Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[C:13]([C:16]([OH:18])=O)[N:12]=[CH:11][C:10]=3[N:9]=[CH:8]2)=[CH:4][CH:3]=1.[O:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[C:13]([C:16]([NH:28][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:18])[N:12]=[CH:11][C:10]=3[N:9]=[CH:8]2)=[CH:19][CH:20]=1
Reactant: O=C(O)c1cc2c(cn1)ncn2Cc1ccc(F)cc1
Reactant: NOc1ccccc1
Product: O=C(NOc1ccccc1)c1cc2c(cn1)ncn2Cc1ccc(F)cc1

Procedure:
The title compound can be prepared from 1-(4-fluoro-benzyl)-1H— imidazo[4,5-c]pyridine-6-carboxylic acid and N-phenoxyamine under the same conditions as those in step (c) of Example 1.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5][O:6][CH2:7][C:8]([OH:10])=O)[CH3:2].[NH2:12][C@H:13]([C:26]([N:28]([CH2:38][C:39]1[C:40]2[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=2[S:42][CH:43]=1)[C@@H:29]([CH3:37])[CH:30]([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>>[S:42]1[CH:43]=[C:39]([CH2:38][N:28]([C@@H:29]([CH3:37])[CH:30]([O:31][CH2:32][CH3:33])[O:34][CH2:35][CH3:36])[C:26]([C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[NH:12][C:8](=[O:10])[CH2:7][O:6][NH:5][C:4](=[O:11])[NH:3][CH2:1][CH3:2])=[O:27])[C:40]2[CH:47]=[CH:46][CH:45]=[CH:44][C:41]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: CCNC(=O)NOCC(=O)O
Product: CCNC(=O)NOCC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N(Cc1csc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 47 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-((benzo[b]thiophen-3-ylmethyl)((S)-1,1-diethoxypropan-2-yl)amino)-6-oxohexylcarbamate (Compound IV-15) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:21])=[C:6]([Br:20])[CH:7]=[C:8]2[C:12]=1[C@H:11]([CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:2]=C.[O:22]=[O+][O-].[BH4-].[Na+].Cl>CO>[Br:20][C:6]1[CH:7]=[C:8]2[C:12](=[C:4]([CH2:1][CH2:2][OH:22])[C:5]=1[OH:21])[C@H:11]([CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH2:10][CH2:9]2
Reactant: C=CCc1c(O)c(Br)cc2c1[C@H](CCNC(=O)CC)CC2
Reactant: O=[O+][O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(=O)NCC[C@@H]1CCc2cc(Br)c(O)c(CCO)c21
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of (S)-N-[2-(7-allyl-5-bromo-6-hydroxyindan-1-yl)ethyl]propionamide (588 mg, 1.67 mmol.) in methanol (30 mL) was cooled to about −70° C., to which was introduced ozone for 5 minutes. After confirming the disappearance of the starting material, an excess amount of powdery sodium borohydride (510 mg, 13.4 mmol.) was added to reaction mixture at about −70° C. to decompose ozonide. The reaction mixture was warmed to room temperature, which was neutralized with dilute hydrochloric acid, followed by extracting the organic matter with a mixture of ethyl acetate:butanol=1:1. The extract solution was dried over anhydrous magnesium sulfate, from which the solvent was distilled off under reduced pressure. The residue was then washed with diethyl ether to afford the title compound (yield 0.59 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[N:13]=[CH:12][N:11]=2.C(N(CC)CC)C.[CH2:38]([N:40]=[C:41]=[O:42])[CH3:39]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:41]([NH:40][CH2:38][CH3:39])=[O:42])[CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: CCN=C=O
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(N[C@H]4CCCNC4)ncnc32)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)N1CCC[C@H](Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C1
Reaction time: 16 h
Yield: 87.1 %

