
Yield: 89.6 %

Procedure:
A solution of (2S,4R)-1-benzyloxycarbonyl-2-(2-fluoroethyloxymethyl)-4-methanesulfonyloxypyrrolidine (8.37 g) in a mixture of concentrated hydrochloric acid (4.3 ml) and methanol (86 ml) was hydrogenated under atmospheric pressure of hydrogen at ambient temperature for 3 hours in the presence of 10% palladium on carbon (0.86 g). The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give a syrup. The syrup was dissolved in a mixture of water (50 ml) and tetrahydrofuran (50 ml). To the solution was dropwise added a solution of allyl chloroformate (2.87 ml) in tetrahydrofuran (5 ml) under ice-cooling with stirring, while keeping the pH between 8 and 9 with 4N aqueous sodium hydroxide. The mixture was stirred at the same condition for one hour, extracted with ethyl acetate (100 ml), washed in turn with water (100 ml) and brine (100 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (75 g) and eluted with a mixture of methanol and chloroform (1:99 V/V) to give (2S,4R)-1-allyloxycarbonyl-2-(2-fluoroethyloxymethyl)-4-methanesulfonyloxypyrrolidine (6.50 g).
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].[CH:25](I)([CH3:27])[CH3:26].C(N1C2C(=CC(F)=CC=2)N(C(=O)C2C=CC=C(OC)C=2)[C@H](CC)C1=O)C>>[CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH:25]([CH3:27])[CH3:26])[C:4]1=[O:24])[CH3:2]
Reactant: CC[C@@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Reactant: CC(C)I
Agent: CC[C@@H]1C(=O)N(CC)c2ccc(F)cc2N1C(=O)c1cccc(OC)c1
Product: CC[C@@H]1C(=O)N(C(C)C)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Yield: 54 %

Procedure:
(3R)-3-Ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (see Example 8) was treated with isopropyl iodide at reflux according to the procedure for the preparation of (3R)-1,3-diethyl-6-fluoro-4-(3-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (see Example 8) to yield (3R)-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-1-isopropyl-3,4-dihydroquinoxalin-2(1H)-one (54%). MS (ESI) m/z 371 ([M+H]+).
Reaction SMILES: [BH4-].[Na+].[Si:3]([O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([C:21]1[N:25]3[CH:26]=[CH:27][C:28]([CH:30]=[O:31])=[CH:29][C:24]3=[N:23][N:22]=1)[CH:17]=[CH:16]2)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>CO>[Si:3]([O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([C:21]1[N:25]3[CH:26]=[CH:27][C:28]([CH2:30][OH:31])=[CH:29][C:24]3=[N:23][N:22]=1)[CH:17]=[CH:16]2)([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:4])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(-c3nnc4cc(C=O)ccn34)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(-c3nnc4cc(CO)ccn34)nc12
Temperature: 25 °C

Procedure:
NaBH4 (0.124 g, 3.28 mmol was added to a solution of 3-(8-(tert-butyldimethylsilyloxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde (1.328 g, 3.283 mmol) in MeOH (20 mL) at 0° C. The cold bath was removed and the reaction allowed to warm to ambient temperature over 1 hour. HCl was added and the solution was concentrated. The residue was triturated with DCM. The resulting solid was filtered and concentrated to provide the crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([O:25][CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:24])[CH:20]=2)[N:15]([CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][C:36]([Cl:42])=[CH:37][CH:38]=3)[N:33]=2)[CH:14]=1)[C:6](O)=[O:7].[CH3:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50]([NH2:53])(=[O:52])=[O:51].Cl.CN(C)CCCN=C=NCC.CC(O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([O:25][CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:24])[CH:20]=2)[N:15]([CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][C:36]([Cl:42])=[CH:37][CH:38]=3)[N:33]=2)[CH:14]=1)[C:6]([NH:53][S:50]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=1[CH3:43])(=[O:52])=[O:51])=[O:7]
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(Cc2ccc3ccc(Cl)cc3n2)c2ccc(NC(=O)OC3CCCC3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(Cc2ccc3ccc(Cl)cc3n2)c2ccc(NC(=O)OC3CCCC3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution the acid from Step 4 (159 mg) and 2-methylbenzenesulfonamide (70 mg) in CH2Cl2 (3 ml) was added successively 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (78 mg) and DMAP (50 mg). After stirring at r.t. overnight, HOAc (200 μl) was added and the mixture was concentrated. Chromatography of the residue using EtOAc/hexane (2:3) containing 1% HOAc afforded 172 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]1[CH:17]=[N:18][C:19]([N:26]2[CH2:29][CH:28](OS(C)(=O)=O)[CH2:27]2)=[C:20]([CH:25]=1)[C:21]([O:23][CH3:24])=[O:22]>C(#N)C>[Cl:15][C:16]1[CH:17]=[N:18][C:19]([N:26]2[CH2:29][CH:28]([O:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH2:27]2)=[C:20]([CH:25]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: Oc1cccc(F)c1
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cnc1N1CC(Oc2cccc(F)c2)C1
Temperature: 180 °C

