Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3](CC)CC)C.[ClH:8].Cl.[N:10]1([CH2:15][CH:16]([N:18]2[C:31]3[CH:30]=[C:29]([C:32](=[NH:36])OCC)[CH:28]=[CH:27][C:26]=3[S:25][C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C>[ClH:8].[N:10]1([CH2:15][CH:16]([N:18]2[C:31]3[CH:30]=[C:29]([C:32]([NH2:36])=[NH:3])[CH:28]=[CH:27][C:26]=3[S:25][C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=N)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCO
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=N)N)cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Triethylamine (8.4 cc) is added to a solution of ethyl 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboximidate dihydrochloride (13.63 g) in absolute ethanol (150 cc), and the reaction mixture is diluted with dry ethanol (100 cc). Gaseous ammonia is bubbled for 4 hours into the reaction mixture, which is then stirred for 12 hours at 25° C. The suspension obtained is filtered on sintered glass and the filtrate is concentrated to dryness at 25° C. under reduced pressure (30 mm Hg; 4 kPa) to give a yellow product of meringue-like consistency, which is purified by chromatography on a column of alumina (height: 23 cm; diameter: 4 cm), eluting with mixtures of methylene chloride and methanol in proportions of 95:5 (750 cc) and 50:50 (1,500 cc) and collecting 125-cc fractions. The first 900 cc of eluate are discarded and fractions 8 to 11 are combined and concentrated to dryness at 25° C. under reduced pressure (30 mm Hg; 4 kPa) to give 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamidine hydrochloride (4.5 g) in the form of a yellow product of meringue-like consistency.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH2:18][N:19]([CH:29]1[C:38]2[N:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH2:32][CH2:31][CH2:30]1)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1.[BH4-].[Na+]>CO>[CH2:1]([NH:28][CH2:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:19]([CH2:18][C:10]2[NH:9][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH:29]2[C:38]3[N:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH2:32][CH2:31][CH2:30]2)=[CH:22][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNCc2ccc(CN(Cc3nc4ccccc4[nH]3)C3CCCc4cccnc43)cc2)cc1
Yield: 25.9 %

Procedure:
Benzaldehyde (0.5 mL, 4.92 mmol) was condensed with N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (170 mg, 0.428 mmol) in dry MeOH (3 mL) for 17 h at room temperature and the resultant imine was reduced with sodium borohydride (329 mg, 8.70 mmol) for 1 h (see General Procedures A and B). Purification of the crude product by flash chromatography (14 g silica, 30:1:1 EtOAc/CH3OH/NH4OH) followed by radial chromatography (2 mm TLC plate, 100:1:1 CH2Cl2/CH3OH/NH4OH) gave the N-alkylated product (54 mg, 26%) as a foam.
Reaction SMILES: [C:1]([O:9][CH:10]([C:18](=[O:20])[CH3:19])[C:11](=[O:17])[CH:12]=[CH:13]N(C)C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C>[C:1]([O:9][C:10]1[C:11](=[O:17])[CH:12]=[CH:13][O:20][C:18]=1[CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(OC(=O)c1ccccc1)C(=O)C=CN(C)C
Solvent: CC(=O)O
Product: Cc1occc(=O)c1OC(=O)c1ccccc1
Yield: 97.1 %

Procedure:
4-Benzoyloxy-1-dimethylamino-1-hexene-3,5-dione (24.75 g, 90 mmol) is refluxed in 180 ml of acetic acid for 90 minutes. The reaction mixture is concentrated at 30°-35° C. on a rotary evaporator, the residue is dissolved in 200 ml of dichloromethane and washed twice with 100 ml of saturated sodium bicarbonate solution each time. The organic phase is dried over magnesium sulphate, concentrated on a rotary evaporator and gives 20.11 g (97.1%) of 3-benzoyloxy-2-methyl-4-pyrone. Content 86%, m.p. 106°-110° C.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21])[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:29]1[C:30]([CH3:38])=[CH:31][C:32]2[N:33]([N:35]=[CH:36][N:37]=2)[N:34]=1>O1CCCC1>[C:22]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][C:29]3[C:30]([CH3:38])=[CH:31][C:32]4[N:33]([N:35]=[CH:36][N:37]=4)[N:34]=3)[CH2:14][CH2:15]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cc2ncnn2nc1Cl
Reactant: OCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2ncnn2nc1OCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Yield: 48.2 %