Procedure:
To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3S)-piperidin-3-yl]-9H-purin-6-amine (16 mg, 0.036 mmol, 1 eq.) in 2 mL of THF was added triethylamine (0.015 mL, 0.109 mmol, 3 eq.) and ethyl isocyanate (0.004 mL, 0.055 mmol, 1.5 eq). The reaction is stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 16 mg (86%) of (3S)-3-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}-N-ethylpiperidine-1-carboxamide. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.06-1.34 (m, 3 H) 1.53-1.95 (m, 4 H) 2.12-2.29 (m, 1 H) 3.07 (br. s., 2 H) 3.32 (br. s., 1 H) 3.72-4.41 (m, 3 H) 5.06 (br. s., 1 H) 6.02 (d, J=6.12 Hz, 1 H) 7.08-7.66 (m, 8 H) 8.45 (br. s., 1 H), [M+H]+ 510.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[CH:21](=O)[CH3:22].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH2:21][CH3:22])[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: CC=O
Reactant: CCc1c(NC2CCOCC2)cc(Cl)cc1C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: CCc1c(C(=O)O)cc(Cl)cc1N(CC)C1CCOCC1
Yield: 86.2 %

Procedure:
To a solution of methyl 5-chloro-2-ethyl-3-[(oxan-4-yl)amino]benzoate (350 mg, 1.18 mmol) in DCE (10 ml) at room temperature and under nitrogen was added acetaldehyde (0.66 ml, 11.75 mmol) followed by acetic acid (0.4 ml, 7.05 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (2.49 g, 11.75 mmol) at room temperature. After stirring for 23 h further acetaldehyde (0.66 ml, 11.75 mmol) was added followed sodium triacetoxyborohydride (2.49 g, 11.75 mmol). After stirring for a further 3 hours deionized water (15 ml) was added and the mixture was neutralized with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×15 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolate cartridge, gradient of eluents; 99:1 Heptane:EtOAc to 85:15 Heptane:EtOAc) to afford the title compound (317 mg) as a 2:1 mixture of methyl and ethyl esters that were used in the next stage.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=12.CI.[C:22](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:22][O:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=12
Reactant: O=C([O-])[O-]
Reactant: Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1cc2c(c3ccccc13)Nc1ccccc1S2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.7 %

Procedure:
To a solution of 5-hydroxy-12H-benzo[a]phenothiazine (2.65 g) and methyl iodide (2.5 ml) in DMF (dimethylformamide) (10 ml) there was added powdered potassium carbonate (2.0 g). The mixture was stirred at room temperature and after 15 minutes, another addition of potassium carbonate (2.0 g) and methyl iodide (2.0 ml) was done. The mixture was stirred for a further 20 minutes, then it was diluted with ethyl acetate (100 ml and washed with water (60 ml) twice, dried and evaporated down. The residue was triturated with ether to afford solid crude product which was filtered (1.7 g). This crude product was chromatographed on a column of silica gel, eluting with dichloromethane to afford pure title compound (1.33 g), m.p. 168°-170° C.
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[CH:15]1([C:18]2[CH:22]=[C:21]([NH2:23])[NH:20][N:19]=2)[CH2:17][CH2:16]1>CCCCO>[Br:8][C:7]1[C:2]([NH:23][C:21]2[CH:22]=[C:18]([CH:15]3[CH2:17][CH2:16]3)[NH:19][N:20]=2)=[N:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][CH:6]=1
Reactant: Brc1cnc(-c2ccccc2)nc1Br
Reactant: Nc1cc(C2CC2)n[nH]1
Solvent: CCCCO
Product: Brc1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 90 °C
Yield: 64 %

Procedure:
To a solution of 4,5-dibromo-2-phenylpyrimidine (0.82 g, 3.29 mmol, 1.0 eq) in n-BuOH (20 mL), 3-cyclopropyl-1H-pyrazol-5-amine (0.811 g, 6.58 mmol, 2 equiv.) was added and the reaction mixture was heated to 90° C. for 24 hours, filtered to produce 5-Bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-phenylpyrimidin-4-amine (Compound 8) (0.75 g, 64.1%). LC-MS (m/z): 357.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6): δ 0.74-0.77 (m, 2H), 0.98-1.02 (m, 2H), 1.96-2.01 (m, 1H), 6.40 (s, 2H), 7.50-7.54 (m, 3H), 8.27-8.30 (m, 2H), 8.63 (s, 1H), 8.88 (s, 2H), 12.32 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:21](=[O:22])[C:20]3[CH:24]=[CH:25][C:17]([F:16])=[CH:18][CH:19]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccc(F)cc1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-fluorobenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 4-fluorobenzoyl chloride in a similar manner as described above to give a white solid (15% yield). 1H-NMR (DMSO-d6): δ 11.03 (s, 1H), 8.90 (d, 1H), 8.05 (m, 2H), 7.61 (d, 1H), 7.34 (d, 2H), 7.30 (s, 1H), 7.17 (dd, 1H), 5.38 (m, 1H), 2.68 (m, 2H), 2.09 (m, 2H), 1.86 (m, 2H); MS m/z 387 (M−1).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)C=C.CN(C)[C:24]1[CH:29]=CC=C[CH:25]=1>C(OCC)(=O)C>[CH2:29]([C:21]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=2)=[CH:6][C:5]=1[OH:4])[CH:24]=[CH2:25]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1cccc(Oc2ccc(C(=O)OC)cc2)c1
Solvent: CCOC(C)=O
Product: C=CCc1ccc(Oc2ccc(C(=O)OC)cc2)cc1O
Yield: 92 %

