Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:14][C:15]([OH:17])=[O:16])[C:12](=[O:13])[C:11]2[N:9](C)C=N[C:6]=2N(C)[C:2]1=O.O1C=CC[CH2:20][CH2:19]1>C(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CCOC(C)=O>[NH2:9][C@H:11]([C:12]([N:1]1[CH2:2][CH2:20][CH2:19][C@H:14]1[C:15]([OH:17])=[O:16])=[O:13])[CH3:6]
Reactant: Cn1cnc2c1c(=O)n(CC(=O)O)c(=O)n2C
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
The compound 1 and 3,4-dihydro-2H-pyran in CH2Cl2 and pyridinium p-toluenesulfonate are stirred at room temperature for 12 h as indicated in the schematic below. Then the solution is diluted with EtOAc and washed with half-saturated brine to remove the catalyst. The solvent is evaporated and the residue is treated with NaOH(1N) and EtOH for 30 min. The solution is acidified with AcOH, and the product is extracted with EtOAc. The EtOAc solution is dried, evaporated to give the THP ether 2. The compound 2, DCC and HOBT in CH2Cl2 are stirred at room temperature for 60 min. Then MEEA-EDA HCI (N-(2-aminoethyl)[2-(2-maleiimidoethoxy)ethoxy]acetamide) and N-methylmorpholine are added. The reaction is stirred for 2 h., and then quenched by addition of AcOH. The precipitate is removed by filtration. The filtrate is washed with diluted HCl, NaHCO3, and dried. The crude product is used for the next step. The crude product is treated with 2N HCI H2O/EtOH 1:1) for 30 min. EtOH is evaporated. The product is extracted with CH2Cl2. The combined CH2Cl2 layers are washed with NaHCO3, and dried. Evaporation of the solvent gives a residue, which is purified by flash column chromatography to afford 3. This compound can be purified further by HPLC on a reverse phase column and lyophilized to produce the modified MMPI.
Reaction SMILES: C=[C:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1.[O:14]=[O+][O-].CCOC(C)=O>C(Cl)Cl.CO>[O:14]=[C:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1
Reactant: O=[O+][O-]
Reactant: C=C1CC(NC(=O)OC(C)(C)C)C1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC(=O)C1
Yield: 70 %

Procedure:
To a solution of tert-butyl (3-methylidenecyclobutyl)carbamate (165 g, 0.91 mol) in CH2Cl2 (1000 mL) and MeOH (1000 mL) was bubbled O3 at −78° C. until the solution turned blue. TLC (petroleum ether:EtOAc=10:1) showed that the starting material was consumed completely. Nitrogen gas was then bubbled through the reaction to remove excess O3, and then the mixture was quenched with Me2S (200 mL) and stirred for an hour. The solution was concentrated to give a residue, which was washed with sat. NaHCO3 and water to yield the title compound (118 g, 70% yield) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]([NH2:26])[C:16]=2[N:15]=[C:14]1[CH2:27][CH3:28].[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[NH2:26][C:17]1[C:16]2[N:15]=[C:14]([CH2:27][CH3:28])[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][S:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:37])=[O:36])[C:25]=2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]=1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1ccccc1
Yield: 26.6 %

Procedure:
Triethylamine (1.18 mL, 8.5 mmol) was added to a mixture of 1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 7.1 mmol) and chloroform (200 mL). The resulting solution was chilled in an acetone/ice bath for 10 minutes. Benzenesulfonyl chloride (0.90 mL, 8.5 mmol) was slowly added over a period of 5 minutes. After 45 minutes 0.2 equivalents of triethylamine was added. After 6 hours the reaction mixture was washed with brine (2×250 mL) and with water (1×100 mL), dried over magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from N,N-dimethylformamide. The recrystallized material and the filtrate were both slurried with methanol. The resulting solids were isolated by filtration, combined, and then dried in an Abderhalden drying apparatus overnight to provide 0.80 g of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamide as a white solid, m.p. 180.6–182.0° C. Analysis: Calculated for C22H25N5O2S.0.25H2O: % C, 61.73; % H, 6.00; % N, 16.36. Found: % C, 61.79; % H, 6.04; % N, 16.43.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH2:20][CH2:21][CH:22]([C:26]([OH:28])=[O:27])[CH2:23]4)=[CH:18][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=CC=1.C1(OC)C=CC=CC=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][CH:22]([C:26]([OH:28])=[O:27])[CH2:23]3)=[CH:18][CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2cc(Oc3ccc4c(c3)CC(C(=O)O)CC4)ccn2)cc1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Nc1cc(Oc2ccc3c(c2)CC(C(=O)O)CC3)ccn1
Yield: 94.5 %

