Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[C:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=2)[CH:11]=1)(=[O:8])[O:5]CC)C.Br[Si](C)(C)C.CO>ClCCl>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=2[O:16][CH2:17][CH2:18][OH:19])[CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[CH:26][CH:25]=1)[CH3:28]
Reactant: CCOP(=O)(Cc1ccc(OCCO)c(Cc2ccc(CC)cc2)c1)OCC
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Product: CCc1ccc(Cc2cc(CP(=O)(O)O)ccc2OCCO)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 84.5 %

Procedure:
To a solution of [3-(4-ethylbenzyl)-4-(2-hydroxyethoxy)benzyl]phosphonic acid diethylester (0.70 g) in dichloromethane (11.0 mL) was added bromotrimethylsilane (1.1 mL) at 0° C., and the reaction mixture was stirred for 14 hr at room temperature. Methanol (6.0 mL) was added to the reaction mixture, and the mixture was stirred for 10 min at room temperature. Evaporation of the solvent gave the title compound (0.51 g) as a light gray oil.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:16])[C:6](=[CH:10][C:11]=1[C:12](=[O:15])[CH2:13][CH3:14])C(O)=O)[CH3:2].C>C(O)C>[CH2:1]([C:3]1[NH:4][C:5](=[O:16])[CH:6]=[CH:10][C:11]=1[C:12](=[O:15])[CH2:13][CH3:14])[CH3:2]
Reactant: CCC(=O)c1cc(C(=O)O)c(=O)[nH]c1CC
Solvent: CCO
Product: CCC(=O)c1ccc(=O)[nH]c1CC

Procedure:
C-2. 6-Ethyl-5-(n-propanoyl)-2(1H)-pyridinone--A 15 g portion of 6-ethyl-1,2-dihydro-2-oxo-5-(n-propanoyl)nicotinic acid was heated in an oil bath at 235°-240° C. for 5 hours, cooled and the reaction mixture dissolved in hot ethanol, treated with decolorizing charcoal and filtered. The filtrate was evaporated in dryness and the residue recrystallized from isopropyl alcohol to yield 8.2 g of 6-ethyl-5-(n-propanoyl)-2(1H)-pyridinone, m.p. 138°-140° C.
Reaction SMILES: C([Li])CCC.BrC1C=CC=CC=1[C:13]1[CH:14]=[CH:15][C:16]2[N:17](C3C=CC=CC=3)[C:18]3[C:23]([C:24]=2[CH:25]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3.[Br:32][C:33]1[CH:34]=[C:35]([C:40]2([C:53]3[CH:58]=[C:57]([Br:59])[CH:56]=[C:55]([Br:60])[CH:54]=3)[C:52]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[C:46]3[C:41]2=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:36]=[C:37]([Br:39])[CH:38]=1>C1COCC1>[Br:32][C:33]1[CH:34]=[C:35]([C:40]2([C:53]3[CH:58]=[C:57]([Br:59])[CH:56]=[C:55]([Br:60])[CH:54]=3)[C:52]3=[CH:51][C:50]4[N:17]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[C:16]5[C:15]([C:49]=4[CH:48]=[C:47]3[C:46]3[C:41]2=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:14][CH:13]=[CH:25][CH:24]=5)[CH:36]=[C:37]([Br:39])[CH:38]=1
Reactant: Brc1cc(Br)cc(C2(c3cc(Br)cc(Br)c3)c3ccccc3-c3ccccc32)c1
Reactant: Brc1ccccc1-c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1cc(Br)cc(C2(c3cc(Br)cc(Br)c3)c3ccccc3-c3cc4c5ccccc5n(-c5ccccc5)c4cc32)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
24.0 ml (60 mmol) of n-butyllithium (2.5 N in hexane) are added dropwise to a solution, cooled to −78° C., of 23.9 g (60 mmol) of 3-(2-bromophenyl)-N-phenylcarbazole in 500 ml of THF, the mixture is subsequently stirred at −78° C. for a further 30 min., and a solution of 38.0 g (60 mmol) of 9,9-bis-(3,5-dibromophenyl)fluorene in 100 ml of THF is then added dropwise. When the addition is complete, the mixture is allowed to warm to room temperature, the THF is removed in vacuo, the residue is taken up in 500 ml of glacial acetic acid, 5 ml of hydrogen bromide are added, and the suspension is heated under reflux for half an hour. After cooling, the solid is filtered off with suction, washed three times with 300 ml of ethanol and recrystallised once from toluene/ethanol. Yield: 36.2 g (45 mmol), 75.3%, purity about 97% (HPLC).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20](O)=[O:21])[CH2:9]2)=[CH:4][C:3]=1[F:23].S(Cl)([Cl:26])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([Cl:26])=[O:21])[CH2:9]2)=[CH:4][C:3]=1[F:23]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)c(F)c2)C1
Product: O=C(Cl)C1=NN(c2ccccc2Cl)C(c2ccc(Br)c(F)c2)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
5-(4-Bromo-3-fluoro-phenyl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (820.0 mg, 2.1 mmol) prepared in Step 4 was added to thionyl chloride (7.0 mL). The reaction mixture was stirred at 100° C. for 2 hours and then concentrated under reduced pressure. The resulting residue was concentrated under reduced pressure three times, along with using toluene, to give 5-(4-bromo-3-fluoro-phenyl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carbonyl chloride as a dark brown liquid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:8]=2)[C:3]1=O.[BH4-].[Na+]>>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[C:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:8]=2
Reactant: CC(C)Cc1ccc2c(c1)CC(C)C2=O
Agent: [BH4-]
Agent: [Na+]
Product: CC1=Cc2ccc(CC(C)C)cc2C1
Yield: 93.9 %