Procedure:
A solution of methyl 4-(3-allyloxyphenoxy)benzoate in N,N-dimethylaniline was heated at 190° C. for 19 hours, cooled, diluted with ethyl acetate, washed with aqueous hydrochloric acid, dried, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl ether to give a 40:60 mixture of the title compounds as an oil in 92% yield. NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH:28]([CH2:32][C:33]2[CH:43]=[CH:42][C:36]([O:37][CH2:38][C:39](O)=[O:40])=[CH:35][CH:34]=2)[S:27]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH:28]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:37][CH2:38][C:39]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:40])=[CH:42][CH:43]=2)[S:27]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)cc2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 105 %

Procedure:
Using 0.79 g of t-butyl N-[2-amino-5-(4-hydroxyphenoxy)phenyl]-N-methylcarbamate, 0.84 g of 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid, 0.49 g of diethyl cyanophosphonate, 0.30 g of triethylamine and 60 ml of anhydrous tetrahydrofuran, reaction and purification were carried out in a similar manner to that described in Example (2-1), whereby 1.49 g of the desired compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Cl.[N:13]1([CH:28]2[CH2:34][CH:33]3[N:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:30]([CH2:31][CH2:32]3)[CH2:29]2)[CH2:18][CH2:17][C:16]2([C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][NH:20][CH2:19]2)[CH2:15][CH2:14]1>C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:20]2[CH2:19][C:16]3([CH2:17][CH2:18][N:13]([CH:28]4[CH2:29][CH:30]5[N:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:33]([CH2:32][CH2:31]5)[CH2:34]4)[CH2:14][CH2:15]3)[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)N1C2CCC1CC(N1CCC3(CC1)CNCc1ccccc13)C2
Reactant: COc1cccc(B(O)O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)N1C2CCC1CC(N1CCC3(CC1)CN(c1cccc(OC)c1)Cc1ccccc13)C2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of 3-methoxyphenylboronic acid (30 mg, 0.2 mmol), Cu(OAc)2H2O (2 mg, 5 mol %), 3 Å molecular sieves (75 mg) in 1 mL of CH2Cl2 were stirred at room temperature for 5 min. Ethyl 3-(2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate hydrochloride 5c (42 mg, 0.1 mmol) was added to the reaction and mixture was stirred at room temperature for 24 h. The reaction was diluted with methanol, filtered and subjected to reverse-phase HPLC purification (2-50% CH3CN—H2O gradient, with 0.05% TFA, 15 min) to give pure ethyl 3-(2-(3-methoxyphenyl)-2,3-dihydro -1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. LC-MS: m/z [M+H]+ 490.0, retention time 2.61 min (10-90% CH3CN—H2O gradient, with 0.05% TFA, 5 min).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)=[O:7].[C:17]([C:20]1[C:21](=[O:29])[N:22]([CH3:28])[C:23]([CH3:27])=[CH:24][C:25]=1[OH:26])(=[O:19])[CH3:18]>C(O)C>[OH:26][C:25]1[CH:24]=[C:23]([CH3:27])[N:22]([CH3:28])[C:21](=[O:29])[C:20]=1[C:17](=[O:19])[CH:18]=[CH:12][C:11]1[CH:14]=[CH:15][CH:16]=[C:9]([NH:8][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:7])[CH:10]=1
Reactant: COCCOC(=O)Nc1cccc(C=O)c1
Reactant: CC(=O)c1c(O)cc(C)n(C)c1=O
Solvent: CCO
Product: COCCOC(=O)Nc1cccc(C=CC(=O)c2c(O)cc(C)n(C)c2=O)c1
Yield: 60.7 %

