Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[C:9]1[C:17]([O:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:34](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].[OH-].[Na+].Cl>CN(C=O)C.O.CCOC(C)=O>[CH2:1]([N:8]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[C:9]1[C:17]([O:18][CH2:19][CH2:20][CH2:21][O:22][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(OCCCO)cccc2C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(OCCCO[Si](C)(C)C(C)(C)C)cccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
To a solution of 0.145 g (0.308 mmol) of the product of Example 172 in 5.0 mL of DMF was added 0.105 g (1.539 mmol) of iidazle and 0.111 g (0.739 mmol) of t-butyidimethylsilyl chloride. The reaction was stirred at room temperature for 18 h and then 0.40 mL of 1N sodium hydroxide solution was added and the resulting mixture was sired for 1 h. The reaction mixture was then diluted with water, acidified with 5% HCl solution and extted with EtOAc. The combined organics were washed with water, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc/Hexanes to provide 0.089 g (50%) of the desired product as a white foam. Electrospray Mass Spec: 586 (M+H).
Reaction SMILES: CN(C1C=CC([C:10]([C:12]2[CH:13]=CC(N(C)C)=C[CH:17]=2)=[O:11])=CC=1)C.CN(C1C=CC(C(C2C=CC(N(C)C)=CC=2)C2C=CC(N(C)C)=CC=2)=CC=1)C.CC(Cl)(Cl)Cl.[CH2:54]([O:56]CCO)C>CC(=O)CC>[C:10]([O:56][CH3:54])(=[O:11])[C:12]([CH3:13])=[CH2:17].[C:10]([OH:56])(=[O:11])[C:12]([CH3:13])=[CH2:17]
Reactant: CN(C)c1ccc(C(=O)c2ccc(N(C)C)cc2)cc1
Reactant: CCOCCO
Agent: CN(C)c1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)cc1
Solvent: CC(Cl)(Cl)Cl
Solvent: CCC(C)=O
Product: C=C(C)C(=O)O
Product: C=C(C)C(=O)OC

Procedure:
A solution of 15.0 g of a 9:1 copolymer of methyl methacrylate and methacrylic acid in 50 g of 2-butanone was prepared, and to it was added 15.0 g of Epocryl® 12, 1.2 g of 2-o-chlorophenyl-4,5-diphenylimidazolyl dimer, 0.9 g of Michler's ketone, 0.06 g of Leuco Crystal Violet, 0.30 g of C.I. Solvent Red Dye #109, 16.7 g of methyl chloroform and 150 g of 2-ethoxyethanol. The resulting 13% solids solution was coated onto oriented polyester film substrates using a 0.5 mil (0.00127 cm) doctor knife and dried.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2C(=O)NC3[C:19]=2[CH:18]=[C:17]2[C:13](=[C:14]([C:21]4[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=4)[C:15](=[O:20])[NH:16]2)[CH:12]=3)=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:33])[CH:31]=[O:32].C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:31](=[O:32])[N:30]([CH2:33][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][CH3:8])[C:29]3[C:19]=2[CH:18]=[C:17]2[C:13](=[C:14]([C:21]4[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=4)[C:15](=[O:20])[N:16]2[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH:12]=3)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc3c(cc2=C1c1ccc(Br)cc1)NC(=O)C=3c1ccc(Br)cc1
Reactant: CN(C)C=O
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCCCCCN1C(=O)C(c2ccc(Br)cc2)=c2cc3c(cc21)=C(c1ccc(Br)cc1)C(=O)N3CCCCCCCC
Temperature: 90 °C
Yield: 73 %

Procedure:
3,7-Bis-(4-bromo-phenyl)-1H,5H-pyrrolo[2,3-f]indole-2,6-dione (1.250 g, 2.519 mmol) (1.3) is dissolved into anhydrous dimethylformamide (50 cm3) and then potassium carbonate (3.482 g, 25.19 mmol) and 1-bromo-octane (1.1 cm3, 6.3 mmol) is added. The resulting mixture is heated to 90° C. for 21 hours before being cooled down, poured into methanol (500 cm3) and filtered to recover the pure product (1.320 g, Yield: 73%). NMR (1H, 300 MHz, CDCl3): δ 7.64 (d, J=8.7 Hz, 4H); 7.57 (d, J=8.7 Hz, 4H); 6.26 (s, 2H); 3.62 (t, J=7.1 Hz, 4H); 1.63 (m, 4H); 1.32 (m, 8H); 1.26 (m, 12H); 0.87 (t, J=6.8 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[F:26][C:27]([F:37])=[CH:28][C@H:29]1[C@H:31]([C:32](Cl)=[O:33])[C:30]1([CH3:36])[CH3:35].O>C(OCC)C>[F:26][C:27]([F:37])=[CH:28][C@H:29]1[C@H:31]([C:32]([O:9][CH2:8][C:7]2[C:2]([F:1])=[C:3]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:4]([F:12])=[C:5]([F:11])[C:6]=2[F:10])=[O:33])[C:30]1([CH3:35])[CH3:36]
Reactant: OCc1c(F)c(F)c(F)c(-c2ccccc2)c1F
Reactant: CC1(C)[C@@H](C=C(F)F)[C@@H]1C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC1(C)[C@@H](C=C(F)F)[C@@H]1C(=O)OCc1c(F)c(F)c(F)c(-c2ccccc2)c1F