Procedure:
Analogously to Example D, 8.3 g (41 mmol) of 2-methyl-5-isobutyl-1-indanone (7) were reduced with 2.4 g (62 mmol) of NaBH4. The alcohol, which was not purified further, was then further reacted in the presence of 0.4 g of p-toluenesulfonic acid in 100 ml of toluene at 80° C. Chromatography on 400 g of silica gel (hexane) gave 7.17 g (95%) of 2-methyl-6-insobutylindene (8).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:22][C:23]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([NH:18][C:19]2[CH:20]=[C:21]([CH:33]=[CH:34][C:35]=2[F:36])[CH2:22][C:23]2([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]2)=[O:11])=[CH:6][CH:7]=1
Reactant: C[C@H](C(C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(F)c(N)c2)CC1
Product: C[C@H]([C@H](C(=O)Nc1cc(CC2(C(=O)OC(C)(C)C)CC2)ccc1F)c1ccc(Cl)cc1)C(F)(F)F

Procedure:
According to General Procedure 6, 1.2 g (4.5 mmol) of (2RS,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid and 1.3 g (4.95 mmol) of tert-butyl 1-(3-amino-4-fluorobenzyl)-cyclopropanecarboxylate gave, after purification of the crude product by flash chromatography (silica gel; mobile phase cyclohexane/ethyl acetate 20:1), 1.6 g (69% of theory) of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][N:17]([C:19]2[CH:24]=[N:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:20]=2)[CH3:18])[CH:10]=1)C1C=CC=CC=1.Cl.C(=O)([O-])O.[Na+]>C(O)C>[C:25]1([C:22]2[N:23]=[CH:24][C:19]([N:17]([CH2:16][CH2:15][C:11]3[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=3)[CH3:18])=[N:20][C:21]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN(CCc1cccc(OCc2ccccc2)c1)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(CCc1cccc(O)c1)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 17 h
Yield: 91.9 %

