Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3]C(=O)C1C=C(Br)C=NC=1)C.N1C=CC=C(B(O)O)C=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH:30]1[CH:35]=[CH:34][C:33]([P:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:32][CH:31]=1>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[P:36]([C:33]1[CH:32]=[CH:31][CH:30]=[CH:35][CH:34]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:3]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Referring to Scheme 1 (synthesis of B-1, B-2, B-3 and B-4), synthesis of compound 2, to a 500-mL oven-dried round-bottomed flask with a sidearm and condenser, was added ethyl-5-bromonicotinate (38.0 g, 0.17 mol), 3-pyridineboronic acid (22.5 g, 0.18 mol), and anhydrous 1,4-dioxane (220 mL) under argon. An aqueous solution of K3PO4 (2 M, 182 mL) was added, followed by the addition of Pd(OAc)2 (1.86 g, 8.3 mmol) and PPh3 (8.7 g, 33.0 mmol). The reaction was refluxed for 2 h. while a gentle and steady stream of argon was bubbled through the solution. After cooling to room temperature, the POPh3 crystals which formed were filtered from the biphasic reaction mixture. The aqueous layer was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (1×200 mL), dried over MgSO4, and evaporated under reduced pressure until ˜50 mL remained. To this crude mixture of 1, was added methanol (25 mL) and water (20 mL). After cooling to 0° C., LiOH (8.0 g, 0.33 mmol) was added, and the reaction was stirred for 30 min. at room temperature. The organics were evaporated under reduced pressure. The remaining basic aqueous phase was diluted with water (50 mL) and washed with EtOAc several times until the EtOAc washes remained colorless. The basic water was acidified with KHSO4 (1M) until pH-4. The white precipitate (compound 2) which formed was collected by filtration, washed with water, acetone, and air dried. Further drying under reduced pressure yielded 20.3 g (61%) of white powder. 1H NMR (CD3OD, 500 MHz) δ 7.61 (ddd, J=8.0, 5.0, 0.77 Hz, 1H), 8.23 (ddd, J=8.0, 2.3, 1.6 Hz, 1H), 8.64 (dd, J=5.0, 1.5 Hz, 1H), 8.65 (t, J=2.0 Hz, 1H), 8.92 (dd, J=2.3, 0.66 Hz, 1H), 9.04 (d, J=2.3 Hz, 1H), 9.17 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[N:6]2[C:7](=[O:20])[C:8]([N:11]3[C:15]4[N:16]=[CH:17][N:18]=[CH:19][C:14]=4[CH:13]=[CH:12]3)=[CH:9][CH:10]=[C:5]2[C:4](=[O:21])[NH:3]1.[H][H]>CO.[Pd]>[CH3:1][C:2]1([CH3:22])[N:6]2[C:7](=[O:20])[C:8]([N:11]3[C:15]4[N:16]=[CH:17][N:18]=[CH:19][C:14]=4[CH2:13][CH2:12]3)=[CH:9][CH:10]=[C:5]2[C:4](=[O:21])[NH:3]1
Reactant: CC1(C)NC(=O)c2ccc(-n3ccc4cncnc43)c(=O)n21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)NC(=O)c2ccc(N3CCc4cncnc43)c(=O)n21

Procedure:
To a stirred solution of 3,3-dimethyl-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (1, 0.095 g, 0.32 mmol) in methanol (25 ml), 10% palladium on carbon (25 mg) was added. The reaction mixture was hydrogenated under balloon pressure hydrogen gas for 24 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to obtain a crude residue. The residue was purified by prep HPLC to afford the product as a light yellow solid. Yield: 8.0 mg, 8%; MS (ESI) m/z 298.20 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.15 (s, 1H), 7.96 (d, J=7.4 Hz, 1H), 6.81 (d, J=7.5 Hz, 1H), 4.17 (t, J=8.6 Hz, 2H), 3.13 (t, J=8.6 Hz, 2H), 2.59 (s, 2H), 1.79 (s, 6H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[C:22]([N+:24]([O-])=O)[CH3:23])=[CH:17][C:16]=1[O:27][CH3:28])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>O1CCCC1>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH2:24])[CH3:23])=[CH:17][C:16]=1[O:27][CH3:28])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1cc(C=C(C)[N+](=O)[O-])ccc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CC(C)N)ccc1OCc1ccccc1
Reaction time: 1.5 h
Yield: 93.9 %

