Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([NH2:14])[CH2:5][NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:16]1([CH3:28])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25].CCN(C(C)C)C(C)C>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:15])[CH:4]([NH:14][S:24]([C:17]1[C:18]([CH3:23])=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=1[CH3:28])(=[O:26])=[O:25])[CH2:5][NH:6][C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: COC(=O)C(N)CNC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(CNC(=O)OC(C)(C)C)NS(=O)(=O)c1c(C)cc(C)cc1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
A mixture of 3-tert-Butoxycarbonylamino-2-aminopropionic acid methyl ester (3.5 g, 13.7 mmol), mesitylsulfonyl chloride (3.9 g, 17.8 mmol), DIEA (7.2 mL, 41.1 mmol) in dichloromethane (100 mL) was stirred at 0° C. for one hour and overnight at room temperature. The solvent was removed and the crude reaction product was taken up in ethyl acetate (340 mL). The solution was washed with 5% solution of sodium carbonate (30 mL), 5% solution of hydrochloric acid (30 mL), with saturated sodium chloride solution (30 mL). Solvent was than dried over sodium sulfate and evaporated. Purification of the residue on silica gel (10%MeOH-EtOAc) gave 5.00 g of pure compound O-1 (84% yield).
Reaction SMILES: [C:1]([N:4]1[C:8]2([CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:7][CH2:6][CH:5]1[C:14]([OH:16])=O)(=[O:3])[CH3:2].CC(C)[C@H](NC(OC)=O)C(N1C(C([NH:39][CH2:40][C:41]([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[CH:54]=[CH:53][C:52]([C:55]4[N:56]=[C:57]([C@@H:60]5[CH2:64][CH2:63][CH2:62][N:61]5[C:65](=[O:75])[C@@H:66]([NH:70][C:71]([O:73][CH3:74])=[O:72])[CH:67]([CH3:69])[CH3:68])[NH:58][CH:59]=4)=[CH:51][CH:50]=3)=[CH:45][CH:44]=2)=[O:42])=O)CC2(CN(C(OC(C)(C)C)=O)C2)C1)=O>>[C:1]([N:4]1[C:8]2([CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH2:7][CH2:6][CH:5]1[C:14]([NH:39][CH2:40][C:41]([C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:50]=[CH:51][C:52]([C:55]3[N:56]=[C:57]([C@@H:60]4[CH2:64][CH2:63][CH2:62][N:61]4[C:65]([C@@H:66]([NH:70][C:71](=[O:72])[O:73][CH3:74])[CH:67]([CH3:69])[CH3:68])=[O:75])[NH:58][CH:59]=3)=[CH:53][CH:54]=2)=[CH:45][CH:44]=1)=[O:42])=[O:16])(=[O:3])[CH3:2]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CC1C(=O)NCC(=O)c1ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc1)CN(C(=O)OC(C)(C)C)C2)C(C)C
Reactant: CC(=O)N1C(C(=O)O)CCC12CCOCC2
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)CNC(=O)C4CCC5(CCOCC5)N4C(C)=O)cc3)cc2)c[nH]1)C(C)C
Yield: 66.2 %

Procedure:
This compound was prepared in an analogous fashion to 169 from 1-acetyl-8-oxa-1-azaspiro[4.5]decane-2-carboxylic acid (171) (56 mg, 0.25 mmol) and methyl {(1S)-[((2S)-2-{4-[4′-(aminoacetyl)-4-biphenylyl]-1H-imidazol-2-yl}-1-pyrrolidinyl)carbonyl]-2-methylpropyl}carbamate dihydrochloride (1) (142 mg, 0.25 mmol) to afford the title compound as an off-white solid (118 mg, 67% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:15])=[N-]>ClCCl.CO>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1cc(F)c(F)cc1Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a mixture of 2-bromo-4,5-difluorobenzoic acid (1 g, 4.22 mmol) in dichloromethane (10 mL) and MeOH (1 mL) was added trimethylsilyl)diazomethane (2.110 mL, 4.22 mmol) and the reaction was stirred at rt for 1 h. It was then concentrated to obtain methyl 2-bromo-4,5-difluorobenzoate (1 g, 3.98 mmol, 94% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.76 (dd, J=10.5, 8.3 Hz, 1H), 7.57-7.49 (m, 1H), 3.96 (s, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH:15]=CN=[CH:12][C:11]=3[N:10]=[CH:9]2)=[N:6][CH:7]=1.Br[C:18]1C(F)=CC=C[N:19]=1>>[N:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[N:8]1[C:16]2[CH:15]=[N:19][CH:18]=[CH:12][C:11]=2[N:10]=[CH:9]1
Reactant: Fc1ccc(-n2cnc3cnccc32)nc1
Reactant: Fc1cccnc1Br
Product: c1ccc(-n2cnc3ccncc32)nc1

