Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14](O)=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[NH:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=2[N:22]=1.[CH2:32]([O:34][CH2:35][CH2:36][NH2:37])[CH3:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:32]([O:34][CH2:35][CH2:36][NH:37][C:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:29])([F:31])[F:30])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:7][C:8]=2[CH:13]=1)=[O:15])[CH3:33]
Reactant: CCOCCN
Reactant: COCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CCOC
Yield: 42.3 %

Procedure:
1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide (49.0 mg) was prepared by following General Procedure F starting from 1-(2-methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-ethoxy-ethylamine (30.0 mg), HBTU (130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 525; and 1H NMR (DMSO-d6, 400 MHz): δ 8.44 (1H, br. s), 8.06 (1H, br. s), 7.91 (1H, br. s), 7.71 (1H, br. m), 7.49-7.47 (1H, m), 7.35-7.34 (1H, m), 4.34 (2H, br. s), 3.72-3.69 (2H, br. t), 3.52-3.40 (6H, m), 3.22 (3H, s), 1.13-1.09 (3H, t), 2 —NH proton signals were not observed.
Reaction SMILES: [O:1]=[C:2]1[C:11]([CH2:12][C:13]([O:15]CC)=[O:14])=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[C:4](=[CH:5][C:6]3[C:26](=[O:27])[O:25][CH2:24][C:7]=3[CH:8]=2)[O:3]1.Cl>C(O)(=O)C.C1COCC1.C(OCC)(=O)C>[O:1]=[C:2]1[C:11]([CH2:12][C:13]([OH:15])=[O:14])=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[C:4](=[CH:5][C:6]3[C:26](=[O:27])[O:25][CH2:24][C:7]=3[CH:8]=2)[O:3]1
Reactant: CCOC(=O)Cc1c(-c2ccccc2)c2cc3c(cc2oc1=O)C(=O)OC3
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)Cc1c(-c2ccccc2)c2cc3c(cc2oc1=O)C(=O)OC3
Yield: 134.5 %

Procedure:
Ethyl 2-(2,8-dioxo-4-phenyl-6,8-dihydro-2H-furo[3,4-g]chromen-3-yl)acetate (58 mg) was dissolved in acetic acid (2 ml) and concentrated hydrochloric acid (1 ml), and heated under reflux for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain the residue, which was dissolved in a solvent mixture of THF (10 ml) and ethyl acetate (50 ml), and then washed with water followed by a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from THF-isopropyl ether to obtain the title compound (72 mg, yield: 92%). Melting point: 226-227° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[N:9][C:8]2[C:11]3[CH:17]=[CH:16][C:15]([CH3:18])=[N:14][C:12]=3[S:13][C:7]=2[C:6]=1[OH:19])([O:3][CH3:4])=[O:2].[C:20](=O)(O)[O-].[K+].[CH2:25](Br)[CH3:26]>CN(C=O)C>[C:1]([C:5]1[N:10]=[N:9][C:8]2[C:11]3[CH:17]=[CH:16][C:15]([CH3:18])=[N:14][C:12]=3[S:13][C:7]=2[C:6]=1[O:19][CH2:25][CH3:26])([O:3][CH2:4][CH3:20])=[O:2]
Reactant: O=C([O-])O
Reactant: COC(=O)c1nnc2c(sc3nc(C)ccc32)c1O
Reactant: CCBr
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nnc2c(sc3nc(C)ccc32)c1OCC
Reaction time: 3 h
Yield: 46 %

Procedure:
To a mixture of 3.3 g (0.013 mol) of 3-carbomethoxy-4-hydroxy-7-methyl-pyrido[3',2':4,5]thieno[3,2-C]pyridazine, 3.8 g potassium bicarbonate, in 90 ml of anhydrous DMF was slowly added 9 ml of ethyl bromide and stirring was continued at 60°-70° C. for 3 hours. The solvent was then removed, the residue was diluted with water and filtered to give 3.4 g of crude product. Crystallization from EtoAc-hexane gave 1.8 g (46%) of pure 3-carbethoxy-4-ethoxy-7-methyl pyrido[3',2':4,5]thieno[3,2-C]pyridazine; m.p. 158°-160° C.