Procedure:
To 1.17 g of 1-(benzyloxy)-3-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]ethyl}benzene, 12 ml of ethanol and 6 ml of hydrochloric acid were added, followed by heating with stirring at 80° C. for 17 hours. The reaction solution was air-cooled to room temperature, neutralized with an aqueous saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The crude crystal was washed with diisopropyl ether and then dried to obtain 0.87 g of the desired compound as a pale yellow crystal having a melting point of 158 to 161° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.[CH2:24]([O:26][CH2:27][C:28](O)=[O:29])[CH3:25]>>[CH:21]1[C:22]2[C:9]3([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:28](=[O:29])[CH2:27][O:26][CH2:24][CH3:25])[CH2:3][CH2:4]4)[CH2:23][CH:16]([C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: CCOCC(=O)O
Product: CCOCC(=O)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1

Procedure:
Using a procedure similar to that described in Example 1 except starting with 4-amino-1-[9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]piperidine and 2-ethoxyacetic acid, the title compound was obtained as a white solid (76%), mp 158.0°-9.0° C.; MS(CI): 391 (M+H); NMR (300 MHz,DMSO-d6): 1.12(t, 3H, J=7.0 Hz), 1.41-1.69(m, 4H), 2.27(m, 2H), 2.45(s, 2H), 2.95(m, 2H), 2.95(m, 2H), 3.45(q, 2H, J=7.0 Hz), 3.63(m, 1H), 3.78(s, 2H), 4.31(s, 1H), 6.92(m, 4H), 7.17-7.23(m, 4H), 7.47(d, 2H, J=8.0 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH2:7][N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([O-])=O.[NH4+].[Cl-]>O.CO.[Fe]>[N:8]1([CH2:7][C:6]2[CH:5]=[C:4]([CH:17]=[CH:16][CH:15]=2)[NH2:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=[N+]([O-])c1cccc(CN2CCCCCC2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1cccc(CN2CCCCCC2)c1
Yield: 89.6 %

Procedure:
To a solution of 1-(3-nitro-benzyl)-azepane (4.0 g, 17.05 mmol) in 120 mL of 20% H2O/MeOH is added 5.05 g (102.3 mmol) of fresh iron powder, 8.25 g (153.5 mmol) of NH4Cl and the reaction mixture is refluxed under N2 for 45 min. The reaction mixture is filtered through a pad of celite to give yellow solution. After evaporating to dryness, the yellow residue is dissolved in EtOAc, washed twice with saturated NaHCO3 solution. After drying over Mg2SO4, the organic solution is filtered and concentrated to give 3.12 g (89.4% yield) of yellow oil.
Reaction SMILES: [O:1]=[C:2]([CH2:16][C@@H:17]([O:23][C:24]([O:26][CH2:27][C:28]([Cl:31])([Cl:30])[Cl:29])=[O:25])[C@@H:18]([CH3:22])[CH2:19][CH:20]=[CH2:21])[C:3]([CH3:15])([CH3:14])[C@@H:4]([OH:13])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].N1C=CN=C1.[CH2:37]([Si:39](Cl)([CH2:42][CH3:43])[CH2:40][CH3:41])[CH3:38].O>CN(C)C=O>[O:1]=[C:2]([CH2:16][C@@H:17]([O:23][C:24]([O:26][CH2:27][C:28]([Cl:29])([Cl:30])[Cl:31])=[O:25])[C@@H:18]([CH3:22])[CH2:19][CH:20]=[CH2:21])[C:3]([CH3:14])([CH3:15])[C@@H:4]([O:13][Si:39]([CH2:42][CH3:43])([CH2:40][CH3:41])[CH2:37][CH3:38])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: C=CC[C@H](C)[C@@H](CC(=O)C(C)(C)[C@@H](O)CC(=O)OC(C)(C)C)OC(=O)OCC(Cl)(Cl)Cl
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C=CC[C@H](C)[C@@H](CC(=O)C(C)(C)[C@H](CC(=O)OC(C)(C)C)O[Si](CC)(CC)CC)OC(=O)OCC(Cl)(Cl)Cl