Procedure:
Intermediate 69 was prepared in a manner analogous to Intermediate 1, substituting 2-bromopyrimidine for 2-bromo-fluoropyridine. MS (ESI): mass calculated for C11H8N4, 196.07; m/z found 197.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][C:6]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:17][C:5]=2[CH2:4][N:3]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1.Cl.[H][H]>[Pd].C(O)(=O)C>[O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][C:6]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]3[NH:28][CH2:27][CH2:26][CH2:25][N:24]=3)=[CH:17][C:5]=2[CH2:4][N:3]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1
Reactant: [H][H]
Reactant: COC(=O)C[C@@H]1Cc2ccc(OCCCNc3ncccn3)cc2CN(Cc2ccc(C(F)(F)F)cc2)C1=O
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)C[C@@H]1Cc2ccc(OCCCNC3=NCCCN3)cc2CN(Cc2ccc(C(F)(F)F)cc2)C1=O
Reaction time: 5 h
Yield: 118.9 %

Procedure:
A Parr hydrogenation apparatus was charged with methyl (S)-3-oxo-8-[3-(pyrimidin-2-ylamino)-1-propyloxy]-2-[4-(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (42 mg, 0.08 mmol), glacial acetic acid (2 mL), concentrated HCl (0.2 mL), and 10% Pd/C (10 mg). The mixture was shaken under hydrogen (40 psi) for 5 h, then the hydrogen was vented and the catalyst was removed by filtration through celite®. Evaporation of the solvents gave the crude title compound (52 mg) as a dark residue. This was used without further purification. MS (ES) m/e 547.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:8](I)=[CH:7][N:6]=[C:5]([Cl:10])[CH:4]=1.[C:11]([N:14]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[CH:18]C2N=C(Cl)C(F)=CC=2C1)(=[O:13])[CH3:12]>>[C:11]([N:14]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[CH:18][C:8]2[CH:7]=[N:6][C:5]([Cl:10])=[CH:4][C:3]=2[CH2:2]1)(=[O:13])[CH3:12]
Reactant: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Reactant: Clc1cc(CBr)c(I)cn1
Product: CC(=O)N1Cc2cc(Cl)ncc2C=Cc2ccccc21