Procedure:
To a mixture of 1.03 g (27.1 mmol) of lithium aluminum hydride and 20 ml of anhydrous tetrahydrofuran, an anhydrous tetrahydrofuran solution of 2.70 g (9.03 mmol) of 1-benzyloxy-2-methoxy-4-(2-nitropropenyl)benzene was added dropwise under vigorous stirring over about 90 minutes and refluxed for 2 hours by heating. The reaction mixture was cooled and aqueous sodium hydroxide solution was added thereto. After the precipitates were filtered off with celite-precoated glass filter, the solvent was distilled off from the filtrate under reduced pressure. The residue was extracted with ethyl acetate, washed with saturated brine, dried over potassium carbonate and the solvent was distilled off under reduced pressure to give 2.30 g of crude 2-(4-benzyloxy-3-methoxyphenyl)-1-methylethylamine.
Reaction SMILES: [CH3:1][C:2]([NH2:22])([C:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:8][N:7]([S:10]([CH2:13][CH2:14][CH3:15])(=[O:12])=[O:11])[CH2:6][CH2:5]1)[CH3:3].CCN(C(C)C)C(C)C.[Cl:32][C:33]1[C:41]([F:42])=[CH:40][CH:39]=[C:38]([F:43])[C:34]=1[C:35](Cl)=[O:36]>CN(C=O)C>[Cl:32][C:33]1[C:41]([F:42])=[CH:40][CH:39]=[C:38]([F:43])[C:34]=1[C:35]([NH:22][C:2]([CH3:3])([C:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:8][N:7]([S:10]([CH2:13][CH2:14][CH3:15])(=[O:12])=[O:11])[CH2:6][CH2:5]1)[CH3:1])=[O:36]
Reactant: CCCS(=O)(=O)N1CCC(c2ccccn2)(C(C)(C)N)CC1
Reactant: O=C(Cl)c1c(F)ccc(F)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)N1CCC(c2ccccn2)(C(C)(C)NC(=O)c2c(F)ccc(F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of {1-Methyl-1-[1-(propylsulfonyl)-4-pyridin-2-ylpiperidin-4-yl]ethyl}amine (II-1, 43 mg, 0.13 mmol) in DMF (0.7 mL) was treated with i-Pr2NEt (0.066 mL, 0.38 mmol) and 2-chloro-3,6,-difluorobenzoyl chloride (0.2 mL, 0.8 mmol) and stirred at room temperature for 1.5 h. The reaction mixture was purified directly by reverse phase HPLC to afford 2-chloro-3,6-difluoro-N-{1-methyl-1-[1-(propylsulfonyl)-4-pyridin-2-ylpiperidin-4-yl]ethyl}benzamide (II-2). Analytical LCMS: single peak (214 nm), 2.803 min. 1H NMR (CD3OD, 300 M ) δ 8.67 (d, J=3.9 Hz, 1H), 8.51 (s, 1H), 8.15 (ddd, J=1.8, 7.8, 8.1 Hz, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.60 (dd, J=5.5, 6.9 Hz, 1H), 7.34 (ddd, J=4.8, 9.3, 14.1 Hz, 1H), 7.21 (ddd, J=4.2, 8.4, 12.3 Hz), 1H), 3.76-3.65 (m, 2H), 2.86-2.78 (m, 4H), 2.69-2.54 (m, 2H), 2.25-2.15 (m, 2H), 1.76-1.63 (m, 2H), 1.43 (s, 6H), 0.98 (t, J=7.2 Hz, 3H); RMS m/z 500.1572 (C22H28ClF2N3O3S+H+ requires 500.1581).
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH2:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:17][NH:18][C:19]([NH2:21])=[NH:20])[CH3:7].[CH2:22]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[CH2:33][NH:34][C:35]([NH2:37])=[NH:36])[CH3:23]>C(O)(=O)C.S(=O)(=O)(O)O.[Pd].S([O-])([O-])(=O)=O.[Ba+2]>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH2:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[CH2:17][NH:18][C:19]([NH2:21])=[NH:20])[CH3:7].[CH2:22]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH:25]1[CH2:33][NH:34][C:35]([NH2:37])=[NH:36])[CH3:23]
Reactant: CCn1c(CNC(=N)N)cc2ccccc21
Agent: [Pd]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Product: CCN1c2ccccc2CC1CNC(=N)N

