Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[C:12]=1[C:19]1[N:24]=[CH:23][C:22]([CH:25]=[O:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH3:10].[Cl-].[NH4+]>CCOCC>[CH:1]1([CH:25]([C:22]2[CH:23]=[N:24][C:19]([C:12]3[C:13]([CH2:17][CH3:18])=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:9][CH3:10])=[CH:20][C:21]=2[O:27][CH2:28][CH3:29])[OH:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: CCOc1cc(-c2c(CC)cccc2CC)ncc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOc1cc(-c2c(CC)cccc2CC)ncc1C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A cyclohexylmagnesium chloride solution (2 M in THF, 1 mL) is slowly added to a solution of 6-(2,6-diethyl-phenyl)-4-ethoxy-pyridine-3-carbaldehyde (prepared as described D above) (142 mg, 0.5 mmol) in ether (2 mL) at 0° C., and the resulting mixture is stirred at room temperature for 30 minutes. Saturated ammonium chloride solution (1 mL) is added to quench the reaction. The organic layer is separated and dried over anhydrous Na2SO4. The solvents are removed in vacuo and the crude is purified with PTLC (hexanes/ethyl acetate 3:1) to give cyclohexyl-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-methanol. 1H NMR: (CDCl3) 8.40 (s, 1H), 7.28 (t, 1H), 7.16 (d, 2H), 6.76 (S, 1H), 4.54 (t, 1H), 4.08 (q, 2H), 2.32 (m, 4H), 2.05 (br, 1H), 1.75 (m, 4H), 1.40 (m, 4H), 1.05 (m, 10H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=5)[C:19]([C:33](O)=[O:34])=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN.O1CCCC1.C[CH2:44][N:45](CC)CC.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([N:29]([CH3:30])[CH3:31])=[O:32])=[CH:24][CH:23]=5)[C:19]([C:33]([NH:45][CH3:44])=[O:34])=[CH:18][CH:17]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C(=O)O)cc1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(=O)N(C)C)cc1
Reaction time: 3 h
Yield: 10.3 %

Procedure:
5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4′-(dimethylcarbamoyl)biphenyl-2-carboxylic acid (47 mg, 0.10 mmol) and 75 μl of a 2.0 M solution of methylamine in tetrahydrofuran (0.15 mmol) were dissolved in DMF (1.0 mL) containing Et3N (28 μL, 0.20 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 3 hours. The mixture was filtered and purified by reverse phase HPLC to yield 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-N2,N4′,N4′-trimethylbiphenyl-2,4′-dicarboxamide (5.0 mg, 10%). ESI-MS m/z calc. 485.5. found 486.5 (M+1)+; retention time 2.54 minutes.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([NH:7][CH2:8][CH3:9])[CH3:6].CO[C:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[NH2:24])[N:15]=1)=[O:13].O>C1(C)C=CC=CC=1>[CH2:5]([N:7]([CH2:8][CH3:9])[C:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[NH2:24])[N:15]=1)=[O:13])[CH3:6]
Reactant: CCNCC
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)C(=O)c1ccc2c(N)cccc2n1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A suspension that consists of 1.06 g (7.95 mmol) of aluminum chloride in 35 ml of toluene is mixed with 1.70 ml (15.7 mmol) of diethylamine while being cooled with ice. After one hour at room temperature, 350 mg (1.73 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester is added, and the reaction mixture is allowed to stir for 5 hours at 40° C. The reaction is halted by adding water. It is extracted with dichloromethane, and the combined organic phases are dried on sodium sulfate. After removal of the solvent and purification on silica gel with dichloromethane-methanol (0-10%), 210 mg (50% of theory) of the product is obtained.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:23](=[O:25])[CH3:24])[CH:10]=[CH:11][C:12]=2[CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]([CH3:22])([CH3:21])[CH2:14]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:26](=O)[CH2:27][CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)C.O1CCCC1>[CH2:26]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]([C:23](=[O:25])[CH3:24])[CH:10]=[CH:11][C:12]=2[CH:13]2[CH2:14][C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:19])([CH3:20])[CH2:18]2)[CH2:2][CH2:3]1)[CH2:27][CH3:28]
Reactant: CCC=O
Reactant: CC(=O)c1ccc(C2CC(C)(C)CC(C)(C)C2)c(N2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCN1CCN(c2cc(C(C)=O)ccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-[3-piperazin-1-yl-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]ethanone (19 mg, 0.0555 mmol) produced in Example (82b), propionaldehyde (0.0119 mL, 0.166 mmol) and tetrahydrofuran (0.3 mL) was added sodium triacetoxyborohydride (35 mg, 0.166 mmol), followed by stirring for 1 hour at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with diethyl ether. The solvent was distilled off by nitrogen stream to the separated organic layer. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-[3-(4-propylpiperazin-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]ethanone.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:19](Br)=[CH:18][C:17]([O:21][C:22](=[O:24])[CH3:23])=[CH:16][C:14]=3[N:15]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC.CC1C=CC(C)=CC=1>C(OCC)C.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[C:22]([O:21][C:17]1[CH:18]=[C:19]([CH:26]=[CH2:27])[C:13]2[O:12][C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]([F:25])[CH:7]=3)=[N:15][C:14]=2[CH:16]=1)(=[O:24])[CH3:23]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(=O)Oc1cc(Br)c2oc(-c3ccc(OC(C)=O)c(F)c3)nc2c1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccc(C)cc1
Solvent: CCOCC
Product: C=Cc1cc(OC(C)=O)cc2nc(-c3ccc(OC(C)=O)c(F)c3)oc12
Temperature: 130 °C
Reaction time: 5 h
Yield: 56.9 %

