Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N+:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([O-:29])=[O:28].C1CCN2C(=NCCC2)CC1>>[N+:27]([CH:30]([CH2:31][CH2:32][CH2:33][CH3:34])[C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([O-:29])=[O:28]
Reactant: CCCCC[N+](=O)[O-]
Reactant: O=C(O)CCCCCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCC(C(=O)CCCCCc1ccccc1)[N+](=O)[O-]

Procedure:
6-Phenylhexanoic acid (0.100 g, 0.52 mmol) and CDI (0.169 g, 1.04 mmol) were added together and then reacted with nitropentane (0.091 g, 0.78 mmol) and DBU (0.198 g, 1.30 mmol) according to the general procedure. Purification by column chromatography gave 0.049 g (32%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 2H), 7.17 (m, 3H), 5.10 (dd, J=4.4, 10.0 Hz, 1H), 2.61 (m, 4H), 1.63 (m, 6H), 1.35 (m, 6H) 0.92 (t, J=6.8 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 199.5, 142.5, 128.6, 128.5, 126.0, 94.5, 39.5, 35.9, 31.3, 29.6, 28.7, 28.1, 23.3, 22.2, 13.9 ppm; IR νmax (cm−1) 3027, 2931, 2859, 1731, 1559, 1454, 1363, 1030, 748, 700; HRMS (FAB) calcd for C17H25NO3 (MNa+) 314.1727, found 314.1722.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][C:21](=[O:29])[CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]#[N:19])[CH2:14][CH2:13]1)[CH:6]=[CH:5]2.[NH2:30][OH:31]>C(O)C>[NH2:19][C:18](=[N:30][OH:31])[CH:15]1[CH2:14][CH2:13][N:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[C:3]=3[NH:20][C:21](=[O:29])[CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[N:8]=2)[CH2:17][CH2:16]1
Reactant: NO
Reactant: N#CC1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)CC1
Solvent: CCO
Product: NC(=NO)C1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)CC1
Temperature: 25 °C

Procedure:
N-[6-Chloro-2-(4-cyano-1-piperidinyl)-5-quinolinyl]-cyclohexaneacetamide (Example 113) (0.2 g), hydroxylamine (50% w/v in H2O) (0.23 mL) and ethanol (2.5 mL) were heated within a microwave in a sealed 10 mL vial at 90° C. for 100 minutes. The reaction was cooled to room temperature and the resulting precipitate was filtered and washed with ethanol to afford the subtitle compound as a solid (0.18 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH3:13].[CH3:14][N:15]1[CH2:21][C:20]2[CH:22]=[C:23]([CH:26]=[CH:27][C:28](O)=[O:29])[CH:24]=[N:25][C:19]=2[NH:18][C:17](=[O:31])[CH2:16]1>>[CH3:1][N:2]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH3:13])[C:28](=[O:29])/[CH:27]=[CH:26]/[C:23]1[CH:24]=[N:25][C:19]2[NH:18][C:17](=[O:31])[CH2:16][N:15]([CH3:14])[CH2:21][C:20]=2[CH:22]=1
Reactant: CNCc1c(C)[nH]c2ccccc12
Reactant: CN1CC(=O)Nc2ncc(C=CC(=O)O)cc2C1
Product: Cc1[nH]c2ccccc2c1CN(C)C(=O)/C=C/c1cnc2c(c1)CN(C)CC(=O)N2
Yield: 9.9 %

