Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)CCN.[C:7]([O:11][C:12]([C:14]1[CH:18]=[CH:17][NH:16][CH:15]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=1>O1CCOCC1.[Cu](I)I.O>[C:7]([O:11][C:12]([C:14]1[CH:18]=[CH:17][N:16]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=2)[CH:15]=1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)c1cc[nH]c1
Reactant: Clc1ccc(Br)nc1
Agent: I[Cu]I
Agent: CN(C)CCN
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccn(-c2ccc(Cl)cn2)c1
Temperature: 120 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
N,N-dimethylethylenediamine (1.9 ml) was added to 1H-pyrrole-3-carboxylic acid tert-butyl ester (2.0 g) described in Reference Example 50, copper iodide (2.28 g), tripotassium phosphate (12.7 g) and 2-bromo-5-chloropyridine (2.78 g) in 1,4-dioxane (120 ml), and stirred at 120° C. for four hours. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo. n-Hexane was added to the resulting residue and the precipitated solid was washed with n-hexane to give 1-(5-chloropyridin-2-yl)pyrrole-3-carboxylic acid tert-butyl ester (3.0 g) as a gray solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[CH3:30][C:31]1([CH3:47])[O:36][CH:35]([C:37]([NH:39][CH2:40][CH2:41][C:42](O)=[O:43])=[O:38])[C:34]([CH3:46])([CH3:45])[CH2:33][O:32]1>>[C:11]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:42](=[O:43])[CH2:41][CH2:40][NH:39][C:37]([CH:35]1[C:34]([CH3:45])([CH3:46])[CH2:33][O:32][C:31]([CH3:47])([CH3:30])[O:36]1)=[O:38])(=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCCCCCCN
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCCCCCCNC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 21 %

Procedure:
N-(8-Aminooctyl)oleamide (4.08 9) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 1 to obtain 1.36 g of the title compound (yield: 21%).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[OH:14])[CH:2]=[CH2:3].C(O)(=O)C.Br>CCOCC>[CH3:3][CH:2]1[CH2:1][C:4]2[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=2[O:14]1
Reactant: C=CCc1c(C)ccc([N+](=O)[O-])c1O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1ccc([N+](=O)[O-])c2c1CC(C)O2

Procedure:
47 g of 1B was added to a mixture of 100 ml of glacial acetic acid and 100 ml of 48% aqueous hydrobromic acid and the mixture was heated at 114°-115° C. for 2.5 hours. The resulting mixture was stripped to dryness, the residue was taken up in 500 ml of ether, and filtered. The filtrate was concentrated to 100 ml, 300 ml of hexane was added, the mixture was chilled and filtered to give 2,3-dihydro-2,4-dimethyl-7-nitrobenzofuran (1C), as a tan solid, m.p.: 69°-71° C.
Reaction SMILES: [CH2:1]([C:5]1([CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:13][C:12]2[C:7](=[C:8]([Cl:34])[C:9]([Cl:33])=[C:10]([C:14](C(OCC)=O)([CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[C:15]([O:17]CC)=[O:16])[CH:11]=2)[C:6]1=[O:35])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO.O>[CH2:1]([C:5]1([CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40]2)[CH2:13][C:12]2[C:7](=[C:8]([Cl:34])[C:9]([Cl:33])=[C:10]([CH:14]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:15]([OH:17])=[O:16])[CH:11]=2)[C:6]1=[O:35])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(C2CCCC2)Cc2cc(C(CCCC(=O)OCC)(C(=O)OCC)C(=O)OCC)c(Cl)c(Cl)c2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCC1(C2CCCC2)Cc2cc(C(CCCC(=O)O)C(=O)O)c(Cl)c(Cl)c2C1=O
Yield: 84.2 %