Procedure:
A solution of tert-butyl (3S,7R,8S)-5-oxo-3-hydroxy-4,4,8-trimethyl-7-(2,2,2-trichloroethoxycarbonyloxy)-10-undecenoate (1.7 g), imidazole (0.48 g), and triethylsilyl chloride (0.68 g) in 5 mL of dimethylformamide is stirred for 2 hours at ambient temperature, then poured into water and extracted with ether. The extract is washed with sat. aq. NaCl, dried over MgSO4, filtered, and evaporated. The product is purified by chromatography on SiO2.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([Cl:10])[CH:3]=1.Cl.[CH3:12][O:13][C:14](=[O:17])[CH2:15][NH2:16].C(N(CC)CC)C.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:16][CH2:15][C:14]([O:13][CH3:12])=[O:17])=[C:4]([Cl:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1Cl
Reactant: COC(=O)CN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)CNCc1ccc(Br)cc1Cl
Temperature: 50 °C
Yield: 31.5 %

Procedure:
4-bromo-2-chlorobenzaldehyde (2B1) (4.56 mmol, 1.0 g) and glycine methyl ester hydrochloride (2C2) (4.56 mmol, 572 mg) were dissolved in ethanol (15 ml) under nitrogen with stirring and triethylamine (135 mmol, 19.0 ml, 13.7 g) was added. The reaction mixture was heated to 50° C. for 1 hour, then evaporated to dryness and the residue taken up in methanol (15 ml) and cooled in an ice bath. Sodium borohydride (5.01 mmol, 0.190 g) was added portionwise and stirring continued until no starting material remained as determined by TLC. The reaction mixture was concentrated to dryness and partitioned between DCM and water and the phases separated. The organic layer was dried over sodium sulphate, filtered and concentrated before purification on silica eluting with 15% EtOAc/heptane to yield methyl 2-(4-bromo-2-chlorobenzylamino)acetate (2C3) 420 mg (31%); 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H) 7.38 (d, 1H) 7.31 (d, 1H) 3.86 (s, 2H) 3.73 (s, 3H) 3.43 (s, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:16]2[CH2:17][CH2:18][N:19]([CH:22]3[CH2:25][O:24][CH2:23]3)[CH2:20][CH:21]=2)=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=1.CCOC(C)=O>CCO.[Pd]>[F:1][C:2]1[C:3]([CH:16]2[CH2:17][CH2:18][N:19]([CH:22]3[CH2:25][O:24][CH2:23]3)[CH2:20][CH2:21]2)=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(F)c1C1=CCN(C2COC2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cncc(F)c1C1CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 46 h
Yield: 96.7 %