Procedure:
To a stirred solution of 0.97 g (3.8 mmole) of 2,4,5,6-tetrafluoro[1,1'-biphenyl]-3-methanol and 1 ml of dry triethylamine in 8 ml of dry diethyl ether was added 4 ml of a dry diethyl ether solution of trans-3-(2,2-difluoroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride (0.95 mmole/ml). The resultant mixture was stirred at room temperature for approximately 18 hours, then poured into 50 ml of water. The organic phase was separated, washed with a 5% aqueous sodium bicarbonate solution followed by a water wash, then dried over anhydrous magnesium sulfate. The organic phase was filtered, and the filtrate evaporated under reduced pressure to give an oil. The oil was purified by column chromatography on silica gel, eluted with ethyl acetate:hexanes (10:90), to yield 0.92 g of (2,4,5,6-tetrafluoro[1,1'-biphenyl]-3-yl)methyl trans-3-(2,2-difluoroethenyl)-2,2-dimethylcyclopropanecarboxylate as a solid (m.p. 69°-72° C.).
Reaction SMILES: [CH2:1]([N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](OCC1C2C=CC=CC=2C2C1=CC=CC=2)=[O:13])[CH:2]([CH3:4])[CH3:3].[C:42]([NH:50][C@H:51](C(O)=O)[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH3:41][C:38]1[CH:39]=[CH:40][C:35]([S:32]([N:5]([C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@@H:51]([NH:50][C:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:49])[CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:13])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:33])=[O:34])=[CH:36][CH:37]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NC(=O)c2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from solid phase bound Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine as described in general procedure Bb using Nα-benzoyl-L-phenylalanine (321 mg, 1.2 mmol). The final product was purified by preparative HPLC to yield 44 mg (58%) of the desired material.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][CH:6]=[CH2:7])[CH:3]=[O:4].[CH2:9]([Li])[CH2:10][CH2:11][CH3:12].[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]([CH3:8])([CH:3]([OH:4])[CH2:9][CH2:10][CH2:11][CH3:12])[CH2:5][CH:6]=[CH2:7]
Reactant: C=CCC(C)(C)C=O
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(C)(C)C(O)CCCC
Temperature: -60 °C
Yield: 100 %

Procedure:
15 g (133 mmol) of 2,2-dimethyl-4-pentenal was added to 600 mL of THF in a 2 L, 3-neck flask, flushed with N2, and sealed with rubber stoppers. The reaction mixture was cooled to −60° C. in a dry ice/acetone bath. Butyllithium solution (2.5 M in hexane, 64.4 mL, 160.7 mmol) was added 4–5 mL at a time from a 20 mL glass syringe. The reaction temperature was kept at −65° C., during addition and afterwards was stirred for an additional hour. The reaction mixture was allowed to warm to −5° C. over 1 hour, cooled to −60° C. again, and slowly quenched with ammonium chloride solution (10.5 g/200 mL water, 200 mmol). THF was evaporated using a rotary evaporator, keeping the water bath temperature set at 30° C. The resultant aqueous solution was first extracted with CH2Cl2 (3×200 mL), and then with ether (1×200 mL). The organic extracts were combined, dried, and concentrated on a rotary evaporator (30° C. water bath) to yield 22.64 g of 4,4-dimethyl-non-1-en-5-ol, TLC Rf=0.67 (1:1 ethyl acetate:hexanes, visualization by I2). 1H NMR (CDCl3, 500 MHz) δ (ppm): 5.86 (m, 1H), 5.06 (m, 1H)), 5.03 (s, 1H), 3.26 (d, 1H), 2.15 (m, 1H), 1.95 (m, 1H), 1.5 (m, 2H), 1.3 (m, 4H), 0.95, (t, 3H), 0.90 (s, 3H), 0.89 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([N:31]2[C:35]3=[N:36][CH:37]=[N:38][C:39]([NH2:40])=[C:34]3[CH:33]=[N:32]2)[CH2:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:25]4[CH2:30][CH2:29][CH:28]([N:31]5[C:35]6=[N:36][CH:37]=[N:38][C:39]([NH2:40])=[C:34]6[CH:33]=[N:32]5)[CH2:27][CH2:26]4)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: Nc1ncnc2c1cnn2C1CCNCC1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1nc2nc(-c3ccc(CN4CCC(n5ncc6c(N)ncnc65)CC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 120 h
Yield: 14.5 %