Procedure:
Compound 25E was prepared from 25D and bb in two steps by a route analogous to that used for the preparation of 1D. HPLC Rt=2.506 min; LCMS Found: (M+H)+=285.
Reaction SMILES: [C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]([CH3:41])[C:20](=[O:40])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[C:30]([O:32]C(C)(C)C)=[O:31])[CH2:13][CH2:12]1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]([CH3:41])[C:20](=[O:40])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[C:30]([OH:32])=[O:31])[CH2:13][CH2:12]1)=[O:9]
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1cccc(C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The compound (80.0 mg, 0.124 mmol) obtained in Example 43a was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1 mL) was added under ice cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1.5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to give a crude title compound.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[S:26][C:27]([CH2:30][CH3:31])=[N:28][N:29]=1>>[CH2:30]([C:27]1[S:26][C:25]([NH:24][C:1]([C:4]23[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:6][CH2:5]2)[CH2:8][CH2:9]3)=[O:2])=[N:29][N:28]=1)[CH3:31]
Reactant: CCc1nnc(N)s1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CCc1nnc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)s1
Yield: 51.8 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-amino-5-ethyl-1,3,4-thiadiazole (43.9 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(5-ethyl-1,3,4-thiadiazol-2-yl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (34.8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.[N:41]1(O)[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2N=N1.C(N(C(C)C)C(C)C)C>O.C(OCC)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([NH:41][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:44]=3)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccccc1)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (100 mg, 0.252 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (97 mg, 0.504 mmol), and 1H-benzo[d][1,2,3]triazol-1-ol (68.1 mg, 0.504 mmol) were dissolved 2.0 mL of DCM. The reaction was stirred at room temperature for ten minutes before N-ethyl-N-isopropylpropan-2-amine (0.088 mL, 0.504 mmol) and aniline, HCl (65.3 mg, 0.504 mmol) as a 1.0 mL DCM solution was added. The reaction was allowed to stir at room temperature overnight. The reaction was diluted with water and ethyl acetate. The organic phase was washed with water, saturated sodium bicarbonate (twice), and saturated sodium chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated. The crude material was recrystallized with ether and ethyl acetate and filtered to obtain white solid as a product. (Yield: 77 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 9.89, 7.66-7.52, 7.37-7.18, 7.13-7.07, 7.02, 6.75, 5.51, 4.44, 4.03, 2.95, 2.64-2.55, 1.79, 1.47
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.CO>O>[C:14]1([CH:13]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1C(=Cc2ccccc2)CCc2cc(O)ccc21
Temperature: 25 °C

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and benzaldehyde 0.42 ml were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for two hours and cooled to room temperature, and water 400 ml was added. The precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for six hours under reduced pressure to obtain the desired compound 0.756 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:9]=2)=[C:4]([O:45][CH3:46])[CH:3]=1.N1C=CC=CC=1.[O:53]1[CH2:58][CH2:57][CH:56]([CH2:59][S:60](Cl)(=[O:62])=[O:61])[CH2:55][CH2:54]1>O1CCCC1>[CH3:46][O:45][C:4]1[CH:3]=[C:2]([NH:1][S:60]([CH2:59][CH:56]2[CH2:57][CH2:58][O:53][CH2:54][CH2:55]2)(=[O:62])=[O:61])[CH:7]=[CH:6][C:5]=1[C:8]1[C:16]2[C:15]([NH:17][C@H:18]([C:20]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:24](=[O:32])[C:23]4=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]4[N:21]=3)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=2[N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:43])([CH3:42])[CH3:44])[CH:9]=1
Reactant: COc1cc(N)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Reactant: O=S(=O)(Cl)CC1CCOCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(NS(=O)(=O)CC2CCOCC2)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Temperature: 50 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
(S)-2-(1-((5-(4-Amino-2-methoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was treated with pyridine (19 μL, 0.23 mmol) and (tetrahydro-2H-pyran-4-yl)methanesulfonyl chloride (31 mg, 0.16 mmol) in tetrahydrofuran (0.5 ml) according to the method described in Preparation 175 but stirring at 50° C. overnight. The title compound was obtained (54 mg, 68% yield, 80% purity) without further purification.
Reaction SMILES: [OH-].[Na+].[C:3]1(CC(=O)C(O)=O)C=CC=CC=1.CI.Cl.[O:18]=[C:19]([CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:20]([OH:22])=[O:21]>CN(C)C=O>[O:18]=[C:19]([C:23]([CH3:3])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:20]([OH:22])=[O:21]
Reactant: CC(C(=O)C(=O)O)c1ccccc1
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C(=O)C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 59 %