Procedure:
A solution of 7-({2-[(4-methoxybenzyl)amino]pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (21.5 g, 0.0532 mol), anisole (52 mL, 0.48 mol) and TFAA (100 mL, 2 mol) in DCM (400 mL) was stirred at 37° C. overnight. The solvent was removed by evaporation at 30° C. To the resulting mixture was added 1N NaOH (300 mL) and the solution was extracted with ether. The aqueous solution was acidified with conc. HCl to pH=3. The water layer was discarded, the residue was washed with water (3×). The solid was dried in vacuo overnight to give 7-[(2-aminopyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (14.3 g). The combined yield for steps 2 and 3 was 94%. 1H NMR (DMSO-d6, 400 MHz) 7.83 (d, 1H); 7.30 (s, 2H); 7.20 (d, 1H); 6.98 d, 1H); 6.95 (dd, 1H); 6.46 (dd, 1H); 5.95 (d, 1H); 3.70 (s, 2H); 2.60-3.00 (m, 5H); 2.09 (m, 1H); 1.72 (m, 1H). LCMS ES+ 285.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]2[C:11]3[C:12](Cl)=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:9]=2[C:8]([O:19][CH:20]([F:22])[F:21])=[CH:7][CH:6]=1)=[O:4].[OH-].[NH4+].[H][H]>CO.CN(C)C=O.O.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:10]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:9]=2[C:8]([O:19][CH:20]([F:22])[F:21])=[CH:7][CH:6]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(OC(F)F)c2oc3ccnc(Cl)c3c12
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc(OC(F)F)c2oc3ccncc3c12

Procedure:
A mixture of Methyl-1-chloro-6-difluoromethyloxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylate (8.0 g), ammonium hydroxide (2.0 mL) and 10% Pd/C (4.0 g) in a mixture of methanol (100 mL) and dimethylformamide (5.0 mL) was hydrogenated in a Parr apparatus at 40-45 psi of hydrogen for 5-6 hrs. catalyst was removed by filtration and residue obtained was diluted with water. The solid product obtained was filtered and dried. Yield=6.5 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:15]O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a stirring solution of 3-nitrophenylacetic acid (10.4 g, 57.3 mmol) in MeOH (250 ml) at RT was added HCl gas until saturation was achieved. The resulting solution was stirred at 70° C. for 1 h. The reaction was cooled and concentrated under reduced pressure. The semisolid residue was dissolved in Et2O, washed with H2O (2×), satd. NaHCO3 (2×), brine (1×) and dried (MgSO4). Filtration and evaporation provided methyl 2-(3-nitrophenyl)acetate as a low-melting solid (10.7 g, 96% yield), which was used without further purification. 1H NMR (300 MHz, CDCl3): δ 8.14-8.04 (m, 2H), 7.64-7.58 (m, 1H), 7.47 (brt, J=8.10 Hz, 1H), 3.72 (s, 2H), 3.68 (s, 3H); MS (ESI) m/z: 196.0 (M+H+).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-:13].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([OH:12])=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:11]=1
Reactant: [Br-]
Reactant: Oc1ccccc1C1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Br)cc1C1CCCC1
Temperature: 25 °C