Procedure:
200 mg (0.64 mmol) 4-(2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde and 194 mg (0.64 mmol) 1-piperidine-4-yl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine were treated as described in example 2. Additional NaBH(OAc)3 has been added after 24 and 26 hours (two equivalents each). After five days stirring at room temperature the solvents have been evaporated and the residue was purified via chromatography. 48 mg of the desired compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[CH:9]([O:12][C:13]1[CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]2=[C:20]([C:22](OC)=[O:23])[CH:21]=1)([CH3:11])[CH3:10]>>[CH:9]([O:12][C:13]1[CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]2=[C:20]([C:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=2)=[O:23])[CH:21]=1)([CH3:11])[CH3:10]
Reactant: COC(=O)c1cc(OC(C)C)cc2occc12
Reactant: Cc1ccc(N)nc1
Product: Cc1ccc(NC(=O)c2cc(OC(C)C)cc3occc23)nc1

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from 2-amino-5-methyl pyridine and methyl 6-isopropoxybenzofuran-4-carboxylate (344a) to give a white solid (28 mg, 37% yield). 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1 H) 8.29 (d, J=8.56 Hz, 1 H) 8.04 (d, J=2.52 Hz, 1 H) 7.65 (d, J=2.27 Hz, 1 H) 7.58 (dd, J=8.31, 2.27 Hz, 1 H) 7.34 (d, J=2.01 Hz, 1 H) 7.21-7.23 (m, 2 H) 4.55-4.64 (m, 1 H) 2.30 (s, 3 H) 1.37 (d, J=6.04 Hz, 6 H); LCMS for C18H18N2O3m/z 311.10 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[O:14][CH:13]([CH2:16][NH2:17])[CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:2]=1.C(N(C(C)C)CC)(C)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[O:14][CH:13]([CH2:16][NH:17][C:28](=[O:29])[O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:2]=1
Reactant: NCC1Cc2cccc(-c3cccnc3)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3cccnc3)c2O1)OCc1ccccc1
Yield: 57.3 %

Procedure:
Treatment of (±)-1-(7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methanamine (0.770 g, 3.40 mmol) with diisopropylethylamine (0.660 g, 5.1 mmol) and benzyl chloroformate (0.778 g, 4.08 mmol) generally according to the procedure described for Intermediate 12 provided 0.702 g (57%) of (±)-benzyl [(7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]carbamate as an amber oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[NH:23][C:22]3[C:17]2=[N:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N:20][C:21]=3[NH2:26])=[CH:7][CH:6]=1.Cl[CH2:34][C:35](Cl)=[O:36].[CH3:38][C:39]#[N:40]>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[NH:23][C:22]3[C:17]2=[N:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N:20][C:21]=3[NH2:26])[C:35](=[O:36])[CH2:34][N:40]2[CH2:8][CH2:11][N:12]([CH3:13])[CH2:38][CH2:39]2)=[CH:7][CH:6]=1
Reactant: CC#N
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCc3ccc(CC(=O)OC)cc3)c2n1
Reactant: O=C(Cl)CCl
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3ccc(CC(=O)OC)cc3)C(=O)CN3CCN(C)CC3)c2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The product from step (ix) (200 mg) was suspended in MeCN. Chloroacetyl chloride (0.02 ml) added and the mixture stirred at rt for 4 h. The mixture was concentrated under reduced pressure, piperazine (0.02 ml) in DMSO (1 ml) was added and the mixture heated at 60° C. for 24 h. The mixture was purified by RPHPLC. Yield 80 mg.
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])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(C)nc(O)c(Cc3ccc4ccccc4n3)c2cc1OC
Temperature: 115 °C
Reaction time: 0.42 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (147 mg, 0.67 mmol) in toluene (3 mL) in a 10 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.70 mL, 1.40 mmol) at RT followed by 2-(chloromethyl)quinoline hydrochloride (158 mg, 0.74 mmol) and the mixture was stirred at 115° C. for 25 min under microwave irradiation. Another portion of a 2 N aq. KOH solution (0.30 mL, 0.60 mmol) was then added at RT followed by 2-(chloromethyl)quinoline hydrochloride (70 mg, 0.33 mmol) and the mixture was stirred at 115° C. for 10 min under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (5 mL) and neutralised with a 10% aqueous citric acid solution before extraction with CH2Cl2 (50 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 100:7) gave 49 mg of 6,7-dimethoxy-1-methyl-4-(quinolin-2-ylmethyl)isoquinolin-3-ol as a yellow solid. The free base (45 mg) was dissolved in MeOH (10 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (5.5 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-1-methyl-4-(quinolin-2-ylmethyl)isoquinolin-3-ol hydrochloride 23 as a yellow solid (54 mg, 19% yield).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=CC=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:15]([OH:18])(=O)[CH3:16].Br([O-])(=O)=[O:20].[K+].BrBr>O>[C:15]1(=[O:18])[C:16]2[CH:8]=[CH:7][C:6]3[C:5](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=[CH:2][C:1]1=[O:20]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: c1ccc2c(c1)ccc1ccccc12
Reactant: CC(=O)O
Agent: BrBr
Agent: [K+]
Solvent: O
Product: O=C1C=Cc2c(ccc3ccccc23)C1=O
Temperature: 72.5 °C
Yield: 80 %