Procedure:
According to the same manner as that of Example a-1 except that 1.00 g of 3-[(2-methoxyethoxy)carbonylamino]benzaldehyde was used in place of 3-[(methoxycarbonyl)methoxy]benzaldehyde, 0.742 g of 3-acetyl-4-hydroxy-1,6-dimethyl-2(1H)-pyridinone was used in place of 3-acetyl-4-hydroxy-6-methyl-2(1H)-pyridinone, and 20 ml of ethanol was used in place of pyridine, 0.96 g of 4-hydroxy-3-[3-[3-[(2-methoxyethoxy)carbonylamino]phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (42a)] was obtained as a yellow crystal.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21](Br)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>>[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:6]3[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=3)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: O=Cc1ccc(-c2ccc(Cn3ccnc3)cn2)cc1

Procedure:
Synthesized using 4-formylphenylboronic acid (252 mg, 1.68 mmol) and 1a (200 mg, 0.84 mmol) according to Method C. Brown solid. Yield: 150 mg, 0.57 mmol, 68%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.21 (s, 2H), 6.94 (t, J=1.3 Hz, 1H), 7.14 (t, J=0.9 Hz, 1H), 7.53 (dd, J=8.2, 2.0 Hz, 1H), 7.60 (brs, 1H), 7.79 (dd, J=8.2, 0.6 Hz, 1H), 7.98 (d, J=8.4 Hz, 2H), 8.16 (d, J=8.4 Hz, 2H), 8.63 (d, J=2.0 Hz, 1H), 10.08 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.0, 119.0, 121.2, 127.5, 130.2, 130.5, 131.3, 135.9, 136.7, 137.3, 144.0, 148.8, 156.1, 191.8; MS (ESI): m/z=264.16 [M+H]+.
Reaction SMILES: [CH:1]1(B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:22]1[C:23]([C:51]#[N:52])=[CH:24][CH:25]=[C:26]2[C:34]=1[NH:33][C:32]1[C:31]([CH3:36])([CH3:35])[C:30]3[CH:37]=[C:38]([O:41][CH2:42][C@H:43]4[CH2:47][O:46][C:45]([CH3:49])([CH3:48])[O:44]4)[CH:39]=[CH:40][C:29]=3[C:28](=[O:50])[C:27]2=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.Cl>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]1([C:22]2[C:23]([C:51]#[N:52])=[CH:24][CH:25]=[C:26]3[C:34]=2[NH:33][C:32]2[C:31]([CH3:35])([CH3:36])[C:30]4[CH:37]=[C:38]([O:41][CH2:42][C@H:43]5[CH2:47][O:46][C:45]([CH3:48])([CH3:49])[O:44]5)[CH:39]=[CH:40][C:29]=4[C:28](=[O:50])[C:27]3=2)[CH2:3][CH2:2]1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4c(Br)c(C#N)ccc4c2C3=O)O1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Product: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4c(C5CC5)c(C#N)ccc4c2C3=O)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.2 %

