Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([OH:9])=O)[O:3]1.[NH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>>[O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([NH:10][CH2:11][CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)=[O:9])[O:3]1
Reactant: O=C(O)c1c[nH]c(=O)o1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Product: CC(C)(C)OC(=O)N1CCC(CCNC(=O)c2c[nH]c(=O)o2)CC1

Procedure:
The title compound was prepared from 2-oxo-2,3-dihydrooxazole-5-carboxylic acid (step 1) and tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate analogously to Example 20 step 4;
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([CH3:8])[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:16]>O1CCOCC1>[ClH:16].[ClH:16].[CH3:8][N:7]1[CH2:6][CH2:5][NH:4][CH2:3][C@@H:2]1[CH3:1]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CNCCN1C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl (3S)-3,4-dimethyl-1-piperazinecarboxylate (3.15 g, 14.7 mmol) in 1N HCl (40 mL) was stirred overnight. Then 4M HCl in 1,4-dioxane (25 mL) was added and the reaction was left to stir overnight. Removed volatiles in vacuo to provide (2S)-1,2-dimethylpiperazine dihydrochloride as a white solid (2.88 g). LCMS: (M+H)+=115.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][C:10](O)=[S:11].S(Cl)([Cl:15])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][C:10]([Cl:15])=[S:11]
Reactant: O=S(Cl)Cl
Reactant: OC(=S)Cc1cc(Cl)ccc1Cl
Solvent: ClCCl
Product: S=C(Cl)Cc1cc(Cl)ccc1Cl
Temperature: 25 °C
Yield: 106.5 %

Procedure:
A solution of 2,5-dichlorophenylthioacetic acid (13.0 g, 54.9 mmol) in methylene chloride (55 mL) and thionyl chloride (10 mL, 137 mmol) was heated at reflux for 3 h. The reaction mixture was allowed to cool to room temperature and was concentrated in vacuo. The residue was evaporated two times from toluene to give 14 g of 2,5-dichlorophenyl-thioacetyl chloride (100% yield) as a slightly colored product which was used in the next step without purification. 1H NMR (300 MHz, CDCl3) δ4.13 (s, 2H), 7.22 (dd, J=2, 9 Hz, 1H), 7.35 (d, J=9 Hz, 1H), 7.39 (d, J=2 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH:28]([C:29]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:20])[CH3:21])[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CO)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1COC(=O)Nc1ccccc1

Procedure:
Using ethyl 3-[3-(hydroxymethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and phenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:36]=[CH:37][C:38]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][N:15]4[CH2:16][CH2:17][CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:19][CH2:20]4)=[CH:6][CH:7]=3)=[CH:39][CH:40]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CN1CCC(c2ccccc2)CC1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN4CCC(c5ccccc5)CC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-4-phenyl-piperidine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[N+:9]([C:12]1[O:16][C:15]([C:17]2[C:21]([CH:22]=O)=[CH:20][N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:18]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]>CN(C)C=O>[N+:9]([C:12]1[O:16][C:15]([C:17]2[C:21]([CH:22]=[N:7][OH:8])=[CH:20][N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:18]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: NO
Reactant: O=Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2nn(-c3ccccc3)cc2C=NO)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Add (while stirring) 7.61 g of sodium acetate and 6.58 g of hydroxylamine hydrochloride to 25.0 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxaldehyde in 75 ml of dimethylformamide, the temperature rising slightly. Stir for a further 45 minutes at from 30° to 35° C and for one hour at room temperature. Clafify with degased active charcoal and then pour the solution onto 1 kg of ice and water. Vacuum filter and wash with water to obtain 98% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxaldehydeoxime [m.p. 199° to 201° C with decomposition (from toluene)].
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][C@H:8]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:17][C:16]=1[O:26][CH2:27][CH2:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:14])=[O:13])[CH:9]=[O:10])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:29]1([CH2:28][CH2:27][O:26][C:16]2[CH:17]=[C:18]([N:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[CH:19]=[CH:20][C:15]=2[S:12]([NH:11][C@H:8]([CH:9]=[O:10])[CH2:7][C:6]([OH:39])=[O:5])(=[O:13])=[O:14])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](C=O)NS(=O)(=O)c1ccc(N2CCCC2)cc1OCCc1cccc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C[C@H](CC(=O)O)NS(=O)(=O)c1ccc(N2CCCC2)cc1OCCc1cccc2ccccc12
Yield: 34.8 %