Procedure:
A solution of 26.5 g of 1-ethyl-2-guanidinomethylindole hemisulphate (obtainable from ethyl indole-2-carboxylate via ethyl 1-ethyl-indole-2-carboxylate, 1-ethyl-2-hydroxymethyl-indole, 1-ethyl-2-chloromethyl-indole, 1-ethyl-2-phthalimidomethyl-indole and 1-ethyl-2-aminomethyl-indole) in a mixture of 300 ml of acetic acid and 70 ml of 2 N sulphuric acid is hydrogenated at 60° C. with 10 g of palladium/barium sulphate (5%) under normal pressure. After the absorption of hydrogen has ceased, the solution is filtered. The filtrate is evaporated and 1-ethyl-2-guanidinomethylindoline hemisulphate is obtained, m.p. 199° C.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[NH2:25][CH2:26][CH2:27][C:28]1[N:32]=[CH:31][NH:30][CH:29]=1>C(O)CCC>[NH:30]1[CH:29]=[C:28]([CH2:27][CH2:26][NH:25][C:2]2[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[CH:10]=3)=[O:7])=[C:4]([CH3:24])[N:3]=2)[N:32]=[CH:31]1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: NCCc1c[nH]cn1
Solvent: CCCCO
Product: Cc1nc(NCCc2c[nH]cn2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 60 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 93 mg of histamine in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield 6-(2-(1H-imidazol-4-yl)ethylamino)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide. MS (Q1) 433.0 (M)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[N:3]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](B2OC(C)(C)C(C)(C)O2)=[N:20]1>>[NH:19]1[C:27]2[C:22](=[C:23]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([N:12]4[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]4)[N:3]=3)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[N:20]1
Reactant: CN1CCN(c2nc(Cl)nc3c2cnn3C)CC1
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Product: CN1CCN(c2nc(-c3cccc4[nH]ncc34)nc3c2cnn3C)CC1

Procedure:
6-Chloro-1-methyl-4-(4-methyl-piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine was reacted with indazole boronic acid pinacol ester using General Procedure A. Purification on silica yielded 148. NMR (CDCl3): 2.41 (3H, s), 2.60-2.66 (4H, m), 4.15-4.19 (7H, m), 7.50-7.53 (1H, m), 7.61 (1H, d), 8.00 (1H, s), 8.41 (1H, d), 9.13 (1H, s). MS: (ESI+) MH+=349
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CCCCCC.CN(C)[CH:30]=[O:31]>C1COCC1.ClCCl.O>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[O:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:30]=[O:31]
Reactant: Brc1cccc(CCOC2CCCCO2)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1cccc(CCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.14 g (7.52 mmol) 2-[2-(3-Bromo-phenyl)-ethoxy]-tetrahydro-pyran in 9 ml dry THF were cooled to −78 C and treated dropwise with 9.87 ml of 1.6M solution of butyl lithium in hexane (15.79 mmol). After stirring for 30 min, 2.31 g (31.58 mmol) N,N-dimethylformamide were added dropwise and stirring was continued for another 15 min at −78 C. The mixture was slowly warmed to room temperature and stirred for and another 60 min. Water and dichloromethane were added, the organic phase separated, and the aqueous phase extracted several times with dichloromethane. The combined organic phases were dried, evaporated and the residue purified by chromatography on silica in ethyl acetate heptane mixtures. Yield 1.66 g of the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19](Cl)[N:18]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([O:35][CH3:36])[CH:29]=1>>[CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([O:35][CH3:36])[CH:29]=3)[N:18]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(-c2ccnc(Cl)n2)cc1)OCc1ccccc1
Reactant: COc1cc(CCN)ccc1O
Product: COc1cc(CCNc2nccc(-c3ccc(NC(=O)OCc4ccccc4)cc3)n2)ccc1O