Procedure:
To a solution of 3-Fluorophenol (0.005 ml, 0.056 mmole) in acetonitrile (1 ml), potassium carbonate (10 mg, 0.0728 mmol) were added followed by the addition of methyl 5-chloro-2-(3-((methylsulfonyl)oxy)azetidin-1-yl)nicotinate (D63) (20 mg, 0.062 mmol). The reaction mixture was heated at 150° C. under microwave irradiation for 10 min (2 cycle of 5 min each) then at 180° C. for 5 min. After solvent evaporation the obtained residue was purified by SPE-Si (10 g) eluting with mixture cyclohexane/ethyl acetate from 95/5 to 90/10. Collected fractions, after solvent evaporation, afforded the title compound D77 (10 mg)
Reaction SMILES: [I-].[NH:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([CH2:15][N+:16]([CH3:19])([CH3:18])C)=[N:3]1.[C:20]1(/[CH:26]=[CH:27]/[C:28]2[CH2:29]CNC[CH:33]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[C:20]1(/[CH:26]=[CH:27]/[C:28]2[CH2:29][CH2:19][N:16]([CH2:15][C:4]3[C:5]4[CH2:6][CH2:7][C:8]5[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=5[C:10]=4[NH:2][N:3]=3)[CH2:18][CH:33]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C1=C(/C=C/c2ccccc2)CCNC1
Reactant: C[N+](C)(C)Cc1n[nH]c2c1CCc1ccccc1-2
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C1=C(/C=C/c2ccccc2)CCN(Cc2n[nH]c3c2CCc2ccccc2-3)C1

Procedure:
A solution of (4,5-dihydro-1H-benzo[g]indazol-3-ylmethyl)-trimethylammonium iodide (0.20 g), 4-((E)-2-phenylethenyl)-1,2,3,6-tetrahydropyridine (0.085 g) and diisopropylethylamine (0.10 cm3) in DMF (10 cm3) was heated under nitrogen at 80° C. for 48 hours. The mixture was cooled, poured into water (50 cm3) and extracted with 10% ethyl acetate-diethyl ether (2×50 cm3). The extracts were dried (MgSO4), filtered and concentrated to give a brown oil. Preparative thin layer chromatography on silica gel, eluting with 5% methanol-dichloromethane+1% ammonia, gave the title compound as a brown foam, which was crystallised as the oxalate salt from ethanol to give beige granules (0.007 g; 3%), m.p. 205°-210° C. (from EtOH); δH (360 MHz; d6 -DMSO+CF3CO2H) 2.54-2.70 (2H, m, NCH2CH2), 2.76 (2H, t, J 7.5, --CH2 --), 2.92 (2H, t, J 7.5, --CH2 --), 3.12-3.32 (1H, m, NCHAHBCH2), 3.60-3.78 (1H, m, NCHAHBCH2), 3.82-4.00 (2H, m, NCH2CH=C), 4.40 (2H, broad s, --CH2N), 5.90 (1H, s, NCH2 CH=C), 6.60 (1H, d, J 16.3, CH=CHPh), 6.96 (1H, d, J 16.3, CH=CHPh) 7.22-7.35 (6H, m, 6 of ArH), 7.49 (2H, d, J 7.4, 2 of ArH) and 7.64 (1H, d, J 6.6, 1 of ArH); m/z (CI+ ; NH3) 368 (MH+ ; 10%), 298 (10), 188 (15), 186 (20) and 184 (100). Found: M+ 367.2039. C25H25N3 requires 367.2048.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([I:42])[CH:37]=1>C1COCC1>[C:33]([C:27]1[CH:28]=[N:29][C:30]2[C:25]([C:26]=1[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([I:42])[CH:37]=1)=[CH:24][C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])=[CH:32][CH:31]=2)#[N:34]
Reactant: CC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(I)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(I)c3)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 38.8 %

