Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=1)[CH2:10][NH:11][C@H:12]([CH3:35])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1OC)=[O:24])=[CH:17]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:45][C:46]([F:56])([F:55])C1C=CC(CN)=CC=1>>[Si:1]([O:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=1)[CH2:10][NH:11][C@H:12]([CH3:35])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:46]([F:56])([F:55])[F:45])=[CH:29][CH:28]=1)=[O:24])=[CH:17]2)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: COc1ccccc1CNC(=O)c1cc2cc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)ccc2[nH]1
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: C[C@H](Cc1ccc2[nH]c(C(=O)NCc3ccc(C(F)(F)F)cc3)cc2c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1

Procedure:
Prepared analogously to 5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-(2-methoxybenzyl)-1H-indole-2-carboxamide using 4-trifluoromethylbenzylamine to give the title compound as a pale brown foam.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:14]([OH:18])[CH2:15][C:16]#[CH:17]>CCN(CC)CC.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([C:17]#[C:16][CH2:15][CH2:14][OH:18])=[CH:3][CH:4]=1
Reactant: Ic1ccc(-c2ccccc2)cc1
Reactant: C#CCCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCC#Cc1ccc(-c2ccccc2)cc1
Temperature: 23 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
A sample of 4-iodobiphenyl (400 mg, 1.40 mmol) and (PPh3)4Pd (32 mg, 0.02 mmol) were dissolved in Et3N (6 mL) and stirred at 23° C. for 15 min before CuI (13.5 mg, 0.071 mmol) and but-3-yn-1-ol (0.129 mL, 1.71 mmol) were added. The reaction mixture was stirred at 23° C. for 3 h and then diluted with CH2Cl2, washed with saturated aqueous NH4Cl and saturated aqueous NaCl, and dried over Na2SO4. Evaporation in vacuo yielded the crude product. Flash chromatography (SiO2, 20% EtOAc-hexanes) afforded the title compound (270 mg, 85%) as a white solid: 1H NMR (CDCl3, 500 MHz) δ 7.59 (dd, 2H, J=8.5 Hz), 7.54 (dd, 4H, J=8.5 Hz), 7.44 (t, 2H, J=7.5 Hz), 7.36 (t, 1H, J=7.5 Hz), 3.84 (t, 2H, J=6.5 Hz), 2.73 (t, 2H, J=6.0 Hz); 13C NMR (CDCl3, 125 MHz) δ 140.6, 140.2, 132.0, 128.7, 127.5, 126.9, 126.8, 122.2, 87.0, 82.2, 61.1, 23.9.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][S:12][C:13]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][NH:22][C:21](=[O:25])[CH:20]=2)[CH:16]=[CH:15][N:14]=1.CS(O[C@H:31]([C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([F:48])[CH:42]=1)[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])(=O)=O>C1COCC1>[Si:34]([O:33][CH2:32][C@@H:31]([N:22]1[CH:23]=[CH:24][C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([S:12][CH3:11])[N:18]=2)=[CH:20][C:21]1=[O:25])[C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([F:48])[CH:42]=1)([C:37]([CH3:39])([CH3:40])[CH3:38])([CH3:36])[CH3:35]
Reactant: CSc1nccc(-c2cc[nH]c(=O)c2)n1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](OS(C)(=O)=O)c1ccc(Cl)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CSc1nccc(-c2ccn([C@H](CO[Si](C)(C)C(C)(C)C)c3ccc(Cl)c(F)c3)c(=O)c2)n1
Temperature: 25 °C
Yield: 62.9 %

Procedure:
1.0M KHMDS (5.09 mL, 5.09 mmol) as a solution in THF was added to a cold (0° C.) suspension of 4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (0.93 g, 4.24 mmol) in THF (20 mL) The reaction mixture was stirred at 0° C. for 10 minutes before (R)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl methanesulfonate (2.44 g, 6.36 mmol) was added as a solution in THF (5 mL) The reaction was heated to reflux for 30 hours and then cooled to room temperature and concentrated. The residue was taken up in ethyl acetate (200 mL) and washed with water. The organics were dried, filtered and concentrated. The crude product was purified via column chromatography, eluting with hexanes/ethyl acetate (4:1) to give (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (1.35 g, 63%) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J=5.0 Hz, 1H), 7.43 (m, 2H), 7.34 (d, J=5.0 Hz, 1H), 7.32-7.28 (m, 2H), 7.16 (m, 1H), 6.85 (m, 1H), 6.24 (m, 1H), 4.35 (m, 1H), 4.23 (m, 1H), 2.65 (s, 3H), 0.88 (s, 9H), 0.03 (s, 3H), −0.03 (s, 3H); m/z (APCI-pos) M+1=506.1, 508.1.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1F)=O.[NH2:13][NH2:14]>O>[CH3:11][O:10][C:7]1[CH:6]=[C:5]2[C:4]([C:2]([CH3:1])=[N:13][NH:14]2)=[CH:9][CH:8]=1
Reactant: NN
Reactant: COc1ccc(C(C)=O)c(F)c1
Solvent: O
Product: COc1ccc2c(C)n[nH]c2c1
Temperature: 25 °C