Procedure:
Intermediate 48 was coupled with 4-(2-Amino-ethyl)-2-methoxy-phenol following procedure F. LC-MS showed the product had the expected M+H+ of 471. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.28 (m, 1H) 8.0 (d, 2H) 7.5 (d, 2H) 7.4 (m, 4H) 7.05 (s, 1H) 6.9 (d, 1H) 6.83 (m, 1H) 6.7 (m, 2H) 5.55 (br s, 1H) 5.21 (s, 2H) 3.81 (s, 3H) 3.7 (t, 2H) 2.9 (t, 2H).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C:16](NC)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33].N[CH2:35][C@H](O)C.CN1CCOCC1>>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C@H:16]([OH:17])[CH3:35])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33]
Reactant: CNC(=O)CNC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Reactant: C[C@@H](O)CN
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)NC[C@@H](C)O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Yield: 55 %

Procedure:
The title compound was prepared by a procedure similar to the one described for 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-{1-[(methylamino)carbonyl]methyl}benzamide using (R)-(−)-1-amino-2-propanol (0.16 mL 2.5 mmol) as the amine and without the addition of a second equivalent of N-methylmorpholine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (377.8 mg, 55%) as beige solid. 1H-NMR (CD3OD, 400 MHz) δ 8.32 (s, 1H), 7.93 (dd, 1H, J=1.6 Hz), 7.77 (d, 1H, J=1.6 Hz), 7.62 (m, 1H), 7.53 (d, 1H, J=8 Hz), 7.01 (m, 2H), 5.60 (q, 2H, J=12.4 Hz), 3.93 (m, 1H), 3.32 (m, 2H), 2.19 (s, 3H), 1.18 (d, 3H, J=6.4 Hz); ES-HRMS m/z 508.0687 (M+H C22H21BrF2N3O4 requires 508.0678).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:22]3[C:35]4[C:36]5=[C:37]6[C:32](=[CH:33][CH:34]=4)[CH:31]=[CH:30][CH:29]=[C:28]6[CH:27]=[CH:26][C:25]5=[CH:24][CH:23]=3)[C:10]3[CH2:11][C:12]4[C:17]([C:18]=3[C:19]=2[C:20]#[N:21])=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].C1C[O:43]CC1>>[O:43]=[C:11]1[C:10]2[C:9]([C:22]3[C:35]4[C:36]5=[C:37]6[C:32](=[CH:33][CH:34]=4)[CH:31]=[CH:30][CH:29]=[C:28]6[CH:27]=[CH:26][C:25]5=[CH:24][CH:23]=3)=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:19]([C:20]#[N:21])[C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccc3ccc4cccc5ccc2c3c45)c2c1-c1ccccc1C2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccc3ccc4cccc5ccc2c3c45)c2c1-c1ccccc1C2=O
Temperature: 2.5 °C

Procedure:
A solution of 3-(piperidin-1-yl)-1-(pyren-1-yl)9H-fluorene-4-carbonitrile (474 mg) in THF was added sodium hydride (48 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Yellow solid; mp 220-222° C.; MS (FAB) 488 (M+); IR (KBr) 2218 (CN), 1708 cm−1 (CO).
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[C:9]([O-:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[CH:14]1[N:15]=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.CN.S(=O)(=O)(O)O.[OH-].[Na+]>>[CH3:14][NH:15][C@H:8]([C:9]([OH:11])=[O:10])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Reactant: O=C([O-])C(=O)Cc1ccccc1
Agent: CN
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)O
Product: CN[C@@H](Cc1ccccc1)C(=O)O

