Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1[O:5][CH:6]=[C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:18]3[CH:36]=[CH:35][C:21]([O:22][C:23]4[CH:24]=[CH:25][C:26]([C:31]([F:34])([F:33])[F:32])=[C:27]([CH:30]=4)[C:28]#[N:29])=[CH:20][CH:19]=3)[CH:10]=2)N=1)C.[BH4-].[Na+].CC[OH:41].C1COCC1>>[OH:41][CH:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:19]=[CH:20][C:21]([O:22][C:23]3[CH:24]=[CH:25][C:26]([C:31]([F:34])([F:33])[F:32])=[C:27]([CH:30]=3)[C:28]#[N:29])=[CH:35][CH:36]=2)[CH:10]=1)[CH2:6][OH:5]
Reactant: CCO
Reactant: CCOc1nc(-c2cn(-c3ccc(Oc4ccc(C(F)(F)F)c(C#N)c4)cc3)c3ccccc23)co1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cc(Oc2ccc(-n3cc(C(O)CO)c4ccccc43)cc2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A mixture of compound 50 (0.15 g) and NaBH4 (100 mg) in 10 mL of EtOH/THF (1/1) was shaken at room temperature for 2 hours. The reaction was quenched with water, extracted with TCM and purified by column (MeOH/TCM 0.5/10, Rf 0.5) to give the title compound 51 as a white solid (90 mg, 70%): 1H-NMR (400 MHz, CD3OD) δ: 7.83 (d, 1H, 8.9 Hz), 7.76-7.78 (m, 1H), 7.6-7.63 (m, 2H), 7.57 (s, 1H), 7.54-7.56 (m, 1H), 7.49-7.5 (m, 1H), 7.39-7.42 (m, 1H), 7.15-7.3 (m, 4H), 4.68-4.71 (m, 1H), 3.97-4.02 (m, 1H), 3.8-3.84 (m, 1H); LC/MS: m/z=461.0 [M+Na+] (Calc: 438.4).
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]([OH:24])=[O:23])[C:13]=2[CH3:25])=[N:4][N:3]1[CH2:26][CH2:27][C:28]1[CH:33]=CC=C[CH:29]=1.BrCCC(C)C>>[CH3:25][C:13]1[N:14]([CH2:21][C:22]([OH:24])=[O:23])[C:15]2[C:20]([C:12]=1[C:5]1[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[S:2](=[O:1])(=[O:34])[N:3]([CH2:26][CH2:27][CH:28]([CH3:33])[CH3:29])[N:4]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: Cc1c(C2=NN(CCc3ccccc3)S(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)O
Solvent: CC(C)CCBr
Product: Cc1c(C2=NN(CCC(C)C)S(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)O

Procedure:
The title compound was prepared from the product of example 19, step a) and 1-bromo-3-methyl-butane using the procedure described in example 17, step d). 1H NMR (DMSO-d6) δ 8.09 (d, J=7.2 Hz, 1H), 7.90 (t, J=7.5 Hz, 1H), 7.81 (t, J=7.8 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.38 (d, J=8.1 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.09 (t, J=7.8 Hz, 1H), 4.52 (s, 2H), 3.89 (t, J=6.9 Hz, 2H), 1.90 (s, 3H), 1.74 (q, J=6.9 Hz, 2H), 1.64 (sept., J=6.7 Hz, 1H), 0.92 (d, J=6.3 Hz, 6H); MS: ESI (negative): 438 (M−H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]2=[C:9]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=[C:11]([C:12]([CH:14]3[CH2:18][CH2:17][NH:16][CH2:15]3)=[O:13])[N:7]2[N:6]=[CH:5][N:4]=1.C([O-])([O-])=O.[Na+].[Na+].[C:41](Cl)(=[O:43])[CH3:42]>CC#N.CO>[NH2:2][C:3]1[C:8]2=[C:9]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:23]=4)[CH:10]=[C:11]([C:12]([CH:14]3[CH2:18][CH2:17][N:16]([C:41](=[O:43])[CH3:42])[CH2:15]3)=[O:13])[N:7]2[N:6]=[CH:5][N:4]=1
Reactant: Nc1ncnn2c(C(=O)C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(=O)N1CCC(C(=O)c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.8 %

Procedure:
[4-Amino-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-pyrrolidin-3-yl-methanone hydrochloride salt (80 mg, 0.17 mmol) was dissolved in CH3CN/MeOH (1:1, 2 mL) and 2N Na2CO3 (0.84 mL, 1.68 mmol) was added, followed by acetyl chloride (0.013 mL, 0.19 mmol). The resulting mixture was stirred at rt for 12 h. The mixture was concentrated, diluted with EtOAc and layers were separated. The organic layer was washed with brine and concentrated. The residue was purified by short silica-gel column eluting with EtOAc, then 10% MeOH in EtOAc to give 39 mg (48%) of the desired product. 1H-NMR (CD3OD-d4) 8.39-8.35 (m, 1H), 8.03 (d, 1H), 7.81 (dt, 1H), 7.69-7.67 (m, 1 H), 7.47 (d, 1H), 7.37-7.27, (m, 5 H), 7.19 (fit, 1 H), 5.64 (s, 1 H), 4.53-4.38 (m, 1 H), 3.92-3.72 (m, 2 H), 3.62 (t, 1H), 3.52 (t, 1 H), 2.38-2.07 (m, 2 H), 2.10 (d, 3 H); LC-MS [M+H]+=480.1, RT=2.64 min.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.[N:35]1([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][N:42]=2)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)CC>[O:17]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][N:38]3[CH2:39][CH2:40][N:35]([C:41]4[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][N:42]=4)[CH2:36][CH2:37]3)[CH:12]=[N:11][C:10]=2[N:9]2[CH2:13][CH2:14][CH2:15][CH2:16][C@@H:8]12
Reactant: N#Cc1ccc(N2CCNCC2)nc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: N#Cc1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 35.2 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (89.0 mg, 0.382 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (111.0 mg, 0.458 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (200 ul, 1.1 mmol). To the stirred mixture was then added 6-(piperazin-1-yl)nicotinonitrile (79 mg, 0.420 mmol). The reaction was heated to 90° C. with stirring for 16 h. The crude reaction was cooled to room temperature and concentrated to a residue, then taken up in 3 mL DMSO and purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered off and dried in vacuum to afford the title compound (54.2 mg, 35.2%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.48 (br. s., 1H), 8.46 (d, J=2.3 Hz, 1H), 7.83 (dd, J=9.1, 2.5 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H), 6.97 (d, J=1.8 Hz, 1H), 6.90 (d, J=9.1 Hz, 1H), 4.50 (d, J=12.9 Hz, 1H), 3.83 (dd, J=11.4, 2.8 Hz, 1H), 3.55-3.70 (m, 4H), 3.34 (s, 2H), 2.59 (td, J=12.6, 2.4 Hz, 1H), 2.40 (t, J=4.8 Hz, 4H), 2.03 (d, J=12.6 Hz, 1H), 1.84 (d, J=12.1 Hz, 1H), 1.63 (d, J=13.6 Hz, 1H), 1.29-1.56 (m, 3H). [M+H] calc'd for C22H25N7O, 404. found, 404.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:21]=[C:22]([O:30][CH3:31])[CH:23]=[C:24]4[C:29]=3[N:28]=[CH:27][CH:26]=[CH:25]4)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(OC(Cl)=O)=C>C(Cl)Cl>[CH3:31][O:30][C:22]1[CH:23]=[C:24]2[C:29](=[C:20]([N:17]3[CH2:16][CH2:15][N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH2:19][CH2:18]3)[CH:21]=1)[N:28]=[CH:27][CH:26]=[CH:25]2
Reactant: COc1cc(N2CCN(C3CCN(Cc4ccccc4)CC3)CC2)c2ncccc2c1
Agent: C=COC(=O)Cl
Solvent: ClCCl
Product: COc1cc(N2CCN(C3CCNCC3)CC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
A solution of 8-[4-(1-benzylpiperidin-4-yl)piperazin-1-yl]-6-methoxyquinoline (Step 1, 0.22 g) and vinylchloroformate (0.067 mL) in anhydrous CH2Cl2 (5 mL) was stirred at reflux for 1 hour. The reaction was cooled to room temperature and then concentrated on a rotary evaporator. The residue was taken up in dioxane (5 mL), treated with concentrated HCl (0.35 mL) and stirred at room temperature for 1 hour. The resulting reaction was concentrated on a rotary evaporator, taken up in ethanol (1 mL) and stirred at 50° C. for 30 minutes. The reaction was again concentrated on a rotary evaporator and partitioned between CH2Cl2 and 1N aqueous NaOH. The organic layer was washed with water and then brine and was then dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel using ethyl acetate/methanol/conc, NH4OH to give 0.14 g of the desired product as a yellow oil; MS (ES) m/z (relative intensity); 326 (M+H)+ (100).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].CN(C)C=O.[H-].[Na+].[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29]OC1C(Cl)=CC(C=O)=C(F)C=1>>[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][O:10][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([Cl:1])[CH:9]=1
Reactant: O=Cc1cc(Cl)c(OCc2nc3ccccc3[nH]2)cc1F
Reactant: COc1cc(C=O)c(Cl)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(Cl)cc1OCc1nc2ccccc2[nH]1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
2-Chloro-4-hydroxy-5-methoxy-benzaldehyde (136, 2.30 g, 0.0123 mol) was dissolved in N,N-dimethylformamide (89.5 mL, 1.16 mol) and sodium hydride (60% dispersion in mineral oil, 541 mg, 0.0135 mol) was added. After 20 minutes, 2-chloromethyl-1H-benzoimidazole (106, 2.05 g, 0.0123 mol) was added to the reaction. The reaction was stirred at 80° C. overnight. The reaction was concentrated in vacuo to an oil. Ethyl acetate was added and washed with saturated sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30-70% ethyl acetate in hexane over 30 minutes to provide a white solid (137, 1.79 g, 46%). MS (ESI) [M+H+]+=317.1, 319.1.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].Br[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[OH:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[N:9]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:8]1=[O:21]
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccccc43)c2=O)c(OC)c1
Reactant: BrCCc1ccccc1
Product: O=c1c2sc3ccccc3c2n(CCc2ccccc2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was alkylated with 2-Bromoethylbenzene and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 3.08-3.14 (m, 2H); 4.67-4.73 (m, 2H); 7.24-7.38 (m, 5H); 7.61-7.69 (m, 2H); 8.20 (dd, J1=7 Hz, J2=2 Hz, 1H); 8.30 (dd, J1=7 Hz, J2=2 Hz, 1H); Ret. time=2.77 min., m/z=339.0.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:11]=[C:10](Cl)[C:9]([C:13]#[N:14])=[CH:8][C:7]=1[F:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN1CCCC1=O>[CH2:16]([NH:23][C:10]1[C:9]([C:13]#[N:14])=[CH:8][C:7]([F:15])=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[N:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)Nc1nc(Cl)c(C#N)cc1F
Reactant: NCc1ccccc1
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1nc(NCc2ccccc2)c(C#N)cc1F
Temperature: 160 °C
Reaction time: 3 h
Yield: 25.4 %

Procedure:
To 40 ml of N-methylpyrrolidone solution of 6 g 6-t-butylamino-2-chloro-3-cyano-5-fluoropyridine was added 6.3 g of benzylamine, and the mixture was stirred under nitrogen atmosphere at 160° C. for 3 hours and allowed to cool. The reaction solution was separated by adding chloroform and water, and the organic layer was dried over magnesium sulfate, and the solvent was distilled off. The precipitated crystals were collected from the residue by filtration to obtain 2 g of the title compound as a pale yellow powder.
Reaction SMILES: [CH2:1]([C:9]1[N:10]([CH2:22][CH2:23][O:24][CH2:25][C:26]#[CH:27])[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([C:9]1[N:10]([CH2:22][CH2:23][O:24][CH2:25][C:26]#[C:27][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Ic1ccccc1
Reactant: C#CCOCCn1c(CCCCCCCC)nc2cnc3ccccc3c21
Product: CCCCCCCCc1nc2cnc3ccccc3c2n1CCOCC#Cc1ccccc1
Reaction time: 0.75 h
Yield: 71.7 %

Procedure:
Using the general method of Example 12 Part A, 2-octyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline (4.84 g, 13.32 mmol) was reacted with iodobenzene (1.7 mL, 14.65 mmol) at 40° C. After 45 minutes the reaction was judged complete. The volatiles were removed under reduced pressure and the resulting oil purified by chromatography over silica gel (98/2 (dichloromethane/methanol) to provide 4.2 g of 2-octyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline as pale yellow solid.
Reaction SMILES: [CH2:1]1[C@@H:3]([NH3+:4])[C@H:2]1[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1.C1C=CC(C(O)C([O-])=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:31]1[C:32]2[N:43]=[N:42][N:41]([C@H:44]3[C@@H:48]4[O:49][C:50]([CH3:53])([CH3:52])[O:51][C@@H:47]4[C@@H:46]([O:54][CH2:55][CH2:56][OH:57])[CH2:45]3)[C:33]=2[N:34]=[C:35]([S:37][CH2:38][CH2:39][CH3:40])[N:36]=1>O>[F:12][C:7]1[CH:6]=[C:5]([C@@H:2]2[CH2:1][C@H:3]2[NH:4][C:31]2[C:32]3[N:43]=[N:42][N:41]([C@H:44]4[C@@H:48]5[O:49][C:50]([CH3:52])([CH3:53])[O:51][C@@H:47]5[C@@H:46]([O:54][CH2:55][CH2:56][OH:57])[CH2:45]4)[C:33]=3[N:34]=[C:35]([S:37][CH2:38][CH2:39][CH3:40])[N:36]=2)[CH:10]=[CH:9][C:8]=1[F:11]
Reactant: CCCSc1nc(Cl)c2nnn([C@@H]3C[C@H](OCCO)[C@H]4OC(C)(C)O[C@H]43)c2n1
Reactant: [NH3+][C@@H]1C[C@@H]1c1ccc(F)c(F)c1
Agent: O=C([O-])C(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCSc1nc(N[C@@H]2C[C@H]2c2ccc(F)c(F)c2)c2nnn([C@@H]3C[C@H](OCCO)[C@H]4OC(C)(C)O[C@H]43)c2n1

Procedure:
trans-(1R,2S)-2-(3,4-Difluorophenyl)cyclopropanaminium (2R)-2-hydroxy-2-phenylethanoate (146 kg, prepared as described in WO2008/018822, WO2008/018823, WO01/92200) and potassium carbonate (156 kg) were dissolved in water (576 kg) and charged to the 2-({(3aR,4S,6R,6aS)-6-[7-Chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3 aH-cyclopenta[d][1,3]dioxol-4-yl}oxy)ethanol solution with a rate that kept the temperature of the reaction ≦30° C. After the conversion criterion was reached (>99%) the water layer was separated off. The organic layer was washed twice with acetic acid (18 kg) and sodium chloride (13 kg) in water (560 kg) and then twice with sodium chloride (54 kg) in water (438 kg), whereafter the organic layer was used in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=1.[BH3-]C#N.[Na+]>ClCCCl>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:19][CH2:18][C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NCc1ccncc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc(CNCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 27 %

Procedure:
A mixture of 4-nitrobenzaldehyde (3.0 g, 19.8 mmol), 4-pyridylmethylamine (2.36 g, 21.8 mmol), and NaBH3CN (1.75 g, 27.7 mmol) in 1,2-dichloroethane (40.0 mL) was stirred at room temperature for 36 h and then concentrated to dryness. The residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (2×), dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (MeOH/DCM=1/400) to afford 1.3 g of N-(4-nitrobenzyl)-1-(pyridin-4-yl)methanamine as brown oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH2:10])=[O:9])[C:3]1=[O:11].O[C@H]1CCN(CC(OCC)=O)C1>>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH2:10])=[O:9])[C:3]1=[O:11]
Reactant: NC(=O)CN1CCC(O)C1=O
Agent: CCOC(=O)CN1CC[C@H](O)C1
Product: NC(=O)CN1CC[C@H](O)C1=O

Procedure:
According to the process described in paragraph (b) of Example 1, from ethyl (S)-(-)-2-(3-hydroxy-1-pyrrolidinyl)acetate there is obtained (S)-(-)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide which has a melting point of 197°--198°; [α]D20 =-82°, [α]54620 =-99°, [α]36520 =-313° (dimethylformamide c=1.00).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([O:52][CH3:53])([C:31]2[NH:32][N:33]=[C:34](/[CH:36]=[CH:37]/[C:38]3[CH:43]=[CH:42][C:41]([N:44]4[CH:48]=[C:47]([CH3:49])[N:46]=[CH:45]4)=[C:40]([O:50][CH3:51])[CH:39]=3)[N:35]=2)[CH2:28][CH2:29]O)=[CH:23][CH:22]=1>C(Cl)(Cl)(Cl)Cl.C1COCC1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([O:52][CH3:53])[C:31]3[N:32]([N:33]=[C:34](/[CH:36]=[CH:37]/[C:38]4[CH:43]=[CH:42][C:41]([N:44]5[CH:48]=[C:47]([CH3:49])[N:46]=[CH:45]5)=[C:40]([O:50][CH3:51])[CH:39]=4)[N:35]=3)[CH2:29][CH2:28]2)=[CH:23][CH:22]=1
Reactant: COc1cc(/C=C/c2n[nH]c(C(CCO)(OC)c3ccc(F)cc3)n2)ccc1-n1cnc(C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(/C=C/c2nc3n(n2)CCC3(OC)c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 1.9 %

Procedure:
Triphenylphosphine (22 mg) was added to a suspension of 3-(4-fluorophenyl)-3-methoxy-3-(5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-2H-[1,2,4]triazol-3-yl)propan-1-ol (38 mg) in carbon tetrachloride (2 mL) and THF (2 mL), and the reaction solution was heated under reflux for seven hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ethyl acetate and a saturated sodium bicarbonate solution were added to the resulting residue, and the organic layer was separated. The organic layer washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane-ethyl acetate system), again purified with silica gel column chromatography (elution solvent: ethyl acetate-methanol system) and then purified by LC-MS. After concentrating the target fraction, ethyl acetate and a saturated sodium bicarbonate solution were added to the residue, and the organic layer was separated. The organic layer washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 0.69 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH:5]=[CH:4][C:3]=1[C:24](=[O:26])[CH3:25]>C(O)C.CN(C)C=O.[Pd]>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH:5]=[CH:4][C:3]=1[C:24](=[O:26])[CH3:25]
Reactant: CCCc1c(OCCOc2ccc([N+](=O)[O-])cc2)ccc(C(C)=O)c1O
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCc1c(OCCOc2ccc(N)cc2)ccc(C(C)=O)c1O
Reaction time: 2 h

Procedure:
1-{2-Hydroxy-3-propyl-4-[2-(4-nitrophenoxy)ethoxy]phenyl}ethanone (6.0 g) was dissolved in a mixture of ethanol (250 ml) and dimethylformamide (60 ml) to which was added, under nitrogen, a slurry of palladium on charcoal (500 mg, 5%) in ethanol (50 ml). The suspension was then hydrogenated on a Parr at 60 psi and room temperature for 2 hours. The suspension was filtered over Celite, washed with ethanol and the filtrate evaporated under reduced pressure to give a brown oil. The oil was triturated with water and filtered to give a brown solid. The solid was recrystallised from ethanol to give a cream solid, m.p. 73°-74° C.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:9]=[C:10](OS(C(F)(F)F)(=O)=O)[CH:11]=[C:12]([OH:14])[CH:13]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][C:25]=2[O:24]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[O:24]1[C:25]2[CH:26]=[CH:27][C:28]([C:10]3[CH:9]=[C:8]([C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[O:7])[CH:13]=[C:12]([OH:14])[CH:11]=3)=[CH:29][C:30]=2[O:31][CH2:23]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: O=C(c1cc(O)cc(OS(=O)(=O)C(F)(F)F)c1)C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C(c1cc(O)cc(-c2ccc3c(c2)OCO3)c1)C1CCCC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 3-cyclopentanecarbonyl-5-hydroxy-phenyl ester (300 mg) in 1,2-dimethoxyethane (4 mL) were added 3,4-methylenedioxyphenylboronic acid (295 mg), 2 M aq. sodium carbonate solution (0.9 mL) and Pd(PPh3)4 (10 mg) and the resulting mixture was stirred at 90° C. for 3 h. Then the reaction mixture was diluted with ethyl acetate, filtered through Celite and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 100 mg of the title compound (36% yield). HRMS calcd for C19H18O4 [M+H]+ 311.1278, observed 311.1277.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:19])=[O:5])[CH3:2].[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[N:19]1[C:23](=[O:24])[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=[O:25])=[O:5])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(-c2ccc(CC)cc2)csc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccc(CC)cc2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(4-ethylphenyl)-thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 12, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O)=[N+:2]=[N-:3].Cl.[NH2:20][OH:21]>N1C=CC=CC=1.C(O)C>[N:1]([C:4]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:5]=1[C:6](=[N:20][OH:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: [N-]=[N+]=Nc1ccc(Cl)cc1C(=NO)c1ccccc1
Reaction time: 5 h

Procedure:
25.8 G (0.100 mol) of 2-azido-5-chlorobenzophenone [compare Example 1a] are dissolved in 500 ml of pyridine/ethanol (1:1). 14.0 G (0.200 mol) of hydroxylamine hydrochloride are added to the solution and the mixture is boiled for 5 hours under reflux and evaporated in vacuo at 60°C. The residue is taken up in 250 ml of methanol and the solution is poured into 250 ml of 2 N hydrochloric acid. The crude product which precipitates is filtered off, suspended in 250 ml of 75% strength methanol, again filtered off and dried in vacuo. 2-Azido-5-chloro-benzophenone-oxime of melting point 125°-132°C is obtained. A sample of the crude product is recrystallised from benzene/cyclohexane, after which the pure compound melts at 135°-137°C.