Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH2:10][OH:11])=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:2]1.[N:12]1([C:17](N2C=CN=C2)=[O:18])[CH:16]=[CH:15][N:14]=[CH:13]1>C(Cl)Cl>[N:12]1([C:17]([O:11][CH2:10][C:6]2[C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=[CH:8][CH:7]=2)=[O:18])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCc1cccc2c1OCO2
Solvent: ClCCl
Product: O=C(OCc1cccc2c1OCO2)n1ccnc1
Yield: 86.5 %

Procedure:
A solution of (benzo[d][1,3]dioxol-7-yl)methanol (2 g, 13.14 mmol) and di(1H-imidazol-1-yl)methanone (4.26 g, 26.28 mmol) in 20 mL CH2Cl2 was heated overnight at 50° C. The reaction was quenched with water, extracted with CH2Cl2, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 10-70% EtOAc in CH2Cl2 gave (benzo[d][1,3]dioxol-7-yl)methyl 1H-imidazole-1-carboxylate (2.8 g, 86%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([Br:12])[C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:15])=[N-].C(O)(=O)C>CCOCC.C(OCC)(=O)C>[CH3:15][O:5][C:4](=[O:6])[C:3]1[C:7]([Br:12])=[CH:8][C:9]([Br:11])=[CH:10][C:2]=1[NH2:1]
Reactant: C=[N+]=[N-]
Reactant: Nc1cc(Br)cc(Br)c1C(=O)O
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(N)cc(Br)cc1Br
Reaction time: 2 h
Yield: 83.5 %

Procedure:
To a solution of 2-amino-4,6-dibromo-benzoic acid (17.5 g, 59.3 mmol) in ether (150 mL) and ethyl acetate (15 mL) kept in an ice bath was added a solution of diazomethane (approximately 70.0 mmol, prepared from diazald 118.6 mmol) in ether (500 mL) over 1 hour. The reaction mixture was then stirred in an ice water bath for 2 hours. The resultant was treated with acetic acid 10 mL and washed with 2N NaHCO3 and brine. The organic layer was concentrated in vacuo. The residue was purified by chromatography (hexane:EtOAc=8:1) to give the objective compound (15.3 g, 83%) as brown solid: 1H NMR (200 MHz, CDCl3) δ 3.92 (s, 3H), 4.92 (br s, 2H), 6.80 (d, J=7.73, 2H), 7.11 (d, J=7.73, 1H); MS(EI) m/e 307 [M+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[CH:11][C:10]=1[Br:16])([CH3:4])([CH3:3])[CH3:2].BrC1C=C([C:25]([F:28])([F:27])[F:26])C=CC=1O.BrCC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:25]([F:28])([F:27])[F:26])=[CH:11][C:10]=1[Br:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Reactant: Oc1ccc(C(F)(F)F)cc1Br
Agent: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)COc1ccc(C(F)(F)F)cc1Br

Procedure:
Following the general method as outlined in Intermediate 1, starting from 2-bromo-4-(trifluoromethyl)phenol and tert-butyl bromoacetate (Aldrich), the title compound was obtained as a dark orange sticky solid in quantitative yield.
Reaction SMILES: N1CCCCC1.[ClH:7].[CH2:8]([C:11]1([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:16][C:15]([CH3:18])([CH3:17])[CH2:14][C:13]([CH3:20])([CH3:19])[CH2:12]1)[CH:9]=[CH2:10].BrCC#C>>[ClH:7].[CH3:17][C:15]1([CH3:18])[CH2:14][C:13]([CH3:19])([CH3:20])[CH2:12][C:11]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)([CH2:8][C:9]#[CH:10])[CH2:16]1
Reactant: C=CCC1(N2CCCCC2)CC(C)(C)CC(C)(C)C1
Agent: C#CCBr
Agent: Cl
Solvent: C1CCNCC1
Product: C#CCC1(N2CCCCC2)CC(C)(C)CC(C)(C)C1
Yield: 6 %

