Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([NH:26][N:27]([CH3:31])[C:28](=[O:30])[CH3:29])=[CH:22][CH:21]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH3:32]I.[H-].[Na+]>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([N:26]([CH3:32])[N:27]([CH3:31])[C:28](=[O:30])[CH3:29])=[CH:22][CH:21]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)N(C)Nc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)N(C)N(C)c1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
N′-[4-[2-[6-(4-Chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl]ethyl]phenyl]-N-methylacetohydrazide (106 mg) was suspended in DMF (7.0 ml), and methyl iodide (17 μl) and then sodium hydride (60%, 10 mg) were added at 0° C. The obtained mixture was stirred at room temperature for 4.5 hr, and methyl iodide (17 μl) and then sodium hydride (60%, 10 mg) were added at 0° C. The obtained mixture was stirred at room temperature for 24 hr, diluted with chloroform, and washed with water and then saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=50:1 (volume ratio)) and further washed with ethyl acetate to give the title compound (50.1 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[C:4]1[C:5]([F:19])=[C:6]([F:18])[C:7]2[O:11][N:10]=[C:9]([C:12]([O:14]CC)=O)[C:8]=2[CH:17]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[CH3:21][O:20][CH:3]([O:2][CH3:1])[C:4]1[C:5]([F:19])=[C:6]([F:18])[C:7]2[O:11][N:10]=[C:9]([C:12]([NH:25][CH:22]([CH3:24])[CH3:23])=[O:14])[C:8]=2[CH:17]=1
Reactant: CCOC(=O)c1noc2c(F)c(F)c(C(OC)OC)cc12
Reactant: CC(C)N
Product: COC(OC)c1cc2c(C(=O)NC(C)C)noc2c(F)c1F

Procedure:
Starting materials: ethyl 5-(dimethoxymethyl)-6,7-difluorobenzo[d]isoxazole-3-carboxylate (Intermediate 206) and isopropyl amine.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]([OH:11])=O.[CH2:14]([O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1)[CH3:15].Cl.CN(C)CCCN=C=NCC>C1COCC1.CCCCCC.C(OCC)(=O)C>[F:12][C:2]([F:1])([F:13])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]([NH:21][C:20]1[CH:22]=[CH:23][C:17]([O:16][CH2:14][CH3:15])=[CH:18][C:19]=1[N+:24]([O-:26])=[O:25])=[O:11]
Reactant: O=C(O)c1cnccc1C(F)(F)F
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOc1ccc(NC(=O)c2cnccc2C(F)(F)F)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 9.4 %

Procedure:
A mixture of 4-(trifluoromethyl)pyridine-3-carboxylic acid (100 mg, 0.52 mmol), 4-ethoxy-2-nitroaniline (94.7 mg, 0.52 mmol), and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (199.3 mg, 1.04 mmol) in THF (5 ml) was refluxed overnight. The mixture was cooled to room temperature, diluted with 100 ml of hexane:ethyl acetate (1:1), wash with 2 N NaOH (50 ml), water (50 ml), saturated aqueous NaCl (50 ml), dried over anhydrous sodium sulfate and evaporated. The crude product was purified by column chromatography using hexane:ethyl acetate (2:1) to give 17.3 mg (9.4% yield) of the title compound as yellow solid. 1H NMR (CDCl3): 10.48 (s, 1H), 9.01-8.96 (m, 2H), 8.74 (d, J=9.3 Hz, 1H), 7.74-7.69 (m, 2H), 7.32 (dd, J=3.0, 9.3 Hz, 1H), 4.13 (q, J=6.9 Hz, 2H), 1.48 (t, J=6.9 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([NH:11][NH2:12])[N:8]=[N+:9]([O-:10])[C:4]=2[CH:3]=1.[CH2:15](OC(OCC)OCC)C>C(O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]3[CH:15]=[N:12][N:11]=[C:7]3[N:8]=[N+:9]([O-:10])[C:4]=2[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: NNc1nc2ccc(Br)cc2[n+]([O-])n1
Solvent: CCO
Product: [O-][n+]1nc2nncn2c2ccc(Br)cc21
Temperature: 145 °C
Yield: 65.4 %