Procedure:
260 mg of 60% sodium hydride dispersion in mineral oil was suspended in 20 ml of tetrahydrofuran; 1.15 g of 4-(diphenylmethyl)-1-[2-(2-hydroxyethoxy)ethyl]piperazine was added, followed by heating and refluxing for 1 hour. After cooling, 540 mg of 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine was added, followed by heating and refluxing for 3 hours. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. After the dry product was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with dichloromethane-ethyl acetate-methanol (10:10:1). The desired fraction was collected; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 730 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C([Li])CCC.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].[NH4+].[Cl-]>C1COCC1.ClCCl>[CH:7]1[C:8]2[C:3](=[C:2]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Brc1cccc2cnccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
The product from Example 57A (11.80 g, 56.6 mmol) in THF (200 mL) at −78° C. was treated with n-butyllithium (30 mL, 75.0 mmol, 2.5M in hexanes) dropwise. After 30 minutes, the mixture was treated with diethyl oxalate (25.0 mL, 184 mmol). After 20 minutes, the solution was allowed to warm to room temperature and was treated with saturated NH4Cl (150 mL). The mixture was conentrated under reduced pressure. The residue was treated with dichloromethane (100 mL) filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (20% ethyl acetate/hexanes) to provide the title compound as light brown oil (4.57 g, 35%). MS (ESI+) m/z 248 (100), 230 (M+H)+, (ESI−) m/z 200 (M−Et)−; 1H NMR (DMSO-d6, 300 MHz) rotomers δ 1.26 (t, J 7.1, 0.6H), 1.37 (t, J 7.1, 2.4H), 4.21 (q, J 7.1, 0.4H), 4.47 (q, J 7.1, 1.6H), 7.89 (t, J 7.5, 1H), 8.41 (dd, J 1.0, 7.5, 1H), 8.57 (d, J 8.1, 1H), 8.64 (d, J 5.7, 1H), 8.73 (d, J 6.3, 1H), 9.50 (s, 1H).
Reaction SMILES: [CH2:1]1[CH2:8][CH2:7][O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[C:9](=O)([O-])[O-:10].[K+].[K+]>CO>[CH3:9][O:10][C:4](=[O:5])[CH2:3][CH2:2][CH2:1][CH2:8][CH2:7][OH:6]
Reactant: O=C([O-])[O-]
Reactant: O=C1CCCCCO1
Agent: [K+]
Solvent: CO
Product: COC(=O)CCCCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 556.4 %

Procedure:
A mixture of 10.6 ml (0.1 mol) e-caprolactone and 1.97 g (0.015 mol) potassium carbonate in 50 ml methanol is stirred for one hour at room temperature, then the potassium carbonate is removed by filtration and the mother liquor is evaporated to dryness in a vacuum. The residue is taken up in 20 ml saturated ammonium chloride solution and the solution is extracted three times with 50 ml diethyl ether each time. After drying the combined organic phases over sodium sulfate and removing the solvent, 12.2 g 6-hydroxycaproic acid methyl ester is obtained which is reacted further without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][NH:23][C:24](=[O:37])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)=[CH:27][CH:26]=3)=[CH:16][CH:15]=2)[C:8]([O:10]CC)=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][NH:23][C:24](=[O:37])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)=[CH:27][CH:26]=3)=[CH:18][CH:19]=2)[C:8]([OH:10])=[O:9])=[CH:38][CH:39]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)Oc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCOc1ccc(CC(Oc2ccc(Cl)cc2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Yield: 92.6 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-(4-chlorophenoxy)-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (950 mg), which is the product of Example 120, was reacted with aqueous sodium hydroxide solution (1N, 3.49 ml) and the reaction mixture was treated to give the title compound (834 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5]([O:30][CH2:31][CH3:32])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)C.[Mg]>CO>[CH3:1][O:3][C:4](=[O:33])[CH:5]([O:30][CH2:31][CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1
Reactant: CCCCCCCN(CCc1ccc(C=C(OCC)C(=O)OCC)cc1)C(=O)OC(C)(C)C
Agent: [Mg]
Solvent: CO
Product: CCCCCCCN(CCc1ccc(CC(OCC)C(=O)OC)cc1)C(=O)OC(C)(C)C
Yield: 87.6 %