Procedure:
Prepared from piperidine 12 according to the procedure for compound 13 (Example 5, b) using 3-bromopropyne instead of allylbromide. Yield: 6%. 1H NMR (CDCl3, TMS): 1.07 (6H, s, 3′,5′-CH3eq), 1.11 (6H, s, 3′,5′-CH3ax); 1.23 and 1.44 (total 2H, both d, 14.3 Hz, 4′-CH2); 1.75-2.00 (4H, m, piperidine 3,5-CH, 4-CH2,); 1.91 (2H, d, 13.2 Hz, 2′,6′-CHax); 2.28 (1H, s, HCC); 2.34 (2H, d, 13.2 Hz, 2′,6′-CHeq); 2.40-2.70 (2H, m, piperidine 3,5-CH); 2.81 (2H, s, CH2CC); 2.85-3.10 (2H, m, piperidine 2,6-CH); 3.69 (2H, d, 10.2 Hz, piperidine 2,6-CH) and 11.12 ppm (1H, br s, NH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]1[C:27]([O:28][C:29]2[C:38]3[C:33](=[CH:34][C:35](O)=[C:36]([O:39][CH3:40])[CH:37]=3)[N:32]=[CH:31][N:30]=2)=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[C:22]([CH3:42])[NH:23]2>>[F:18][C:19]1[C:27]([O:28][C:29]2[C:38]3[C:33](=[CH:34][C:35]([O:17][CH2:16][CH2:15][CH2:14][N:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]4)=[C:36]([O:39][CH3:40])[CH:37]=3)[N:32]=[CH:31][N:30]=2)=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[C:22]([CH3:42])[NH:23]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Yield: 70 %

Procedure:
Using an analogous procedure to that described for the preparation of the starting material in Example 11, 1-tert-butoxycarbonyl-4-(3-hydroxypropyl)piperazine (432 mg, 1.77 mmol) was reacted with 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazoline (500 mg, 1.47 mmol), (prepared as described for the starting material in Example 7). The product was purified by column chromatography, eluting with 2%-5% methanol/methylene chloride to give tert-butyl 4-[3-(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline-7-yloxy)propyl]piperazine-1-carboxylate (582 mg, 70%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH3:10][O-:11].[Na+]>C1COCC1.CO>[C:4]1([CH:1]=[CH:2][C:10]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C[O-]
Reactant: CC(=O)c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(C=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Reaction of Aldehydes with Wang Resin-bound Acetophenones: Each packet of Acetophenone-Wang resin was transferred to a 250 mL PP bottle, to which a solution of NaOMe (51.2 mmol, 20 eq, 0.25 M) in 50% THF-MeOH (205 mL) and an aldehyde (51.2 mmol, 20 eq, 0.25 M) were added sequentially. After shaking at room temperature for 3 days, the packet was washed several times with MeOH (3×80 mL) and alternatively with DMF (80 mL) and MeOH (80 mL) for 3 cycles, followed by washes of DCM (2×80 mL) and MeOH (3×80 mL). The packet was air-dried overnight to afford a resin-bound Chalcone, that varied in color from yellow to dark red depending on the aldehyde used.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17](Cl)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:21])=[O:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:25]2[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: O=S(=O)(Nc1nccnc1Cl)c1ccccc1Cl
Product: O=C(O)c1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2Cl)cc1
Yield: 83 %

Procedure:
Following the general method as outlined for Intermediate 4, starting from 2-chloro-N-(3-chloropyrazin-2-yl)benzenesulfonamide and 4-carboxybenzene boronic acid, the title compound was isolated, after evaporation and recrystallization, as a yellowish solid in 83% yield (96% purity by HPLC).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[N:9]=[C:8]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH2:19][CH2:18]3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][S:31](O)(=[O:33])=[O:32]>C(Cl)Cl.CCOCC.CCOCC>[CH3:30][S:31]([O:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][N:20]1[CH2:19][CH2:18][N:17]([C:8]2[N:7]=[C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:11]=[C:10]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[N:9]=2)[CH2:22][CH2:21]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)O
Reactant: OCCCCCCN1CCN(c2nc(N3CCCC3)nc(N3CCCC3)n2)CC1
Solvent: CCOCC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCCN1CCN(c2nc(N3CCCC3)nc(N3CCCC3)n2)CC1