Procedure:
Under nitrogen atmosphere, 2-cyclopropyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (13.2 mg, 78.73 μmol) and potassium phosphate (212.27 mg, 212.0 μmol) were dissolved in water (0.20 mL), and the mixture was stirred at room temperature for 15 min. To the reaction solution, 4-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound U8-1, 30.0 mg, 60.56 μmol), palladium acetate (1.36 mg, 6.056 μmol), and tricyclohexylphosphine (toluene solution, 20 wt %, 17.0 mg, 12.11 μmol) were added and the mixture was stirred at 80° C. for 24 hr. The reaction solution was poured into hydrochloric acid (1 M), extracted with ethyl acetate, washed with saturated aqueous solution of sodium bicarbonate and saturated brine, dried over sodium sulfate, and then filtered. The residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (13.6 mg, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)=[CH:11][C:10]([CH:21]=O)=[N:9]1.[CH3:23][NH2:24].CO.CO.[BH4-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)=[CH:11][C:10]([CH2:21][NH:24][CH3:23])=[N:9]1
Reactant: CN
Reactant: Cc1cccc(Sc2cc(C=O)nn2-c2ccccc2Cl)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNCc1cc(Sc2cccc(C)n2)n(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(2-chlorophenyl)-5-[(6-methylpyridin-2-yl)thio]-1H-pyrazole-3-carbaldehyde (415 mg) in tetrahydrofuran (4 mL) were added 40% methylamine-methanol solution (1.5 mL) and methanol (4 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. Sodium borohydride (905 mg) was added to the reaction mixture at 0° C. and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 450 mg, yield quantitative).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19]([NH:21][C@@H:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][C@@H:23]1[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.O1CCCC1.O>[CH2:11]([O:18][C:19]([NH:21][C@@H:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][C@@H:23]1[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(N[C@H]1CC(O)CC[C@H]1NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C1CC[C@@H](NC(=O)OCc2ccccc2)[C@@H](NC(=O)OCc2ccccc2)C1
Temperature: -40 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
Dimethylsulfoxide (8.2 ml) was added to a solution of oxalyl chloride (9.9 ml) in dichloromethane (90 ml) at −60° C., and a solution of (1R*,2S*)-N1,N2-bis(benzyloxycarbonyl)-4-hydroxy-1,2-cyclohexanediamine (9.2 g) in tetrahydrofuran (90 ml) was added to the mixture in one portion. After 1 hour, the temperature of the mixture was raised to −40° C., and triethylamine (26 ml) was added in one portion. The mixture was heated to room temperature as it is, and stirred for 3 hours. The reaction mixture was poured into water and extracted with methylene chloride. The resultant organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1) to obtain the title compound (8.0 g) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].[C:13]([NH:23][C:24]([CH3:29])([C:26](O)=[O:27])[CH3:25])([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[C:1]([O:5][C:6]([CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:26](=[O:27])[C:24]([NH:23][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])([CH3:29])[CH3:25])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCCN1C(=O)C(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a solution of proline-tert-butyl ester (47) (2.00 g, 12 mmol, in CH2Cl2 (15 ml) was added N-carbobenzyloxy-2-methylalanine (3.05 g, 13 mmol), HOBT (2.36 g, 17 mmol) and EDC: (3.43 g, 18 mmol) and the solution was stirred at room temperature under N2 for 48 hours. The solvent was evaporated, the crude material dissolved in EtOAc and washed with 0.5N NaHSO4 (2×), saturated NaHCO3 (2×) and brine and was dried over anhydrous Na2SO4, filtered and evaporated to give a white solid (4.68 g, 100%). 1H-NMR (500 MHz, CDCl3) δ 1.20-2.15 (m, 4H), 1.43 (s, 9H), 1.59 (d, 6H), 3.21-3.79 (m, 2H), 4.35 (br s, 1H), 4.82-5.19 (m, 3H), 5.74 (br s, 1H), 7.17-7.49 (m, 5H). Analytical HPLC (C18 column) 10.66 min. LC-MS (ES+) m/e=391.3 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[CH3:11])([O-:3])=[O:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16].CN(C)C=O>CO>[CH3:14][N:15]([CH3:17])/[CH:16]=[CH:11]/[C:5]1[CH:6]=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(C)c([N+](=O)[O-])c1
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(/C=C/N(C)C)c([N+](=O)[O-])c1
Yield: 82.6 %

Procedure:
A 12-l. three-necked flask, equipped with a thermometer, a mechanical stirrer and a 60 cm. vacuum-jacketed silvered column with glass helice packing connected to a total-condensation, variable take-off still head with receiver was charged under nitrogen with 675 g (4.46 moles) of 2-nitro-1,4-dimethylbenzene, 736 g (6.17 moles) of N,N-dimethylformamide dimethyl acetal and 3.0 l of N,N-dimethylformamide. The mixture was stirred and heated with a heating mantle for 37 hours. The pot temperature was gradually raised from 130° and 144° while the formed methanol was removed by distillation. The fractionating column was replaced by a distilling head with condenser and receiver (cooled in a dry ice-acetone bath). The dimethylformamide was removed by distillation, first at aspirator vacuum and then at high vacuum (water bath 70°), giving a residue of 924 g (100%) of crude product as a dark red viscous oil. This material was poured into a beaker and mixed thoroughly with 640 ml of methyl alcohol. The mixture was stirred in an ice bath until the product crystallized in mass and was then refrigerated overnight. The precipitate was collected by suction filtration, washed with 320 ml of methyl alcohol and dried in vacuo at room temperature (constant weight) to afford 760 g (83%) of product as a free-flowing, dark-red crystalline solid, m.p. 41.5°-43.5° C.