Procedure:
To a solution of 3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-2-ethoxy-acrylic acid ethyl ester (1.11 mmol, 510 mg) dissolved in anhydrous methanol (20 mL) was added dry magnesium turnings (2.77 mmol, 67 mg). The resulting solution was allowed to stir at room temperature, with additional portions of magnesium being added after dissolution of the previous portion until the starting material had been consumed as determined by mass spectrometry. The mixture was poured over 25 mL of ice cooled 2M HCl. The acidic mixture was brought to pH 9 by the addition of concentrated aqueous ammonia, then was extracted with diethyl ether (3×). The organic layers were combined, washed with saturated NaCl (3×), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-2-ethoxy-propionic acid methyl ester as a clear oil (437 mg, 88%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[N:4]([CH3:15])[N:3]=1.C([Mg]Cl)(C)C.[CH2:21]([Sn:25]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])Cl)[CH2:22][CH2:23][CH3:24]>C1COCC1>[CH3:15][N:4]1[C:5]2[C:10](=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=2)[C:2]([Sn:25]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:21][CH2:22][CH2:23][CH3:24])=[N:3]1
Reactant: Cn1nc(I)c2cc(C(F)(F)F)ccc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
To a solution of 3-iodo-1-methyl-5-(trifluoromethyl)-1H-indazole (400 mg, 1.2 mmol) in dry THF (15 mL) was added isopropylmagnesium chloride (0.7 mL, 1.3 mmol, 2 M in THF) drop-wise at −16° C. under nitrogen atmosphere, stirred for 30 minutes, then tributylchlorostannane (0.4 mL, 1.3 mmol) was added drop-wise at −16° C. under nitrogen, the reaction mixture was warmed to room temperature slowly and stirred for 2 hours, then quenched with a solution of saturated NH4Cl (40 mL) and product extracted with EtOAc (3×30 mL) then dried over Na2SO4, filtered and concentrated, under reduced pressure to give 1-methyl-3-(tributylstannyl)-5-(trifluoromethyl)-1H-indazole (500 mg, crude) as an oil which was used directly to next step without any further purification.
Reaction SMILES: [CH2:1]1[C@H:14]2[C@@H:5]([NH:6][C:7]3[C:12]([CH2:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.C1[C@@H]2[C@H:18]([NH:19]C3C=CC=CC=3C2)[CH2:17]C1>>[CH2:11]1[C@H:12]2[C@@H:7]([N:6]([CH2:17][C:18]#[N:19])[C:5]3[C:14]([CH2:13]2)=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:8][CH2:9][CH2:10]1
Reactant: c1ccc2c(c1)C[C@H]1CCCC[C@@H]1N2
Reactant: c1ccc2c(c1)C[C@@H]1CCC[C@H]1N2
Product: N#CCN1c2ccccc2C[C@H]2CCCC[C@@H]21

Procedure:
The title compounds were prepared according to the procedure of Example 1 step 3 except that Cis and Trans-1,2,3,4,4a,9,9a,10-octahydroacridine were used instead of Cis and Trans 2,3,3a,4,9,9a-Hexahydro-1H-cyclopenta[b]quinoline, respectively.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29]Br)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][N:10]1[C:11](=[O:15])[C:12]([CH3:14])=[CH:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:16])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1cn(Cc2ccccc2)c(=O)[nH]c1=O
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(Cc2ccccc2)c(=O)n(CCCNC(=O)OC(C)(C)C)c1=O
Temperature: 60 °C

