Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:25][C:26](OC(C)(C)C)=[O:27])[C:10](=[O:24])[N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl.CCN(C(C)C)C(C)C.[N:43]1([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:45][C@H:44]1C(O)=O.CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:25][C:26]([C@@H:44]2[CH2:45][C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:52][N:43]2[C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])=[O:27])[C:10](=[O:24])[N:11]2[CH2:12][CH2:13][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:15][CH2:16]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(Cc2ccccn2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(Cc2ccccn2)CC1

Procedure:
tert-Butyl 3-(N-{(1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-[4-(2-pyridylmethyl)-piperazinyl]ethyl}carbamoyl)-(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared from N-{(1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-[4-(2-pyridylmethyl)piperazinyl]ethyl}(tert-butoxy)carboxamide (Step 1) (270 mg, 0.58 mmol) according to the procedure used for Example 93, Step 2 using 25 mL HCl satd EtOAc, for the first step, then DIEA (100 μl, 0.574 mmol), Boc-L-Tic-OH (82 mg, 0.296 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (101 mg, 0.340 mmol), and HOAT (50 mg, 0.367 mmol) for the second step (139 mg). MS (ESI, pos. ion) m/z: 618 (M+H), (ESI, neg. ion) m/z: 616 (M−H). Calc'd for C34H40ClN5O4: 618.17.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][CH2:45][OH:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:41]3[CH2:42][CH2:43][N:38]([CH2:44][CH2:45][OH:46])[CH2:39][CH2:40]3)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OCCN1CCNCC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCO)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-ethanol (Chemical Dynamics) to give the title compound. HR-MS (ES, m/z) calculated for C34H42N6O3Cl2 [(M+H)+] 653.2768 observed 653.2766.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][N:3]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1>ClCCl.CC1C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)=[CH:4][N:3]=1
Reactant: C1=COCCC1
Reactant: OCc1ccc(Br)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Brc1ccc(COC2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.7 %

Procedure:
To a solution of 2-bromo-5-hydroxymethylpyridine (4 Scheme 27, 7.3 g, 38.8 mmol) and 3,4-dihydro-2H-pyran (3.6 g, 42.7 mmol) in dichloromethane (150 mL) was added p-TsOH (200 mg) and the mixture was stirred for 5 h at room temperature. The reaction mixture was concentrated and purified by column chromatography (1:5 ethyl acetate/hexanes) to give the desired compound as a liquid (10 g, 95%); 1H NMR (300 MHz, CDCl3) δ 1.42-1.81 (6 H), 3.48 (m, 1 H), 3.80 (m, 1 H), 4.43 (m, 1 H), 4.62-4.73 (2 H), 7.42 (m, 1 H), 7.53 (m, 1 H), 8.30 (m, 1 H); 13C NMR (75 MHz, CDCl3) 19.5, 25.5, 30.6, 62.5, 65.8, 98.3, 128.0, 133.5, 138.4, 141.3, 149.7. HRMS (EI) calcd for C11H14BrNO2 271.0208 and 273.0187, found 271.0207 and 273.0171.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:31]=3[C:32](O)=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12>>[CH3:2][O:3][C:4](=[O:16])[C@@H:5]([NH:6][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:30]=1[NH:29][S:26]([C:22]1[C:19]2=[N:20][S:21][N:17]=[C:18]2[CH:25]=[CH:24][CH:23]=1)(=[O:28])=[O:27])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(F)c(Br)c1)NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
The title compound was prepared from 3-bromo-4-fluoro-L-phenylalanine methyl ester hydrochloride and 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoic acid as in Example 1, Part C. HPLC: RT=10.36 min. MS (ESI−): mass calcd. for C23H17BrClFN4O5S2, 627.89; m/z found, 625/627 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.46 (s, 1H), 8.37 (dd, J=7.0, 0.8, 1H), 8.22 (dd, J=8.8, 0.9, 1H), 7.75-7.68 (m, 2H), 7.32-7.14 (m, 2H), 7.09-6.88 (m, 3H), 6.53 (d, J=6.8, 1H), 4.98-4.90 (m, 1H), 3.82 (s, 3H), 3.24-3.10 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[N:7]([CH3:33])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH:30]([CH3:32])[CH3:31])[N:9]=3)[CH2:2]1.[CH3:34][C:35]1([O:38][CH2:37]1)[CH3:36].CN(C=O)C>O>[CH:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([O:5][CH:3]4[CH2:4][N:1]([CH2:34][C:35]([CH3:37])([OH:38])[CH3:36])[CH2:2]4)[N:7]3[CH3:33])=[C:12]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)([CH3:31])[CH3:32]
Reactant: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(OC3CNC3)n(C)c2n1
Reactant: CC1(C)CO1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(OC3CN(CC(C)(C)O)C3)n(C)c2n1
Temperature: 60 °C