Procedure:
A mixture of 4-[4,6-bis(1-pyrrolidinyl)-1,3,5-triazin-2-yl]-1-piperazinehexanol (EXAMPLE 1, 1.22 g) in methylene chloride/ether (1/1, 30 ml) is mixed with a solution of methanesulfonic acid (0.28 g) in ether (15 ml). The mixture is concentrated and the residue crystallized twice from methanol/ether to give the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([C:13]1[C:14]([CH3:20])=[N:15][N:16]([CH3:19])[C:17]=1[F:18])=[O:12])(=[O:3])[CH3:2].[CH2:21]([Mg]Cl)[CH:22](C)[CH3:23].[C:27]1(C)C=CC=CC=1.[Cl-].[NH4+]>C1COCC1>[F:18][C:17]1[N:16]([CH3:19])[N:15]=[C:14]([CH3:20])[C:13]=1[C:11]([NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:1]([OH:3])([CH3:27])[CH2:2][CH:22]([CH3:23])[CH3:21])=[O:12]
Reactant: CC(=O)c1ccccc1NC(=O)c1c(C)nn(C)c1F
Reactant: CC(C)C[Mg]Cl
Reactant: Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nn(C)c(F)c1C(=O)Nc1ccccc1C(C)(O)CC(C)C
Temperature: -10 °C