Procedure:
A mixture of 7-bromo-3-hydrazino-1,2,4-benzotriazine 1-oxide (1 g, 3.91 mmol) and 1,1,1-triethoxymethane (6.24 g, 42.08 mmol) was heated to 145° C. for 3 h, and the ethanol formed during the reaction was continuously distilled off. After cooling in a refrigerator for 12 h, the solid filtered off and washed with ether to give 7-bromo[1,2,4]triazolo[3,4-c][1,2,4]benzotriazine-5-oxide, (Compound Number 5, 0.68 g, 63% yield), 1H-NMR (300 MHz; DMSO): 9.95 ppm (s,1H, H-1); 8.60 ppm (d,1H, H-6); 8.47 ppm (d, 1H, H-9) and 8.38 ppm (dd,1H, H-8).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[N:31][CH:30]=1>>[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:8](=[O:10])[CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH:13]=[N:12]2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:31][CH:30]=1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2F)cc1=O
Reactant: COC(=O)c1ccc(N)nc1
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3F)cc2=O)nc1
Yield: 30 %

Procedure:
Using the method described in Example 66, 3-cyclopentyl-2-[4-(2-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 43) and 6-amino-nicotinic acid methyl ester afforded 6-{3-cyclopentyl-2-[4-(2-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionylamino}-nicotinic acid methyl ester as a yellow solid (200 mg, 30%); ESI-LRMS m/e calcd for C25H25F N4O5 [M+] 481, found 481 [M+H+]. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.00-1.21 (m, 1H) 1.26-1.84 (m, 8H) 1.87-2.05 (m, 1H) 2.22-2.40 (m, 1H) 3.86 (s, 3H) 5.58 (dd, J=10.9, 4.2 Hz, 1H) 5.82 (d, J=2.8 Hz, 1H) 7.29-7.56 (m, 4H) 8.10 (d, J=9.0 Hz, 1H) 8.24 (d, J=2.8 Hz, 1H) 8.28 (dd, J=9.0, 2.3 Hz, 1H) 8.87 (d, J=2.3 Hz, 1H) 11.42 (s, 1H).
Reaction SMILES: [N:1]1([C:6]2[CH:23]=[CH:22][C:9]([CH2:10][C:11]3[CH:19]=[C:18]4[C:14]([CH2:15][NH:16][C:17]4=[O:20])=[CH:13][C:12]=3[CH3:21])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:31]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:32]=1[C:33]#[N:34]>CN(C=O)C.O.C(OCC)(=O)C>[F:39][C:38]1[C:31]([N:16]2[CH2:15][C:14]3[C:18](=[CH:19][C:11]([CH2:10][C:9]4[CH:22]=[CH:23][C:6]([N:1]5[CH:5]=[CH:4][CH:3]=[N:2]5)=[CH:7][CH:8]=4)=[C:12]([CH3:21])[CH:13]=3)[C:17]2=[O:20])=[C:32]([CH:35]=[CH:36][CH:37]=1)[C:33]#[N:34]
Reactant: Cc1cc2c(cc1Cc1ccc(-n3cccn3)cc1)C(=O)NC2
Reactant: N#Cc1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1Cc1ccc(-n3cccn3)cc1)C(=O)N(c1c(F)cccc1C#N)C2
Temperature: 150 °C
Reaction time: 8 h
Yield: 11.2 %

Procedure:
To a solution of 6-(4-(1H-pyrazol-1-yl)benzyl)-5-methylisoindolin-1-one (0.05 g) in DMF (1.00 mL) were added potassium carbonate (0.07 g) and 2,3-difluorobenzonitrile (0.05 g), and the mixture was stirred overnight at 150° C. under argon atmosphere. The reaction mixture was diluted with water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and then HPLC (water/methanol) to give the title compound (7.80 mg).
Reaction SMILES: [C:1]([O:10]CC)(=[O:9])[CH2:2][CH2:3][C:4]([O:6]CC)=[O:5].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[CH:18]=O.[H-].[Na+].[OH-].[Na+]>C(O)C>[CH3:26][O:25][C:21]1[CH:20]=[C:17]([CH:18]=[C:3]([CH2:2][C:1]([OH:10])=[O:9])[C:4]([OH:6])=[O:5])[CH:16]=[C:15]([O:14][CH3:13])[C:22]=1[O:23][CH3:24]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C=C(CC(=O)O)C(=O)O)cc(OC)c1OC
Temperature: 0 °C
Yield: 83.9 %

Procedure:
To a stirred mixture of 17.4 g of diethyl succinate, 19.6 g of 3,4,5-trimethoxybenzaldehyde in 175 ml of ethanol chilled to 0° C. under argon was added 5.0 g of sodium hydride (60% in oil) in three equal portions. The solution was then refluxed for 30 minutes and 125 ml of 2N sodium hydroxide added. The solution was refluxed for 2 hours and concentrated under vacuum. The residue was diluted with water, extracted with ether and the aqueous layer acidified with concentrated hydrochloric acid. The mixture was extracted three times with 45 ml of ether and the ether extracts washed with saturated sodium chloride solution. The ether layer was dried (MgSO4) and the solvent removed under vacuum to give 24.82 g of [(3,4,5-trimethoxyphenyl)methylene]butanedioic acid as a yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10]O.C1C=CC(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:26]([CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[N+:27]=[N-:28]
Reactant: OCc1cc2ccccc2o1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 12.5 h