Procedure:
The mixture of 4-(8-(azetidin-3-yloxy)-2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine (46.3 mg), isobutylene oxide (0.0183 mL), DMF (0.75 mL) and water (0.25 mL) was heated at 60° C. for 3 h. The contents were concentrated. Diluted aqueous Na2CO3 solution was added. The mixture was extracted with DCM (2×). The DCM extracts were dried with Na2SO4. The crude was purified with HPLC to give the product (17.2 mg). 1H NMR (400 MHz, CDCl3) δ 7.83 (dd, J=6.9, 2.0 Hz, 1H), 7.77 (dd, J=6.8, 1.9 Hz, 1H), 7.25-7.20 (m, 2H), 5.41 (p, J=5.8 Hz, 1H), 4.21 (s, 4H), 3.95 (ddd, J=20.5, 14.5, 7.9 Hz, 3H), 3.87-3.79 (m, 4H), 3.61 (s, 3H), 3.48-3.37 (m, 2H), 2.56 (s, 2H), 1.44 (d, J=6.8 Hz, 6H), 1.17 (s, 6H). LCMS: M+H+=521.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:21]([CH3:26])[C:22]([O:24]C)=[O:23])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:21]([CH3:26])[C:22]([OH:24])=[O:23])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2

Procedure:
Prepared analogously to Example 6 from methyl 2-(2-p-chlorobenzenesulphonamido-indan-5-yl)-propionate by hydrolysis with sodium hydroxide.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:17][OH:18])[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[N:10]([CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:12][N:13]=2)[CH2:4]1.[CH:19]([C:22]1[CH:23]=[N:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1)([CH3:21])[CH3:20].C(N(CC)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[OH:18][CH2:17][C:3]1([NH:2][C:28]([C:25]2[N:24]=[CH:23][C:22]([CH:19]([CH3:21])[CH3:20])=[CH:27][N:26]=2)=[O:29])[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[N:10]([CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:12][N:13]=2)[CH2:4]1
Reactant: CC(C)c1cnc(C(=O)O)nc1
Reactant: NC1(CO)CCN(c2nccn3cccc23)C1
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1cnc(C(=O)NC2(CO)CCN(c3nccn4cccc34)C2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
To a suspension of (±)-(3-amino-1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)methanol hydrochloride salt (62 mg, 0.2 mmol) and 5-isopropylpyrimidine-2-carboxylic acid (40 mg, 0.22 mmol) in DMF (5 mL) was added diethylisopropyl amine (650 mg, 5 mmol), followed by HATU (76 mg, 0.2 mmol). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solutions of KH2PO4 and NaHCO3, followed by brine. The organic layer was concentrated in vacuo and the residue purified by reverse phase HPLC (acetonitrile-H2O with 0.1% TFA as eluent) to give 25 mg of the title compound (32% yield) as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH3:28])[C:4]([C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]2[C:18]3[CH:19]=[C:20]([CH3:22])[O:21][C:17]=3[CH:16]=[C:15]([C:23]([O:25]CC)=O)[CH:14]=2)=[CH:8][N:7]=1)=[O:5])[CH3:2].[CH3:29][C:30]1[N:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=1.[Cl-].C[Al+]C>>[CH2:1]([N:3]([CH3:28])[C:4]([C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]2[C:18]3[CH:19]=[C:20]([CH3:22])[O:21][C:17]=3[CH:16]=[C:15]([C:23](=[O:25])[NH:36][C:33]3[CH:32]=[N:31][C:30]([CH3:29])=[CH:35][N:34]=3)[CH:14]=2)=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Oc2cnc(C(=O)N(C)CC)nc2)c2cc(C)oc2c1
Reactant: Cc1cnc(N)cn1
Agent: C[Al+]C
Agent: [Cl-]
Product: CCN(C)C(=O)c1ncc(Oc2cc(C(=O)Nc3cnc(C)cn3)cc3oc(C)cc23)cn1
Yield: 60.3 %