Procedure:
Under argon and with stirring at −10° C., N-(2-acetylphenyl)-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide (as a solid, 10 g, 36.3 mmol) and isobutylmagnesium chloride (as a 2 M solution in THF, 41.7 ml; 83.55 mmol) are added simultaneously and continuously to 400 ml of toluene over a period of 150 minutes. The mixture is allowed to warm to room temperature, 200 ml of ammonium chloride solution are added, the mixture is extracted three times with in each case 100 ml of ethyl acetate and the organic phases are dried using sodium sulphate and concentrated under reduced pressure. This gives 5-fluoro-N-[2-(1-hydroxy-1,3-dimethylbutyl)phenyl]-1,3-dimethyl-1H-pyrazole-4-carboxamide (14.2 g, purity (GC/MS) 72.8%; 85% of theory) which still contains 14% of starting material.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2].[O:64]([CH2:72][C:73]1[CH:74]=[C:75]([CH:84]=[CH:85][CH:86]=1)[CH2:76]N=C([O-])C(Cl)(Cl)Cl)[Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:76][C:75]3[CH:84]=[CH:85][CH:86]=[C:73]([CH2:72][O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[CH:74]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:60])([CH3:61])[CH3:62])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CN=C([O-])C(Cl)(Cl)Cl)c1
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCc4cccc(CO[Si](C)(C)C(C)(C)C)c4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4 -azatricyclo [22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (230 mg in 3 ml 33% methylene chloride in cyclohexane) was added m-(tert-butyldimethylsiloxymethyl)-benzyltrichloroacetimidate (198 μl neat) and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (4.5 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 1 hour the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×8 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate: hexane (1:2)+1% methanol) gave the title compound (165 mg)
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([CH3:16])=[C:7]([C:14]#[CH:15])[CH:8]=2)[O:3]1.Cl[C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:20]=1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:26]([O:25][C:23](=[O:24])[C:22]1[CH:28]=[CH:29][C:19]([C:15]#[C:14][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][C:6]=2[CH3:16])[O:3][C:2]([CH3:17])([CH3:1])[CH2:11][C:10]3([CH3:12])[CH3:13])=[N:20][CH:21]=1)[CH3:27]
Reactant: C#Cc1cc2c(cc1C)OC(C)(C)CC2(C)C
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2cc3c(cc2C)OC(C)(C)CC3(C)C)nc1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
A solution of 300 mg (1.316 mmol) of 2,2,4,4,7-pentamethyl-6-ethynyl-chroman (Compound 48) and 245.6 mg (1.3276 mmol) of ethyl 6-chloro-nicotinate (Compound 29) in 2 ml of triethylamine was placed in a pressure tube and a stream of nitrogen was bubbled through the solution for 15 min. The tube was then flushed with argon and a finely ground mixture of 100 mg (0.1425 mmol) of his (triphenylphosphine) palladium (II) chloride and 50 mg (0.2625 mmol) of cuprous iodide was added to the solution. The pressure tube was then sealed and the reaction mixture heated at 60 degrees C. for 72 h. The mixture was cooled to room temperature and the triethylamine removed under vacuum. The residue was purified by flash chromatography (silica; 10% ethyl acetate in hexane) to give the title compound as a yellow solid. PMR (CDCl3): δ1.37 (6H, s), 1.38 (6H, s), 1.44 (3H, t, J-7.2 Hz), 1.85 (2H, s), 2.49 (3H, s), 4.43 (2H, q, J-7.2 Hz), 6.70 (1H, s), 7.55-7.61 (2H, m), 8.28 (1H, dd, J-8.2 Hz, 2.1 Hz), 9.22 (1H, d, J-2.1 Hz). MS exact mass, m/e 377.1982 (calcd. for C24H27O3N, 377.1991).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C@@H:4]([C:5]#[C:6][C:7]([O:9][C:10]([CH2:13][CH3:14])([CH3:12])[CH3:11])=[O:8])[C@H:3]1[C:15]([O:17][C@H:18]([C:32]#[N:33])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16].N1C2C(=CC=CC=2)C=CC=1>[OH-].[Pd+2].[OH-].C(OCC)(=O)C>[CH3:34][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][C:10]([CH2:13][CH3:14])([CH3:11])[CH3:12])=[O:8])[C@H:3]1[C:15]([O:17][C@H:18]([C:32]#[N:33])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:20]=1)=[O:16]
Reactant: CCC(C)(C)OC(=O)C#C[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CCC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A mixture of 1.34 g of the product of Step A, 220 mg of 10% palladium hydroxide on barium sulfate, 20 ml of ethyl acetate and 0.25 ml of quinoline was hydrogenated for 30 minutes and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 9:1 cyclohexane-ethyl acetate mixture yielded 1.05 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[Z-2-(tert.-amyloxycarbonyl)-ethenyl]cyclopropane-carboxylate with a specific rotation of [α]D20 =+63.5°±2.5° (c=0.7% in chloroform).
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:8]2=[N:9][C:10]([CH:22]=[O:23])=[C:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]([OH:13])=[C:7]2[CH:6]=[N:5]1)[CH3:3].[OH:24]O>C(O)(=O)C>[CH2:2]([N:4]1[C:8]2=[N:9][C:10]([C:22]([OH:24])=[O:23])=[C:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:12]([OH:13])=[C:7]2[CH:6]=[N:5]1)[CH3:3]
Reactant: OO
Reactant: CCn1ncc2c(O)c(CCc3ccccc3)c(C=O)nc21
Agent: Cl
Solvent: CC(=O)O
Product: CCn1ncc2c(O)c(CCc3ccccc3)c(C(=O)O)nc21
Reaction time: 20 h