Procedure:
According to the method of example 35g, methyl-(2-methyl-1H-indol-3-ylmethyl)amine (115 mg, 0.66 mmol) and 3-(4-Methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)-acrylic acid (192 mg, 0.6 mmol) were coupled to give crude product. Purification by column chromatography (silica gel, CH2Cl2/MeOH/NH3, 9:4.55:0.05) gave title compound (24 mg, 9%) as a white solid and as a mixture of amide rotomers. 1H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.95-8.01 (m, 2H), 7.56-7.60 (m, 2H), 7.47-7.50 (m, 1H), 7.16-7.26 (m, 2H), 6.92-7.05 (m, 2H), 3.90 (s, 2H), 3.56 (s, 2H), 3.02 (s, 2H), 2.93 (s, 3H), 2.83 (s, 3H), 2.46 (s, 3H); MS (ESI) m/e 404 (C23H25N5O2+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][C:10]=3[O:18]C)[NH:8][C:4]=2[CH:3]=1.ClC1C(Cl)=CC2N=C(C3C=CC(C(O)=O)=CC=3O)NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:56][N:57]1[C:62]([CH3:64])([CH3:63])[CH2:61][CH:60]([NH2:65])[CH2:59][C:58]1([CH3:67])[CH3:66]>C1COCC1>[Cl:22][C:21]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([NH:65][CH:60]4[CH2:59][C:58]([CH3:66])([CH3:67])[N:57]([CH3:56])[C:62]([CH3:64])([CH3:63])[CH2:61]4)=[O:17])=[CH:11][C:10]=3[OH:18])[NH:6][C:5]=2[CH:20]=1
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Reactant: COc1cc(C(=O)O)ccc1-c1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)c1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)c(O)c1
Solvent: C1CCOC1
Product: CN1C(C)(C)CC(NC(=O)c2ccc(-c3nc4cc(Cl)c(Cl)cc4[nH]3)c(O)c2)CC1(C)C
Temperature: 25 °C

Procedure:
A solution of 5,6-dichloro-2-(4-carboxy-2-methoxyphenyl)benzimidazole and 5,6-dichloro-2-(4-carboxy-2-hydroxyphenyl)benzimidazole (0.5 g, 1.48 mmol), prepared as described in Preparation 3,1-hydroxybenzotriazole (0.21 g, 1.56 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.35 g, 1.82 mmol) in THF (20 ml) was refluxed for 5 h. A solution of 1,2,2,6,6-pentamethyl-4-aminopiperidine (0.25 g, 1.5 mmol) in THF (3 ml) was added dropwise and refluxed for 3 h. After cooling to room temperature the solvent was evaporated under vacuum and the crude residue was purified by column chromatography eluting with CH2Cl2/MeOH/NH4OH 86:10:0.6 to give 10 mg of the title compound, mp>250° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[N:5]=[C:4]([CH2:16][CH3:17])[N:3]=1.[NH2:18][NH2:19].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:16]([C:4]1[N:3]=[C:2]([NH:18][NH2:19])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[N:5]=1)[CH3:17]
Reactant: NN
Reactant: CCc1nc(Cl)cc(-c2ccccc2OC)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCc1nc(NN)cc(-c2ccccc2OC)n1

Procedure:
[2-Ethyl-6-(2-methoxy-phenyl)-pyrimidin-4-yl]-hydrazine was prepared from 4-chloro-2-ethyl-6-(2-methoxy-phenyl)pyrimidine (0.91 g, 3.7 mmol), hydrazine (0.69 mL, 22 mmol), sodium carbonate (0.76 g, 7.1 mmol) and potassium carbonate (0.79 g, 5.5 mmol) in dioxane (10 mL) by a procedure similar to example 3, step 1 yielding 0.77 g (86%) of a white solid.
Reaction SMILES: [O:1]=[C:2]([NH:18][CH2:19][CH2:20][C:21]([O:23]CC1C=CC=CC=1)=[O:22])/[C:3](/[CH2:13][S:14]C(=O)C)=[CH:4]\[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1>CCOCC>[O:1]=[C:2]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])/[C:3](/[CH2:13][SH:14])=[CH:4]\[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COc1ccc(/C=C(/CSC(C)=O)C(=O)NCCC(=O)OCc2ccccc2)cc1
Solvent: CCOCC
Product: COc1ccc(/C=C(/CS)C(=O)NCCC(=O)O)cc1
Yield: 69 %