Procedure:
The title compound (5) was prepared by a method analogous to that described in Example 1 using ethyl 4-(2-(ethyl(methyl)carbamoyl)pyrimidin-5-yloxy)-2-methylbenzofuran-6-carboxylate (I-5a: 99 mg, 0.26 mmol), 5-methyl-2-aminopyrazine (84 mg, 0.77 mmol), dimethylaluminium chloride (1.29 mmol, 1M in hexane) and dimethylethere (4.5 mL) to afford N-ethyl-N-methyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide (5: 70 mg, 61%) as an off white solid.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[C:18]2[N:19]([CH:23]=[CH:24][N:25]=2)[CH:20]=[CH:21][CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[CH2:9]([O:16][C:17]1[C:18]2[N:19]([C:23]([I:1])=[CH:24][N:25]=2)[CH:20]=[CH:21][CH:22]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ccc(COc2cccn3ccnc23)cc1
Solvent: CC#N
Product: Ic1cnc2c(OCc3ccccc3)cccn12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
As shown in FIG. 6, N-iodosuccinimide (7.0 g, 31.2 mmol) was added to a solution of 8-benzyloxy-imidazo[1,2-α]pyridine (Example 19) 24 (7.0 g, 31.2 mmol) in dry acetonitrile (100 mL) at 0° C. The reaction was warmed to room temperature and then stirred for 12 hours. The mixture was filtered and the cake washed with acetonitrile and water and dried under high vacuum to afford 8-benzyloxy-3-iodo-imidazo[1,2-α]pyridine 31 as colorless solid. 9.0 g, 83%, yield.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:15][C:14]([O:16][CH3:17])=[CH:13][C:12]2=[O:18])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:30]=[CH:29][N:28]([CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])[N:27]=1.C(N(CC)C(C)C)(C)C>C1C=CC=CC=1.CN(C)C=O.ClCCl>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:15][C:14]([O:16][CH3:17])=[CH:13][C:12]2=[O:18])[C:8]([NH:25][C:26]2[CH:30]=[CH:29][N:28]([CH2:31][C:32]([OH:34])([CH3:33])[CH3:35])[N:27]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)O)C1
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.9 %

Procedure:
A solution of (S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (643 mg, 2.53 mmol) in benzene (8 mL) was treated with oxalyl chloride (342 mg, 2.7 mmol), and N,N-dimethylformamide (1 drop). Effervescence was observed. The reaction mixture was stirred for 3 h at 25° C., under nitrogen. The reaction mixture was concentrated, and dissolved in dichloromethane (8 mL) and treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 442 mg, 2.8 mmol), and N,N-diisopropylethylamine (497 mg, 3.8 mmol). The reaction mixture was stirred at 25° C., under nitrogen for 18 h. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium chloride solution and dried. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 80 g; 0% to 10% methanol/dichloromethane) to afford (S)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (542 mg, 55%) as an off-white powder: LR-ES-MS m/z calculated for C20H30N4O4 [M]+ 390, observed [M+H]+ 391; 1H NMR (DMSO-d6, 300 MHz) δ ppm 1.04 (s, 3 H), 1.06 (s, 3H), 1.08 (m, 1H), 1.26 (m, 1H), 1.44 (m, 2H), 1.50-1.86 (m, 7H), 3.78 (s, 3H), 3.88 (s, 2H), 3.95 (d, Jgem=18.0 Hz, 1H), 4.33 (d, Jgem=18.0 Hz, 1H), 4.66 (s, 1H), 4.78 (dd, J=4.6 Hz, 10.6 Hz, 1H), 5.15 (s 1H), 6.42 (d, J=2.3 Hz, 1H), 7.52 (d, J=2.3 Hz, 1H), 10.70 (s, 1H).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH3:4].C([Li])CCC.[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([O:42][CH2:43][C:44]#[CH:45])[C:37]=1[O:38][CH2:39][C:40]#[CH:41])[CH:33]=O>C(OCC)C>[Cl:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:2][CH2:3][CH3:4])[CH:35]=[C:36]([O:42][CH2:43][C:44]#[CH:45])[C:37]=1[O:38][CH2:39][C:40]#[CH:41]
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C#CCOc1cc(C=O)cc(Cl)c1OCC#C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: C#CCOc1cc(C=CCC)cc(Cl)c1OCC#C
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
n-Propyltriphenylphosphonium bromide (4.66 g) was dissolved in dry diethyl ether (50 ml), and n-butyl lithium (7.6 ml; 1.6N) was added thereto at 0° C. under nitrogen stream, followed by stirring at room temperature for 3 hours. A solution of 3-chloro-4,5-dipropargyloxybenzaldehyde (3.0 g) in dry diethyl ether (50 ml) was dropwise added to the resultant mixture, which was stirred at room temperature overnight, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using toluene as an eluent to give 1-(3-chloro-4,5-dipropargyloxyphenyl)butene (2.7 g). nD25.0 1.5602.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([SH:12])[C:5]2[CH:11]=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1.[CH3:13]I>[OH-].[K+]>[NH2:1][C:2]1[N:3]=[C:4]([S:12][CH3:13])[C:5]2[CH:11]=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: Nc1nc(S)c2cccnc2n1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Product: CSc1nc(N)nc2ncccc12