Procedure:
Phenanthrene (16 g, Aldrich Tech Grade (90 percent), 0.081 mol) and acetic acid (200 ml) were stirred and heated to 70-75° C. Potassium bromate (32 g, 0.19 mol) was added in 2 portions. After the addition of the first portion the temperature rose to reflux with evolution of bromine vapors. The second portion was added and the condenser was replaced by a distillation head. The heating was continued until the distillate was colorless. The deep red solution was cooled and poured into water (300 ml) and the precipitate was isolated by filtration. The crude product was purified by reslurrying in 100 ml of hot (70° C.) aqueous sodium bisulfite solution (40 percent) and filtering while hot. The deep red filtrate was cooled and treated with aqueous sodium carbonate until basic. The precipitated product was recovered by extraction with methylene chloride, dried and concentrated to yield 13.4 g (80 percent yield) of orange yellow solid: mp 182-184° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[CH:15][C:7]2[C:8]([CH3:14])=[C:9]([C:11]([OH:13])=O)[O:10][C:6]=2[C:5]=1[O:17][CH2:18][CH3:19])[CH3:2].[CH2:20]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:26]1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:32]=[CH:33][C:34]([NH:37][C:11]([C:9]3[O:10][C:6]4[C:5]([O:17][CH2:18][CH3:19])=[C:4]([O:3][CH2:1][CH3:2])[CH:16]=[CH:15][C:7]=4[C:8]=3[CH3:14])=[O:13])=[CH:35][CH:36]=2)[CH2:26]1)=[O:24])[CH3:21]
Reactant: CCOC(=O)N1CCC(Oc2ccc(N)cc2)C1
Reactant: CCOc1ccc2c(C)c(C(=O)O)oc2c1OCC
Product: CCOC(=O)N1CCC(Oc2ccc(NC(=O)c3oc4c(OCC)c(OCC)ccc4c3C)cc2)C1

Procedure:
With a procedure similar to example above, 3-{4-[(6,7-diethoxy-3-methyl-benzofuran-2-carbonyl)-amino]-phenoxy}-pyrrolidine-1-carboxylic acid ethyl ester was prepared from 6,7-diethoxy-3-methyl-benzofuran-2-carboxylic acid and 3-(4-amino-phenoxy)-pyrrolidine-1-carboxylic acid ethyl ester. LCMS calcd for C27H32N2O7 (m/e) 496, obsd 497 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C=C(CC(N[C@@H](C2C=CC=CC=2)C(N[C@H]2[C@@H](C3C=CC=CC=3)SCCNC2=O)=O)=O)C=C(F)C=1.[Br:59]C1SC(C=O)=CC=1>>[CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[S:19][C:20]([Br:59])=[CH:21][CH:22]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: COC(=O)/C(=C/c1cccs1)NC(=O)OCc1ccccc1
Agent: O=C(Cc1cc(F)cc(F)c1)N[C@H](C(=O)N[C@@H]1C(=O)NCCS[C@@H]1c1ccccc1)c1ccccc1
Product: COC(=O)/C(=C/c1ccc(Br)s1)NC(=O)OCc1ccccc1