Procedure:
Saponification of the (E) diester obtained in Example 18 is carried out according to the experimental procedure described in Example 4. Yield: 69% (after flash chromatography, eluent: ether) m.p. 160° C. IR (nujol): 3340, 1730, 1620, 1580 cm-1 1H NMR (CDCl3): 9.10 (broad s, 1H); 7.75 and 7.15 (AB, 4H, J=8Hz); 6.60 (s, 1H); 6.15 (broad t, 1H): 3.75 (s, 3H); 3.50 to 3.45 (m, 4H); 2.50 (t, 2H, J=5 Hz): 1.70 (t; 1H, J=7 Hz). Microanalysis: C14H17O4NS Calc. % C=56.92 H=5.80 N=4.74 Found. % C=57.11 H=5.86 N=4.91
Reaction SMILES: CC1(C)N([O])C(C)(C)CCC1.CC(O[Na])=[O:14].[F:17][C:18]([F:38])([CH:21]([F:37])[O:22][C:23]([F:36])([F:35])[C:24]([F:34])([F:33])[C:25]([F:32])([F:31])[O:26][C:27]([F:30])([F:29])[F:28])[CH2:19][OH:20]>O.O.O.O.[N+]([O-])([O-])=O.[Mn+2].[N+]([O-])([O-])=O.O.O.O.O.O.O.[N+]([O-])([O-])=O.[Co+2].[N+]([O-])([O-])=O.C(O)(=O)C>[F:17][C:18]([F:38])([CH:21]([F:37])[O:22][C:23]([F:36])([F:35])[C:24]([F:33])([F:34])[C:25]([F:31])([F:32])[O:26][C:27]([F:28])([F:29])[F:30])[C:19]([OH:14])=[O:20]
Reactant: CC(=O)O[Na]
Reactant: OCC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Agent: [Co+2]
Agent: [Mn+2]
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Yield: 70.6 %

Procedure:
50 mL of acetic acid, 0.137 g of manganese nitrate tetrahydrate, 0.159 g of cobalt nitrate hexahydrate, TEMPO (0.42 g), CH3CO2Na (2.24 g) and 10 g of 2,2,3-trifluoro-3-(1,1,2,2,3,3-hexafluoro-3-trifluoromethoxy-propoxy)-propan-1-ol were placed in a reaction vessel as described in example 17 except that a 100 mL vessel instead of a 200 mL vessel was used. The reaction was carried out and worked up as described in example 9. Distillation gave 7.29 g of acid (1.6 mmHg, 58° C.). Yield: 70%.
Reaction SMILES: [CH:1]1([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:25])=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:26]=[S:27]1(=[O:41])[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:41]=[S:27]1(=[O:26])[CH2:28][CH2:29][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:22]([C:19]3[CH:20]=[CH:21][C:16]([C:14]4[CH:15]=[C:10]([NH:9][C:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:8])[CH:11]=[CH:12][C:13]=4[Cl:25])=[CH:17][CH:18]=3)=[O:23])=[CH:36][CH:35]=2)[CH2:31][CH2:32]1
Reactant: O=C(O)c1ccc(-c2cc(NC(=O)C3CCCCC3)ccc2Cl)cc1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(CN2CCS(=O)(=O)CC2)cc1)c1ccc(-c2cc(NC(=O)C3CCCCC3)ccc2Cl)cc1
Reaction time: 18 h
Yield: 21.6 %

