Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:13]1[O:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH2:28])[CH2:24][CH:25]([CH3:27])[CH3:26]>C(O)(C)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:13]([OH:15])[CH2:14][NH:28][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCN
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Solvent: CC(C)O
Product: CC(C)CCNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 81 %

Procedure:
Part C. A solution of N-benzyloxycarbonyl 3(S)-amino-1,2-(S)-epoxy-4-phenylbutane (30.1 g, 0.10 mol) and 165mL of isoamylamine in 150 mL of isopropyl alcohol was heated to reflux for 2.5 hours. The solution was cooled to room temperature, concentrated/n vacuo and then recrystallized. The product was isolated by filtration and from ethylacetate/hexane to afford 1.7 g (81%) of N[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]N-isoamylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Br[C:29]1[N:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:31][CH:30]=1>CCCCCCC.C(OCC)(=O)C>[CH2:38]([O:37][C:35]([C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[N:34]=1)=[O:36])[CH3:39]
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: CCOC(=O)c1cccc(Br)n1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)n1

Procedure:
The title compound was prepared in analogy to Example 26, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and ethyl 6-bromo-2-pyridinecarboxylate (commercially available) using a gradient of n-heptane:ethyl acetate (100:0 to 60:40). Light yellow foam (89%). MS (Turbo Spray): m/z=540.2 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([N:8]([CH2:10][CH2:11]Cl)[CH3:9])=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([CH3:9])[CH2:10][CH2:11][NH:13]2
Reactant: CN(CCCl)c1ccc(Br)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCNc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.1 %

Procedure:
A solution of 4-bromo-N1-(2-chloroethyl)-N1-methylbenzene-1,2-diamine (25D) (0.611 g, 2.3 mmol) and K2CO3 (0.634 g, 4.6 mmol) in DMF (7 mL) was heated to 80° C. for 1 hour and then at 100° C. for 1.5 hours, cooled to rt, diluted with water and extracted with EtOAc. The organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide 0.528 g (100%) of the desired product 6-bromo-1-methyl-1,2,3,4-tetrahydroquinoxaline (25E): 1H NMR (300 MHz, CDCl3) δ 6.72 (1H, dd), 6.56 (1H, d), 6.38 (1H, d), 3.74 (1H, bs), 3.47 (2H, t), 3.22 (2H, t), 2.82 (3H, s).
Reaction SMILES: [I:1][C:2]1[N:3]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:4]=[C:5]([C:7](O)=[O:8])[N:6]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[NH2:48][C@H:49]([C:56]([O:58][CH3:59])=[O:57])[CH2:50][CH2:51][C:52]([O:54][CH3:55])=[O:53]>O1CCCC1>[I:1][C:2]1[N:3]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:4]=[C:5]([C:7]([NH:48][C@H:49]([C:56]([O:58][CH3:59])=[O:57])[CH2:50][CH2:51][C:52]([O:54][CH3:55])=[O:53])=[O:8])[N:6]=1
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Reactant: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(I)n1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)CC[C@H](NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(I)n1)C(=O)OC
Yield: 75.3 %

Procedure:
2-Iodo-1-triphenylmethylimidazole-4-carboxylic acid (1.443 g, 3.0 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (553 mg, 3.15 mmol), 4-methylmorpholine (0.614 mL, 6.6 mmol), dimethyl L-glutamate hydrochloride (698 mg, 3.3 mmol), and tetrahydrofuran (20 mL) were then allowed to react in the manner described in Example 15 to yield dimethyl N-(2-iodo-1-triphenylmethylimidazol-4-ylcarbonyl)--L-glutamate (1.44 g, 75%, mp 86-88° C.): 1H N (CDCl3) δ 7.47 (s, 1H), 7.44 (d, 1H, J=8.6 Hz), 7.32-7.26 (m, 9H), 7.21-7.05 (m, 6H), 4.72 (m, 1H), 3.71 (s, 3H), 3.62 (s, 3H), 2.41 (m, 2H), 2.27 (m, 1H), 1,99 (m, 1H). HRMS calcd for C30H28IN3O5 637.1074, found 637.1054. Anal. Calcd for C30H28IN3O5 : C, 56.52; H, 4.43; N, 6.59. Found: C, 56.36; H, 4.45, N, 6.57.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[O:8][C:7](=[O:11])[C:6](=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH3:13])[C:5]=1[OH:22])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>O1CCCC1>[C:30]([O:21][C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:12](=[C:6]2[C:5]([OH:22])=[C:4]([C:1](=[O:3])[CH3:2])[C:9](=[O:10])[O:8][C:7]2=[O:11])[CH3:13])=[CH:20][CH:19]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)C1=C(O)C(=C(C)Nc2ccc(O)cc2)C(=O)OC1=O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(NC(C)=C2C(=O)OC(=O)C(C(C)=O)=C2O)cc1