Procedure:
A solution of (S)-3-[2-(2-naphthalen-1-yl-ethoxy)-4-pyrrolidin-1-yl-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester (0.60 g, 1.10 mmol) in TFA (2 mL) and CH2Cl2 (20 mL) was stirred for 3 h. After the solvent was removed under vacuum, the residue was subjected to preparative reverse-phase HPLC (VYDAC, C18) using linear gradient of water containing 0.1% TFA and acetonitrile containing 0.1% TFA (20-65% acetonitrile, in 120 min) at a flow rate of 20 mL/min. Fractions containing the major peak were pooled and lyophilized to yield 0.190 g (60%) of (S)-3-[2-(2-naphthalen-1-yl-ethoxy)-4-pyrrolidin-1-yl-benzenesulfonyl amino]-4-oxo-butyric acid. MS (APCI) m/z 496.1 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:18]([O-])=O)[C:12]=1[NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]([O:8][CH3:9])=[O:7])=[O:2]>C(O)C.[Pt]=O>[NH2:18][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([CH2:1][OH:2])[C:12]=1[NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(C=O)c(NS(C)(=O)=O)c([N+](=O)[O-])c1
Agent: O=[Pt]
Solvent: CCO
Product: COC(=O)c1cc(N)c(NS(C)(=O)=O)c(CO)c1
Yield: 44.2 %

Procedure:
Methyl 3-formyl-4-[(methylsulfonyl)amino]-5-nitrobenzoate (2.0 g, 0.0066 mol) was dissolved in ethanol (50 mL) and hydrogenated at 30 psi in the presence of platinum oxide (Aldrich, 0.1 g) for 4 h. The catalyst was removed by filtration through Celite and the filtrate was concentrated to dryness. The residue was recrystallized from methanolethyl acetate-hexane to give 0.8 g (44%) of methyl 3-amino-5-hydroxymethyl-4-[(methylsulfonyl)amino]benzoate as a light brown powder, mp 150°-155° C.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[CH3:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[O:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=2)=[CH:11][CH:10]=1.C(Cl)Cl>O>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2=[C:13]3[C:18]=1[CH:17]=[CH:16][CH:15]=[C:14]3[C:2](=[O:3])[C:23]1[C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[O:20][C:19]=12
Reactant: COc1ccc(-c2cc3ccccc3o2)c2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c3c(cccc13)C(=O)c1c-2oc2ccccc12
Reaction time: 1.5 h

Procedure:
Alternatively, 3-methoxy-7-oxo-7H-benzo[b]-phenaleno[2,1-d]furan was prepared by addition of 0.38 ml. (45 mmol.) of oxalyl chloride followed by 1.2 ml. (0.01 mol.) of stannic chloride to a solution of 1 g. (37 mmol.) of 2-(4-methoxynaphthyl)benzofuran in 100 ml. of methylene chloride at 0°. The reaction mixture was stirred for 1.5 hours at 0° then poured into water. The layers were separated and the organic phase was washed with 10% aqueous sodium carbonate, dried (MgSO4) and evaporated to dryness. The residue was chromatographed on silica with chloroform as eluant to give the product.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[CH2:19][CH2:18]2)[N:4]=1>O1CCCC1>[NH2:1][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[CH2:19][CH2:18]2)[N:4]=1
Reactant: N
Reactant: COc1cc2nc(N3CCN(C(=O)C4CCCC4)CC3)nc(Cl)c2cc1OC
Solvent: C1CCOC1
Product: COc1cc2nc(N3CCN(C(=O)C4CCCC4)CC3)nc(N)c2cc1OC