Procedure:
2-fluoro-4-methoxyacetophenone (5.0 g) was treated with hydrazine (75 ml) under argon and the mixture was heated to reflux for 12 hours. After cooling to room temperature, the reaction mixture was poured into water (200 ml) then extracted three times with ethyl acetate (50 ml). The combined extracts were dried over sodium sulphate then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:3, v/v) to yield the title compound (4.05 g).
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:8])=[CH:5][C:6]=1[Br:7].CCCCCC.[Li]CCCC.[CH3:20][C:21]([CH3:23])=[O:22]>CCOCC>[Br:7][C:6]1[CH:5]=[C:4]([Br:8])[S:3][C:2]=1[C:21]([OH:22])([CH3:23])[CH3:20]
Reactant: Brc1cc(Br)c(Br)s1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(O)c1sc(Br)cc1Br
Reaction time: 0.17 h

Procedure:
A solution of 2,3,5-tribromothiophene (8.17 g, 25 mmol) in Et2O (N2 atmosphere) was cooled to −78° C. and treated with a 1.6 M hexane solution of nBuLi (15.6 mL, 25 mmol). The mixture was then stirred for 10 minutes, then treated with acetone (1.84 mL, 25 mmol). The mixture was then stirred for 30 minutes and quenched with H2O. The mixture was extracted with Et2O; the organic layers were combined, dried (MgSO4), and the solvent removed in vacuo. The residue was filtered through a plug of silica gel (gradient elution from hexanes to EtOAc) to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([CH3:29])[CH:23]=3)([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:14][C:13]=2[CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:24]([CH3:29])[CH:23]=3)([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:14][C:13]=2[CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1cc2cc(OCc3ccccc3)ccc2o1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(OCc3ccccc3)ccc2o1
Yield: 63.5 %

Procedure:
4-[1-(5-Benzyloxy-benzofuran-2-yl)-1-ethyl-propyl]-2-methyl-phenol (4.05 g, 10.1 mmol) and 1-bromopinacolone (2.17 g, 12.1 mmol) and K2CO3 (2.79 g, 20.2 mmol) in acetone (50 mL) are reacted analogous to Example 18-E to give the title compound (3.20 g, 63%).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:31])[C:26](OCC)=[O:27])=[CH:20][C:19]=1[F:32])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:31])[C:26]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:27])=[CH:20][C:19]=1[F:32])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(=O)Nc1ccc(OCc2ccccc2)c(F)c1
Reactant: NCCc1ccccc1
Product: O=C(NCCc1ccccc1)C(=O)Nc1ccc(OCc2ccccc2)c(F)c1
Yield: 98 %