Procedure:
2-Amino-4-mercaptopyrido[2,3-d]pyrimidine (1.78 gm; 10 mmol) is dissolved in aqueous potassium hydroxide solution (1.0 gm of KOH in 25 ml of H2O), and 1 ml of methyl iodide is added at ambient temperature with stirring. After 30 minutes' reaction, the precipitated substance is subjected to suction filtration, triturated with a small amount of ethanol, and dried.
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][CH2:8][S:9]([OH:12])(=[O:11])=[O:10])[CH2:5][CH2:4]O[CH2:2]1.[CH3:13][C:14]1[N:19](C)N(C2C=CC=CC=2)C(=O)C=1N.P(OCC(O)CO)(O)(O)=O.[N-]=[N+]=[N-].[Na+].C[C@@H]([C@@H]1[C@@]2(C)[C@@H](O)C[C@@H]3[C@@]4(C)CC[C@@H](O)C[C@H]4C[C@@H](O)[C@@]3(C)[C@@H]2CC1)CCC([O-])=O.[Na+].C(OC1C=CC=CC=1)CCCCCCCC.C(OCCCCCCCCCCCC)CCCCCCCCCCC>OCC(CO)O>[CH2:2]1[N:19]([CH2:14][CH2:13][S:9]([OH:12])(=[O:11])=[O:10])[CH2:4][CH2:5][N:6]([CH2:7][CH2:8][S:9]([OH:12])(=[O:11])=[O:10])[CH2:1]1
Reactant: O=S(=O)(O)CCN1CCOCC1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Agent: CCCCCCCCCCCCOCCCCCCCCCCCC
Agent: CCCCCCCCCOc1ccccc1
Agent: C[C@H](CCC(=O)[O-])[C@H]1CC[C@@H]2[C@]1(C)[C@@H](O)C[C@@H]1[C@@]3(C)CC[C@@H](O)C[C@H]3C[C@@H](O)[C@@]21C
Solvent: OCC(O)CO
Product: O=S(=O)(O)CCN1CCN(CCS(=O)(=O)O)CC1

Procedure:
MES (Dojindo Laboratories); EMSE (Daito Chemix Corporation); 4-aminoantipyrine (Saikyo Kasei), CEBP-M (enzyme having an activity of lipoprotein lipase; Asahi Kasei Corporation); GYK-301 (glycerol kinase; Toyobo Co., Ltd.); GPOM (glycerol 3-phosphate oxidase; Asahi Kasei Corporation), catalase (Sigma), peroxidase (Toyobo Co., Ltd.), sodium azide (Kanto Chemicals Co., Inc.), Emulgen B66 (Kao Corporation), Newcol 610 (Nippon Nyukazai Co., Ltd.), Newcol 2608F (Nippon Nyukazai Co., Ltd.), New Calgen GP120 (Takemoto Oil & Fat, Co. Ltd.), NIKKOL R1020 (Nikko Chemicals Co., Ltd.), Emulgen A60 (Kao Corporation), BLAUNON DSP12.5 (Aoki Oil Industrial Co., Ltd.), HI-TENOL N08 (Daichi Kogyo Co., Ltd.), Emulgen L40 (Kao Corporation), Newcol 707SF (Nippon Nyukazai Co., Ltd.), Wondersurf S1400 (Aoki Oil Industrial Co., Ltd.), New Calgen E150 (Takemoto Oil & Fat, Co. Ltd.), Sodium cholate (Acros), Emulgen 909 (POE nonylphenyl ether HLB 12.4; Kao Corporation), Emulmin NL70 (POE lauryl ether HLB 12.4; Sanyo Chemicals Industries, Ltd.).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1.S(=O)(=O)(O)O.[CH3:19]O>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:19])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc2c(c1)C(=O)CC2
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2c(c1)C(=O)CC2
Temperature: 0 °C
Yield: 58 %