Procedure:
To a stirring solution of 1.00 g (6.77 mmol) of benzofuran-2-ylmethanol in 10 mL of toluene at r.t. was added 1.7 mL (7.89 mmol) of DPPA. The solution was cooled to 0° C. and 1.2 ml (8.02 mmol) of DBU was added. The ice bath was removed, and the mixture was stirred with warming to r.t. After 12.5 h, 1N HCl was added to a pH=4, and the aqueous layer was extracted with EtOAc. The pH of the aqueous layer was then adjusted to pH=6 with saturated NaHCO3 solution, and the aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (5% EtOAc/hexanes) provided 2-(azidomethyl)benzofuran as a pale yellow oil in quantitative yield.
Reaction SMILES: CC(C1[N:8]([CH2:9][CH2:10][C@@H:11](O)[CH2:12][C@@H:13](O)[CH2:14][C:15](O)=O)[C:7](C2C=CC(F)=CC=2)=[C:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)C=1C(NC1C=CC=CC=1)=O)C>C(#N)C>[CH2:9]([NH:8][CH2:7][CH2:6][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)O
Solvent: CC#N
Product: c1ccc(CCNCc2ccccc2)cc1

Procedure:
The benethamine salt of atorvastatin (Form A) was synthesized by preparing a stock solution of the free acid of atorvastatin (U.S. Pat. No. 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of N-benzyl-2-phenylethylamine (benethamine) was prepared by dissolving 378.59 mg (1.0 equivalents) in acetonitrile (10 mL). The stock solution of atorvastatin free acid was added to the counterion solution with stirring. Over time, an additional 40 mL of acetonitrile was added to prevent the formation of a gel. After 5 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a Buchner funnel fitted with a paper filter (#2 Whatman). The solids were rinsed with acetonitrile (75 mL), and placed in a 25′C oven under nitrogen to dry overnight to afford atorvastatin benethamine Form A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:18]([CH2:19][CH3:20])[CH2:16][CH3:17])=[O:15]
Reactant: CCNCC
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Product: CCN(CC)C(=O)c1cnoc1-c1ccccc1Cl

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and diethylamine (4.4 mg, 0.060 mmol) as described in synthetic method A and thereafter purified by preparative HPLC method A to give a solid (3.8 mg). MS (pos) m/z 279.1 (M+1).
Reaction SMILES: O[C:2]1([C:20]2[C:29]([OH:30])=[CH:28][C:23]3[O:24][CH2:25][CH2:26][O:27][C:22]=3[CH:21]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[N:13]=[CH:12][S:11][C:9]3=2)[N:4]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:3]1=[O:19].C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(O)(C3C=CC(OC)=CC=3O)C2=O)C=CC=CC=1>>[OH:30][C:29]1[C:20]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]4[N:13]=[CH:12][S:11][C:9]4=3)[N:4]([CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:3]2=[O:19])=[CH:21][C:22]2[O:27][CH2:26][CH2:25][O:24][C:23]=2[CH:28]=1
Reactant: CC(C)CCN1C(=O)C(O)(c2cc3c(cc2O)OCCO3)c2c1ccc1ncsc21
Agent: COc1ccc(C2(O)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)c(O)c1
Product: CC(C)CCN1C(=O)C(c2cc3c(cc2O)OCCO3)c2c1ccc1ncsc21

Procedure:
Following the procedure as described in PREPARATION 12B, and making non-critical variations using 8-hydroxy-8-(7-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-isopentyl-6H-thiazolo[5,4-e]indol-7(8H)-one to replace 1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one, 8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-(3-methylbutyl)-6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-one was obtained (93%): MS (ES+) m/z 411.0 (M+1).
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C@H:9]([NH:16]C(=O)C(F)(F)F)[CH2:10]2.[ClH:23].C>CO.O>[ClH:23].[F:4][C:5]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C@H:9]([NH2:16])[CH2:10]2
Reactant: O=C(N[C@H]1CCc2c(F)cc(F)cc2C1)C(F)(F)F
Agent: C
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Product: N[C@H]1CCc2c(F)cc(F)cc2C1
Reaction time: 60 h