Procedure:
To a solution of 1-benzyl-5-methyl-1H-pyrimidine-2,4-dione (1.0 g, 4.6 mmol) in N,N-dimethylformamide (15 mL) was added tetrabutylammonium bromide (60 mg, 0.2 mmol) and sodium hydroxide (200 mg, 5.1 mmol). The suspension was stirred vigorously, heated to 60° C. for 1.5 h and then cooled to ambient temperature. N-tert-butoxycarbonyl-3-bromopropylamine (1.2 g, 5.1 mmol) was added, the reaction was heated to 40° C. for 20 h and then concentrated in vacuo. The residue was taken up in ethyl acetate:water (1:1 200 mL), the layers separated and the aqueous layer extracted with ethyl acetate (4×50 mL). The organic layers were combined and washed with 0.5 M sodium hydroxide (1×50 mL), water (1×50 mL), brine (1×100 mL), dried with magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was purified by pressurized silica gel chromatography (40% ethyl acetate in hexane) to provide 3-(3-tert-butoxycarbonylaminopropyl)-1-benzyl-5-methyl-1H-pyrimidine-2,4-dione.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]3[N:20]([CH3:34])[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)[CH:23]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[CH3:34][N:20]1[C:19]([CH2:18][CH2:17][CH2:16][O:15][C:12]2[CH:13]=[C:14]3[C:9]([CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:35])=[O:3])=[CH:10][CH:11]=2)=[CH:23][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=2)=[N:21]1
Reactant: CCOC(=O)Cn1ccc2ccc(OCCCc3cc(-c4ccc(C(F)(F)F)cc4)nn3C)cc21
Agent: [Li+]
Agent: [OH-]
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CCCOc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described for example 1 f], (6-{3-[2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-propoxy}-indol-1-yl)-acetic acid ethyl ester was treated with LiOH to obtain (6-{3-[2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-propoxy}-indol-1-yl)-acetic acid as colorless crystals.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][O:7][CH2:8][CH3:9])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][O:7][CH2:8][CH3:9]
Reactant: CCOC[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCOC[C@@H](CN)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
A mixture of (R)-tert-butyl 1-azido-3-ethoxypropan-2-ylcarbamate (1.2 g, 4.91 mmol) in MeOH (10 mL) was added palladium on carbon (0.523 g, 4.91 mmol). The mixture was stirred under hydrogen atmosphere overnight at RT. The resulting crude material was reconstituted in MeOH (1.0 mL) and purified via reverse phase preparative HPLC. The fractions were collected and solvent was stripped to dryness via rotary evaporation to give the title compound as clear oil (722 mg, 67%). [M+H] calc'd for C10H22N2O3, 219. found, 219.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[S:16]([OH:19])(=[O:18])=[O:17].[OH-].[Na+:21].[N+:22]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29])([O-:24])=[O:23].Cl>O>[Na+:21].[Na+:21].[N+:22]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[S:16]([O-:19])(=[O:18])=[O:17])=[O:29])([O-:24])=[O:23]
Reactant: Nc1ccc2c(S(=O)(=O)O)cccc2c1S(=O)(=O)O
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1ccc2c(S(=O)(=O)[O-])cccc2c1S(=O)(=O)[O-])c1cccc([N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
A 48.5 g portion of 2-amino-1,5-naphthalenedisulfonic acid is suspended in 80 ml of water and 160 ml of 1N sodium hydroxide is added, then 60.0 g of m-nitrobenzoyl chloride is added all at once. The mixture is shaken for about 15 minutes and another 160 ml of 1N sodium hydroxide is added with shaking for 1/2 hour. The latter addition of sodium hydroxide and shaking is repeated two more times, then 100 ml of water is added and the mixture is acidified with 17 ml of concentrated hydrochloric acid. The resulting mixture is then copiously extracted with ether with the addition of 700 ml of water during the ether extraction. The ether is removed by vacuum siphoning and the aqueous solution is filtered. The filtrate is then concentrated in vacuo at 55°-60° C. until formation of crystals. The material is then allowed to stand 48 hours at room temperature and the solid residue of fine feathery needles is broken up and is filtered. The residue is washed with two 100 ml portions of saturated saline solution and then is slurried with two 200 ml portions of 90% ethyl alcohol followed by 200 ml of absolute ethyl alcohol and two 300 ml portions of ether. The product is then dried at 120° C. overnight to give 52.8 g of product. A 27.8 g portion of this material is dissolved in 110 ml of boiling water. The solution is then cooled to room temperature and the crystallized final product is filtered and is washed with a small amount of cold water then is dried at 120° C. overnight.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:29])([CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([N+:20]([O-])=O)=[CH:17][CH:18]=2)[CH:13]=[N:12]1.[H][H]>CO.[Pd]>[NH2:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([CH2:10][C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:29])[CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[NH:12][CH2:13]2
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(cnn2CC(O)(Cn2cncn2)c2ccc(F)cc2F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CNN2CC(O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 12 h
Yield: 87 %

Procedure:
To a solution of 2-(2,4-difluorophenyl)-1-(5-nitro-1H-indazol-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (3.57 g, 8.92 mmol) in methanol (50 ml) was added 5% palladium charcoal (Pd/C) (0.35 g) and hydrogen gas, followed by stirring for 12 hours. The reaction solution was filtered through celite. The filtrate was concentrated through vacuum evaporation to produce the title compound. (Yield 87%).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([C:17]1[CH:40]=[CH:39][C:20]([C:21]([NH:23][CH:24]([C:29]2[NH:33][C:32]3[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:31]=3[N:30]=2)[CH2:25][C:26]([NH2:28])=[O:27])=[O:22])=[CH:19][C:18]=1[Cl:41])=[O:16])=O)(C)(C)C.FC(F)(F)C(O)=O.ClCl>ClCCl.CO>[NH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([C:17]1[CH:40]=[CH:39][C:20]([C:21]([NH:23][CH:24]([C:29]2[NH:33][C:32]3[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:31]=3[N:30]=2)[CH2:25][C:26]([NH2:28])=[O:27])=[O:22])=[CH:19][C:18]=1[Cl:41])=[O:16]
Reactant: CC(C)(C)OC(=O)NCC1CCCN1C(=O)c1ccc(C(=O)NC(CC(N)=O)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Agent: ClCl
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NCC1CCCN1C(=O)c1ccc(C(=O)NC(CC(N)=O)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Yield: 59 %