Procedure:
To a solution of 3.03 g. (0.01 m.) of 5-acetyl-4-hydroxy-3-[1-(p-hydroxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, 1.0 g. (0.01 m.) of triethylamine in 150 ml. of tetrahydrofuran is added 0.78 g. (0.01 m.) of acetyl chloride. The resulting mixture is refluxed for two hours, cooled and filtered. The solid is recrystallized to give 3-[1-(p-acetoxyphenylamino)ethylidene]-5-acetyl-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 199°-201° C.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[NH2:30][CH:31]([C:33]1[C:34](=[O:50])[NH:35][C:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=2)=[N:37][N:38]=1)[CH3:32].[C:51]([CH:54]([CH2:58][CH2:59][CH2:60][CH:61]1[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1)[C:55](O)=[O:56])(=[O:53])[CH3:52]>>[C:51]([CH:54]([CH2:58][CH2:59][CH2:60][CH:61]1[CH2:62][CH2:63][CH2:64][CH2:65][CH2:66]1)[C:55]([NH:30][CH:31]([C:33]1[C:34](=[O:50])[NH:35][C:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=2)=[N:37][N:38]=1)[CH3:32])=[O:56])(=[O:53])[CH3:52]
Reactant: COc1ccc(Cc2nnc(C(C)N)c(=O)[nH]2)cc1OC
Reactant: CC(=O)C(CCCC1CCCCC1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: COc1ccc(Cc2nnc(C(C)NC(=O)C(CCCC3CCCCC3)C(C)=O)c(=O)[nH]2)cc1OC

Procedure:
The amount of 2-acetyl-5-cyclohexylpentanoic acid in dichloromethane from Example 36A is reacted analogously to Example 39A with 280 mg (2.08 mmol) of 1-hydroxy-1H-benzotriazole, 610 mg (6.00 mmol) of 4-methylmorpholine, 400 mg (2.08 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 600 mg (2.08 mmol) of 6-(1-aminoethyl)-3-(3,4-dimethoxybenzyl)-1,2,4-triazin-5(4H)-one to give 2-acetyl-5-cyclohexyl-N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl }pentanamide.
Reaction SMILES: [NH2:1][OH:2].[CH2:3]([N:5]([CH2:22][CH3:23])[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[N:9]=[C:8]([CH2:18][CH3:19])[C:7]=1[C:20]#[N:21])[CH3:4]>CS(C)=O>[CH2:22]([N:5]([CH2:3][CH3:4])[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[N:9]=[C:8]([CH2:18][CH3:19])[C:7]=1/[C:20](=[N:1]/[OH:2])/[NH2:21])[CH3:23]
Reactant: CCc1nn(-c2ccc(O)cc2)c(N(CC)CC)c1C#N
Reactant: NO
Solvent: CS(C)=O
Product: CCc1nn(-c2ccc(O)cc2)c(N(CC)CC)c1/C(N)=N/O
Temperature: 160 °C
Yield: 32.7 %

Procedure:
Hydroxylamine (50 wt % solution in water, 0.45 mL, 7.3 mmol) was added to 5-(diethylamino)-3-ethyl-1-(4-hydroxyphenyl)-1H-pyrazole-4-carbonitrile (16 mg, 0.06 mmol) dissolved in DMSO (1 mL) in a microwave vial. The reaction was heated at 160° C. in the microwave for 30 min. Purification using preparative HPLC gave (Z)-5-(diethylamino)-3-ethyl-N′-hydroxy-1-(4-hydroxyphenyl)-1H-pyrazole-4-carboximidamide (6.22 mg, 35%). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 318.29 (M+H), 316.32 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.40 (m, 2H), 6.90 (m, 2H), 2.96 (q, 4H, J=7.2 Hz), 2.65 (q, 2H, J=7.4 Hz), 1.19 (t, 3H, J=7.4 Hz) and 0.95 (t, 6H, J=7.2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:14])[CH:6]=[C:7]([O:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH:8]=1.Cl[CH2:16][CH2:17][C:18](Cl)([CH3:20])[CH3:19].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH:11]([CH3:12])[CH3:13])[CH:6]=[C:5]2[C:4]=1[CH:16]=[CH:17][C:18]([CH3:20])([CH3:19])[O:14]2
Reactant: CC(C)(Cl)CCCl
Reactant: COc1cc(O)cc(OCC(C)C)c1
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Product: COc1cc(OCC(C)C)cc2c1C=CC(C)(C)O2
Temperature: 125 °C
Reaction time: 60 h
Yield: 69 %