Procedure:
The diethyl 2-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihyro-1-oxo-1H-inden-5-yl)-2-(ethoxycarbonyl)-1,6-hexanedioate (6.5 g) was refluxed with sodium hydroxide (5 g) dissolved in methanol (100 ml) and water (20 ml) for 3 hours. The mixture was cooled, diluted with water, acidified with hydrochloric acid and extracted with diethyl ether. The organic extracts were washed with water, dried over MgSO4 and concentrated to obtain 2-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)-1,6-hexanedioic acid (4.3 g). The dioic acid was heated at 130°-135° C. for 25 minutes with copper powder (1.52 g) in quinoline (35 ml). The mixture was cooled, poured into water and extracted with diethyl ether after acidification with hydrochloric acid. The organic extracts were washed with water, dried over MgSO4 and concentrated under vacuum. The residue was chromatographed twice on silica eluting with a mixture of toluene, dioxane and acetic acid in the ratio of 900:80:10 to obtain 2.9 g of the product as viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)=[C:17]([CH2:22]O)[N:18]([CH3:21])[C:19](=[O:20])[C:8]2=3)=[CH:4][CH:3]=1.S(Br)(Br)=O.[C-:37]#[N:38].[K+]>[Cl-].[Na+].O>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3[C:16]([C:24]4[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=4)=[C:17]([CH2:22][C:37]#[N:38])[N:18]([CH3:21])[C:19](=[O:20])[C:8]2=3)=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: Cc1ccc(-c2c(CO)n(C)c(=O)c3c2c2ccccc2n3Cc2ccc(F)cc2)cc1
Agent: O=S(Br)Br
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(-c2c(CC#N)n(C)c(=O)c3c2c2ccccc2n3Cc2ccc(F)cc2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
A solution of 9-(4-fluorobenzyl)-3-(hydroxymethyl)-2-methyl-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one (125 mg, 0.293 mmol) 1,2-Dichloroethane (DCE) (3 mL) was treated with Thionyl bromide (0.022 mL, 0.293 mmol), heated at 70° C. for 2 hours and then concentrated to dryness. The resultant was dissolved in DMF (2 mL), treated with KCN (76 mg, 1.17 mmol) and then stirred at room temperature overnight. Brine was added and the mixture was extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-70% ethyl acetate/hexanes) to afford 2-(9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-3-yl)acetonitrile (110 mg, 0.253 mmol, 86% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.29-7.44 (m, 4H) 7.17-7.24 (m, 1H) 6.91-6.99 (m, 4H) 6.62-6.70 (m, 1H) 6.10-6.16 (m, 2H) 3.90 (s, 3H) 3.67 (s, 2H) 2.51 (s, 3H); LCMS (m/z) ES+=436 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([O:31][CH2:32][O:33][CH3:34])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.C(=O)(O)[O-].[Na+].[CH3:40][N:41]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.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>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([O:31][CH2:32][O:33][CH3:34])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:40]#[N:41])[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: CN1CCCC1=O
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(I)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
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: [C-]#N
Product: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(C#N)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Temperature: 150 °C