Procedure:
Lithium hydroxide monohydrate (7.8 g, 0.2 mol) was added to a solution of (S)-5,7-difluoro-2-[(trifluoroacetyl)amino]-1,2,3,4-tetrahydronaphthalene (20.8 g, 74.5 mmol) in 187 mL of methanol and 21 mL of water. The mixture was stirred at reflux for 30 minutes and diluted with 200 mL of methanol. The diluted mixture then was combined with 60 mL of water, 24.8 mL of concentrated hydrochloric acid and 4.2 g of activated carbon, Darco®. The mixture was stirred for 30 minutes and then filtered through Celite. The filtrate was distilled until the head temperature reached 75° C. The remaining mixture was allowed to cool and let stand for approximately 60 hours. The mixture then was cooled in an ice bath giving a crystalline material. The material was isolated by filtration and the filter residue was washed with water. Drying to constant weight in vacuo at room temperature under a nitrogen stream gave (S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloride (14.8 g, 67.6 mol), m.p. >280° C. [α]D -66.2° (c=0,162, CH3OH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(NC2C3C(=CC=CC=3)[S:43]CC2)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[S:43][CH2:20][CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(NC2CCSc3ccccc32)c(CC)nc1Br
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCSc2ccccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-N-(3,4-dihydro-2H-thiochromen-4-yl)-3,6-diethylpyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.51, 7.36, 7.32, 7.29, 7.20, 7.07, 5.49, 4.64, 3.23, 3.02, 2.72, 2.64, 2.53, 2.20, 1.27, 1.22; 13C NMR (100 MHz, CDCl3) δ 151.42, 150.26, 140.63, 137.74, 137.67, 135.29, 134.57, 134.22, 132.88, 131.23, 129.81, 129.11, 128.53, 127.52, 127.28, 124.87, 48.48, 27.58, 26.34, 23.18, 23.11, 13.30, 11.64; HRMS (FAB) calcd for C23H23Cl2N3S+H 444.1068, found 444.1055.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10](N)=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].N([O-])=O.[Na+].[I-:19].[I-].[K+]>Cl.O>[I:19][C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:11]=1
Reactant: [I-]
Reactant: Nc1ccc2ccc([N+](=O)[O-])cc2c1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc2ccc(I)cc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 7-nitro-2-aminonaphthalene (260 mg, 1.38 mmol) in concentrated HCl (10 mL) is cooled to 0° C. Sodium nitrite (105 mg, 1.53 mmol) is added in portions and the reaction is allowed to stir at 0° C. for 30 minutes. A solution of iodide (175 mg, 253.8 mmol) and potassium iodide (459 mg, 2.76 mmol) in water (5 mL) is added dropwise. After stirring at 0° C. for 1 hour, the solid is removed by filtration. The solid is dissolved in EtOAc and washed with sodium metabisulfite solution, water and brine. The organic layer is dried (Na2SO4) and the solvents evaporated to give 2-iodo-7-nitronaphthalene as an orange solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:2].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:2]
Reactant: CCNc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Yield: 75.3 %

Procedure:
A suspension of N-ethyl-5-fluoro-2-nitroaniline (1.5 g, 8.12 mmol), piperazine (0.979 g, 11.37 mmol), K2CO3 (3.36 g, 24.3 mmol) in DMF (40 mL) was heated in a microwave oven for 1 min at 100 W. The reaction mixture was allowed to cool and then heated for another minute at 100 w. This procedure was repeated 5 times. The suspension was filtered and then concentrated. The crude oil was purified via flash chromatography on silica using CHCl3/MeOH/NH3 9:1:0.4% as eluent to give 1.53 g (75%) of a yellow solid. 1H NMR (CDCl3) δ 8.30 (br s, 1H), 8.08-8.04 (m, 1H), 6.25-6.20 (m, 1H), 5.88-5.86 (m, 1H), 3.39-3.28 (m, 6H), 3.03-2.97 (m, 4H), 1.37 (tr, J=7.2 Hz, 3H); 13C NMR (CDCl3) δ 156.27, 147.74, 128.96, 124.13, 104.28, 93.34, 48.22, 45.99, 37.73, 14.15; MS (posEI) m/z=250 (M+); MS (posESI) m/z=found 250.1429, calc 250.1430. Anal (C12H18N4O2) C, H, O.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[N:18][C:19]([CH3:23])=[C:20](Br)[CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[N:18][C:19]([CH3:23])=[C:20]([C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=5)[CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccccc1
Temperature: 80 °C