Procedure:
A mixture of 3.9 g (20 millimoles) of 3-methoxy-5-isobutoxy-phenol, 2.8 g (20 millimoles) of 1,3-dichloro-3-methyl-butane and 0.26 g (1 millimole) of bis-(acetyl-acetonato)-nickel is heated at 125° C. for 8 hours. The mixture is cooled, the solvent removed, the residue taken up in 40 ml of anhydrous benzene and 0.8 g (3.5 millimoles) of DDQ (dichloro-dicyano-benzoquinone) are added. The mixture is heated to boiling for 60 hours. The solution is filtered, the filtrate evaporated and the residue purified as described in Example 3. Thus 3.6 of the desired compound are obtained in the form of a colorless oil, yield 69%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:28])[C:10]1[N:14]([CH2:15][CH2:16][CH2:17]O)[C:13]2[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:20][CH:21]=[CH:22][C:12]=2[N:11]=1.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]2=[N:11][C:12]3[C:13](=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:20]=[CH:21][CH:22]=3)[N:14]2[CH2:15][CH2:16][CH2:17][O:28]1
Reactant: CCN(CC)c1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCN(CC)c1cccc2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a stirred solution of 3-{2-[(2,4-dichlorophenyl)(hydroxy)methyl]-7-(diethylamino)-1H-benzimidazol-1-yl}propan-1-ol (Reference example 207, 1.37 g, 3.24 mmol) in pyridine (16 mL) was added methanesulfonyl chloride (502 μL, 6.49 mol) at 0° C. After 1 h, the reaction mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in N,N-dimethylformamide (32 mL) and potassium carbonate (897 mg, 6.49 mmol) was added. After being stirred for 12 h at 80° C., the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (341 mg, 0.844 mmol, 26%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C:25]2[N:26]=[C:27]([CH:35]3[CH2:38][CH2:37][CH2:36]3)[N:28]3[C:33]=2C(=O)NC=N3)[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C:25]2[N:26]=[C:27]([CH:35]3[CH2:36][CH2:37][CH2:38]3)[N:28]3[C:33]=2[C:5]([NH2:1])=[N:4][CH:3]=[N:2]3)[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=c1[nH]cnn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4)c3)c12
Reactant: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Nc1ncnn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,2,4-triazole (167 mg, 2.417 mmol) in anhydrous pyridine (1.5 mL) was added phosphorous oxychloride (POCl3) (75 μL, 0.806 mmol) and stirred at rt for 15 min. To this mixture was added dropwise a solution of 5-(3-benzyloxy-phenyl)-7-cyclobutyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (100 mg, 0.269 mmol) in anhydrous pyridine (2.5 mL) over a 3.5 min period and stirred at rt for an additional 3 h. The reaction was cooled to 0° C. and quenched with 2M NH3 in i-PrOH (10 mL ) and stirred for an additional 30 min at rt. The mixture was filtered through a fritted funnel and the filtrate was concentrated in vacuo, partitioned between CHCl3 and H2O and separated. The aqueous layer was re-extracted with CHCl3 (3×) and the combined CHCl3 fractions were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo and the crude material was chromatographed on silica gel [eluting with 2% MEOH in CHCl3] resulting in a dark brown oil which was crystallized from EtOAc/hexanes to obtain the title compound as a light tan solid. 1H NMR (CDCl3, 400 MHz) δ 1.95-2.08 (m, 1H), 2.09-2.22 (m, 1H), 2.39-2.50 (m, 2H), 2.59-2.72 (m, 2H), 4.14 (quint, J=8.4 Hz, 1H), 5.16 (s, 2H), 5.57 (brs, 2H), 7.02-7.09 (m, 1H), 7.22-7.28 (m, 3H), 7.31-7.50 (m, 5H), 7.85 (s, 1H); MS (ES+): m/z 372.1 (100) [MH+]; HPLC: tR=3.05 min (MicromassZQ, nonpolar—5 min).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:20]1[CH:21]=[CH:22][N:23]2[CH2:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[NH:26][CH2:25][C:24]=12.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([N:26]3[C:27]4[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=4[CH2:29][N:23]4[CH:22]=[CH:21][CH:20]=[C:24]4[CH2:25]3)=[O:16])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)c2ccc(C(=O)Cl)cc2)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)cc1
Reaction time: 16 h
Yield: 54.1 %