Procedure:
A nitrogen-sparged solution of Example 1F (0.2 g, 0.318 mmol) in 1-methyl-2-pyrrolidinone (4.5 mL) was treated with zinc cyanide (0.039 g, 0.333 mmol) and tetrakis(triphenylphosphine)palladium (0.022 g, 0.019 mmol). The reaction was heated at 150° C. for 20 minutes in a Biotage Initiator microwave reactor. The reaction was cooled to ambient temperature, treated with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel, eluting with a gradient of from 0% to 15% ethyl acetate in hexane, to provide the title compound. MS ESI(+) m/z 529.0 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:14])[N:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:56]([CH:58]([CH2:61][CH3:62])[CH2:59][NH2:60])[CH3:57]>CN(C=O)C>[CH2:56]([CH:58]([CH2:61][CH3:62])[CH2:59][NH:60][C:11](=[O:13])[CH2:10][N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]1=[O:14])[CH3:57]
Reactant: O=C(O)Cn1cccc([N+](=O)[O-])c1=O
Reactant: CCC(CC)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(CC)CNC(=O)Cn1cccc([N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude product 2-(3-nitro-2-oxopyridin-1(2H)-yl)acetic acid (˜14.7 mmol), 4.71 g (14.7 mmol) of TBTU, 1.98 g (14.7 mmol) of HOBT and 4.99 mL (29.3 mmol, 2 eq) of DIPEA are dissolved in 60 mL of DMF (argon atmosphere). 1.97 mL (14.7 mmol) of 2-ethyl-butylamine ((→pH=6) and another eq DIPEA (→pH=8) are added. After 1 h a half eq DIPEA is further titrated and stirred overnight at RT. If the TLC control shows incomplete conversion, it is stirred for further 3 h at 45° C. The solvent is removed in vacuo and the residue is taken up in 500 mL of DCM/MeOH (8/2). It is subsequently washed with 10% citric acid (3×100 mL), saturated NaHCO3 solution (3×100 mL) and brine (75 mL). The organic phase is dried over sodium sulfate and the solvent is removed in vacuo. The crude product (3.5 g) is treated with 10 mL of ethyl acetate, 30 mL of PE (40-60) is added and stirred for 15 min at RT. The solid is filtered off, washed with some amount of PE and dried.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([NH2:17])=[S:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19]I>CO>[C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[NH:17])[S:16][CH3:19])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(N)=S)CC1
Reactant: CI
Solvent: CO
Product: CSC(=N)N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
A mixture of 1.19 g of (trans-4-thioureido-cyclohexyl)-carbamic acid tert-butyl ester and 0.41 ml of methyliodide in 50 ml of MeOH is stirred at RT. From the mixture obtained solvent is evaporated and [trans-4-(2-methyl-isothioureido)-cyclohexyl]-carbamic acid tert-butyl ester in the form of a hydrolodide is obtained.
Reaction SMILES: CC1(C)[O:6][C@H:5]([C:7]([N:9]2[CH2:14][CH2:13][C:12]([C:15]3[C:20]([F:21])=[CH:19][C:18]([N:22]4[CH2:26][C@H:25]([CH2:27][N:28]([C:36]5[S:40][N:39]=[C:38]([CH3:41])[CH:37]=5)C(OC(C)(C)C)=O)[O:24][C:23]4=[O:42])=[CH:17][C:16]=3[F:43])=[CH:11][CH2:10]2)=[O:8])[CH2:4][O:3]1.CO>ClCCl>[OH:6][C@@H:5]([CH2:4][OH:3])[C:7]([N:9]1[CH2:14][CH2:13][C:12]([C:15]2[C:20]([F:21])=[CH:19][C:18]([N:22]3[CH2:26][C@H:25]([CH2:27][NH:28][C:36]4[S:40][N:39]=[C:38]([CH3:41])[CH:37]=4)[O:24][C:23]3=[O:42])=[CH:17][C:16]=2[F:43])=[CH:11][CH2:10]1)=[O:8]
Reactant: Cc1cc(N(C[C@H]2CN(c3cc(F)c(C4=CCN(C(=O)[C@@H]5COC(C)(C)O5)CC4)c(F)c3)C(=O)O2)C(=O)OC(C)(C)C)sn1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(NC[C@H]2CN(c3cc(F)c(C4=CCN(C(=O)[C@@H](O)CO)CC4)c(F)c3)C(=O)O2)sn1
Yield: 47.2 %

Procedure:
Using essentially the technique of Example 20, but starting from 3-(4-(1-(2,2-dimethyl-1,3-dioxolan-4-(S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)-(N-(t-butoxycarbonyl)-3-methylisothiazol-5-ylaminomethyl)oxazolidin-2-one (250 mg, 0.39 mM), and using a gradient increasing in polarity from 0 to 20% methanol in dichloromethane for chromatography, gave the desired product (92 mg). NMR (DMSO-d6) δ: 2.16 (s, 3H); 2.29 (m, 1H); 2.37 (m, 1H); 3.42 (t, 2H); 3.47 (m, 1H); 3.55 (m, 1H); 3.73 (m, 1H); 3.76 (dd, 1H); 4.10 (m, 2H); 4.14 (t, 1H); 4.24 (m, 1H); 4.36 (t, 1H); 4.68 (t, 1H); 4.87 (m, 1H); 4.97 (m, 1H); 5.86 (s, 1H); 6.97 (s, 1H); 7.31 (d, 2H); 7.38 (t, 1H). MS (ESP): 495 (MH+) for C22H24F2N4O5S
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH3:10]>CO.[Ni]>[NH2:10][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: N
Agent: [Ni]
Solvent: CO
Product: NCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of 4-hydroxybenzaldehyde (10 g, 81.9 mmol) in methanol (45 mL) was added Raney nickel (3 g) and 7N aqueous ammonia solution (45 mL), and the solution was stirred under hydrogen atmosphere (1 atm) at room temperature for 21 hours. The reaction solution was filtered through Celite pad to remove the catalyst, the filtrate was concentrated, and 4-aminomethyl-phenol (10 g, quantitatively) was obtained as a pale green solid.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[F-].[Cs+].[CH:30](/B(O)O)=[CH:31]\[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>COCCOC.CO.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](/[CH:30]=[CH:31]/[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)/C=C/c1ccccc1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: CO
Solvent: COCCOC
Product: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(/C=C/c3ccccc3)ccc12
Temperature: 150 °C
Yield: 76.2 %