Reaction SMILES: [Br-].[PH4+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=O.O.C[CH2:19][O:20][C:21]([CH3:23])=[O:22]>C1COCC1>[CH3:19][O:20][C:21](=[O:22])[CH2:23][CH2:9][CH2:4][CH2:5][CH:6]=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1
Reactant: O=C(c1ccccn1)c1ccccn1
Reactant: CCOC(C)=O
Agent: [Br-]
Agent: [PH4+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCCCC=C(c1ccccn1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
NHMDS (2.26 mL, 2.26 mmol) as a solution in THF was added to methyl 6-triphenylphosphonium bromide hexanoate II (1.072 g, 2.38 mmol) in THF (8 mL) at 0° C. under Ar(g). After 15 min, di-pyridin-2-yl-methanone (220 mg, 1.2 mmol) in THF (4 mL) was added; the reaction mixture was stirred for 1 h, and was then allowed to warm to rt. After 20 h stirring, water (15 mL) and EtOAc (15 mL) were added, the phases were separated, and the aqueous phase was extracted with EtOAc (2×10 mL). The organic phases were combined, dried over MgSO4, filtered, and then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using CH2Cl2/MeOH (100:0.5 to 100:2) as eluant to furnish III as a colourless oil (155 mg, 44%).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[S:7]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)(=[O:9])=[O:8].Cl.[NH2:25][OH:26].C([O-])(=O)C.[K+]>CO>[OH:26][N:25]=[C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[S:7]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)(=[O:9])=[O:8]
Reactant: NO
Reactant: O=C1CCCCC1S(=O)(=O)N1CCN(c2ccc(F)cc2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: O=S(=O)(C1CCCCC1=NO)N1CCN(c2ccc(F)cc2)CC1
Temperature: 70 °C
Yield: 96.5 %

Procedure:
A mixture of 1-(cyclohexanone-2-sulfonyl)-4-(4-fluorophenyl)piperazine (50 mg, 0.14 mmol), hydroxylamine hydrochloride (51 mg, 0.73 mmol) and potassium acetate (72 mg, 0.73 mmol) in methanol (5 ml) was heated at 70° C. for 4 h. The solvents were evaporated. After partitioning between EtOAc and water, the organic layer was washed with brine and dried over MgSO4 to give 1-[2-(N-hydroxyimino)cyclohexane-1-sulfonyl]-4-(4-fluorophenyl)piperazine as a white solid (48 mg, 94%): MS (ESI): 356 (MH+).
Reaction SMILES: [CH3:1][C@@:2]1([O:25][C:26](/[CH:28]=[CH:29]/[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[C@H:6]2[C@H:7]([O:11][C@@H:12]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:15]([OH:20])[C@H:14]([OH:21])[C@H:13]3[OH:22])[O:8][CH:9]=[CH:10][C@@:5]2([OH:23])[C@H:4]([OH:24])[CH2:3]1.[OH-].[Na+:37]>CO>[CH3:1][C@@:2]1([OH:25])[C@H:6]2[C@H:7]([O:11][C@H:12]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:15]([OH:20])[C@H:14]([OH:21])[C@H:13]3[OH:22])[O:8][CH:9]=[CH:10][C@@:5]2([OH:23])[C@H:4]([OH:24])[CH2:3]1.[C:26]([O-:27])(=[O:25])[CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Na+:37]
Reactant: C[C@]1(OC(=O)/C=C/c2ccccc2)C[C@@H](O)[C@]2(O)C=CO[C@@H](O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@]1(O)C[C@@H](O)[C@]2(O)C=CO[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@@H]21
Product: O=C([O-])C=Cc1ccccc1
Reaction time: 8 h

Procedure:
560 mg of harpagoside (LN-1) was dissolved in 20 ml of methanol, mixed with 1 ml of 1N sodium hydroxide, allowed to stand overnight at room temperature and then passed through Sephadex LH-20 (solvent: 80% methanol) column. 400 mg of harpagide and 125 mg of sodium cinnamate were obtained from the eluate.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:23]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]2)=[O:24])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1>[CH2:35]([N:22]([CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6](=[O:7])(=[O:8])[NH2:5])=[CH:20][CH:19]=1)[C:23]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24])[CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)N1CCCc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCCCN(Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)C(=O)N1CCCc2ccccc21