Procedure:
A mixture of 2.13 g of 4-[(4-methylphenyl)sulfonyl]benzoyl chloride (Reference Example 42) and 1.0 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 30 ml of methylene chloride containing 7 ml of triethylamine is stirred under nitrogen atmosphere for 16 hours. The reaction mixture is diluted with ? ml of chloroform and washed with 2N HCl, water, saturated NaHCO3 and water. The organic layer is dried (Na2SO4) and columned on silica gel by elution with 7:1 to 3:1 ethyl acetate:hexane to give 1.3 g of the desired product as a solid. M+H 443.2; M+Na 465.2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[O:17][CH3:18]>>[CH3:18][O:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: C1COCCN1
Product: COc1cc([N+](=O)[O-])ccc1N1CCOCC1
Temperature: 100 °C
Yield: 18.6 %

Procedure:
Mix morpholine (1.50 mL, 17.20 mmol) and 1-chloro-2-methoxy-4-nitro-benzene (1.06 g, 5.65 mmol) and heat to 100° C. for 4 h while stirring. Cool the solution to room temperature, then partition between EtOAc (40 mL) and 1N HCl (20 mL). Wash the organic solution with water (20 mL) and brine (20 mL), dry, filter, and concentrate. Purify the crude material by flash chromatography, using a linear gradient of 100% hexanes to 50% EtOAc/hexanes, to give the title compound as a yellow solid (250 mg, 18%). MS (ES+) 239.0 (M+1)+. 1H NMR (400 MHz, CDCl3) δ: 7.86 (dd, 1H, J=8.8, 2.6 Hz), 7.71 (d, 1H, J=2.2 Hz), 6.87 (d, 1H, J=9.2 Hz), 3.94 (s, 31), 3.87 (m, 4H), 3.21 (m, 4H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.Cl[CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:12]1[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][O:1][CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)=[CH:6][CH:7]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: ClCc1cccnc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCc3cccnc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1 (g) by alkylating tert-butyl (3RS,4RS)-4-(4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 53 (c)] with 3-chloromethyl-pyridine there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-{4-[2-(pyridin-3-ylmethoxy)-ethoxy]-phenyl}-piperidine-1-carboxylate; MS: 569 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>C(#N)C.N1C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: O=S(Cl)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(Cl)c1ccc(O)nc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
13.92 g (0.1 mol) of 6-hydroxynicotinic acid and 0.04 g (0.5 mmol) of pyridine were heated in 60 ml of acetonitrile to 80° C. 12.49 g (0.105 mol) of thionyl chloride was instilled and the reaction again stirred for 30 minutes at 80° C. After cooling, the precipitate was filtered off, washed twice each with 10 ml of cold acetonitrile and concentrated by evaporation in a vacuum. 13.38 g (0.085 mol) of 6-hydroxynicotinoyl chloride was obtained as a light yellowish powder, corresponding to a yield of 85 percent relative to the 6-hydroxynicotinic acid. Further data concerning the product was:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([S:21][CH:22]([CH3:25])[CH2:23][CH3:24])=[CH:17][CH:16]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[O-:26]I(=O)(=O)=O.[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH:22]([CH3:25])[CH2:23][CH3:24])=[O:26])=[CH:17][CH:16]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: CCC(C)Sc1ccc(OCC2COC(c3ccc(Cl)cc3)O2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(C)S(=O)c1ccc(OCC2COC(c3ccc(Cl)cc3)O2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-chlorophenyl)-4-[4-(1-methylpropylthio)phenoxymethyl]-1,3-dioxolane (7.1 mmol) in 10 ml of methanol at 0° is added, dropwise over 5 min., sodium m-periodate (1.67 g, 7.8 mmol) in 13 ml of water. The mixture is stirred for 3 hours while warming to RT. The reaction mixture is poured into water and extracted with ether. The combined organic extracts are washed with saturated sodium thiosulfate, with water and with brine, dried and rotoevaporated to give 2-(4-chlorophenyl)-4-[4-(1-methylpropylsulfinyl)phenoxymethyl]-1,3-dioxolane.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:7]([NH:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[S:19])=[CH:13][CH:12]=1)=[O:8].C(NNC1C=CC(NC(N(CC2C=CC=CC=2)CC2C=CC=CC=2)=S)=CC=1)=O>>[CH:7]([NH:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[S:19])=[CH:13][CH:12]=1)=[O:8]
Reactant: C1COCCN1
Reactant: O=CNNc1ccc(N=C=S)cc1
Agent: O=CNNc1ccc(NC(=S)N(Cc2ccccc2)Cc2ccccc2)cc1
Product: O=CNNc1ccc(NC(=S)N2CCOCC2)cc1