Procedure:
A mixture of anhydrous ammonia and 4-chloro-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline in 100 ml. of tetrahydrofuran is heated at 100° C. for a period of 16 to 24 hours and the product isolated according to the procedure of Example 127(a) to provide 4-amino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl)-6,7-dimethoxyquinazoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:6]=[CH:5][N:4]=1.[CH3:15][S:16]([C:19]1[CH:20]=[C:21]([C:31](O)=[O:32])[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)(=[O:18])=[O:17]>>[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:21]([C:31]([N:12]2[CH2:13][CH2:14][N:9]([C:7]3[N:8]=[C:3]([O:2][CH3:1])[N:4]=[CH:5][N:6]=3)[CH2:10][CH2:11]2)=[O:32])[CH:20]=1)(=[O:17])=[O:18]
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Reactant: COc1ncnc(N2CCNCC2)n1
Product: COc1ncnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3-c3ccccc3)CC2)n1

Procedure:
The tide compound was prepared according to the procedure E described for Example 9 from 2-Methoxy-4-piperazin-1-yl-[1,3,5]triazine [59215-45-1] and 4-Methanesulfonyl-biphenyl-2-carboxylic acid (Example V). MS (ISP): 454.5 MH+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH2:30][CH:31]=[CH2:32])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:42])C=1.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH2:30][CH:31]3[CH2:32][O:42]3)[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC(=O)N1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C(=O)CC2CO2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-(3-Butenoyl)-piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (27) (1.00 g; 2.24 mmol) and m-chloroperbenzoic acid (Aldrich Chemical Company; 71% by assay; 0.65 g; 2.91 mmol) are combined in 10 mL of methylene chloride and refluxed for 24 hours. The solution is stirred at ambient temperature for 72 hours, diluted with methylene chloride (50 mL) and shaken with 10% aqueous Na2SO3 (50 mL). The methylene chloride layer is separated and washed successively with saturated aqueous NaHCO3 solution and brine. The organic layer is dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel using a gradient elution (80%→90% ethyl acetate in hexanes, then 50%→60% acetone in hexanes) affording 28 as a solid. CIMS (NH3Cl): 463 (MH+)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:4]=1[OH:12].[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>C(O)C>[F:1][C:2]([F:13])([F:14])[C:3]1[C:4]([OH:12])=[C:5]([CH:6]=[CH:7][CH:8]=1)[NH2:9]
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc(C(F)(F)F)c1O
Temperature: 25 °C
Yield: 94.6 %