Yield: 69.9 %

Procedure:
A solution of 86 mg (0.16 mmole) of 1-[N-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-N-pentylcarbamoyl]-1,2,3,4-tetrahydroquinoline (from Step A), 30 μL of anisole, and 0.8 mL of anhydrous TFA was stirred at room temperature for 16 hours. The residue obtained after evaporation of excess TFA was flash chromatographed over silica gel (elution with 0.5% MeOH in CH2Cl2) to give 55 mg (71%) of the title compound as an off-white foam, homogeneous by TLC (95:5 MeOHCH2Cl2), FAB-MS m/e 492 (M+1)+.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].C[C:7]([O-])([CH3:9])[CH3:8].[K+].[C:12]([SiH2:16][O:17][C:18](C1C=CC=CC=1)(C1C=CC=CC=1)[C:19]1[C:20]([N:30]2[CH2:35][C@H:34]([CH3:36])[O:33][C@H:32]([CH3:37])[CH2:31]2)=[C:21]([F:29])[C:22](F)=[C:23]([C:25](=[O:27])[CH3:26])[CH:24]=1)([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[Si:16]([O:17][CH2:18][C:19]1[C:20]([N:30]2[CH2:31][C@H:32]([CH3:37])[O:33][C@H:34]([CH3:36])[CH2:35]2)=[C:21]([F:29])[C:22]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])=[C:23]([C:25](=[O:27])[CH3:26])[CH:24]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([C:8]1[CH:7]=[CH:9][CH:14]=[CH:12][CH:13]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)c1cc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F
Reactant: CC(C)=NO
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1ON=C(C)C
Reaction time: 0.75 h
Yield: 203 %

Procedure:
To a stirred solution of propan-2-one oxime (913 mg, 12.50 mmol) in THF (15 ml) was added KOtBu (935 mg, 8.33 mmol) at room temperature. After stirring for 45 minutes, 1-{5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2,3-difluorophenyl}ethanone (Intermediate 9, 2240 mg, 4.17 mmol) dissolved in 10 ml of THF was added. After stirring for 3 hours reaction quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, and concentrated to give the crude title compound (2.5 g). LCMS and NMR indicates >90% purity. Used in the next step without any further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2].C[O:30]C1C=C2C(=CC=1OC)C(C(=O)C1C=CC=C(OC)C=1)=NC=C2CC(O)=O.[Se](=O)=O>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20](=[O:30])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(Cc2cccc(OC)c2)c2cc(OC)c(OC)cc12
Reactant: COc1cccc(C(=O)c2ncc(CC(=O)O)c3cc(OC)c(OC)cc23)c1
Agent: O=[Se]=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(C(=O)c2cccc(OC)c2)c2cc(OC)c(OC)cc12
Yield: 82 %

Procedure:
1-(3-methoxybenzyl)-6,7-dimethoxyisoquinoline-4-carboxylic acid ethyl ester (159 mg, 0.417 mmol, the intermediate in the preparation of [6,7-Dimethoxy-1-(3-methoxy-benzoyl)-isoquinolin-4-yl]-acetic acid) (Example 7) was dissolved into 4 ml of acetic acid. Then selenium dioxide (69.5 mg, 1.50 eq) was added. The mixture was refluxed for 20 minutes and then evaporated to dryness. The residue was suspended into ethyl acetate and the mixture was passed through a layer of silica gel. The filtrate was evaporated to give 1-(3-methoxybenzoyl)-6,7-dimethoxyisoquinoline-4-carboxylic acid ethyl ester as a solid (135 mg, 82%). This material (95.6 mg, 0.242 mmol) was suspended into 5 ml of methanol. Then 1N sodium hydroxide solution (0.5 ml) was added. The mixture was refluxed for 1 hr. TLS showed complete disappearance of the starting material. The mixture was evaporated and the residue was dissolved into 5 ml of water and then filtered. The filtrate was acidified with 1N hydrochloric acid to give 6,7-Dimethoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid as a solid (76 mg, 86%). ES-MS calculated for C20H17NO6 (m/e) 367.36, observed 368.4 (M+1). 