Procedure:
Morpholine (0.087 g, 0.001 mole) and 4-(2-formylhydrazino)phenyl isothiocyanate (0.19 g, 0.001 mole) were reacted according to the procedure described for NA-11 in Example 3. Yield 0.22 g (79 percent), m.p. 204°-206° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:29])[CH2:21][N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:29])[CH2:21][N:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: CN1CCN(CC(=O)N2CCC(c3ccc(NC(=O)OC(C)(C)C)cc3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(CC(=O)N2CCC(c3ccc(N)cc3)CC2)CC1
Reaction time: 1 h
Yield: 70.2 %

Procedure:
(4-Piperidin-4-yl-phenyl)-carbamic acid tert-butyl ester (0.20 g, 0.72 mmol), (4-methyl-piperazin-1-yl)-acetic acid (0.11 g, 0.72 mmol), HOBt (0.10 g, 0.72 mmol), DCI (0.14 g, 0.72 mmol), and DIEA (0.10 g, 0.72 mmol) were all combined in DMF (5 mL). After 16 h, water (10 mL) and CH2Cl2 (10 mL) were added. The organic layer was washed with water (3×10 mL), dried (MgSO4) and concentrated. Chromatography (0-15% EtOAc/hexanes gradient) provided 0.24 g (83%) of (4-{1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenyl)-carbamic acid tert-butyl ester. (4-{1-[2-(4-Methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenyl)-carbamic acid tert-butyl ester (0.72 mmol) was diluted in CH2Cl2 (3 mL) and TFA (3 mL) was added. After 1 h, the reaction mixture was concentrated. Water (2 mL) was added and the solution was frozen and lyophilized overnight to provide (0.16 g) (72%) of 1-[4-(4-Amino-phenyl)-piperidin-1-yl]-2-(4-methyl-piperazin-1-yl)-ethanone. 8-Indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (32.5 mg, 0.079 mmol) and 1-[4-(4-Amino-phenyl)-piperidin-1-yl]-2-(4-methyl-piperazin-1-yl)-ethanone tri-TFA salt (52 mg g, 0.079 mmol) were combined in i-PrOH (1 mL) and TEA (25 mg, 0.25 mmol) was added and the mixture was heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/min 5-100% MeCN/H2O gradient over 10 min) and lyophilized to provide 8.6 mg of 8-indan-5-yl-2-(4-{1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.23 (s, 1H), 8.39 (s, 1H), 7.40-7.42 (m, 2H), 7.17-7.26 (m, 3H), 7.06-7.09 (m, 2H), 4.30 (q, 2H, J=7.1 Hz), 3.07 (br s, 1H), 2.87-2.93 (m, 6H), 2.48-2.67 (m, 7H), 2.28 (br s, 3H), 2.05-2.12 (m, 2H), 1.72-1.82 (m, 2H), 1.49 (br s, 2H), 1.31 (t, 3H, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3](=O)[CH2:4][C:5](=O)[CH3:6].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.Cl>COCCO.C(O)(=O)C>[F:1][C:2]([F:10])([F:9])[C:3]1[CH:4]=[C:5]([CH3:6])[N:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[N:20]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: Cl
Solvent: CC(=O)O
Solvent: COCCO
Product: COc1ccc(-n2nc(C(F)(F)F)cc2C)cc1
Yield: 87.8 %

Procedure:
A mixture of 1,1,1-trifluoro-2,4-pentanedione (0.02 mol, 2.4 mL) and 4-methoxyphenyl hydrazine.HCl (4.54 g, 1.3 eq.) in 2-methoxyethanol (100 mL) and acetic acid (30 mL) was refluxed for 6 h. The reaction mixture was evaporated and purified by flash chromatography on a silica gel column (400 g) eluted with 4:1 hexane:ethyl acetate to give 4.5 g of pure product (88%).