Procedure:
Dissolved 275 mg (3.27 mmol) 2-butynoic acid in 20 ml THF under N2 and chilled to 0° C. Added 420 μl (3.23 mmol) isobutyl chloroformate and 355 μl (3.24 mmol) N-methylmorpholine and stirred for 10 minutes. Added dropwise a solution of 500 mg (1.30 mmol) 6-amino-4-[(3-iodophenyl)amino]-3-quinolinecarbonitrile and after 15 minutes, removed ice bath and stirred overnight at 25° C. Stripped solvent, washed with water and collected solids. Boiled in ethyl acetate, collected, and dried in vacuo, giving 228 mg of orange-brown solid: mass spectrum (electrospray m/e): M+H=453.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:20])[CH2:18][CH3:19])=[CH:13][C:12]=1[CH2:21][CH2:22][CH3:23])[CH3:2].Cl.N1C=CC=CC=1>O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:20])[CH2:18][CH3:19])=[CH:13][C:12]=1[CH2:21][CH2:22][CH3:23])[CH3:2]
Reactant: CCCc1cc(C(=O)CC)ccc1-c1cc(OC)ccc1CC
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCc1cc(C(=O)CC)ccc1-c1cc(O)ccc1CC
Temperature: 30 °C

Procedure:
413 g (1.33 mol) of 1-(2′-ethyl-5′-methoxy-2-propylbiphenyl-4-yl)propan-1-one and 768 g (6.64 mol) of pyridine hydrochloride are placed in a round-bottomed flask. The mixture is heated at 160°-170° C. for 4 hours with stirring. The reaction medium is allowed to return to 100°-110° C. and 800 ml of water are added. The mixture is cooled to 30° C. and extracted with 1.6 liters of ethyl acetate. After separating by settling, the aqueous phase is extracted with 600 ml of ethyl acetate. The organic phases are combined and washed twice with 800 ml of water. After evaporating under reduced vacuum, 410 g of 1-(2′-ethyl-5′-hydroxy-2-propylbiphenyl-4-yl)propan-1-one are obtained in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([NH:13][C:14](=[O:18])[O:15][CH2:16][CH3:17])[C:9]2=[O:12])=[CH:5][CH:4]=1>O1CCCC1>[CH2:7]([C:9]1([OH:12])[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[CH2:7][CH:8]1[NH:13][C:14](=[O:18])[O:15][CH2:16][CH3:17])[C:6]1[CH:10]=[CH:11][CH:3]=[CH:4][CH:5]=1
Reactant: CCOC(=O)NC1Cc2ccc(OC)cc2C1=O
Solvent: C1CCOC1
Product: CCOC(=O)NC1Cc2ccc(OC)cc2C1(O)Cc1ccccc1
Temperature: 25 °C

Procedure:
To ice cold 2M benzylmagnesium chloride in tetrahydrofuran (6.14 ml, 12.28 mmol) was added dropwise a solution of ethyl 6-methoxy-1-oxo-2,3-dihydro-1H-inden-2-ylcarbamate (1.02 g. 4.09 mmol) in tetrahydrofuran (30 ml) and stirred over night, while the reaction mixture was allowed to warm up to room temperature. The reaction mixture was quenched with sat. ammonium chloride and the organic layer was evaporated. The residue was extracted twice with dichloromethane and the combined organic layers were washed subsequently with sodium bicarbonate and brine, dried, filtered and evaporated to obtain a dark gooey oil, that was purified by flash silica gel chromatography on 12 g SiO2— cartridge using 30% ethyl acetate in cyclohexane to afford the desired ethyl 1-benzyl-1-hydroxy-6-methoxy-2,3-dihydro-1H-inden-2-ylcarbamate as a brown grease. m=1.07 g (77%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1.[Cl:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:12][CH:9]([S:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:10]#[N:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#CCSc1ccc(Cl)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(Cl)Sc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.6 %