1H-NMR is consistent with the desired structure.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)([CH3:5])[CH:3]=O.N1CCCC1.[Si](Cl)(C)(C)C.[NH2:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([CH2:53][C@@H:54]3[CH2:58][CH2:57][CH2:56][N:55]3[C:59](=[O:63])[CH2:60][C:61]#[N:62])[N:37]=[C:38]([C:39]3[CH:44]=[CH:43][C:42]([O:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[CH:41][C:40]=3[F:52])[C:31]=12>C(Cl)Cl.O>[NH2:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([CH2:53][C@@H:54]3[CH2:58][CH2:57][CH2:56][N:55]3[C:59](=[O:63])[C:60]([C:61]#[N:62])=[CH:3][C:2]([N:6]3[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]3)([CH3:1])[CH3:5])[N:37]=[C:38]([C:39]3[CH:44]=[CH:43][C:42]([O:45][C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)=[CH:41][C:40]=3[F:52])[C:31]=12
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: CC(C)(C)OC(=O)N1CCN(C(C)(C)C=O)CC1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: C1CCNC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(C)(C)C=C(C#N)C(=O)N2CCC[C@H]2Cn2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl 4-(1,1-dimethyl-2-oxo-ethyl)piperazine-1-carboxylate (326.2 mg, 1.27 mmol) in DCM (6 mL), was added pyrrolidine (0.17 mL, 2.04 mmol). The reaction mixture was cooled to 0° C., followed by the addition TMS-Cl (0.13 mL, 1.02 mmol). The ice bath was removed and the mixture stirred for 10 min before adding 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (120 mg, 0.250 mol). The mixture was stirred for 4 h at room temperature, at which point TLC and LC-MS showed the reaction was finished. To the mixture was added 30 ml water, the layers separated and the aq. layer was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and the solvent removed in vacuo. The residue was dissolved in minimum CH2Cl2, loaded on a silica gel column and purified by MeOH/CH2Cl2(1/4):EtOAc 20-30% gradient to get pure product tert-butyl 4-[4-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-cyano-1,1-dimethyl-4-oxo-but-2-enyl]piperazine-1-carboxylate as light yellow oil
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31]>CN(C)C=O>[CH3:12][O:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([O:17][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:7][C:8]=1[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: COCCOCCBr
Reactant: COc1cc(C(C)(C)C)c(O)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOCCOc1cc(C(C)(C)C)c(OC)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
2,5-di-tert-butyl-4-methoxyphenol (9 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 ml). Cesium carbonate (13 mmol) and 1-bromo-2-(2-methoxyethoxy)ethane (9 mmol) was added to the solution. The reaction mixture was then stirred at room temperature overnight. After removal of the solvent, the residue was partitioned between dichloromethane (DCM) and aqueous NaHCO3 (0.1 M). The organic portion was separated and dried over Na2SO4 and then the solvent was removed under vacuum. The crude product was chromatographed (silica, hexanes/DCM from 5:1 to 1:1) to provide pure 1-methoxy-4-[2-(2-methoxyethoxy)ethoxy]-2,5-di-tert-butyl-benzene in an 87% yield. 