Procedure:
In a microwave vial, a solution of 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (200 mg, 0.47 mmol), cesium fluoride (213 mg, 1.41 mmol) and trans-styryl boronic acid (160 mg, 1.07 mmol) in 1,2-dimethoxyethane (3.2 ml) and methanol (1.6 ml) was degassed with argon for 20 min and then tetrakis(triphenylphosphine)palladium (30 mg, 0.026 mmol) was added. The vial was sealed and the mixture was heated under microwave irradiation to 150° C. for 5 min. After cooling, the solution was diluted with dichloromethane and absorbed over silica gel for purification by flash chromatography (gradient cyclohexane/dichloromethane: 0-80%) to yield 2-Isoquinolin-3-yl-7-((E)-styryl)-chromen-4-one O-tert-butyl oxime (160 mg, 76%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].CN(C)C=O.[H-].[Na+].I[CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21]>C(OCC)(=O)C>[CH:20]([O:19][CH2:18][CH2:17][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)([CH3:22])[CH3:21]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CC(C)OCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)OCCn1ccc([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
In a round bottom flask was placed 3-nitro-1H-pyrazole (prepared in example 3, 315 mg, 2.79 mmol) and dry N,N-dimethylformamide (5 mL). This solution was then treated with sodium hydride (95%, 80 mg, 3.35 mmol) and gas evolution occurred. It was then stirred another 15 min at 25° C. 2-(2-Iodo-ethoxy)-propane (896 mg, 4.18 mmol) was then added to the reaction mixture and the reaction was stirred at 25° C. for 6 h. The reaction was then diluted with ethyl acetate (10 mL) and washed with water (2×10 mL). The aqueous layers were then combined and extracted with ethyl acetate (2×10 mL). The organic layers were combined and washed with a saturated aqueous brine solution (10 mL) and then dried over sodium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 25% ethyl acetate/hexanes to 35% ethyl acetate/hexanes) afforded 1-(2-isopropoxy-ethyl)-3-nitro-1H-pyrazole (428 mg, 77%) as a light yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=2)[CH:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)(O)[C:31]#[CH:32])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([C:30]2([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=3)[O:1][C:2]3[C:11]4[C:6]([CH:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=3[CH:32]=[CH:31]2)=[CH:7][CH:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:10]=4)=[CH:39][CH:38]=1
Reactant: COC(=O)c1cc(O)c2cc(N3CCOCC3)ccc2c1
Reactant: C#CC(O)(c1ccc(OC)cc1)c1ccc(OC)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2ccc(N3CCOCC3)cc2c2c1C=CC(c1ccc(OC)cc1)(c1ccc(OC)cc1)O2
Yield: 14.9 %