Procedure:
In a 50-mL beaker, 5.88 ml of 40 mM Tris-hydrochloride buffer (pH 8.0) containing 60 mg of sodium phenylpyruvate, 2.3 mg of NADPH, 35 U of glucose dehydrogenase, and 1 g of glucose was placed, to which 5.88 mL of 240 mM methylamine adjusted to pH 8.0 with sulfuric acid and 3.25 mL of the above cell-free extract were added, and the mixture was allowed to react at 30° C. The reaction was conducted while stirring and adjusting pH to 8.0 with 1 N aqueous sodium hydroxide solution. A portion of the reaction solution was analyzed by HPLC at regular intervals. When the substrate sodium phenylpyruvate was depleted, an additional 30 mg was added and the reaction was continued. This process was repeated 8 times during the reaction of 24 hours. Upon completion of the reaction, the amount of N-methylphenylalanine produced was 146 mg.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH:15]1([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:17][CH2:16]1>>[CH:15]1([N:18]2[CH2:23][CH2:22][N:21]([C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:11])[CH2:20][CH2:19]2)[CH2:17][CH2:16]1
Reactant: C1CN(C2CC2)CCN1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Agent: Cl
Product: O=C([C@@H]1C[C@H]1c1ccccc1)N1CCN(C2CC2)CC1

Procedure:
This example was prepared according to Example 4 employing trans-2-phenyl-1-cyclopropanecarbonyl chloride and 1-cyclopropylpiperazine dihydrochloride, which was prepared according to Gillaspy, et. al. Tetrahedron Lett. 1995, 36 (41), 7399-7402. m/z (ES+) M+1=271.2; HPLC tR=1.43 min. 1H NMR (500 MHz, CDCl3) δ 7.29-7.26 (m, 2H), 7.19 (d, J=7.3 Hz, 1H), 7.11 (d, J=7.0 Hz, 2H), 3.69-3.50 (m, 4H), 2.59 (t, J=5.2 Hz, 4H), 2.48 (ddd, J=8.9, 6.3, 4.3 Hz, 1H), 1.96 (ddd, J=8.2, 5.5, 4.3 Hz, 1H), 1.68-1.59 (m, 2H), 1.26 (ddd, J=8.4, 6.3, 4.3 Hz, 1H), 0.49-0.44 (m, 2H), 0.44-0.38 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1(OC)[CH2:15][CH2:14][C:13]([O:21]C)([CH:16]([O:19][CH3:20])[O:17][CH3:18])[O:12]1.CC(C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[CH2:15][CH2:14][C:13](=[O:21])[CH:16]([O:19][CH3:20])[O:17][CH3:18]
Reactant: COC(=O)CCCCCCCC1(OC)CCC(OC)(C(OC)OC)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)CCCCCCCC(=O)CCC(=O)C(OC)OC
Yield: 93.7 %

Procedure:
8-(2,5-Dimethoxy-5-dimethoxymethyl-tetrahydro-2-furyl)-octanoic acid methyl ester (1.00 g, 0.0028 mole), 20 ml of acetone and p-toluenesulfonic acid (0.002 g) were stirred for 2 hours at room temperature. The clear solution was poured into cold water (100 ml, 0° C) and extracted with two 50-ml portions of ether. The combined ethereal extracts were washed with 6% aqueous sodium hydrogen carbonate (30 ml) and then with two 50-ml portions of water, dried with magnesium sulfate, and evaporated to dryness from a water bath (60° C), at last under 15 mm Hg. The distillation of residual oil gave 0.83 g (95%) of the title compound, b0.1 154°-156° C, nD25 1.4531.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1>ClCCl.C(OCC)(=O)C>[CH:24]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.3 %