Procedure:
A 1N aqueous solution of sodium hydroxide (20 ml, 20 mmoles) and 30 ml of dimethylformamide were added to 1.64 g (10.0 mmoles) of phenylpyruvic acid to form a solution. Then, 2.0 ml of methyl iodide was added, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with 150 ml of ether. The ether layer was dried over magnesium sulfate, and concentrated under reduced pressure to give a pale yellowish white solid. Analysis of its NMR spectrum showed that 2-oxo-3-phenylbutanoic acid formed in a yield of 59%, and 2-oxo-3-methyl-3-phenylbutanoic acid, in a yield of 21%. The NMR spectrum of the former is shown in Example 1, and that of the latter is shown in Example 73.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([OH:11])=[CH:6][C:3]=1[CH:4]=[O:5].[C:12]([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[C:3]([CH:4]=[O:5])=[CH:6][C:7]2[O:11][CH2:12][O:10][C:8]=2[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(O)c(O)cc1F
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc2c(cc1F)OCO2
Temperature: 60 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
To a stirred solution of 2-fluoro-4,5-dihydroxy-benzaldehyde (8.0 g) and BrClCH2 (24.8 g, 190 mmol) in dry DMF (50 mL) was added Cs2CO3 (62.0 g, 190 mmol) in portions. The resulting mixture was stirred at 60° C. overnight and then poured into water. The mixture was extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and evaporated in vacuo to give crude product, which was purified by column chromatography on silica gel (5-20% ethyl acetate/petroleum ether) to afford 6-fluoro-benzo[1,3]dioxole-5-carbaldehyde (700 mg, two steps yield: 24%). 1H-NMR (400 MHz, CDCl3) δ 10.19 (s, 1H), 7.23 (d, J=5.6, 1H), 6.63 (d, 9.6, 1H), 6.08 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([I:14])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([I:14])[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(I)cc(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cc(I)cc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Dissolve 5-iodo-isophthalic acid dimethyl ester (10 g, 31.2 mmol) in methanol (90 mL) and cool to 0° C. Add 2 N NaOH (15.6 mL) dropwise and slowly warm up to room temperature. Stir overnight and acidify to about pH=3 with 5 N HCl. Extract with ethyl acetate (2×50 mL). Wash the combined organic layers by water, saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound as a crude residue which is used in the next step without further purification.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[CH2:30][CH2:29][C@:12]2([O:16][CH2:15][C@@H:14]([C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=3[O:27][CH3:28])[CH2:13]2)[C@@H:11]1[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].C(O)C>[F:37][C:34]1[CH:35]=[CH:36][C:31]([C@@H:11]2[C@@H:10]([CH2:9][OH:8])[CH2:30][CH2:29][C@@:12]32[O:16][CH2:15][C@@H:14]([C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:20]=[CH:19][C:18]=2[O:27][CH3:28])[CH2:13]3)=[CH:32][CH:33]=1
Reactant: COc1ccc(C(F)(F)F)cc1[C@@H]1CO[C@]2(CC[C@H](COCc3ccccc3)[C@H]2c2ccc(F)cc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(F)(F)F)cc1[C@@H]1CO[C@]2(CC[C@H](CO)[C@H]2c2ccc(F)cc2)C1
Yield: 80.2 %