Procedure:
Prepared analogously to Example 17 from 4-[2-(N-tert-butoxycarbonylaminomethyl)pyrrolidine-1-carbonyl]-N-[2-aminocarbonyl-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-chlorobenzamide and trifluoroacetic acid. Yield: 59% (mixture of all four stereoisomers); Rf value: 0.23 (silica gel; dichloromethane/methanol=7:3); C23H24Cl2N6O3 (503.39); mass spectrum: (M+H)+=503/505/507 (chlorine isotope).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([O:37][CH3:38])=[C:13]([CH:36]=2)[CH2:14][O:15][CH2:16][C:17]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O.CN(C)C>FC(F)(F)C(O)=O>[CH3:38][O:37][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[N:8][CH:7]=2)=[CH:36][C:13]=1[CH2:14][O:15][CH2:16][C:17]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1
Reactant: COc1ccc(-c2ccc(C#N)nc2)cc1COCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2ccc(C#N)nc2)cc1COCC1(c2ccccc2)CCNCC1
Reaction time: 1 h

Procedure:
tert-Butyl 4-((5-(6-cyanopyridin-3-yl)-2-methoxybenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (46 mg, 0.090 mmol) was dissolved in trifluoroacetic acid (33% in dichloromethane, 4 mL) and stirred for 1 h. The reaction was concentrated and purified by column chromatography (5% methanol/dichloromethane/2% trimethylamine in ethanol→10% methanol/dichloromethane/2% trimethylamine in ethanol) to give 43.6 mg (quant.) as a colorless oil. The product was tainted with trimethylamine 2,2,2-trifluoroacetate. 1H NMR (500 MHz, CDCl3) δ ppm 9.47 (bs, 1H), 9.25 (bs, 1H), 8.79 (m, 1H), 7.84 (m, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.44 (dd, J=8.5, 2.1, 1H), 7.33 (m, 5H), 7.25 (m, 1H), 6.91 (d, J=8.5 Hz, 1H), 4.47 (s, 2H), 3.82 (s, 3H), 3.48 (s, 2H), 3.27 (bd, 2H), 2.90 (m, 2H), 2.44 (m, 2H), 2.26 (m, 2H); 13C NMR (126 MHz, CDCl3) δ ppm 157.8, 149.3, 140.5, 139.5, 134.3, 131.4, 129.1, 128.5, 128.2, 127.9, 127.2, 126.8, 126.6, 117.7, 110.8, 79.9, 67.7, 55.6, 41.1, 40.6, 29.1. Mass spec.: 414.19 (MH)+. Accurate mass spec.: m/z 414.2188 [MH]+, Δ=1.6 ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([CH:24]=1)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:9]=1.[C:26](Cl)(=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([NH:7][C:8]3[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[N:11]=[C:10]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:9]=3)[CH:24]=2)=[O:35])=[CH:28][CH:29]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc(N)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Product: COc1ccc(C(=O)Nc2ccc(C)c(Nc3cc(C(F)(F)F)nc(-c4ccncc4)n3)c2)cc1

Procedure:
The title compound was prepared from a mixture of 4-(5-amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (10 mg, 0.029 mmol) and p-anisoyl chloride (6 mg, 0.035 mmol) similar to Example 139 and isolated as a tan solid (10 mg, 71%). 1H NMR (CDCl3): 8.77 (dd, J=1.5, 4.8 Hz, 2H), 8.29 (dd, J=1.5, 4.8 Hz, 2H), 7.99 (s, 1H), 7.86 (d, J=8.7 Hz, 2H), 7.79 (s, 1H), 7.36 (dd, J=1.8, 8.4 Hz, 1H), 7.32 (d, J=8.7 Hz, 2H), 7.02 (s, 1H), 6.99 (d, J=8.7 Hz, 2H), 3.88 (s, 3H), 2.29 (s, 3H).