Procedure:
Phenethyl-amine (33 mL, 520 mmol) was added to ethyl [(4-benzyloxy-3-fluorophenyl)amino](oxo)acetate (81 g, 260 mmol) and the mixture was sonicated at room temperature for 30 min. The resulting solid was filtered, washed with water and dried to give N-(4-benzyloxy-3-flourophenyl)-N′-(2-phenylethyl)ethanediamide (100 g, 99%). 1H NMR (400 MHz, d6-DMSO): δ 10.72 (br s, 1H), 9.05 (m, 1H), 8.78 (m, 1H), 7.77 (m, 1H), 7.59 (m, 1H), 7.46-7.19 (m, 8H), 5.16 (m, 2H), 3.45 (m, 2H), 2.83 (m, 2H); IR (cm−1): 2980, 2883, 1653, 1522, 1506, 1441, 1385, 1221, 1122, 951, 808, 746, 696, 584; LC/MS (M+H=393).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=2[Cl:21])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>CC(C)=O.CCOC(C)=O.[Zn]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[Cl:21])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(Sc2ccc([N+](=O)[O-])cc2Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(Sc2ccc(N)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-(4-tert-butyl-phenylsulfanyl)-2-chloro-4-nitro-benzene was dissolved in acetone (15 mL), then saturated aqueous NH4Cl (5 mL) was added and the mixture was cooled to 0° C. Solid zinc powder (3.7 g, 56 mmol) was added in portions over 10 min with rapid stirring. The mixture was allowed to warm to rt and was stirred 3 h. The mixture was diluted with EtOAc (250 mL), dried, and filtered through Celite®. Removal of solvent gave a yellow residue, which was used without further purification. MS (ESI): mass calcd. for C16H18ClNS, 291.1; m/z found 292.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 7.33-7.21 (m, 3H), 6.95 (d, J=8.5, 2H), 6.77 (d, J=2.4, 1H), 6.55 (dd, J=8.4, 2.4, 1H), 5.80 (s, 2H), 1.22 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12](OC)=[O:13])=[C:7]([CH3:16])[C:6]=2[CH:17]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([CH2:12][OH:13])=[C:7]([CH3:16])[C:6]=2[CH:17]=1
Reactant: COC(=O)C1=C(C)c2cc(N)ccc2CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1=C(CO)CCCc2ccc(N)cc21
Temperature: 25 °C
Yield: 96 %

Procedure:
To a stirred solution of methyl 2-amino-9-methyl-6,7-dihydro-5H-benzo[7]annulene-8-carboxylate from step J1 (65 mg, 0.281 mmol) in THF (2 mL) was added a solution of LAH in THF (1.0 M, 0.337 mL, 0.337 mmol) at −20° C. The mixture was warmed to rt over 2 h. The reaction was quenched with a couple of drops of 1 N NaOH. EtOAc was added. The mixture was dried over sodium sulfate, filtered, and concentrated in vacuo to afford (2-amino-9-methyl-6,7-dihydro-5H-benzo[7]annulen-8-yl)methanol (55.0 mg, 0.271 mmol, 96% yield). LCMS (M+H)+=204.1. 1H NMR (500 HMz, chloroform-d) δ 6.96 (d, J=7.9 Hz, 1H), 6.63 (d, J=2.4 Hz, 1H), 6.54 (dd, J=7.9, 2.4 Hz, 1H), 4.36 (d, J=3.4 Hz, 2H), 3.59 (br. s., 2H), 2.45 (t, J=6.9 Hz, 2H), 2.19 (d, J=2.9 Hz, 1H), 2.08 (s, 3H), 2.07-2.01 (m, 2H), 1.99-1.94 (m, 2H).
Reaction SMILES: [CH:1](=O)[CH3:2].[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:21][CH2:20][C:15]3([NH:19][CH2:18][CH2:17][CH2:16]3)[CH2:14]2)=[CH:9][C:8]=1[O:22][CH:23]([CH3:25])[CH3:24])([O-:6])=[O:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOCC>[CH2:1]([N:19]1[C:15]2([CH2:20][CH2:21][N:13]([C:10]3[CH:11]=[CH:12][C:7]([N+:4]([O-:6])=[O:5])=[C:8]([O:22][CH:23]([CH3:25])[CH3:24])[CH:9]=3)[CH2:14]2)[CH2:16][CH2:17][CH2:18]1)[CH3:2]
Reactant: CC(C)Oc1cc(N2CCC3(CCCN3)C2)ccc1[N+](=O)[O-]
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOCC
Product: CCN1CCCC12CCN(c1ccc([N+](=O)[O-])c(OC(C)C)c1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.0 ml of acetaldehyde is added to a solution of 500 mg of 7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane in 20 ml of 1,4-dichloroethane, cooled in a bath of ice-cold water. After 30 minutes, 1.12 g of sodium triacetoxyborohydride are added in small portions and the mixture is left to return to ambient temperature. The mixture is stirred at ambient temperature for 15 hours. 1 ml of acetaldehyde is then added and the mixture is stirred for 7 h. The mixture is concentrated to dryness under reduced pressure and the residue is diluted in 100 ml of dichloromethane. The organic phase is washed three times with 50 ml of water and the organic phase is dried over anhydrous magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on silica gel, elution being carried out with a dichloromethane/isopropanol gradient: 100/0 to 50/50, and then by further chromatography on silica gel, elution being carried out with a dichloromethane/acetone gradient: 100/0 to 50/50, so as to obtain a yellow oil. This oil is taken up with ether, and the precipitate obtained is filtered off. The filtrate is concentrated to dryness under reduced pressure, so as to give 250 mg of 1-ethyl-7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane in the form of a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[C@H:3]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([O:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])[CH2:14]1)[C:4]([O:6]C(C)(C)C)=[O:5].[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C(O)=O>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[CH3:1][CH:2]([CH3:34])[C@H:3]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([O:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[O:24][C:25]=2[CH3:26])[CH2:14]1)[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](CN[C@H](C(=O)OC(C)(C)C)C(C)C)C3)c(C)o2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O=CO
Product: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](CN[C@H](C(=O)O)C(C)C)C3)c(C)o2)cc1
Temperature: 25 °C

Procedure:
40 mg of tert-butyl (S)-3-methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}butyrate are dissolved in 1 ml of formic acid, and 0.5 ml of trifluoroacetic acid is added. The solution is stirred at room temperature for 18 and then concentrated completely. The residue is purified by HPLC, which gives 28.2 mg of (S)-3-methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}butyric acid trifluoroacetic acid salt as a colorless solid. C24H34N2O2.C2HF3O2 (414.55); MS (ES−): 413.28 (M+−H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[C:30]([CH2:35][N:36]1[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:38]([CH:47]=O)=[CH:37]1)[CH:29]=[CH:28]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[CH2:17]([O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[C:30]([CH2:35][N:36]1[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:38](/[CH:47]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:37]1)[CH:29]=[CH:28]2)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cn(Cc2ccc3cc(OCc4ccccc4)ccc3c2)cc1-c1ccccc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1cn(Cc2ccc3cc(OCc4ccccc4)ccc3c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Sodium hydride (60%, oily, 0.20 g) was added to a mixture of ethyl diethylphosphonoacetate (0.992 ml) and tetrahydrofuran (20 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. A solution of 1-(6-benzyloxy-2-naphthylmethyl)-4-phenylpyrrole-3-carbaldehyde (2.09 g) in tetrahydrofuran (20 ml) was slowly added to the mixture, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield ethyl(E)-3-[1-(6-benzyloxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]propenoate (1.65 g, yield: 68%). This was recrystallized from ethyl acetate-hexane. Melting point: 119–120° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([N:22]([C:24](=[O:27])[CH2:25][OH:26])[CH3:23])[C:16]=3[Cl:28])[C:7]2=[N:6][C:5]=1[CH3:29].[CH3:30]I.O>CN(C)C=O>[Br:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([N:22]([C:24](=[O:27])[CH2:25][O:26][CH3:30])[CH3:23])[C:16]=3[Cl:28])[C:7]2=[N:6][C:5]=1[CH3:29]
Reactant: CI
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CO)c3Cl)cccn2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Reaction time: 0.17 h
Yield: 19.4 %

Procedure:
To a suspension of sodium hydride (60% in oil, 9 mg) in N,N-dimethylformamide (1 ml) was added 3-bromo-8-[2,6-dichloro-3-(N-glycoloyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (100 mg). After stirring for 10 minutes, methyl iodide (36 mg) was added thereto and the mixture was stirred at ambient temperature for 1 hour. To this mixture were added methyl iodide (36 mg) and N,N-dimethylformamide (1 ml). The mixture was stirred at 60° C. for additional 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate 3 times. The combined organic layers were washed with water 4 times and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane: methanol=20:1, V/V) followed by crystallization from ethanol-diethyl ether to give 3-bromo-8-[3-(N-methoxyacetyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylimidazo[1,2-a]pyridine (20 mg) as crystals.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]([C:12]([O:14]CC)=[O:13])[CH:2]=1.O.[OH-].[Na+].Cl>O1CCOCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]([C:12]([OH:14])=[O:13])[CH:2]=1
Reactant: CCOC(=O)C1C=Nc2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C1C=Nc2ccccc2C1=O
Yield: 100.2 %

Procedure:
A suspension of ethyl 4-quinolone-3-carboxylate (900 mg) (Maybridge Chemical Co. Ltd) in dioxan (6 ml)/water (6 ml) was treated with 40% NaOH solution (8 ml) and refluxed 6 hours. The solution was cooled, acidified to pH2 with conc. HCl and the solid filtered off and dried under vacuum in the presence of P2O5 to provide the title compound (785 mg). MS (−ve ion chemical ionisation) m/z 188([M−H]−, 100%).
Reaction SMILES: [CH:1](/[C:9]1[N:10]=[C:11]2[CH:17]=[CH:16][N:15]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:12]2=[N:13][CH:14]=1)=C\C1C=CC=CC=1.[O:28]1CCOCC1>O.O=[Os](=O)(=O)=O>[S:18]([N:15]1[C:12]2=[N:13][CH:14]=[C:9]([CH:1]=[O:28])[N:10]=[C:11]2[CH:17]=[CH:16]1)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(/C=C/c4ccccc4)cnc32)cc1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C=O)cnc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a solution of (E)-2-styryl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (72.3 g, 193 mmol) in 1,4-dioxane (1500 mL) and water (300 mL) was added NaIO4 (165 g, 770 mmol) followed by OsO4 (5.00 g, 19.7 mmol). The reaction was stirred at about 25° C. for about 16 h. The reaction was concentrated under reduced pressure then was partitioned with 10% aqueous Na2S2O3 (1000 mL) and DCM (1000 mL). The organic layer was washed with water (2×500 mL) and the layers were filtered to remove undissolved precipitate and separated. The organic layer was dried over anhydrous Na2SO4, filtered through Celite®, and concentrated. The residue was purified by filtration through a pad of silica gel (1000 g) eluting with 0-5% EtOAc in DCM. The fractions were concentrated and the solid was triturated with heptane. The mixture was filtered and the filter cake was washed with heptane. This procedure was repeated for the collected undissolved precipitate. The collected solid was then dissolved in 2% EtOAc in DCM and passed through a pad of silica gel (100 g) eluting with 2% EtOAc in DCM. The filtrate was concentrated under reduced pressure. The two batches were combined to give 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (39.1 g, 67%) as an off-white solid: LC/MS (Table 2, Method a) Rt=2.17 min; MS m/z: 302 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:11]([SH:12])=[N:10][N:9]=[N:8]1)(O)=[O:2].C(C[N:17]1C(S)=NN=N1)(O)=O>>[C:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:11]([SH:12])=[N:10][N:9]=[N:8]1)(=[O:2])[NH2:17]
Reactant: O=C(O)CCCn1nnnc1S
Reactant: O=C(O)Cn1nnnc1S
Product: NC(=O)CCCn1nnnc1S

Procedure:
When an equivalent amount of 1-(3-carboxypropyl)tetrazole-5-thiol was substituted in the procedure of Example 5 for 1-carboxymethyltetrazole-5-thiol, 1-(3-carbamoylpropyl)tetrazole-5-thiol was obtained, m.p. 133°-136°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:13](Cl)(=[O:15])=[O:14])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[NH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24].N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([S:13]([NH:17][C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25][CH3:26])=[O:24])(=[O:15])=[O:14])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1N1CCCC1
Reactant: COC(=O)c1sccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(N2CCCC2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 4.1 %

Procedure:
To a solution of 121(1.5 g; 5.5 mmol) in dichloromethane (14 mL) at room temperature, methyl 3-aminothiophene-2-carboxylate (0.86 g; 5.5 mmol) was added followed by pyridine (0.87 g; 11.0 mmol) and then stirred at room temperature under a nitrogen atmosphere for 24 hours. The reaction mixture was concentrated under reduced pressure and then taken up in ethyl acetate (20 mL) and extracted with water. The aqueous layer was separated and extracted with ethyl acetate (2×20 mL). The combined organic phases were successively washed with water and aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 40% v/v over 900 mL gradient elution) to give the title product as a light red solid (86 mg).
Reaction SMILES: [C-:1]#[N:2].[Na+].[O:4]1[CH2:8][CH2:7][O:6][CH:5]1[CH2:9][CH2:10]Br>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O>[O:4]1[CH2:8][CH2:7][O:6][CH:5]1[CH2:9][CH2:10][C:1]#[N:2]
Reactant: BrCCC1OCCO1
Reactant: [C-]#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CCCC1OCCO1
Temperature: 90 °C
Yield: 88 %

Procedure:
58.8 g (1.2 mol) of sodium cyanide and 22.28 g (0.12 mol) of benzyltrimethylammonium chloride are dissolved in 360 ml of water. Thereafter 181.03 g (1.0 mol) of 2-[1,3]-dioxolan-2-yl-1-bromoethane are added dropwise and the reaction mixture is heated at 90° C. After six hours it is cooled, diluted with 400 ml of water and subjected to extraction with ether. Drying over magnesium sulfate and evaporation of the solvent give 111.85 g of 3-[1,3]-dioxolan-2-yl-propionitrile as a reddish oil which is used without further purification in the next stage of the reaction.