Procedure:
Pd on C, wet, Degussa (70 mg, 0.06578 mmol) was added to a stirred solution of tert-butyl N-[5-fluoro-4-[1-(oxetan-3-yl)-3,6-dihydro-2H-pyridin-4-yl]-3-pyridyl]carbamate (180 mg, 0.5152 mmol) in EtOH (5 mL)/EtOAc (5 mL). The reaction was placed under an atmosphere of hydrogen and stirred at ambient temperature for 46 hours. The catalyst was removed by filtration through a pad of celite and the filtrate concentrated in vacuo to give tert-butyl (5-fluoro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-3-yl)carbamate as an off-white solid (175 mg, 97% Yield). MS (ES+) 352.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:29]1[CH2:30][CH2:31][N:26]([C:21]3[N:20]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:27][CH2:28]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2ncccn2)CC1
Yield: 79 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-pyrimidyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 79%). 1H NMR (200 MHz, CDCl3): δ 3.69 (s, 4H), 3.98 (s, 4H), 4.14 (s, 3H), 6.54 (t, J=4.8 Hz, 1H), 7.21-7.41 (m, 3H), 7.79 (t, J=8.4 Hz, 1H), 8.34 (d, J=4.8 Hz, 2H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[O:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1>[Fe].CCO>[F:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1)[NH2:9]
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCCCN1CCCC1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCCCN1CCCC1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Iron powder (61.42 g, 1.1 mol) and hydrochloric acid (6 mL) were added to 90% EtOH (25v/w, 1210 mL). The mixture was warmed up to 80° C. and stirred for 15 min. Then Intermediate VIII (48.42 g, 0.11 mol) was added in batch to the reaction solution. After the addition completion, the reaction was conducted under reflux for 2 h. After completion of the reaction, the reaction was filtered by suction when it is still hot. The filtrate was collected. The solvate was evaporated off to produce a yellow solid (43 g) in a yield of 95%.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[N:18]=[C:17]([O:19][C:20]3[N:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=3)[CH:16]=[C:15]([CH2:29][CH3:30])[N:14]=2)[CH:10]=[CH:11][CH:12]=1>C(=O)(O)[O-].[Na+]>[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[N:18]=[C:17]([O:19][C:20]3[N:25]=[CH:24][C:23]([CH2:26][C:27]([NH2:28])=[O:2])=[CH:22][CH:21]=3)[CH:16]=[C:15]([CH2:29][CH3:30])[N:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CCc1cc(Oc2ccc(CC#N)cn2)nc(-c2cccc(Cl)c2)n1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCc1cc(Oc2ccc(CC(N)=O)cn2)nc(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
Sulfuric acid (2 mL) was added to 2-(6-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)oxy)pyridin-3-yl)acetonitrile (0.061 g, 0.18 mmol) at 0° C. and slowly warmed to rt. The mixture was stirred for 2 h, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/methanol) to afford the title compound (0.020 g, 34%) as a white solid. MW=368.22. 1H NMR (DMSO-d6, 300 MHz) δ 8.44-8.37 (m, 2H), 8.10-8.05 (m, 1H), 7.92 (s, 1H), 7.70-7.56 (m, 2H), 7.53-7.43 (m, 2H), 7.01 (s, 1H), 6.55 (d, J=9.4 Hz, 1H), 3.30 (d, 2H), 2.93 (q, J=7.6 Hz, 2H), 1.33 (t, J=7.6 Hz, 3H); APCI MS m/z 369 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][CH:8]([CH3:24])[CH2:9][CH:10]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH2:13][NH:12][C:11]1=O.C(OCC)(=O)C>C1COCC1>[CH3:7][CH:8]([CH3:24])[CH2:9][CH:10]1[CH2:11][NH:12][CH2:13][CH2:14][N:15]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)CC1C(=O)NCCN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CC1CNCCN1Cc1ccccc1

Procedure:
Lithium aluminum hydride (3.56 g., 0.094 mole) is added to a stirred solution of 3-(2-methylpropyl)-4-(phenylmethyl)piperazinone (XL, Example 72, 17.43 g., 0.075 mole) in THF (720 ml.). The solution is refluxed for 5 hours and is then cooled. Ethyl acetate is added and the product is partitioned between ether and water. The ether is removed and the product is distilled to give the title compound, a b.p. of 98° at 0.05 mm pressure.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23](OCC)=[O:24])[CH2:18][CH2:17]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[NH2:28][NH2:29]>C(O)C>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]([NH:28][NH2:29])=[O:24])[CH2:18][CH2:17]2)=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: NN
Reactant: CCOC(=O)CN1CCN(Cc2c3ccccc3cc3ccccc23)CC1
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2c3ccccc3cc3ccccc23)CC1