Procedure:
16.5 g. of 1-ethyl-4-hydroxy-5-(2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxaldehyde, hydrochloride (1:1) (0.05 mol.) are dissolved in 150 ml. of boiling glacial acetic acid. To the filtered solution, cooled to about 30°, 10 g. of H2O2 (35%) (0.1 mol.) are added in two portions and the mixture is allowed to stand for 20 hours at room temperature. The crystallized 1-ethyl-4-hydroxy-5-(2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid is filtered off, washed with acetic acid and ether, yield: 10.1 g. (65%); m.p. 250°-251° (ethanol).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]3[NH:16][CH:17]=[C:18]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[C:10]=23)[CH2:4]1.Br[CH2:26][CH2:27][O:28][CH3:29].CCN(C(C)C)C(C)C.O>CN(C=O)C>[Br:15][C:14]1[C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@@H:3]([NH:2][CH2:26][CH2:27][O:28][CH3:29])[CH2:4]2)=[C:10]2[C:18]([NH:19][C:20]([CH:22]3[CH2:23][CH2:24]3)=[O:21])=[CH:17][NH:16][C:11]2=[N:12][CH:13]=1
Reactant: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Reactant: COCCBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCCN[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Temperature: 80 °C
Yield: 31 %

Procedure:
(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide hydrochloride (0.100 g, 0.222 mmol; Example 29, Step C), 1-bromo-2-methoxyethane (0.0246 mL, 0.266 mmol), and DIEA (0.154 mL, 0.887 mmol, d 0.742) were placed in DMF (2 mL) and heated to 80° C. for 18 hours. The reaction was then poured into water and extracted with EtOAc. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 20-50% CH3CN/water). The product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)—N-(5-bromo-4-(3-(2-methoxyethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (0.03 g, 30%). 1H NMR (400 MHz, D2O) δ 8.23 (s, 1H), 7.26 (s, 1H), 3.77-3.74 (m, 1H), 3.54-3.50 (m, 3H), 3.28-3.11 (m, 5H), 3.18 (s, 3H), 2.19-2.12 (m, 1H), 1.82-1.61 (m, 4H), 0.90-0.82 (m, 4H). LCMS (APCI+) m/z 436, 438 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([CH:13]=O)[CH:7]=1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1.[BH4-].[Na+].[OH-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:15])[NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([CH2:13][NH:19][CH:16]2[CH2:18][CH2:17]2)[CH:7]=1
Reactant: NC1CC1
Reactant: COC(=O)NCc1ccc(Cl)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)NCc1ccc(Cl)c(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A mixture of (4-chloro-3-formyl-benzyl)-carbamic acid methyl ester (3.22 g, 14.1 mmol) and cyclopropylamine (1.49 mL, 21.2 mmol) in MeOH (50 mL) was stirred at rt overnight. NaBH4 (1.07 g, 28.3 mmol) was added in portions, and the mixture was stirred at rt for 3 h. Aq. 1M NaOH (90 mL) was added, and the solvents were partially removed under reduced pressure. The aq. residue was extracted with EtOAc (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:1) yielded the title compound (3.24 g, 85%). LC-MS: tR=0.59 min; ES+: 310.31.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=2)[O:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][NH:16][C:17](=[O:23])[CH2:18][S:19][CH2:20][CH2:21][NH2:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]([N:29]=[C:30](OC)[CH2:31][CH3:32])#[N:28]>C(#N)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=2)[O:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][NH:16][C:17](=[O:23])[CH2:18][S:19][CH2:20][CH2:21][NH:22][C:30](=[N:29][C:27]#[N:28])[CH2:31][CH3:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCSCC(=O)NC/C=C\COc1cccc(CN2CCCCC2)c1
Reactant: CCC(=NC#N)OC
Solvent: CC#N
Product: CCC(=NC#N)NCCSCC(=O)NC/C=C\COc1cccc(CN2CCCCC2)c1
Yield: 14.2 %

Procedure:
There were dissolved 4.0 g (0.0106 mol) of N-[4-[3-(piperidinomethyl) phenoxy]-cis-2-butenyl]-2-(2-aminoethylthio)acetamide and 2.01 g (0.0159 mol) of methyl N-cyanopropioimidate in 40 ml of acetonitrile, and after reflux with heating for 18 hours the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:ethanol=10:1) to give 0.69 g of the titled compound as oily matter.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[NH:14][C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[C:20]([CH3:23])[CH:19]=[CH:18][CH:17]=3)[CH2:9]1)C1C=CC=CC=1>[C].[Pd].C(O)C>[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[NH:14][C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[C:20]([CH3:23])[CH:19]=[CH:18][CH:17]=3)[CH2:9]1
Reactant: Cc1cccc2c(=O)[nH]c(C3CCN(Cc4ccccc4)C3)cc12
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc2c(=O)[nH]c(C3CCNC3)cc12
Temperature: 50 °C
Reaction time: 6 h
Yield: 85.6 %