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-6-methylpyridin-3-yl)cyclopropanecarboxamide (38 mg, 0.10 mmol) was dissolved in 1 mL of N,N-dimethylformamide (DMF) containing 0.2 mL of a 2M aqueous solution of potassium carbonate and 12 mg of Fibre-Cat 1007. The reaction mixture was then heated to 80° C. for 16 hours. The resulting material was cooled to room temperature, filtered, and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield the pure product. ESI-MS m/z calc. 372.2. Found 373.2 (M+1)+. Retention time 1.80 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:9]([C:23]([OH:25])=O)[CH2:10][CH2:11][C@@H:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[F:22])[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:33]([C:35]1[S:36][CH:37]=[CH:38][N:39]=1)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>ClCCCl.C(=O)(O)[O-].[Na+].ClCCl>[F:22][C:16]1[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=1[C@H:12]1[CH2:13][N:14]([CH2:33][C:35]2[S:36][CH:37]=[CH:38][N:39]=2)[C:23](=[O:25])[C@H:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@H](CN)c1cccc(F)c1F)C(=O)O
Reactant: O=Cc1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(Cc2nccs2)C1=O
Reaction time: 8 h
Yield: 56.3 %

Procedure:
A solution of (5S)—N2,N2-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-D-lysine (0.871 g, 1.90 mmol), 2-formylthiazole (0.183 g, 1.62 mmol) and acetic acid (0.137 g, 2.28 mmol) in 1,2-dichloroethane (20 mL) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (0.604 g, 2.85 mmol) was added and the reaction stirred overnight. The reaction was diluted with saturated aqueous sodium bicarbonate, the layers separated, and the aqueous phase extracted with DCM (2×). The organic washes were combined, dried over magnesium sulfate, and concentrated. This residue was diluted with dichloromethane (20 mL) and EDC (0.569 g, 2.97 mmol), HOAT (0.401 g, 2.97 mmol) were added followed by diisopropylethylamine (1.04 mL, 5.94 mmol). After stirring overnight, NaHCO3 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered, concentrated and the residue purified by silica gel chromatography (0%→40% EtOAc/hexanes) to give the title compound (0.49 g). MS 538.0 (M+1).). 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J=3.5 Hz, 1H), 7.37 (d, J=3.4 Hz, 1H), 7.0 (m, 2H), 6.8 (m, 1H), 5.20 (d, J=10.3 Hz, 1H), 5.03 (d, J=15.5 Hz, 1H), 4.96 (d, J=15.5 Hz, 1H), 3.84 (dd, J=10.3, 15.2 Hz, 1H), 3.48 (d, J=15.5 Hz, 1H), 2.94 (dd, J=11.0, 11.0 Hz, 1H), 2.50 (dd, 1H), 2.0 (m, 4H), 1.5 (s, 18H).
Reaction SMILES: [BH4-].[Na+].[C:3]1([P:9]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:10]2[CH:44]=[CH:43][CH:42]=[CH:41][C:11]=2[CH:12]=[N:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[N:20]=[CH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[P:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O>CO>[C:35]1([P:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][NH:20][C@@H:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]2[NH:13][CH2:12][C:11]2[CH:41]=[CH:42][CH:43]=[CH:44][C:10]=2[P:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: C(=N[C@@H]1CCCC[C@H]1N=Cc1ccccc1P(c1ccccc1)c1ccccc1)c1ccccc1P(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: c1ccc(P(c2ccccc2)c2ccccc2CN[C@@H]2CCCC[C@H]2NCc2ccccc2P(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
1.14 g (30 mmol) of sodium borohydride are added a little at a time to a solution of 3.30 g (5.0 mmol) of trans-N,N′-bis(2-diphenylphosphanylbenzylidene)cyclohexane-1,2-diamine in 60 ml of methanol. The solution is refluxed for 24 hours and, after cooling to room temperature, admixed with 20 ml of water. The organic phase is extracted with 3×50 ml of dichloromethane and the combined organic phases are washed with 2×30 ml of 10% ammonium chloride solution and 30 ml of water. After drying over magnesium sulfate, the solvent is removed under reduced pressure and the residue is recrystallized from 30 ml of ethanol. The product precipitates in the form of light-yellow crystals in a yield of 2.68 g (4.0 mmol, 80%). 1H-NMR (400 MHz, CDCl3): δ=7.65–6.92 (m, 28 H, aromat. H), 4.11, 3.98 (2×d, J=13.4 Hz, 4 H, Ar—CH2), 2.21 (m, 2H, NCH), 1.63–1.27 (m, 8H, (CH2)4) ppm.