Procedure:
To the solution of 2-trifluoromethyl-6-nitrophenol (4.2 g, 20.3 mmol) in ethanol (20 ml, Tin (II) chloride (22.9 g, 101 mmol) was added. The reaction mixture was stirred at reflux for about 4 hours, tThen it was cooled to room temperature. The NaHCO3 (aq) was added until pH=7 was obtained and then the mixture was extracted with ethyl acetate (3×). The combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give desired product (3.4 g, 94%). EI-MS m/z 178 (M+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)=[C:11]([Cl:31])[CH:10]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[Cl:31][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[C:13]([Cl:15])[C:12]=1[O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][N:22]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1ccc(OCCCOc2c(Cl)cc(OCc3ccccc3)cc2Cl)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1cc(Cl)c(OCCCOc2ccc(C(F)(F)F)cn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
A reaction vessel was charged with 0.5 g of 1-benzyloxy-3,5-dichloro-4-(3-(5-trifluoromethylpyridin-2-yloxy)propyloxy)benzene and 50 ml of ethyl acetate, and the air in the vessel was replaced with nitrogen. Then, 0.3 g of 10% palladium carbon was added, and the nitrogen in the vessel was replaced with hydrogen, followed by stirring at room temperature for 24 hours. The hydrogen in the vessel was replaced with nitrogen, after which the reaction mixture was filtered through Celite, and the filtrate was concentrated, which afforded 0.36 g of 3,5-dichloro-4-(3-(5-trifluoromethylpyridin-2-yloxy)-propyloxy)phenol (92% yield).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][N:13]2[CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=3)[O:25][C:26]=2[CH3:27])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: Cc1oc(-c2ccc(C(C)C)cc2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc2cc[nH]c2c1)OCC
Product: CCOC(Cc1ccc2ccn(Cc3nc(-c4ccc(C(C)C)cc4)oc3C)c2c1)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-ethoxy-3-(1H-indol-6-yl)-propionic acid ethyl ester (preparation 11) was reacted with 4-chloromethyl-2-(4-isopropyl-phenyl)-5-methyl-oxazole to give rac-2-ethoxy-3-{1-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-6-yl}-propionic acid as light yellow viscous oil.
Reaction SMILES: [C:1]([C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:12]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[N:26]=[C:25]([O:27]CC=C)[CH:24]=[CH:23][CH:22]=4)[C:16](=[O:31])[CH2:15]3)=[CH:11][N:10]=[C:9]2[CH3:32])=[CH:5][C:4]=1[F:35])#[N:2].[BH4-].[Na+]>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:12]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[N:26]=[C:25]([OH:27])[CH:24]=[CH:23][CH:22]=4)[C:16](=[O:31])[CH2:15]3)=[CH:11][N:10]=[C:9]2[CH3:32])=[CH:5][C:4]=1[F:35])#[N:2]
Reactant: C=CCOc1cccc(CN2CCN(Cc3cnc(C)n3Cc3ccc(C#N)c(F)c3)CC2=O)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncc(CN2CCN(Cc3cccc(O)n3)C(=O)C2)n1Cc1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of the allyl ether from Step E (89.6 mg, 0.189 mmol) in 2 mL of tetrahydrofuran was added tetrakis(triphenylphosphine)palladium (4.3 mg, 0.0037 mmol). After 5 minutes, sodium borohydride was added (10.7 mg, 0.283 mmol), and the reaction was stirred at room temperature for 30 minutes. The reaction was quenched with saturated NH4Cl solution, then partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the desired product as a yellow foam.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.S(=O)(=O)(O)O.[Br:24]N1C(=O)CCC1=O>>[Br:24][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[C:4]=1[CH3:8]
Reactant: Cc1cccc(F)c1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Br)ccc(F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.9 %