Procedure:
Dichlorobis(tri-o-tolylphosphine)palladium (II) (46 mg, 0.06 mmol) was added into a mixture 4-[5-(acetyloxy)-7-bromo-1,3-benzoxazol-2-yl]-2-fluorophenyl acetate (0.8 g, 1.98 mmol), tributyl(vinyl)tin (0.9 g, 2.8 mmol) and p-xylene (9 mL). The reaction mixture was stirred at 130° C. for 5 h, cooled to room temperature, diluted with ethyl ether (10 mL) and treated with activated carbon. The mixture was filtered through MgSO4 and concentrated. Purification by flash chromatography (hexanes/EtOAc 5/1) gave a white solid (0.4 g, 56% yield, m.p. 154–156° C.); MS m/e 356 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][CH:31]=[CH:30][C:4]=1[C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][N:17]3[C:21]4=[N:22][C:23]([CH3:27])=[CH:24][C:25]([CH3:26])=[C:20]4[N:19]=[C:18]3[CH2:28][CH3:29])=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)=[O:6])#[N:2].C[Sn]([N:38]=[N+:39]=[N-:40])(C)C>C1(C)C=CC=CC=1>[NH:38]1[C:1]([C:3]2[CH:33]=[CH:32][CH:31]=[CH:30][C:4]=2[C:5]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH2:16][N:17]4[C:21]5=[N:22][C:23]([CH3:27])=[CH:24][C:25]([CH3:26])=[C:20]5[N:19]=[C:18]4[CH2:28][CH3:29])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[O:6])=[N:2][N:40]=[N:39]1
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(ccn2C(=O)c2ccccc2C#N)c1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(ccn2C(=O)c2ccccc2-c2nnn[nH]2)c1
Yield: 59.5 %

Procedure:
To a solution of the product of Example 8, Step B (75 mg, 0.17 mmol) in 5 mL of toluene was added trimethyltin azide (43 mg, 0.21 mmol, 1.2 eq). The mixture was heated at reflux for 18 hours. Toluene was removed in vacuo and the resultant oil was dissolved in 5 mL of THF and treated with 0.5 mL of 2.5N HCl at 0° C. for 5 minutes. The volatiles were removed in vacuo and the resultant oil was flash chromatographed with 20% of 10/1 methanol/NH4OH mixture in chloroform to yield the titled compound (48.2 mg, 60%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.C[Li].C([Li])(C)(C)C.[CH:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]>CCOCC>[OH:25][CH:20]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCC=O
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CCCCC(O)c1ccc2cc(O)ccc2c1
Reaction time: 0.08 h
Yield: 57.2 %

Procedure:
To a solution of 1.00 g (4.48 mmol, Aldrich) of 6-bromo-2-naphthol in 40 ml of dry ether at -78° was added dropwise 3.2 ml (1.4M in ether, 5.0 mmol) of methyllithium solution. The reaction mixture was stirred for 5 minutes then 5.0 ml (1.8M in pentane, 9.0 mmol) of t-butyllithium solution was added over 5 minutes. The resulting slurry was stirred at -78° C. for 30 minutes then at 0° for 15 minutes, re-cooled to -78° and a solution of 0.50 ml (4.7 mmol) of distilled valeraldehyde in 3 ml of ether was added dropwise over several minutes. After 5 minutes the reaction mixture was warmed to 0°, quenched with 1 ml of H2O, added to 100 ml of ice-cold saturated aqueous NH4Cl solution. The organic layer was separated, washed with 100 ml of H2O, dried (MgSO4) and concentrated in vacuo to give a dark oil. The crude oil was purified by flash chromatography (10×5.0 cm, 1:3 EtOAc/petroleum ether) to afford 590 mg (57%) of title compound as a pale yellow solid, m.p. 109°-111°.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([NH2:22])=[O:21])[C:3]1=[O:23].[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:33](ON1C(=O)CCC1=O)=[O:34]>CN(C)C=O>[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:33]([NH:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([NH2:22])=[O:21])[C:3]1=[O:23])=[O:34]
Reactant: NC(=O)CN1C(=O)[C@@H](N)[C@H](c2ccccc2)Cc2ccccc21
Reactant: O=C(ON1C(=O)CCC1=O)c1cc2ccccc2[nH]1
Solvent: CN(C)C=O
Product: NC(=O)CN1C(=O)[C@@H](NC(=O)c2cc3ccccc3[nH]2)[C@H](c2ccccc2)Cc2ccccc21
Yield: 68.4 %

Procedure:
In 5 ml of dimethylformamide are dissolved 0.2 g of trans-3-amino-2-oxo-4-phenyl 2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetamide and 0.18 g of succinimido 2-indolecarboxylate, and the same reaction and treatment as in Example 12 is carried out to give 0.2 g of trans-3-(2-indolecarboxamido)-2-oxo-4-phenyl-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetamide, m.p. 280°-283° C. (decomposition).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH:19]=2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].C(O[C:23]1(O[Si](C)(C)C)[CH2:25][CH2:24]1)C.C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C>[CH:23]1([N:17]2[CH2:16][CH:15]=[C:14]([C:6]3[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:19][CH2:18]2)[CH2:25][CH2:24]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: O=[N+]([O-])c1cc(C2=CCNCC2)cc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=[N+]([O-])c1cc(C2=CCN(C3CC3)CC2)cc(C(F)(F)F)c1
Yield: 78.6 %

Procedure:
Stir the mixture of 4-(3-nitro-5-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine (150 mg, 0.55 mmol), (1-ethoxycyclopropoxy)trimethylsilane (700 mg, 2.4 mmol), sodium cyanoborohydride (200 mg, 3.3 mmol) and acetic acid (240 mg, 4.0 mmol) in ethanol (10 mL) at 60° C. overnight. Concentrate the mixture to get a residue, partition between EtOAc and water, collect the organic layer, wash with water and brine sequentially, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure to give the product as a yellow solid (135 mg, 79%). MS: (M+1): 313.1.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[NH2:25][C@@H:26]1[CH2:30][CH2:29][N:28]([C:31](=[O:35])[C@H:32]([OH:34])[CH3:33])[CH2:27]1.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>[OH:34][C@H:32]([CH3:33])[C:31]([N:28]1[CH2:29][CH2:30][C@@H:26]([NH:25][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:19]=2)=[O:21])[CH2:27]1)=[O:35]
Reactant: C[C@@H](O)C(=O)N1CC[C@@H](N)C1
Reactant: Cn1c(Nc2nc3ccc(Cl)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: C[C@@H](O)C(=O)N1CC[C@@H](NC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(Cl)cc4s2)n3C)C1
Yield: 28.8 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [(R)-1-((R)-2-hydroxy-propionyl)-pyrrolidin-3-yl]amide (20 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (50 mg), (R)-1-((R)-3-amino-pyrrolidin-1-yl) 2-hydroxy-propan-1-one (100 mg), HBTU (150 mg), and DIEA (100 uL) in DMF (1 mL). LC/MS: m/z 498.6.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])[C:10]([Cl:24])=[N:9][C:8]=2[N:7]=[C:6]1[N:25]1[CH2:30][CH2:29][CH2:28][CH:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]1)[C:2]#[C:3][CH3:4].[C:39](=O)([O-])[O-:40].[K+].[K+].Cl.NC1CCCN(C2N(CC#CC)C3C(=O)N(CC4C=CC=CC=4C#N)C(C#N)=NC=3N=2)C1>CO>[ClH:24].[NH2:31][CH:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:6]2[N:5]([CH2:1][C:2]#[C:3][CH3:4])[C:13]3[C:12](=[O:14])[N:11]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]#[N:23])[C:10]([O:40][CH3:39])=[N:9][C:8]=3[N:7]=2)[CH2:26]1
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2nc(Cl)n(Cc3ccccc3C#N)c(=O)c21
Reactant: O=C([O-])[O-]
Agent: CC#CCn1c(N2CCCC(N)C2)nc2nc(C#N)n(Cc3ccccc3C#N)c(=O)c21
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CC#CCn1c(N2CCCC(N)C2)nc2nc(OC)n(Cc3ccccc3C#N)c(=O)c21
Reaction time: 3 h

Procedure:
A mixture consisting of 15 mg of t-butyl [1-[7-(2-butynyl)-2-chloro-1-(2-cyanobenzyl)-6-oxo-6,7-dihydro-1H-purin-8-yl]piperidin-3-yl]carbamate, 20 mg of anhydrous potassium carbonate and 0.2 ml of methanol was stirred for three hours. Subsequent steps were carried out according to the same procedure as used in Examples 242 (f) and (g). Thus, the title compound was synthesized.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH2:10][CH:11]=[CH2:12].[H][H]>C(O)C.[Rh]>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12]
Reactant: [H][H]
Reactant: C=CCc1cc(CO)ccc1O
Agent: [Rh]
Solvent: CCO
Product: CCCc1cc(CO)ccc1O
Reaction time: 0.5 h

Procedure:
To a solution of 0,370 g (2.25 mmol) of the product of Step E dissolved in 25 mL of absolute ethanol was added 53 mg of a 5% rhodium on carbon catalyst and the mixture was shaken under a 40 psig pressure of hydrogen on a Parr apparatus. After 30 minutes, the reaction mixture was removed, filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 35% ethyl acetate/hexane to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][C:3]=1[C:10]#[N:11].[ClH:12].O>CO.[Pd]>[ClH:12].[ClH:12].[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][C:3]=1[CH2:10][NH2:11]
Reactant: N#Cc1cnn(CCO)c1N
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: NCc1cnn(CCO)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, 10% palladium on active carbon (125 g) and methanol (3.75 L) were placed in a 5.0 L of three-necked flask. To the mixture was added 5-amino-4-cyano-1-(2-hydroxyethyl)-1H-pyrazole (250 g). The mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. To the reaction mixture was added 4N hydrogen chloride solution in methanol (1.65 L), and the mixture was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. To the reaction mixture was added water (1.2 L). The catalyst was filtered off and washed with 50% aqueous methanol, and the filtrate was evaporated in vacuo. The residue was triturated with isopropanol/ethyl acetate (1:1). The precipitate was collected by filtration on a glass filter, washed with ethyl acetate and dried in vacuo to give 5-amino-4-aminomethyl-1-(2-hydroxyethyl)-1H-pyrazole dihydrochloride (358 g) as a white solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26]>C1C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:9][O:10][C:11]1[C:16]([CH2:17][Br:1])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccccc1Oc1cccc(C)c1OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COc1ccccc1Oc1cccc(CBr)c1OC
Yield: 101.6 %

Procedure:
N-Bromosuccinimide (6.56 g) and 2,2'-azobisisobutyronitrile (100 mg) were added to a solution of 2-methoxyphenyl 2-methoxy-3-methylphenyl ether (9.0 g) in benzene (100 ml), and the mixture was refluxed under heating for 2 hrs. The reaction mixture was evaporated, and water was added to the residue. The mixture was extracted with diethyl ether, and the extract was washed with water, dried over magnesium sulfate and then evaporated to give oily residue of 2-methoxyphenyl 2-methoxy-3-bromomethylphenyl ether (12.10 g).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([OH:8])([C:6]#[CH:7])[CH3:5].[CH3:9][O:10][C:11](=[O:15])[CH:12](Br)[CH3:13]>O1CCCC1>[CH3:9][O:10][C:11](=[O:15])[CH:12]([O:8][C:4]([CH3:5])([CH3:3])[C:6]#[CH:7])[CH3:13]
Reactant: COC(=O)C(C)Br
Reactant: C#CC(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(C)(C)OC(C)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a mixture of sodium hydride (23.8 g, 0.595 mol) in tetrahydrofuran (400 ml) cooled to 0° C., is added a solution of 2-methyl-3-butyne-2-ol (50 g, 0.595 mol) in tetrahydrofuran (50 ml). The reaction mixture is stirred at 0° C. for 1 hour. A solution of methyl-2-bromo-propionate (99.36 g, 0.595 mol) in tetrahydrofuran (100 ml) is added to the reaction mixture slowly at 0° C. The reaction mixture is stirred at 0° C. for 2 hours and allowed to come to ambient temperature and stirred for 1 hour. The reaction mixture is cooled to 10° C. and quenched with ice cold water. The mixture is extracted with diethyl ether (3×200 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered and the filtrate is evaporated under reduced pressure to give 2-(1,1-dimethylprop-2-ynyloxy)propionic acid methyl ester (90 g) as a colorless oil, used without further purification in the next step.
Reaction SMILES: [Na].[SH:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[Na+].[I-].Cl[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]>CO>[CH3:7][O:6][C:4](=[O:5])[CH2:3][S:2][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CS
Reactant: COC(=O)CCCCl
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)CCCSCC(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.5 %