Procedure:
A Dess-Martin reagent (7.89 g) was added to a solution of tert-butyl 4-hydroxymethylpiperidine-1-carboxylate (4.00 g) in dichloromethane (40 ml), and the mixture was stirred for 1.5 hours at room temperature. After diluting with ethyl acetate, the reaction solution was washed with a 1% aqueous solution of sodium hydroxide and a brine successively. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1) to yield tert-butyl 4-formylpiperidine-1-carboxylate (2.43 g) as a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:31]=[CH:30][C:10]3[NH:11][C:12]([C:14]4[C:22]5[C:17](=[CH:18][CH:19]=[C:20]([NH2:23])[CH:21]=5)[N:16]([CH:24]5[CH2:29][CH2:28][CH2:27][CH2:26][O:25]5)[N:15]=4)=[N:13][C:9]=3[CH:8]=2)[CH2:3][CH2:2]1.N1(O)C2C=CC=CC=2N=N1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[CH:51]1([C:54](O)=[O:55])[CH2:53][CH2:52]1>CN(C=O)C>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:31]=[CH:30][C:10]3[NH:11][C:12]([C:14]4[C:22]5[C:17](=[CH:18][CH:19]=[C:20]([NH:23][C:54]([CH:51]6[CH2:53][CH2:52]6)=[O:55])[CH:21]=5)[N:16]([CH:24]5[CH2:29][CH2:28][CH2:27][CH2:26][O:25]5)[N:15]=4)=[N:13][C:9]=3[CH:8]=2)[CH2:5][CH2:6]1
Reactant: O=C(O)C1CC1
Reactant: Nc1ccc2c(c1)c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2c(c1)c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1)C1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.1 %

Procedure:
3-(5-Morpholino-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (30 mg, 0.072 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (14.53 mg, 0.108 mmol), EDC (20.61 mg, 0.108 mmol) and sodium bicarbonate (6.02 mg, 0.072 mmol) was added to a solution of cyclopropanecarboxylic acid (6.17 mg, 0.072 mmol) in DMF (6 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash column chromatography (6% CH3OH/CH2Cl2) afforded the title compound (20 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.47 (d, 1H, J=1.6 Hz), 7.75 (dd, 1H, J=2.0 and 9.2 Hz), 7.67 (d, 1H, J=8.8 Hz), 7.55 (d, 1H, J=8.4 Hz), 7.14 (m, 1H), 7.05 (dd, 1H, J=2.0 and 8.4 Hz), 5.86 (dd, 1H, J=2.4 and 9.6 Hz), 3.98 (m, 1H), 3.87 (m 4H), 3.81 (m, 1H), 3.16 (m, 4H), 2.64 (m, 1H), 2.14 (m, 2H), 1.81 (m, 2H), 1.71 (m, 2H), 0.99 (m, 2H), 0.88 (m, 2H); ESI-MS [M+H]+:487.22.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:14])[CH:5]=1.C(N(C(C)C)CC)(C)C.Br[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]([OH:36])[CH:27]=1>CN(C)C=O.Cl.C(OCC)(=O)C>[ClH:1].[OH:14][C:6]1[CH:5]=[C:4]([CH2:3][NH:2][CH2:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]([OH:36])[CH:27]=2)[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(CBr)cc1O
Reactant: COC(=O)c1ccc(CN)cc1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CNCc2ccc(C(=O)OC)c(O)c2)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.1 %

Procedure:
Dissolved methyl 4-aminomethyl-2-hydroxybenzoate hydrochloride (13.07 g, 60.1 mmole) and diisopropylethylamine (28.0 mL, 292 mmole) in 225 mL of N,N-dimethylformamide by heating slightly until a solution was obtained. Allowed the solution to cool to room temperature and added methyl 4-bromomethyl-2-hydroxybenzoate (9.81 g, 40.0 mmole). The reaction was stirred for 1 day at room temperature. The solution was diluted with 200 mL of 1N HCl and 250 mL of ethyl acetate and allowed to cool to room temperature. Precipitate was collected by filtration, washed with ethyl acetate and dried in vacuo under a under high vacuum. Obtained 11.32 grams (74% yield) of product as a white solid.