Procedure:
(3R,5R,6S,7S)-7-(Benzyloxymethyl)-6-(4-fluorophenyl)-3-(-2-methoxy-5-(trifluoromethyl)phenyl)-1-oxaspiro[4.4]nonane (2.4 mg, 0.0047 mmol) was stirred with 0.7 mg of 20% palladium(II) hydroxide m 0.5 mL of 95% ethanol under hydrogen at atmospheric pressure for 1.5 h. The mixture was filtered through a 0.45 micron filter and the catalyst was rinsed with additional 95% ethanol. The filtrate was evaporated to give 1.6 mg of the title compound. 1NMR (400 MHz, CDCl3): δ 7.43-7.32 (m, 4H), 7.03 (t, 2H, J=9 Hz ), 6.80 (d, 1H, J=9 Hz ), 3.75 (s, 3H), 3.72 (t, 1H, J 8 Hz ), 3.65-3.58 (m, 2H), 3.48 (dd, 1H, J=10, 5 Hz ), 2.82 (quintet, 1H, J=8 Hz ), 2.73-2.58 (m, 2H), 2.23 (dd, 1H, J=12, 8 Hz ), 2.18-2.02 (m, 3H), 1.99-1.88 (m, 1H), 1.66-1.54 (m, 1H). Mass spectrum (EI): m/z=424.1 (M+).
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[C:3]#[C:4][C:5](=O)[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[NH:16][NH2:17]>CC(O)C>[C:20]([O:19][C:15]([NH:16]/[N:17]=[C:5](\[C:4]#[C:3][Si:2]([CH3:14])([CH3:13])[CH3:1])/[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: C[Si](C)(C)C#CC(=O)CCCC(=O)O
Reactant: CC(C)(C)OC(=O)NN
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N/N=C(\C#C[Si](C)(C)C)CCCC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 54.0 g (254 mmol) of 7-(trimethylsilyl)-5-oxohept-6-ynoic acid from step A above in 750 mL of IPA under an atmosphere of nitrogen was added 33.6 g (254 mmol) of tert-butyl carbazate. The reaction mixture was stirred for 4 h at ambient temperature then evaporated in vacuo to remove all volatiles. This afforded the title compound as a yellow gum which was used without further purification (77 g, 93%). LC-MS: m/z (ES) 327 (MH)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[BH4-].[Na+].[CH3:11][NH2:12]>CO>[CH3:11][NH:12][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1cccnc1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cccnc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 3-pyridine-carboxaldehyde (0.24 g) in methanol, methylamine (2.0 M solution in tetrahydrofuran, 6 ml) was added, and the mixture was stirred at room temperature for 23 hours. Then, sodium borohydride (0.22 g) was added thereto, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was partially purified on a reverse-phase silica gel column. A crude product was obtained by decantation and directly used in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]([CH3:25])[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[O:22])=[C:8]2[CH3:26])=[CH:4][CH:3]=1>C1COCC1.CO.BrCCBr>[Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]([CH3:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:8]2[CH3:26])=[CH:4][CH:3]=1
Reactant: COC(=O)C=CC(C)c1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Solvent: BrCCBr
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCC(C)c1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Yield: 32.7 %

Procedure:
To the ester (520 mg, 1.17 mmol) of Step 3 dissolved in a THF/MeOH mixture (4.0 mL/20.0 mL) was added an excess of Mg and a few drops of 1,2-dibromoethane. The reduction was initated by heating at reflux. After standing for a few hours at room temperature, the reaction mixture was quenched by the addition of a 25% aqueous NH4OAc solution, extracted with EtOAc, dried over MgSO4 and evaporated in vacuo. The desired reduced product was purified by flash chromatography (25% EtOAc in hexane) to provide 170 mg of an oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:5][NH:6]2.[C:19]([O:22][C@@H:23]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@@H:24]1OC(=N)C(Cl)(Cl)Cl)(=[O:21])[CH3:20]>ClCCl>[C:19]([O:22][C@@H:23]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@H:24]1[O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:5][NH:6]2)(=[O:21])[CH3:20]
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Oc1cccc2[nH]cc(CCc3ccccc3)c12
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3[nH]cc(CCc4ccccc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-hydroxy-3-(2-phenylethyl)indole (70 mg) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (0.22 g) in dichloromethane (3 mL) was added boron trifluoride-diethyl ether complex (0.081 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by preparative thin layer chromatography (eluent: n-hexane/ethyl acetate=1/1) to give 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-(2-phenylethyl)indole. This material was dissolved in tetrahydrofuran (1 mL)-methanol (0.5 mL). To the solution was added sodium methoxide (28% methanol solution, 0.024 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by preparative thin layer chromatography (eluent: dichloromethane/methanol=5/1) to give the title compound (22 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:13])[N:4]([CH2:9][CH2:10][O:11][CH3:12])[N:5]=[CH:6][C:7]=1Cl.[CH3:14][O-:15].[Na+]>CO>[Cl:1][C:2]1[C:3](=[O:13])[N:4]([CH2:9][CH2:10][O:11][CH3:12])[N:5]=[CH:6][C:7]=1[O:15][CH3:14]
Reactant: C[O-]
Reactant: COCCn1ncc(Cl)c(Cl)c1=O
Agent: [Na+]
Solvent: CO
Product: COCCn1ncc(OC)c(Cl)c1=O

Procedure:
The title compound, white crystalline solid, MS: m/e=219.1, 221.1 (M+H+), was prepared in accordance with the general method of example 23e by treatment of 4,5-dichloro-2-(2-methoxy-ethyl)-2H-pyridazin-3-one with sodium methoxide in methanol.