Procedure:
Into a 500 ml four-necked round bottom flask equipped with a stirrer, a thermometer, and a condenser, are placed 300 ml of carbon tetrachloride and 55 g (0.3 mole) of p-chlorophenylthioacetonitrile. To this mixture is added 40 g (0.3 mole) of N-chlorosuccinimide in small portions. The reaction mixture is stirred at room temperature overnight. The white solid which forms is filtered and the filtrate is concentrated under vacuum to give 6.95 g of desired product.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=1.Br[CH:18]([CH2:20][CH3:21])[CH3:19]>CN(C=O)C.O>[Br:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[C:7]2[CH:8]=[CH:9][N:10]([CH:18]([CH2:20][CH3:21])[CH3:19])[C:11]=2[CH:12]=1
Reactant: CCC(C)Br
Reactant: COC(=O)c1cc(Br)cc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)n1ccc2c(C(=O)OC)cc(Br)cc21
Reaction time: 0.33 h
Yield: 38.2 %

Procedure:
To a stirred suspension of sodium hydride (5.66 g, 141.7 mmol) in DMF (100 mL) was added a solution of methyl 6-bromo-1H-indole-4-carboxylate (4) (30 g, 118.1 mmol) in DMF (50 mL) at 0° C. and stirred for 20 min. Then 2-Bromo butane (29.1 g, 212.5 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with cold water and extracted with ethyl acetate (4×150 mL). The combined organic layer was washed with cold water (150 mL), brine (100 mL) and dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude, which was purified by column chromatography over silica gel (60-120 mesh) using 5% EtOAc: Pet ether as eluent to afford the title compound methyl 6-bromo-1-sec-butyl-1H-indole-4-carboxylate, (14 g, 40.1%) as pale yellow solid. 1H NMR (CDCl3, 400 MHz) δ 0.843-0.870 (m, 3H), 1.512 (d, J=6.4 Hz, 3H), 1.844-1.926 (m, 2H), 3.976 (s, 3H), 4.333-4.385 (m, 1H), 7.132 (d, J=3.2 Hz, 1H), 7.302 (d, J=3.6 Hz, 1H), 7.707 (s, 1H), 7.984 (d, J=1.6 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])[CH2:12][CH3:13].S(Cl)(Cl)=O.S(=O)=O.Cl>ClC1C=CC=CC=1>[CH2:11]([O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH:18][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])[CH2:12][CH3:13]
Reactant: CCCOc1cccc(N)c1
Reactant: Cc1ccccc1C(=O)O
Agent: Cl
Agent: O=S=O
Solvent: O=S(Cl)Cl
Solvent: Clc1ccccc1
Product: CCCOc1cccc(NC(=O)c2ccccc2C)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A 13.6 g (0.1 mol) portion of o-methylbenzoic acid and 15.1 g (0.1 mol) of m-n-propoxy-aniline were dissolved in 100 ml of chlorobenzene. An 11.9 g (0.1 mol) amount of thionylchloride was added dropwise to the prepared solution at 40° - 50° C, and the mixture was stirred at 90° - 95° C for 4 hours, whereby sulfur dioxide and hydrogen chloride were continuously generated. After the reaction, the reaction mixture was poured into ice water and extracted with a mixture of benzene and hexane. The product was recrystallized from the mixed solvent to obtain 23.6 g (88%) of white needles having a melting point of 92° -94° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38](I)[C:37]=1[C:43]1[N:47]([CH3:48])[N:46]=[N:45][N:44]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([F:35])[C:37]=2[C:43]2[N:47]([CH3:48])[N:46]=[N:45][N:44]=2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: Cn1nnnc1-c1c(F)cccc1I
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccc(F)c5-c5nnnn5C)ccc(F)c43)ccc21
Temperature: 100 °C
Reaction time: 12 h

Procedure:
In a microwave vial methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (100 mg), 5-(2-fluoro-6-iodophenyl)-1-methyl-1H-tetrazole (78 mg), K3PO4 (136 mg) are suspended in 1,4-dioxane (3 mL) and purged for 10 minutes with argon. [1,3-Bis(2,6-di-3-pentylphenyl)inidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride (8.5 mg) is added, the vial is sealed and the mixture is stirred at 100° C. for 12 hours. After cooling to room temperature the solvents are evaporated and the product thus obtained is used directly in the next step.