1H NMR (300 MHz, CDCl3): δ/ppm 6.83 (s, 1H), 6.82 (s, 1H), 4.14 (t, J=4.5 Hz, 2H), 3.89 (t, J=4.5 Hz, 2H), 3.80 (s, 3H), 3.72 (t, J=4.5 Hz, 2H), 3.58 (t, J=4.5 Hz, 2H), 3.40 (s, 3H), 1.38 (s, 9H)), and 1.35 (s, 9H). The purity was over 99.5% based GC-mass spectroscopy, and the molecular weight was observed at 338.3, which is consistent with the theoretical value, 338.5.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10](OS(C(F)(F)F)(=O)=O)[CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:31]=[N+:32]=[N-:33].[Na+].[N-]=[N+]=[N-]>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH:10]([N:31]=[N+:32]=[N-:33])[CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CC(COCc1ccccc1)OS(=O)(=O)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(COCc1ccccc1)CN1C(=O)c2ccccc2C1=O

Procedure:
2-Benzyloxymethyl-2-(trifluoromethylsulfonyloxy)-1-phthalimido-ethane (8.5 g, 19.1 mmol) and sodium azide (2.5 g, 38.2 mmol) were stirred in dimethylformamide (80 ml) at 60° C. for 6 hours Under nitrogen. TLC in several systems was inconclusive because the Rf of the product was identical to the Rf of the starting material. A small sample was worked up and IR indicated full conversion to the azide. The reaction mixture was transferred to a 1 l extraction funnel and distributed between ethyl acetate (350 ml) and water (130 ml). The aqueous phase was extracted with ethyl acetate (80 ml); the combined organic phases were washed with water (2×120 ml), dried over magnesium sulphate, filtered and concentrated in vacuo to a pale brown oil. Crystallisation was initiated by adding ether (7 ml). Crystals were collected on a glass sinter, washed with cold ether and dried under vacuum for 28 hours. Yield: 4.5 g (70%). The mother liquors were concentrated, diluted with ether and seeded with crystals from the first crop--yielding another 1 g. Total yield: 5.5 g (85%). The structure was confirmed by NMR and IR.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:15])=[CH:11][CH:12]=2)[NH:7][CH2:6]1)[CH3:3].[C:16]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[ClH:61]>C1COCC1>[ClH:61].[C:16]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:17]=[CH:18][C:19]([CH2:22][O:15][C:10]2[CH:9]=[C:8]3[C:13]([CH2:14][CH:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][NH:7]3)=[CH:12][CH:11]=2)=[CH:20][CH:21]=1
Reactant: CN(C)CC1CNc2cc(O)ccc2C1
Reactant: OCc1ccc(-c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CC1CNc2cc(OCc3ccc(-c4ccccc4)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(dimethylamino)methyl-1,2,3,4-tetrahydro-7-quinolinol (344 mg), 4-biphenylylmethanol (368 mg), and triphenylphosphine (525 mg) in THF (20 ml) was added diethyl azodicarboxylate (348 mg). After stirring at room temperature for one hr, the reaction mixture was poured into 1 N aqueous hydrochloric acid and washed with ethyl acetate. The water layer was neutralized by 1 N aqueous sodium hydroxide, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent:ethyl acetate:hexane=1:4) and converted into its hydrochloride, which was further recrystallized from ethanol-diisopropyl ether to obtain the titled compound (214 mg).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][C@H:16]1[CH2:21][CH2:20][CH2:19][O:18][CH2:17]1)[CH2:3][N:4]([CH3:14])[C:5](=[O:13])[O:6][CH2:7][CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10].CCN(C(C)C)C(C)C.C1N=CN([C:36]([N:38]2[CH:42]=N[CH:40]=[CH:39]2)=[O:37])C=1.[Cl:43][C:44]1[CH:45]=[C:46]([C@@H:50]([C@@H:59]2CCCN[CH2:60]2)[O:51][CH2:52][CH2:53][NH:54][C:55](=[O:58])[O:56][CH3:57])[CH:47]=[CH:48][CH:49]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:43][C:44]1[CH:45]=[C:46]([C@@H:50]([C@@H:59]2[CH2:60][CH2:40][CH2:39][N:38]([C:36](=[O:37])[NH:1][C@@H:2]([CH2:15][C@H:16]3[CH2:21][CH2:20][CH2:19][O:18][CH2:17]3)[CH2:3][N:4]([C:5]([O:6][CH2:7][CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10])=[O:13])[CH3:14])[CH2:42]2)[O:51][CH2:52][CH2:53][NH:54][C:55](=[O:58])[O:56][CH3:57])[CH:47]=[CH:48][CH:49]=1