Procedure:
A method similar to that used for the preparation of (99a) was used except that the reaction product was passed through a Dowex ion exchange resin 50×2-200 and 5-bromo-2-thiphenecarboxaldehyde (955 mg) was used as the aldehyde component to afforded the desired product (1.80 g). 1H NMR (300 MHz, CDCl3) δ 3.79 (s, 3H), 5.20 (s, 2H), 5.93 (br., 1H), 6.95 (m, 1H), 7.36 (m, 5H), 7.70 (s, 1H). LC/MS: 2.36 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)[CH3:2].[Cl-].[Br:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH:17]=[N+:18]([CH3:20])[CH3:19].BrC1C=C(C=CC=1)C=O.CNC>>[Br:13][C:14]1[CH:15]=[C:16]([CH:17]([N:18]([CH3:20])[CH3:19])[C:8]2[C:7]3[C:11](=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][CH:6]=3)[NH:10][CH:9]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: C[N+](C)=Cc1cccc(Br)c1
Reactant: CCc1cccc2cc[nH]c12
Agent: CNC
Agent: O=Cc1cccc(Br)c1
Agent: [Cl-]
Product: CCc1cccc2c(C(c3cccc(Br)c3)N(C)C)c[nH]c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 7-ethylindole and (3-bromo-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 3-bromo-benzaldehyde and dimethylamine.
Reaction SMILES: [C:1]([OH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:12]([O:16][C:17]([N:19]1[CH2:23][C@H:22](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:21][C@H:20]1[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:18])([CH3:15])([CH3:14])[CH3:13]>CN(C)C=O.[I-].[Na+]>[C:12]([O:16][C:17]([N:19]1[CH2:23][C@@H:22]([S:8][C:1](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:21][C@H:20]1[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: OC(=S)c1ccccc1
Reactant: CCOC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1C[C@H](SC(=O)c2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 70.5 %

Procedure:
Next, 36.4 g of thiobenzoic acid was dissolved in 300 ml of dimethylformamide and cooled on an ice bath, to which was subsequently added 10.5 g of sodium hydride. To this were added 102 g of (2S,4R)-1-(t-butoxycarbonyl)-2-ethoxycarbonyl -4-(p-toluenesulfonyloxy)pyrrolidine dissolved in 200 ml of dimethylformamide and 37.5 g of sodium iodide, followed by heating at 80° C. for 3 hours. After concentration of the reaction mixture, the thus obtained residue was dissolved in .benzene, and the resulting organic layer was washed with 5% sodium bicarbonate aqueous solution, 10% citric acid aqueous solution and water in that order, followed by drying over sodium sulfate and subsequent evaporation of the solvent under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to yield 66 g of (2S,4S)-1-(t-butoxycarbonyl)-2-ethoxycarbonyl -4-benzoylthiopyrrolidine.
Reaction SMILES: [CH3:1][C:2]1([OH:8])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[H-].[Na+].Cl[C:12]1[C:20]2[C:19]3[CH:21]=[C:22]([C:25]#[N:26])[N:23]=[CH:24][C:18]=3[N:17]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:16]=2[N:15]=[CH:14][CH:13]=1>O1CCCC1.O.C(OCC)(=O)C>[CH3:1][C:2]1([O:8][C:14]2[CH:13]=[CH:12][C:20]3[C:19]4[CH:21]=[C:22]([C:25]#[N:26])[N:23]=[CH:24][C:18]=4[N:17]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:16]=3[N:15]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(Cl)ccnc21
Reactant: CC1(O)CCCNC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(Oc2ccc3c4cc(C#N)ncc4n(COCC[Si](C)(C)C)c3n2)CCCNC1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-methylpiperidin-3-ol (99 mg, 0.86 mmol) in tetrahydrofuran (3.2 mL) was added sodium hydride as 60% dispersion in mineral oil (35 mg, 0.86 mmol). The reaction mixture was stirred at ambient temperature for 5 minutes before 4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (141 mg, 0.39 mmol) was added in one portion and the reaction mixture was stirred at this temperature for 10 minutes before being warmed to 40° C. for 5 hours. The mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 40 g, ISCO, 1-20% methanol in methylene chloride) to afford the title compound as an orange solid, which was used in the next step without any further purification (52 mg, 30%).