Procedure:
2-cyclopentyl phenol (3.0 g, 0.0185 mol) was dissolved in CHCl3 (100 mL) and magnetically stirred at room temperature. To this solution was added a solution of Tetrabutyl ammonium tribromide (8.92 g, 0.0185 mol) in CHCl3 (100 mL). The resulting yellow solution was allowed to stir at room temperature for 1 hour. The reaction was quenched with a 5% solution of sodium thiosulfate (200 mL). The biphasic mixture was stirred for 15 min. The organics were separated and concentrated. The residue was dissolved in EtOAc (100 mL) and washed with water (2×100 mL) and brine (1×100 mL). The organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel) eluting with 3% EtOAc in Hexanes. The result was a yellow oil (3.70 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[NH2:26][C:27]1[CH:32]=[CH:31][C:30](Br)=[CH:29][N:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:30]3[CH:31]=[CH:32][C:27]([NH2:26])=[N:28][CH:29]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1ccc(Br)cn1
Product: Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 2-amino-5-bromopyridine (156 mg, 1.0 mmol) according to general procedure II. Obtained as a dark-red solid (80 mg, 17%). MS (ISP) 448.2 [(M+H)+]; mp 227-229° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[C:47]1([CH2:53][C:54](Cl)=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(CC)CC)C>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:54](=[O:55])[CH2:53][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:43]=[CH:44][CH:45]=2)=[N:8]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.125 g, 0.207 mmol), in tetrahydrofuran (5 mL), were added, phenyl acetyl chloride (0.049 g, 0.315 mmol, 0.025 mL) and triethyl amine (0.107 g, 1.06 mmol, 0.147 mL). The reaction mixture was stirred at room temperature for 12 hours. After evaporation of the solvent, the residue was dissolved in 10 mL of ethyl acetate and was washed 3 times with water (5 mL). The crude was used without further purification (0.186 g, 99% yield): ES-MS (m/z) 721 [M+1]+.
Reaction SMILES: [CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][C@H:26](O)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][C@@H:26]([O:8][C:7](=[O:9])[C@:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)([OH:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OC(=O)[C@](O)(c2ccccc2)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 282.8 %

Procedure:
(R)-Cyclopentylhydroxyphenylacetic acid (20 g, 90.8 mmol), (S)-3-hydroxypyrrolidine-1-carboxylic acid t-butyl ester (18 g, 96.2 mmol) and triphenylphosphine (24 g, 91.5 mmol) were dissolved in THF (100 mL). Diisopropyl azodicarboxylate (19.7 mL, 99.9 mmol) was added slowly at room temperature. The mixture was stirred overnight at room temperature. The solvent was removed by rotary evaporation. EtOAc was then added and the solution was washed with a saturated NaHCO3 solution, then saturated aqueous NaCl. The organic layer was dried over Na2SO4 then concentrated to yield approximately 100 g of crude title compound, which was used immediately without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[CH:27]=[CH:28][C:29](O)=[O:30].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[Cl:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[CH:27]=[CH:28][C:29]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:30]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: O=C(O)C=Cc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1Cl
Yield: 76.2 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), 2-chlorocinnamic acid (2.2 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (2.9 g, 76%) as crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][O:6][P:5]([NH:9][CH:10]([CH3:12])[CH3:11])(=[S:8])[O:4][CH2:3]1.C(N(CC)CC)C.[S:21](Cl)Cl.[CH3:24][NH:25][C:26]([O:28][N:29]=[C:30]([S:32][CH3:33])[CH3:31])=[O:27]>O1CCCC1.O>[CH3:1][C:2]1([CH3:13])[CH2:3][O:4][P:5]([N:9]([CH:10]([CH3:11])[CH3:12])[S:21][CH2:24][NH:25][C:26]([O:28][N:29]=[C:30]([S:32][CH3:33])[CH3:31])=[O:27])(=[S:8])[O:6][CH2:7]1
Reactant: ClSCl
Reactant: CNC(=O)ON=C(C)SC
Reactant: CC(C)NP1(=S)OCC(C)(C)CO1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CSC(C)=NOC(=O)NCSN(C(C)C)P1(=S)OCC(C)(C)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5,5-dimethyl-2-isopropylamino-2-thioxo-1,3,2-dioxaphosphorinane (3.00 g, 13.4 mmol) and triethylamine (1.9 ml, 13.5 mmol) in tetrahydrofuran (20 ml) is added dropwise over 20 minutes to a stirred solution of sulfur dichloride (1.00 ml, 15.7 mmol) in tetrahydrofuran (20 ml) at room temperature. Following the addition the mixture is stirred at room temperature for 1 hour. Cuprous chloride (0.25 g) is added to the mixture followed by dropwise addition of a solution of Methyl N-[[(methylamino)carbonyl]oxy]ethanimidothioate (2.17 g, 13.4 mmol) and triethylamine (1.90 ml, 13.5 mmol) in tetrahydrofuran (20 ml.). The mixture is stirred for two hours at room temperature then diluted with water and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residual oil is chromatographed over silica gel eluting with a mixture of ethyl acetate - Skellysolve B in the ratio of 2 to 3. The chromatographed product is recrystallized from ethyl acetate, to give Methyl N-[[[[[(5,5-dimethyl-2-thioxo-1,3,2-dioxaphosphorinan-2-yl)isopropylamino]thio]methylamino]carbonyl]oxy]ethanimidothioate as a white solid of melting point 114°-115° C. The nmr and ir spectra are consistent with the expected structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5]Br.[CH3:11][C:12]([CH3:14])=[O:13]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][C:12]([CH3:14])([OH:13])[CH3:11])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: CC(C)=O
Reactant: Fc1cc(F)cc(CBr)c1
Product: CC(C)(O)Cc1cc(F)cc(F)c1