Procedure:
A solution of methyl 4-hydroxy-6-morpholino-2-naphthoate (1.0 g, 3.5 mmol) and 1,1-di(4-methoxyphenyl)prop-2-yn-1-ol (0.94 g, 3.5 mmol) in toluene (45 cm3) containing acidic alumina (Brockmann 1), (5.0 g) was refluxed for 100 minutes. The cooled solution was filtered and the alumina was washed well with EtOAc (200 cm3). The organic filtrate was washed with aqueous sodium hydroxide (2M, 2×50 cm3) and water (100 cm3). Removal of the dried (Na2SO4) EtOAc gave an oil which was flash chromatographed over silica using 35% EtOAc in hexane as the eluent to afford a pale yellow solid. Recrystallisation from EtOAc/hexane gave methyl 2,2-bis(4-methoxyphenyl)-9-morpholino-2H-naphtho [1,2-b]pyran-5-carboxylate (yield=0.28 g, theoretical yield=1.87 g 15%, m.p.=153.5-155° C. (uncorrected)).
Reaction SMILES: [Na].[CH:2]([N:4]([CH2:6][CH2:7][CH2:8][P:9](=[O:12])([OH:11])[OH:10])[OH:5])=[O:3].[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.Cl>[OH-].[Na+].O.CC(C)=O.C(OCC)(=O)C>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([O:5][N:4]([CH2:6][CH2:7][CH2:8][P:9](=[O:11])([OH:10])[OH:12])[CH:2]=[O:3])=[O:19])=[CH:16][CH:15]=1
Reactant: O=CN(O)CCCP(=O)(O)O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=CN(CCCP(=O)(O)O)OC(=O)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
Monosodium salt of 3-(N-formyl-N-hydroxyamino)propylphosphonic acid (2.05 g.) was dissolved in a mixture of 1 N aqueous sodium hydroxide solution (20 ml.), water (10 ml.) and acetone (10 ml.). To the solution was added dropwise a solution of p-chlorobenzoyl chloride (2.10 g.) in dry acetone (5 ml.) at 0°-5° C. with stirring. After the stirring was continued at the same temperature for 30 minutes, ethyl acetate (40 ml.) was added to the reaction mixture and then the resultant mixture was adjusted to pH 1 with 10% hydrochloric acid. The ethyl acetate layer was separated and then the aqueous layer was extracted again with ethyl acetate (20 ml.). The combined ethyl acetate layer was washed with aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure to give an oily residue, which was crystallized with ethylether (40 ml.) to give crystals. The crystals were separated by filtration, washed twice with ethylether (10 ml.) to give crystalline 3-[N-(p-chlorobenzoyloxy)-N-formylamino] propylphosphonic acid (2.71 g.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14]Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:16]#[N:17].[K+].CS(C)=O>O.[I-].[K+]>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][C:16]#[N:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1CN(Cc2ccccc2)CCO1
Temperature: 120 °C
Reaction time: 5 h
Yield: 92.8 %

Procedure:
A mixture of 4-benzyl-2-chloromethylmorpholine (22.5 g), potassium cyanide (13 g), potassium iodide (1 g), and dimethyl sulfoxide (40 ml) is heated with stirring at 120° C. for 5 hours. The reaction mixture is cooled, diluted with water, and extracted with diethyl ether. The organic layer is washed with water, dried over sodium sulfate, and evaporated to give the title compound (20 g) as an oil.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][N:15]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][CH2:19][O:18][C:17]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:16]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.CCOCC>C(O)C>[ClH:31].[Cl:31][C:29]1[CH:28]=[CH:27][C:17]2[O:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:15]([CH2:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:16]=2[CH:30]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCCN2c3ccccc3OCOc3ccc(Cl)cc32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCCN2c3ccccc3OCOc3ccc(Cl)cc32)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 135.2 %

Procedure:
The above ester (0.77 g, 1.73 mmol) was dissolved in ethanol (7.5 ml) and 2 N sodium hydroxide (2.86 ml, 5.71 mmol) was added. The mixture was stirred at room temperature for 16 h. The ethanol was evaporated in vacuo and the remainder was diluted with water (25 ml). pH was adjusted to 6 by addition of 6 N hydrochloric acid and the aqueous solution was extracted with dichloromethane (3×15 ml). The combined organic extracts were dried over MgSO4 and evaporated in vacuo. The remainder was dissolved in tetrahydrofuran (15 ml) and 2.5 N hydrogen chloride in ether (0.59 ml, 1.47 mmol) was added dropwise. Ether (30 ml) was added and the mixture was stirred for 3 h, the precipitate was filtered off and dried, to afford 0.53 g (68%) of the title compound as a powder.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:31])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:30])[CH2:20][CH2:21][NH:22]C(OC(C)(C)C)=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1>O1CCOCC1.C(OCC)(=O)C>[ClH:1].[CH3:2][O:3][C:4](=[O:31])[CH2:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:30])[CH2:20][CH2:21][NH2:22])=[CH:16][CH:17]=2)[CH2:10][CH2:11]1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)OC(C)(C)C)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCN)cc2)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
0.4M hydrogen chloride solution dissolved in 1,4-dioxane (3.2 mL) was added to trans-{4-[4-(3-tert-butoxycarbonylaminopropionylamino)phenyl]cyclohexyl}acetic acid methyl ester (800 mg, 1.91 mmol) dissolved in ethyl acetate (16 mL). The reaction mixture was stirred at 50° C. for 4 hours and slowly cooled up to 25° C. The product was collected through filtration and washed with ethyl acetate. The product was dried under vacuum to obtain the desired compound (615 mg, 91%) as a white solid.