Procedure:
To the obtained (−)-3-(1-benzylpyrrolidin-3-yl)-5-methyl-2H-isoquinolin-1-one (27.5 g) were added 50% aqueous lot palladium-carbon (6 g) and ethanol (400 ml), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 6 hr. After celite filtration, the filtrate was concentrated and ethyl acetate was added to the obtained residue. The precipitated crystals were collected by filtration to give (−)-3-(pyrrolidin-3-yl)-5-methyl-2H-isoquinolin-1-one (16.8697 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[C:19]([CH3:22])[CH:18]=[C:17]([OH:23])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:24]([O:26]C)=O)[CH:5]=[CH:6][CH:7]=1.[OH-].[NH4+:29]>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[C:19]([CH3:22])[CH:18]=[C:17]([OH:23])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:24](=[O:26])[NH2:29])[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cc(C)cc1n2Cc1cccc(C)c1
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cccc(Cn2c3cc(C)cc(O)c3c3c(C(N)=O)cccc32)c1
Yield: 63 %

Procedure:
A solution of 9-[(3-methylphenyl)methyl]-2-methyl-4-hydroxy-5-carbomethoxy carbazole (0.92 g, 2.56 mM) in 38 ml THF and 154 mL concentrated aqueous ammonium hydroxide was sonicated for 6 h at 30-40° C. The precipitated solid was filtered, washed with water to afford 0.55 g (63%) of 9-[(3-methylphenyl)methyl]-2-methyl-4-hydroxy-5-carbamoyl carbazole. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (bs, 1H), 8.4 (bs, 1H), 7.75 (m, 1H), 7.4 (m, 2H), 7.15 (dd, J=8 and 8 Hz, 1H), 7.05 (m, 1H), 7.0 (s, 1H), 6.9 (s, 1H), 6.8 (d, J=8 Hz, 1H), 6.45 (s, 1H), 5.65 (s, 2H), 2.4 (s, 3H)., 2.2 (s, 3H). MS (ES) m/e 328, 345.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][I:8].[CH3:14][C:15]([O:17][C@H:18]1[C:28](=[O:29])[N:27]([CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:20][C@H:19]1[C:35]1[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)=[O:16].I>C(OCC)(=O)C>[I-:8].[C:15]([O:17][C@H:18]1[C:28](=[O:29])[N:27]([CH2:30][CH2:31][N+:32]([CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)([CH3:34])[CH3:33])[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:20][C@H:19]1[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)(=[O:16])[CH3:14]
Reactant: COc1ccc(CCI)cc1OC
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Agent: I
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H]2Sc3ccccc3N(CC[N+](C)(C)CCc3ccc(OC)c(OC)c3)C(=O)[C@@H]2OC(C)=O)cc1
Product: [I-]

Procedure:
To a flask under argon containing 4.94 g (0.0119 mole) diltiazem was added 50 ml ethyl acetate and 3.48 g (0.0119 mole) 3,4-dimethoxyphenethyl iodide. The reaction was refluxed for 24 hr then filtered. The filtrate was washed with sodium bicarbonate and brine, dried over K2CO3, and 0.85 g 3,4-dimethoxyphenethyl iodide added and the reaction refluxed for 18 hr then filtered. The last step was repeated but 1.75 g of 3,4-dimethoxyphenethyl iodide was added and the reaction refluxed 5 hr. The filtered materials were combined and recrystallized from 95% ethanol to give a mixture of product and diltiazem hydroiodide.