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1
Reactant: CN(C[C@@H](N)C[C@H]1CCCOC1)C(=O)OCC[Si](C)(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](C[C@H]2CCCOC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
At 0° C., to a solution of 2-(trimethylsilyl)ethyl (S)-2-amino-3-((R)-tetrahydro-2H-pyran-3-yl)propyl(methyl)carbamate (1.9 g, 6 mmol) and DIPEA (3.87 g, 30 mmol) in anhydrous CH2Cl2 (20 mL) was added CDI (1.26 g, 7.8 mmol). After addition, the mixture was stirred for 1 hr at 0° C., followed by addition of methyl 2-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)ethylcarbamate as TFA salt (2.8 g, 6.6 mmol) in anhydrous CH2Cl2 (20 mL). The reaction mixture was allowed to warm to rt and stirred overnight. After the reaction was completed, the solvent was removed in vacuo. The product was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (5:1→2:1) to afford methyl 2-((R)-(3-chlorophenyl)((R)-1-((S)-1-(N-Methyl-2-(trimethylsilyl)ethoxycarbonylamino)-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate (3.0 g, 75% yield).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:19])[CH2:9][CH:10]([CH3:18])[CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH3:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.Cl>[CH3:20][C:21]1[CH:22]=[C:23]([CH2:24][N:13]2[C:12]3[CH2:11][CH:10]([CH3:18])[CH2:9][C:8](=[O:19])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cccc(CBr)c1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CC(C)C3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(C)c2)CC(C)CC1=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 100 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-2-methyl-9H-carbazol-4(3H)-one (1.0 g, 3.89 mM), 3-methylbenzyl bromide (0.54 ml, 3.97 mM), and potassium carbonate (1.07 g, 7.78 mM) in 20 mL DMF was stirred at room temperature for 19 hours. The mixture was diluted with EtOAc and 1N HCl. The layers were separated and the aqueous layer extracted with EtOAc. The combined EtOAc layers were extracted with 1N HCl, water, then brine. After drying (NaSO4), evaporation in vacuo afforded 1.41 g (100%) of 9-[(3-methylphenyl)methyl]-5-carbomethoxy-2-methyl-1,2-dihydrocarbazol-4(3H)-one. 1H NMR (CDCl3) δ 7.4-7.05 (m, 6H), 6.8 (m, 1H), 5.3 (s, 2H), 4.05 (s, 3H), 3.0 (m, 1H), 2.7-2.3 (m, 4H), 2.3 (s, 1H), 1.2 (d, J=7 Hz, 3H). MS (ES) m/e 362.
Reaction SMILES: C(O[C:4]([C:6]1[N:10]2[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)=[O:5])C.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH2:20].ClCCl>CO>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH:20][C:4]([C:6]1[N:10]2[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)=[O:5]
Reactant: CCOC(=O)c1cnc2ccc(Br)cn12
Reactant: CN(C)CCN
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCNC(=O)c1cnc2ccc(Br)cn12

Procedure:
Add 6-bromo-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (0.11 g, 0.41 mmol) to a sealed tube containing N,N-dimethyl-ethane-1,2-diamine (5 mL). Heat the reaction at 150° C. for 24 h. Flash chromatography using appropriate mixtures of dichloromethane/2M ammonia in methanol gives 0.14 g of the product as a yellow oil. This material is progressed further without characterization. MS ES− m/e 269.0, 311.0 (M−1).