Procedure:
3-Oxo-2,3-dihydro-1H-indene-5-carboxylic acid (16.0 g, 90.909 mmol, 1.0 eq.) was dissolved in MeOH (140 ml) and cooled to 0° C.; sulfuric acid (4.5 ml) was added and the mixture was refluxed for 4 hours. The solvent was concentrated under reduced pressure, and the residue was taken up in water, rendered basic with sat. sodium hydrogen carbonate solution (200 ml) and extracted with ethyl acetate (2×400 ml). The combined org. phases were washed with water and sat. NaCl solution (in each case 2×200 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 15% ethyl acetate in hexane). Yield: 58% (10.0 g, 52.63 mmol)
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([O:17]C)=[C:11]2[CH:10]=[C:9]1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-].Cl>CN(C=O)C>[CH2:1]([N:8]1[C:12]2[N:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccnc2c1cc(C)n2Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cc2c(O)ccnc2n1Cc1ccccc1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
To a solution of compound 1-benzyl-4-methoxy-2-methyl-1H-pyrrolo[2,3-b]pyridine 6 (0.45 g, 1.78 mmol) in anhydrous DMF (10 mL) was added NaSMe (0.37 g, 5.35 mmol) under N2. The reaction mixture was stirred at 80° C. for 45 min. After cooling, the mixture was poured into a saturated solution of NH4Cl (20 mL), and 1 N HCl (3-4 mL) was added until pH 4-5. The resultant mixture was extracted with EtOAc (5×30 mL), the combined organic extracts were washed with H2O (2×10 mL) and dried (Na2SO4). The solvent was removed under reduced pressure, and the residue was chromatographed on a silica gel column using 5% methanol in CH2Cl2 as eluent to give 7 as an amorphous white solid. Yield: 0.30 g, 70%; ESI MS: m/z 238.9 (M+1).
Reaction SMILES: [C:1]([C:9]1[CH:38]=[CH:37][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]4[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[O:29][C:28]4=[O:36])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][O:40][NH2:41]>>[CH3:39][O:40][N:41]=[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:38]=[CH:37][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH:27]4[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[O:29][C:28]4=[O:36])=[CH:24][CH:25]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1
Reactant: O=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC2C(=O)Oc3ccccc32)cc1
Reactant: CON
Product: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC2C(=O)Oc3ccccc32)cc1

Procedure:
Starting from the compound obtained in Step A, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine.
Reaction SMILES: [Br-].[C:2]1([C:8]2[CH:12]=[C:11]([CH2:13][N+:14]34CN5CN(CN(C5)C3)C4)[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>>[NH2:14][CH2:13][C:11]1[O:10][N:9]=[C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:12]=1
Reactant: c1ccc(-c2cc(C[N+]34CN5CN(CN(C5)C3)C4)on2)cc1
Agent: Cl
Agent: [Br-]
Product: NCc1cc(-c2ccccc2)no1

Procedure:
A 10 g. portion of the product of Example 4 was reacted with hydrochloric acid as above to obtain 1.1 g. of the desired product, m.p. 50°.
Reaction SMILES: Cl.O1CCOCC1.C(OC(=O)[NH:14][C:15]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[CH:23]=1)([C:17]1[CH:21]=[CH:20][NH:19][N:18]=1)[CH3:16])(C)(C)C>>[Br:28][C:24]1[CH:23]=[C:22]([C:15]([NH2:14])([C:17]2[CH:21]=[CH:20][NH:19][N:18]=2)[CH3:16])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)NC(C)(c1cccc(Br)c1)c1cc[nH]n1
Agent: Cl
Solvent: C1COCCO1
Product: CC(N)(c1cccc(Br)c1)c1cc[nH]n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Hydrochloric acid 4 M in dioxane (7.88 mL, 31.54 mmol) was added to rac-[1-(3-bromo-phenyl)-1-(1H-pyrazol-3-yl)-ethyl]-carbamic acid tert-butyl ester (1.65 g, 4.51 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo. The residue was suspended in DCM and washed with NaHCO3 (aq. sat. solution). The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield rac-1-(3-bromo-phenyl)-1-(1H-pyrazol-3-yl)-ethylamine (1.2 g, 100% yield) as a white solid, which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[F:11].O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(Br)c(F)c1
Temperature: 25 °C

Procedure:
4-Bromo-3-fluorobenzoic acid (40.8 g, 0.187 mol) was dissolved in THF (250 ml) with magnetic stirring under Ar in an ice-H2O bath. The cloudy solution was treated dropwise with borane-THF complex (1 M) (374 mL, 0.374 mol) over a 1 h period maintaining the internal temperature at <10° C. The reaction mixture was left to warm to ambient temperature overnight, then cooled in an ice H2O bath and treated dropwise with H2O (150 mL). The THF was removed on a rotary evaporator, and the residue partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3×100 mL), the organic layers combined, washed with brine, and dried (Na2SO4), filtered, and concentrated to give the title compound as an oil which solidified on standing.