Procedure:
A 250 mL single neck flask equipped with magnetic stirrer was charged with 3-fluoro-2-nitrotoluene (4.75 g, 30.6 mmol) and trifluoroacetic acid (20 mL). Sulfuric acid (96%, 10 mL) was added dropwise over 10 minutes at 0° C. followed by N-bromosuccinimide (8.12 g, 45.6 mmol) in portions over 15 min (causing an exotherm of 3° C.). The reaction was stirred at 0° C. for 20 min and then stirred at mom temperature for 3.5 h. After this time, the reaction mixture was poured in to a 1:1 mixture of ice/water (500 mL), diluted with 95:5 hexanes/methylene chloride (250 mL) and the layers were separated. The aqueous layer was extracted with hexanes (100 mL) and the combined organic layers were washed with water (2×100 mL), saturated aqueous sodium bicarbonate (100 mL), brine (100 mL) and dried over sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was suspended in hexanes (40 mL) and heated until dissolved. The solution was evaporated to a volume to 20 mL and allowed to cool to room temperature overnight. The product was filtered and washed with cold hexanes (3×2 mL) to afford (C) (4.29 g, 60%) as a yellow crystalline solid. The filtrate was concentrated to dryness and the residue was dissolved in hot hexanes (5 mL). After cooling to room temperature, stirring for 2 h, and filtering, an additional 1.30 g of C (18%) was isolated.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[NH2:19][CH2:20][CH2:21][C:22]1[N:26]=[CH:25][NH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[NH:26]1[C:22]([CH2:21][CH2:20][NH:19][CH:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[CH2:12][CH2:13]2)=[CH:23][N:24]=[CH:25]1
Reactant: NCCc1c[nH]cn1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1ncc(CCNC2CCC(Nc3ccc4[nH]ncc4c3)CC2)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 1.2 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and histamine hydrochloride (92 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (1 mg) and a syn-form compound (2 mg).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][C:23](=[O:25])[NH:22][C:21]([CH3:26])=[C:20]2[C:27](O)=[O:28])=[CH:15][C:14]=1[O:30][CH3:31].C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:27]([C:20]3[CH:19]([C:16]4[CH:17]=[CH:18][C:13]([Cl:12])=[C:14]([O:30][CH3:31])[CH:15]=4)[CH2:24][C:23](=[O:25])[NH:22][C:21]=3[CH3:26])=[O:28])[CH:9]=2)[NH:4][N:3]=1
Reactant: COc1cc(C2CC(=O)NC(C)=C2C(=O)O)ccc1Cl
Reactant: Nc1ccc2[nH]nc(Br)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc(C2CC(=O)NC(C)=C2C(=O)Nc2ccc3[nH]nc(Br)c3c2)ccc1Cl
Temperature: 30 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
3-Bromo-1H-indazol-5-amine (126 mg, 0.592 mmol, 1.00 equiv) was combined with the product from Example 93, Step 4 (175 mg, 0.592 mmol, 1.00 equiv), EDC (134 mg, 0.710 mmol, 1.20 equiv) and Et3N (99 μL, 0.710 mmol, 1.20 equiv) in DMF (1.75 mL) and stirred at 30° C. for 18 hours. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. Solid precipitated out of the organic phase and was filtered and triturated with ether to provide 145 mg (50%) of the title compound as a white solid. MS (ES+) m/e 490 [M+H]+
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:22])([F:21])[C:5]1[CH:6]=[C:7]([S:11]([N:14]2[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1>CO>[F:22][C:4]([F:3])([F:21])[C:5]1[CH:6]=[C:7]([S:11]([N:14]2[CH2:15][CH2:16][CH:17]([OH:20])[CH2:18][CH2:19]2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
NaBH4 (180 mg, 4.74 mmol) was added to a solution of 1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-one (2.56 g, 8.34 mmol) in methanol (15 ml) at 0° C., and stirred at room temperature for 1 hour. The reaction was quenched with H2O (50 ml) and extracted with ethyl acetate (20 ml×2). The combined organic phase was washed with H2O (20 ml×2) and brine (20 ml×2), dried over Na2SO4 and concentrated in vacuo to give 1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-ol (2.17 g, 84%) as a white solid: LCMS: 310 [M+1]+.
Reaction SMILES: Br[CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1.[C-:9]#[N:10].[Na+]>C(O)C>[OH:8][CH2:7][C:3]1([CH2:2][C:9]#[N:10])[CH2:6][O:5][CH2:4]1
Reactant: [C-]#N
Reactant: OCC1(CBr)COC1
Agent: [Na+]
Solvent: CCO
Product: N#CCC1(CO)COC1
Temperature: 25 °C

Procedure:
A solution of 42 g (0.23 mol) of [3-(bromomethyl)oxetan-3-yl] methanol (produced according to Example 1) in 420 ml of ethanol was refluxed with 13 g (0.265 mol) of sodium cyanide for 18 hours. After cooling to room temperature, the precipitated sodium bromide was filtered off and the filtrate concentrated by evaporation. The residue was distilled at 0.4 torr. The yield of product as a colorless oil was 16 g (54 percent). The boiling point of the product was 107° C./0.4 torr. Other data concerning the product was: