Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28]#[N:29])=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[OH-:31].[NH4+:32].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28](=[NH:32])[NH:29][OH:31])=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [OH-]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(C#N)ccc32)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(C(=N)NO)ccc32)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-(3-cyanophenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl ester, 4a (130 mg; 0.33 mmol) in ethanol (3 mL) was added ammonium hydroxide hydrochloride (69 mg; 0.99 mmol) and potassium carbonate (91 mg; 0.66 mmol), and the mixture was heated to reflux for 16 h. The mixture was allowed to cool to rt, water (5 mL) was added, and the mixture was extracted with ethyl acetate (2×5 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated, yielding 4-[3-(N-hydroxycarbamimidoyl)-phenoxazin-10-yl]-piperidine-1-carboxylic acid tert-butyl ester, 1b. The crude material was used as such in the next reaction. MS m/z (M+Na) 473.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C1COCC1>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccn1
Reactant: O=Cc1ccc(I)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Ic1ccc(CNc2ccccn2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
2.00 g (8.62 mmol) 4-iodo-benzaldehyde are added to 0.811 g (8.62 mmol) 2-amino-pyridine in 20 mL THF and the mixture is stirred for 1 h at 50° C. After that time, 4.57 g (21.5 mmol) sodium triacetoxyborohydride are added and the mixture is stirred for 1 h at 50° C. Subsequently, water is added and the mixture is extracted with EtOAc. The organic layer is dried over magnesium sulphate and the solvent is removed in vacuo. The residue is purified by RP-HPLC to yield the desired product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH:19]1[CH2:29][CH2:28][CH:27]([OH:30])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]1[F:31].C(N(CC)CC)C>ClCCl>[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH:19]1[CH2:29][CH2:28][C:27](=[O:30])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]1[F:31]
Reactant: OC1CCC(c2cccc(F)c2F)C(F)c2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C1CCC(c2cccc(F)c2F)C(F)c2cccnc21
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (1.2 g, 9.5 mmol) in dichloromethane (15 mL) at −65° C. was added DMSO (0.85 mL, 12 mmol), and the mixture was stirred for 30 min. A solution of 5R,6S,9R and 5S,6R,9S)-6-(2,3-difluorophenyl)-5-fluoro-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (0.35 g, 1.9 mmol) in dichloromethane (3 mL) was added dropwise and the resulting solution was stirred at −65° C. for 30 min. After triethylamine (2.3 mL, 17 mmol) was added, the reaction mixture was gradually warmed to 23° C. over a period of 4 h, and then partitioned between water and dichloromethane. The organic layer was washed with water (3×), brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 50% ethyl acetate in petroleum ether to give the title compound as a racemic mixture. MS: m/z=292.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([CH2:15][CH2:16][CH2:17][CH2:18]Cl)[CH2:13][CH3:14].[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([CH2:13][CH3:14])[CH2:15][CH2:16][CH2:17][CH2:18][N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=2)[CH2:32][CH2:31]1
Reactant: CCC1(CCCCCl)C(=O)Nc2c(Cl)cc(Cl)cc21
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: CCC1(CCCCN2CCN(c3ccc(F)cc3)CC2)C(=O)Nc2c(Cl)cc(Cl)cc21
Product: Cl

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 5,7-dichloro-3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 4-(4-fluoro-phenyl)-piperazine.
Reaction SMILES: O1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2C=C1.OCCS(C1C=C([C@H]2S[C@H](C3C=C(OC)C(OC)=C(OC)C=3)CS2)C=C(OC)C=1OCCC)(=O)=O.[CH2:45]([Li])[CH2:46][CH2:47][CH3:48].OC1C([N+]([O-])=O)=CC([C@H]2S[C@H]([C:65]3[CH:70]=[C:69]([O:71]C)[C:68]([O:73][CH3:74])=[C:67]([O:75][CH3:76])[CH:66]=3)CS2)=CC=1OC.COC1C=C([C@H]2S[C@H](C3C=C(OC)C(OC)=C(OC)C=3)CS2)C=C([N+]([O-])=O)C=1OC>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:47]([CH:46]1[CH2:45][C:70]2[CH:65]=[CH:66][C:67]([O:75][CH3:76])=[C:68]([O:73][CH2:74][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:69]=2[O:71]1)=[CH2:48]
Reactant: c1ccc2occc2c1
Reactant: COc1cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc([N+](=O)[O-])c1O
Reactant: [Li]CCCC
Agent: CCCOc1c(OC)cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc1S(=O)(=O)CCO
Agent: COc1cc([C@@H]2CS[C@@H](c3cc(OC)c(OC)c([N+](=O)[O-])c3)S2)cc(OC)c1OC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CC1Cc2ccc(OC)c(OCc3ccccc3)c2O1
Reaction time: 0.29 h

Procedure:
Using the procedure of Bigi et al, Tetrahedron, 39, 169 (1983), the benzofuran system is constructed. N-butyl lithium (3.95 ml of a 2.2M solution) is added to a solution of 3-benzyloxy-4-methoxyphenol (203, prepared as described in Example 32)(2.0 g, 0.0087 mols) in dry toluene. Upon addition of the n-butyl lithium, a precipitate falls out of solution. After all the n-butyl lithium is added, the reaction is starred for 15-20 minutes at room temperature. Subsequently, the reaction is heated to reflux for twenty one hours. The reaction is then diluted with ethyl acetate and washed with 10% HCl and water. The extract is dried over sodium sulfate. The crude reaction mixture is purified by flash column chromotography using 2:1 hexane-ethyl acetate as eluant to obtain two major products which are (1) unreacted starting material and (2) product (0.979 g, 37.6%)
Reaction SMILES: [Mg].[CH:2]1(Br)[CH2:4][CH2:3]1.[CH3:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].[Cl-].[NH4+]>O1CCCC1.O>[CH:2]1([C:12]([C:8]2[N:7]([CH3:6])[CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[OH:13])[CH2:4][CH2:3]1
Reactant: BrC1CC1
Reactant: Cn1cccc1C(=O)c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cccc1C(O)(c1ccccc1)C1CC1
Yield: 60.5 %

Procedure:
To a suspension of magnesium turnings (5.29 g, 0.22 mole) in anhydrous tetrahydrofuran (70 ml), cyclopropyl bromide (26.35 g, 0.22 mole) in tetrahydrofuran (50 ml) was added dropwise under nitrogen. The reaction mixture was heated at reflux for one h after the initial exotherm had subsided before (N-methylpyrrol-2-yl)phenylketone (13.3 g, 0.072 mole) (J. White and G. McGillivray, J. Org. Chem., (1977), 42, 4248, R. Greenhouse and C. Ramirez, J. Org. Chem., (1985), 50, 2961) in anhydrous tetrahydrofuran (50 ml ) was introduced dropwise. After heating the reaction mixture at reflux for 3 h it was cooled and saturated, aqueous ammonium chloride solution (95 ml) and water (150 ml) were added. The mixture was extracted with ethyl acetate (3×200 ml) and the combined extracts were dried (MgSO4). Flash chromatography of the residue on evaporation on silica gel eluting with heptane/tetrahydrofuran (9:1) provided the title compound as an oil (9.9 g, 46%) which solidified on standing. T.l.c. rf=0.35 (SiO2, heptane/THF (7:3)).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][CH:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:47][CH:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH3:39])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(N)c1ccccc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC(C)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 78 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and (RS)-α-methylbenzylamine: yield 78%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>C(#N)C>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[C:6]#[N:7]
Reactant: COc1cc(C#N)ccc1O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc(COc2ccc(C#N)cc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
To a stirred solution of 4-hydroxy-3-methoxybenzonitrile (2.43 g, 16.29 mmol) in acetonitrile (75 mL) was added cesium carbonate (6.68 g, 20.50 mmol) and p-methoxybenzyl chloride (2.81 g, 17.92 mmol). The reaction mixture was heated to reflux and stirred. After 1 h, the mixture was allowed to cool to room temperature and was filtered. The filtrate was concentrated to provide 4.56 g (>100%) 3-methoxy-4-((4-methoxybenzyl)oxy)benzonitrile as an off-white solid. The crude material was used without purification in the next reaction.
Reaction SMILES: [Br:1][C:2]1[N:24]=[C:5]2[CH:6]=[C:7]([NH:10][C:11]([C:13]3[N:17]([CH3:18])[N:16]=[CH:15][C:14]=3[C:19]([O:21]CC)=[O:20])=[O:12])[CH:8]=[CH:9][N:4]2[N:3]=1.O.[OH-].[Li+]>CO.O>[Br:1][C:2]1[N:24]=[C:5]2[CH:6]=[C:7]([NH:10][C:11]([C:13]3[N:17]([CH3:18])[N:16]=[CH:15][C:14]=3[C:19]([OH:21])=[O:20])=[O:12])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(Br)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(Br)nc2c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
A mixture of ethyl 5-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylate (1.2 g, 3.05 mmol) and lithium hydroxide hydrate (512 mg, 12.2 mmol) in methanol (40 ml) and water (10 ml) was stirred for 4 hours at 50° C. The solvent was evaporated, the residue was dissolved with water and acidified to pH=0 using hydrochloric acid 37%. The precipitated solid was filtered off and washed with water and dried in vacuo affording 5-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (929 mg, 83.4%) as a light brown solid. mp: >250° C., MS: m/z=362.7/364.8 (M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1)[N:6]=[CH:5]2
Reactant: C1=COCCC1
Reactant: Brc1ccc2[nH]ncc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Brc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
To a solution of 5-bromo-1H-indazole (5 g, 25.38 mmol) in DCM (50 mL), 3,4-dihydro-2H-pyran (4.26 g, 50.76 mmol) and PTSA (2.41 g, 12.69 mmol) were added and the reaction was stirred at room temperature for 3 h. Solvent was removed under vacuum. The residue was dissolved in ethyl acetate (150 mL), washed with water (20 mL), brine (20 mL), and dried over sodium sulfate. The organic layer was concentrated under vacuum and the crude product was purified by flash chromatography using hexane/ethyl acetate to give 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole as colorless liquid (6.95 g, 97%). 1HNMR: 400 MHz, DMSO-d6: δ 1.57-1.62 (m, 2H), 1.74-1.76 (m, 1H), 1.96-2.06 (m, 2H), 2.37-2.40 (m, 1H), 3.72-3.78 (m, 1H), 3.87-3.90 (m, 1H), 5.85-5.86 (m, 1H), 7.53-7.54 (m, 1H), 7.74 (d, J=9.20 Hz, 1H), 8.04 (d, J=1.60 Hz, 1H), 8.11 (s, 1H). LCMS: RT 2.033 min; LCMS (ES-API), m/z 283 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].N[C@@H](C1C[CH2:22][O:21][CH2:20]C1)C(O)=O>>[CH3:1][O:2][C:3]([NH:5][CH:6]([CH:7]1[CH2:9][CH2:22][O:21][CH2:20][CH2:8]1)[C:10]([OH:12])=[O:11])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: N[C@H](C(=O)O)C1CCOCC1
Product: COC(=O)NC(C(=O)O)C1CCOCC1

Procedure:
2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid was synthesized similar to N-methoxycarbonyl-L-Valine, using (S)-2-amino-2-(tetrahydro-2H-pyran-4-yl)acetic acid instead of L-Valine.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClCCl.[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[C@H:21]([CH2:22][CH2:23][OH:24])[O:20][CH2:19][CH2:18][C:17]=2[CH:25]=1.C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C>CN(C)C=O>[Si:1]([O:24][CH2:23][CH2:22][C@H:21]1[C:16]2[CH:15]=[CH:14][C:13]([Br:12])=[CH:25][C:17]=2[CH2:18][CH2:19][O:20]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OCC[C@@H]1OCCc2cc(Br)ccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC[C@@H]1OCCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1M solution of tert-butyldimethylsilyl chloride in dichloromethane (30 mL, 30 mmol) was added dropwise under nitrogen to an ice/water-cooled solution of 2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol (6.7 g, 24.4 mmol), diisopropylethylamine (6.7 g. 51.8 mmol) and dimethylaminopyridine (0.32 g, 2.5 mmol) in dry dimethylformamide (70 mL). After stirring overnight at room temperature, the mixture was quenched with ice/water and extracted with ether (2×). The combined organic extracts were washed with water (5×), dried (MgSO4) and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/hexane (0:100 to 10:90), to give the title compound as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:15]=[CH:14][C:13](F)=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].[C:20](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[C:14]([CH3:20])[CH:13]=[CH:12][C:11]=2[N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(Oc2ccc(Cl)cc2)c1
Yield: 75.7 %

Procedure:
A solution of 4-chlorophenol (1 g, 7.78 mmol), 2,5-difluoronitrobenzene (829 mg, 5.21 mmol) and potassium carbonate (1.29 g, 9.34 mmol) in DMF (5 ml) was stirred at reflux for 6 h. The reaction mixture was allowed to cool and then re-dissolved in 2.5M NaOH (10 ml). This aqueous mixture was then extracted with ethyl acetate (3×15 ml) and the combined organics were dried (MgSO4), filtered and concentrated in vacuo. An ethyl acetate solution of the crude material was filtered through a pad of silica which upon evaporation in vacuo afforded 2-(4-chlorophenoxy)-4-methyl-1-nitrobenzene as a yellow oil (1.04 g). This oil was then dissolved in 10:1 EtOH:H2O (10 ml) and added to a refluxing solution of iron powder (1.45 g, 26.05 mmol) and ammonium chloride (195 mg, 2.74 mmol) in 10:1 EtOH:H2O (20 ml). Stirring at this temperature continued for a further 2 h, before the reaction mixture was allowed to cool. The mixture was then filtered through a pad of celite, which was further washed with ethyl acetate (250 ml). Concentration in vacuo followed by purification by flash chromatography (eluant: 8:2 to 1:1 hexane:ethyl acetate) afforded the title compound as a pale yellow solid (1.28 g, 95%).
Reaction SMILES: CCC[C:4]1[C:5]2[N:14]=[C:13](C3C=C(S(N4CCN(C)CC4)(=O)=O)C=CC=3OCC)[NH:12][C:10](=O)[C:6]=2[N:7](C)[N:8]=1.[OH-:34].[Na+]>>[N:7]1[C:6]2[CH:10]=[N:12][CH:13]=[N:14][C:5]=2[C:4](=[O:34])[N:8]=1
Reactant: [OH-]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12
Agent: [Na+]
Product: O=C1N=Nc2cncnc21
Yield: 77 %

Procedure:
Drug preparation: Sildenafil was synthesized in 6 steps according to reported procedures (Terrett et al., 1996) (U.S. Pat. No. 5,346,901. 1994). Briefly, commercially available 2-ethoxybenzoic acid was converted to 2-ethoxybenzoyl chloride with thionyl chloride. Reaction of 2-ethoxybenzoyl chloride with 4-amino-1-methyl-3-N-propylpyrazole-5-carboxamide yielded the amide in 90% yield. Cyclization of the amide using NaOH afforded pyrazolopyrimidinone in 77% yield. Chlorosulfonylation of the pyrazolopyrimidinone in chlorosulfonic acid, followed by reaction with N-methylpiperazine provided sildenafil in 90% yield. Tadalafil was also synthesized according to reported procedures (Daugan et al., 2003b). Briefly, D-tryptophan methyl ester reacted with piperonal under Pictet-Spengler reaction condition (TFA/CH2Cl2/MeOH) and the resulting product condensed with chloroacetyl chloride to provide acylated intermediate. Reaction of the intermediate with N-methyl amine provided tadalafil. Tadalafil was diluted in 0.1% DMSO.
Reaction SMILES: C([O:8][C:9]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:10]=1[O:11][CH2:12][C@H:13]1[CH2:15][O:14]1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+].C1CC=CCC=1>CCO>[N+:20]([C:18]1[CH:17]=[CH:16][C:10]2[O:11][CH2:12][C@H:13]([CH2:15][OH:14])[O:8][C:9]=2[CH:19]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(OC[C@H]2CO2)c(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(c1)O[C@@H](CO)CO2
Temperature: 60 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
A 3 L 3-necked flask equipped with a mechanical stirrer, a reflux condenser, a thermocouple and a heating mantel is charged with EtOH (1500 mL), (2R)-2-{[2-(benzyloxy)-4-nitrophenoxy]methyl}oxirane (70.00 g, 0.232 mol), sodium bicarbonate (38.98 g, 0.464 mol) and 1,4-cyclohexadiene (39.56 mL, 0.418 mol). Argon gas is bubbled through the suspension for 5 min, and then the bubbling is discontinued, and palladium (10% on carbon, 4.9 g) is added. The mixture is heated to an internal temperature of 60° C. and stirred at 60° C. for 1 h. The solution is cooled to rt, filtered through a pad of celite and evaporated to dryness. The residue is dissolved in EtOAc (800 mL), and washed with 1 N HCl (2×100 mL) and brine (100 mL), and the volatiles are removed. The title compound (47.33 g, 93%) is obtained as a tan powder. LCMS (Standard Method): 2.23 min, 212 (M+H)+. 1NMR (300 MHz, CDCl3) δ 7.81-7.76 (m, 2H), 6.96 (d, J=8.5 Hz, 1H), 4.42 (dd, J=2.1, 11.2 Hz, 1H), 4.32-4.18 (m, 2H), 3.98-3.85 (m, 2H), 2.03 (br s, 1H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH3:11])[C:8](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([CH2:27][OH:28])=[CH:21]2>>[C:1]([C:5]1[N:10]=[C:9]([CH3:11])[C:8](/[CH:12]=[CH:13]/[C:14]([NH:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22]([CH2:27][OH:28])=[CH:21]3)=[O:16])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc2[nH]c(CO)cc2c1
Reactant: Cc1nc(C(C)(C)C)ccc1/C=C/C(=O)O
Product: Cc1nc(C(C)(C)C)ccc1/C=C/C(=O)Nc1ccc2[nH]c(CO)cc2c1

Procedure:
Analogous to the procedure used to prepare Example 1, (2E)-3-[6-(tert-butyl)-2-methyl(3-pyridyl)]prop-2-enoic acid, Example 75(c), (10 mg, 0.50 mmol) and (5-aminoindol-2-yl)methan-1-ol, Example 74(b), (81, 0.50 mmol) provided, after purification by silica gel chromatography (25:75 hexane:EtOAc), the title compound as a pale yellow solid. MP 213° C. MS (ESI, pos. ion) m/z: 364 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH:14]1[CH2:16][CH2:15]1)=[O:6].[H-].[Na+].CO>C1COCC1.C(Cl)(Cl)Cl>[CH:14]1([C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[CH2:16][CH2:15]1
Reactant: O=C(NCCCl)Nc1cnccc1C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1NCCN1c1cnccc1C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
1-(2-Chloroethyl)-3-(4-cyclopropylpyridin-3-yl)urea (I-1c: 200 mg, 0.836 mmol) in dry THF was added drop wise to a stirred mixture of NaH (40.16 mg, 1.67 mmol) in dry THF (5 mL) at 0° C. over a period of 10 minutes. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mixture was quenched with methanol and concentrated to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 140 mg of the product (94% yield).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[Cl:36])[CH2:17][CH2:16]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[Cl:36][C:30]1[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:29]=1[O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][CH:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Clc1ccc(Oc2ccccc2NC2CCNCC2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
Trifluoroacetic acid (TFA, 3 mL) was added to a solution of 4-[2-(2,4-dichlorophenoxy)phenylamino]piperidine-1-carboxylic acid tert-butyl ester (AMR01030, 300 mg, 0.686 mmol) in dry DCM (6 mL) at 0° C. After stirring at 0° C. for 30 min, the mixture was poured into solid K2CO3 (8.4 g) and water (33 mL) was added. The solution was extracted with DCM (3×20 mL) and the organic layer was dried (MgSO4), filtered and evaporated to give [2-(2,4-dichlorophenoxy)phenyl]piperidin-4-ylamine (225 mg, 97%) as an oil which was used in the next step without further purification. Rf: 0.13 (DCM/methanol 4:1 plus 3 drops of triethylamine) 1H NMR (270 MHz, CDCl3) δ 1.27 (2H, m, CH2), 1.84 (1H, br s, NH), 2.02 (2H, d, J=12.9 Hz, CH2), 2.72 (2H, t, J=11.9 Hz, CH2), 3.06 (2H, br d, J=12.6 Hz, CH2), 3.39 (1H, m, NH), 4.04 (1H, d, J=6.8 Hz, CH), 6.59 (1H, m, ArH), 6.77 (2H, m, ArH), 7.01 (1H, m, ArH), 7.10 (1H, m, ArH) and 7.42 (1H, m, ArH).