Procedure:
Synthesized according to General Procedure C: 6{21} (6.82 g, 18.8 mmol, 1 equiv.), anhydrous hydrazine (1.8 mL, 56.4 mmol, 3 equiv.), ethanol (38.0 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{21} (3.56 g, 54%) as an orange semi-solid. 1H-NMR (500 MHz, CDCl3): δ 8.46 (d, 2H, J=8.5 Hz), 8.42 (s, 1H), 8.21 (br s, 1H), 8.01 (d, 2H, J=8.5 Hz), 7.53 (ddd, 2H, J=1.5, 6.5, 8.0 Hz), 7.47 (ddd, 2H, J=1.0, 6.5, 8.0 Hz), 4.45 (s, 2H), 3.87 (br s, 2H), 3.04 (s, 2H), 2.64 (br s, 4H), 2.47 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.5, 131.3, 131.3, 129.2, 128.9, 127.5, 125.6, 124.9, 124.8, 60.4, 54.0, 53.7, 53.1.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17]>C(Cl)Cl>[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: COc1ccccc1CCNS(C)(=O)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CS(=O)(=O)NCCc1ccccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
Boron tribromide (1.0 M in CH2Cl2, 80.8 mL, 80.8 mmol) was added to a solution of N-[2-(2-methoxy-phenyl)-ethyl]-methanesulfonamide (18.5 g, 80.8 mmol) in CH2Cl2 (200 mL). The reaction was stirred at room temperature for 2 h and was poured onto water (200 mL). The aqueous layer was extracted with CH2Cl2 (2×) and the organic solution was washed with water (1×) and aqueous NaHCO3 (satd, 1×). The organic solution was dried over MgSO4, filtered, and concentrated to afford N-[2-(2-hydroxy-phenyl)-ethyl]-methanesulfonamide (16.8 g). 1H NMR (400 MHz, CDCl3) δ 7.11 (m, 2H), 6.86 (m, 1H), 6.80 (m, 1H), 4.79 (m, 1H), 3.39 (t, 2H), 2.88 (t, 2H), 2.77 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].[C:25]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1.O>[C:25]1([CH:31]2[CH2:32][CH2:33][N:34]([C:11]([N:9]3[CH2:10][CH:7]([O:6][C:5]4[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=4)[CH2:8]3)=[O:12])[CH2:35][CH2:36]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N1CCC(c2ccccc2)CC1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 37.1 %

Procedure:
A mixture of 2.8 g (0.01 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1.4 g (0.01 mole) of potassium carbonate in 25 ml of tetrahydrofuran was stirred for 10 min then treated with 1.6 g (0.01 mole) of 4-phenylpiperidine. After stirring for 30 min, approximately 2 g of ice was added and stirring continued for 18 hr. The reaction mixture was diluted with 200 ml of water and the oil which separated was extracted into methylene chloride (2×50 ml). The extracts were combined, dried and concentrated in vacuo to yield 4.95 g of crude oil which solidified when cooled to -78° C. Recrystallization from isopropyl ether yielded 1.5 g (37%) of coarse white crystals, m.p. 72°-74° C.
Reaction SMILES: C([NH:4][CH:5]([N:7]1[C:11]([SH:12])=[N:10][N:9]=[N:8]1)[CH3:6])(=O)C.[ClH:13]>>[ClH:13].[NH2:4][CH:5]([N:7]1[C:11]([SH:12])=[N:10][N:9]=[N:8]1)[CH3:6]
Reactant: CC(=O)NC(C)n1nnnc1S
Agent: Cl
Product: CC(N)n1nnnc1S
Yield: 77 %

Procedure:
A mixture of 61.3 g. (0.3274 M.) 1-acetamidoethyl-5-mercaptotetrazole and 313 ml. 6 N HCl (196 mg./ml.; 1.888 M.) was heated at reflux for 2 hours. The resulting solution was treated with 10 g. carbon and evaporated at 45° C. (15 mm.) to a solid which was triturated with 90 ml. glacial acetic acid, washed with 250 ml. ether and dried in vacuo over P2O5 to give 45.6 g. (77% yield) of 1-aminoethyl-5-mercaptotetrazole hydrochloride.