Procedure:
The target compound is obtained by reacting a Grignard compound, prepared from 25.0 g (121 mmol) of 3,5-difluorobenzyl bromide, with 12.6 mL (171 mmol) of acetone. Yellow oil. Yield: 13.5 g (60%).
Reaction SMILES: [BrH:1].Br.[NH2:3][CH2:4][C:5]([NH2:7])=[NH:6].[Cl:8][C:9]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:10]=1[CH:11]=O.[C-:19]#[N:20].[K+]>CO>[BrH:1].[C:19]([CH:11]([NH:3][CH2:4][C:5]([NH2:7])=[NH:6])[C:10]1[CH:13]=[C:14]([Cl:18])[CH:15]=[C:16]([Cl:17])[C:9]=1[Cl:8])#[N:20]
Reactant: [C-]#N
Reactant: O=Cc1cc(Cl)cc(Cl)c1Cl
Reactant: N=C(N)CN
Agent: Br
Agent: [K+]
Solvent: CO
Product: N#CC(NCC(=N)N)c1cc(Cl)cc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Aminoacetamidine dihydrobromide (162.1 g, 0.774 mole) was added in portions to a solution of 2,3,5-trichlorobenzaldehyde (200.0 g, 0.851 mole) in methanol (2.43 litres) at room temperature. Once the addition was complete potassium cyanide (50.4 g, 0.774 mole) was added in one portion to the resulting mixture. The suspension was then stirred at 25° C. for 4 hours before being warmed to 50° C. The mixture is stirred at 50° C. for 24 hours. Methanol was then removed in vacuo, the resulting solid was slurried in water (1.5 litres) and ethyl acetate (2.5 litres) and collected by filtration. The solid was then dried in vacuo at 50° C. overnight to give the desired product. Yield 96.31 g (33.4%), 1H nmr (d-6 DMSO) δ/ppm 8.72 (3H, br, NH); 7.99 (1H, d, J 2.3 Hz, ArH); 7.79 (1H, d, J 2.3 Hz, ArH); 5.39 (1H, d, J 10.6 Hz, ArCH(CN)NH); 4.35 (1H, m, ArCH(CN)NH); 3.56 (2H, d, J 6.4 Hz, ArCH(CN)NHCH2C(═NH)NH2).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][CH:11]([CH2:13]O)[OH:12].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1.C(OC(C)C)(C)C>[OH:12][CH:11]1[CH2:10][O:9][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][CH2:13]1
Reactant: O=Cc1ccccc1
Reactant: OCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: OC1COC(c2ccccc2)OC1
Reaction time: 8 h

Procedure:
To a solution of benzaldehyde (150.0 g, 1.41 mol) in toluene, glycerol (160.0 g, 1.74 mol) was added followed by 4-methylbenzenesulfonic acid (1.0 g) and the mixture was vigorously stirred under reflux with a Dean-Stark water separator. The refluxing was continued until no more water separated in the condenser (6-8 h). The clear solution was treated with 4N NaOH until basic and the organic layer was washed with water (5×100 mL) followed by saturated sodium chloride solution and then dried over anhydrous sodium sulfate. Concentration of the organic layer resulted in an oil which was dissolved in hot isopropylether and then left in the freezer overnight. The colorless solid was filtered and washed with isopropylether to yield the title product as a colorless solid. Yield: 55.0 g (22%). m.p. 83°-84° C. [Lit. m.p. 83°-84° C.; J. S. Briamacombe, A. B. Foster and M. Stacey, Chem. & Ind., 1958, 122814 9]. 1H NMR (CDCl3) ε 3.1 (d, 1H, --OH), 3.7 (d, 1H Ar--CH), 4.3 (m, 4H, O--CH2), 5.6 (s, 1H, O--CH--O) and 7.4 (m, 5H, Ar--H). M/e: [M+H]+ =181.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1OC.COC1C=CC=[C:18]([O:39][CH3:40])[C:19]=1[C:20]1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:40][O:39][CH:18]1[CH2:19][CH:20]1[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: COc1ccc(Cl)c(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COc1ccc(C2CC2OC)cc1
Temperature: 100 °C