Procedure:
Sodium (3.5 g, 0.15 mol) was added to methanol (150 mL) carefully. After cooling to room temperature, methyl 2-mercaptoacetate (15.6 g, 0.13 mol) was added. The mixture was stirred for 30 mins at room temperature and a little of NaI and methyl 4-chlorobutanoate 20.0 g, 0.15 mol) were added. The reaction mixture was refluxed over night. After cooling to room temperature, the solvent was removed under reduced pressure, then the residue was dissolved in CH2Cl2 (100 mL). The solution was washed with H2O (30 mL), brine (30 mL), and dried with Na2SO4. After removing the solvent, 28.3 g of the crude product was obtained (Yield: 94%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28]>C1COCC1>[F:26][C:24]1[CH:23]=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[C:20]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:25]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccc(F)cc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
4-Fluorophenylamine (1.47 g, 13.19 mmol) was dissolved in THF (20 mL) and cooled to −70° C., under an atmosphere of nitrogen. A solution of 1M LiHMDS in THF (25.14 mL, 25.14 mmol) was added dropwise and the mixture stirred at −70° C., under an atmosphere of nitrogen for 15 minutes. A solution of 2,4-difluoronitrobenzene (2.0 g, 12.57 mmol) in THF (10 mL) was added dropwise to the mixture, at −70° C. and the resultant purple solution stirred at −70° C. for 30 min. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted into EtOAc (3×50 mL). The combined organic fractions were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, gradient 0-100% DCM in cyclohexane) to afford the title compound as an orange solid (2.94 g, 100%). 1H NMR (CDCl3, 400 MHz): δ 9.53 (1H, s), 8.27 (1H, dd, J=9.48, 5.98 Hz), 7.29-7.22 (2H, m), 7.20-7.11 (2H, m), 6.64 (1H, dd, J=11.26, 2.65 Hz), 6.48 (1H, ddd, J=9.47, 7.12, 2.65 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Ca+2].[I:18]Cl>CO.O>[I:18][C:3]1[CH:4]=[C:5]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc(-n2cncn2)cc1
Reactant: ClI
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: O
Product: Nc1ccc(-n2cncn2)cc1I
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.1 %

Procedure:
To a stirred solution of 1-(4-aminophenyl)-1,2,4-triazole (1.0 g, 6.25 mmol) in MeOH (10 mL) and water (10 mL) was added CaCO3 (1.2 g, 12.0 mmol), followed by a solution of iodine monochloride (1.2 g, 7.38 mmol) in MeOH (10 mL). The reaction mixture was stirred at r.t. for 1.5 h, and then partitioned between EtOAc (100 mL) and aqueous sat. Na2S2O3 (100 mL). The organic fraction was separated, washed with aqueous sat. Na2S2O3 (100 mL), then water (100 mL), brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 0-100% EtOAc/hexanes) gave the title compound (1.2 g, 67%). LCMS (ES+) 286.9 (M+H)+, RT 2.78 minutes (Method 4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([N:11]2C(=O)C3C(=CC=CC=3)C2=O)[C@H:7]1[C@@H:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1.O.NN>CCO>[NH2:11][C@H:8]1[C@@H:7]([C@@H:22]2[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]2)[N:6]([CH2:5][C:4]2[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:3]=2[O:2][CH3:1])[C:9]1=[O:10]
Reactant: COc1ccc(CN2C(=O)[C@@H](N3C(=O)c4ccccc4C3=O)[C@H]2[C@@H]2COC(C)(C)O2)c(OC)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(CN2C(=O)[C@@H](N)[C@H]2[C@@H]2COC(C)(C)O2)c(OC)c1
Temperature: 25 °C

Procedure:
To a solution of crude 2-((2S,3S)-1-(2,4-dimethoxybenzyl)-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-oxoazetidin-3-yl)isoindoline-1,3-dione (631 g, 1.143 mol, assumed quantitative conversion from step 2) in EtOH (8.2 L) was added hydrazine hydrate (235 mL, 50-60%, ˜4 mol) over 20 min. The resulting mixture was heated to reflux for 3 h, cooled to rt, filtered, washed with EtOH and concentrated in vacuo. The residue was slurried in EtOAc (4 L), filtered and washed with water (2×1 L).