Procedure:
To form 2,4-dimethoxy-cyclopropylbenzene (4cc), the general procedure was followed using 1-chloro-2,4-dimethoxybenzene (3b) (173 mg, 1.00 mmol), cyclopropyl MIDA boronate (2h) (236 mg, 1.20 mmol), SPhos (41 mg, 0.10 mmol) and Pd(OAc)2 (11 mg, 0.048 mmol). The reaction temperature was modified so that the reaction mixture was heated to 100° C. for 6 h. Compound 4cc was isolated as a colorless liquid (175 mg, 97%). TLC (hexanes:EtOAc 9:1) Rf=0.65, visualized by UV (254 nm). 1H-NMR (500 MHz, CDCl3w/ TMS) δ 6.77 (d, J=8.5 Hz, 1H), 6.44 (d, J=2.5 Hz, 1H), 6.39 (dd, J=8.5, 2.5 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 2.03 (m, 1H), 0.85 (m, 2H), 0.57 (m, 2H). 13C-NMR (125 MHz, CDCl3) δ 159.2, 158.6, 125.7, 124.2, 103.8, 98.4, 55.5, 55.3, 9.0, 6.9. HRMS (EI+) Calculated for C11H14O2 (M)+: 178.0994, Found: 178.0995. IR (thin film, cm−1) 3080, 3000, 2955, 2940, 2835, 1615, 1585, 1510, 1464, 1439, 1416, 1370, 1319, 1290, 1261, 1209, 1172, 1158, 1117, 1062, 1037, 938, 884, 834, 823, 799.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[Br:11][C:12]1[CH:16]=[N:15][N:14]([CH3:17])[C:13]=1[C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]([CH3:32])([N+:29]([O-])=O)[CH3:28])[NH2:21].C(N(CC)C(C)C)(C)C>ClCCl>[NH2:29][C:27]([CH3:32])([CH3:28])[CH2:26][O:25][C:24]1[CH:23]=[CH:22][C:20]([NH:21][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)=[CH:19][C:18]=1[C:13]1[N:14]([CH3:17])[N:15]=[CH:16][C:12]=1[Br:11]
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCC(C)(C)[N+](=O)[O-]
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2cccc(Br)c2)ccc1OCC(C)(C)N
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
3-Bromobenzoyl chloride (12 mg, 0.06 mmol) was added to a solution of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline (18 mg, 0.05 mmol) and N,N-diisopropylethylamine (10 μl, 0.06 mmol) in dichloromethane (0.5 mL) and the mixture was stirred at room temperature. After 1 h, the solution was diluted with dichloromethane, washed with 1M hydrochloric acid and saturated sodium bicarbonate, dried with sodium sulfate, filtered, and evaporated to dryness. The residue was dissolved in methanol (0.5 mL). Acetic acid (0.1 mL) was added followed by zinc dust (33 mg) and the mixture was stirred at room temperature. After 4 h, the suspension was made basic with ammonium hydroxide and extracted twice with ethyl acetate. The combined extracts were evaporated to dryness, purified by preparative LCMS and lyophilized to give the product (24 mg, 91%) as a TFA-salt. LCMS m/z (%)=525.5 (M+H 81Br2 34.2%), 523.3 (M+H 79Br 81Br 100.0%), 521.4 (M+H 79Br212.6%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (s, 3H), 1.18 (s, 3H), 3.67 (s, 3H), 3.83 (d, J=9.60 Hz, 1H), 3.99 (d, J=9.60 Hz, 1H), 7.29 (d, J=9.09 Hz, 1H), 7.51 (t, J=7.83 Hz, 1H), 7.67 (s, 1H), 7.69 (d, J=2.53 Hz, 1H), 7.78-7.84 (m, 1H), 7.84-7.92 (m, 3H), 7.92-7.98 (m, 2H), 8.14 (t, J=1.77 Hz, 1H), 10.44 (s, 1H).