Procedure:
A mixture of 5′-(cyclohexanecarbonyl-amino)-2′-chloro-biphenyl-4-carboxylic acid (100 mg), 4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenylamine (67 mg), triethylamine (0.098 ml) and HBTU (159 mg) in dry DMF (5 ml) was stirred at 20 C for 18 h. The mixture was then evaporated to dryness and purified via reversed-phase preparative HPLC (eluting with acetonitrile/water) to afford the title compound as an orange solid (35 mg).
Reaction SMILES: [C:1]([NH:8][CH2:9][C@H:10]1[CH2:12][C@H:11]1[CH2:13][O:14][N:15]1C(=O)C2C(=CC=CC=2)C1=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O>C(Cl)Cl>[O:14]([CH2:13][C@H:11]1[CH2:12][C@H:10]1[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[NH2:15]
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@H]1CON1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@@H]1C[C@@H]1CON
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1.5 g (0.00433 mol) of 2-[cis-2-(N-BOC-aminomethyl)-cyclopropylmethoxy]-1H-isoindole-1,3(2H)-dione and 9 ml of hydrazinc hydrate is stirred at room temperature for 1/2 hour. 9 ml of water are then added to the reaction mixture and, after a further 1/2 hour, 50 ml of methylene chloride are added. The reaction mixture is further stirred for another 3 hours, the methylene chloride phase is then separated off and the aqueous phase is washed twice with 30 ml of methylene chloride each time. The combined organic phases are washed with brine, dried over sodium sulfate and evaporated. The oily cis-2-aminoxymethyl-N-BOC-cyclopropylmethylamine thus obtained, Rf value=0.13 (silica gel/ethyl acetate:hexane (1:1)), is dissolved in 18 ml of 3M methanolic hydrochloric acid and the reaction mixture is stirred at room temperature for 1 hour. After addition of diethyl ether and cooling in an ice-bath, the title compound which has crystallized out is filtered off, washed with diethyl ether and dried, m.p. 178°-180° C. (decomp.).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([N:5]2[CH2:6][CH:2]([OH:1])[CH2:3][C@@H:4]2[C:7]([OH:9])=[O:8])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=C(O)[C@H]1CC(O)CN1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CC(O)C[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To 10 g (76.30 mmol) of 4-hydroxy-D-proline in 75 ml of water was added 17.45 g (91.6 mmol) of 4-toluenesulfonyl chloride and 17 g (160.2 mmol) of sodium carbonate and the mixture was allowed to stir for 24 hours at room temperature. The reaction was then acidified to pH 1 by the careful addition of 10% aqueous HC1 solution and the product was isolated by filtration. After drying at high vacuum, 18.5 g of product was isolated (85% yield). M.P.=145°-146° C.
Reaction SMILES: C1(S(Cl)(=O)=[O:8])C=CC=CC=1.[F:11][C:12]1[C:17]([CH:18]2[CH2:23][CH2:22][C:21](=[N:24]O)[CH2:20][CH2:19]2)=[CH:16][CH:15]=[CH:14][N:13]=1>N1C=CC=CC=1>[F:11][C:12]1[C:17]([CH:18]2[CH2:23][CH2:22][NH:24][C:21](=[O:8])[CH2:20][CH2:19]2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: ON=C1CCC(c2cccnc2F)CC1
Solvent: c1ccncc1
Product: O=C1CCC(c2cccnc2F)CCN1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
Benzenesulfonyl chloride (0.05 mL, 0.40 mmol) was added to a solution of 4-(2-fluoropyridin-3-yl)cyclohexanone oxime (0.075 g, 0.36 mmol) in pyridine (1 mL) at 0° C. The ice bath was removed and the mixture was stirred for 45 min before being heated to 100° C. for 30 minutes. After cooling to room temperature the pyridine was removed in vacuo and the residue was dissolved in 1:1 dioxane/water (5 mL) and stirred overnight. Ammonium chloride (50 mg) was added and stirring continued for 30 minutes. The mixture was extracted with ethyl acetate (3×), the combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to 5-(2-fluoropyridin-3-yl)azepan-2-one. [M+1]=209.1.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:7][C:5]=2[N:6]=1.[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(-c3ccccc3)ccc2o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc2cc(-c3ccccc3)ccc2o1
Yield: 32.3 %

Procedure:
2-Methyl-5-phenyl-benzoxazole 48 (1.05 g, 5.0 mmol), N-bromosuccinimide (89 mg, 5.0 mmol) and azodiisobutyronitrile (AIBN) (41 mg, 0.25 mmol) in 1 ml of CCl4 was heated to reflux. After 5 hrs an additional 50 mg AIBN were added and the mixture was refluxed overnight. The mixture was diluted, washed with water, dried and concentrated. The crude product was chromatographed to give about 465 mg 2-bromomethyl-5-phenyl-benzoxazole 49.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=1[CH3:15])[CH2:4][CH3:5])[CH3:2].[OH:16][C:17]1[C:26]([CH3:27])=[CH:25][C:20]([C:21]([NH:23]O)=[NH:22])=[CH:19][C:18]=1[Cl:28]>>[Cl:28][C:18]1[CH:19]=[C:20]([C:21]2[N:23]=[C:12]([C:10]3[S:11][C:7]([CH2:6][N:3]([CH2:1][CH3:2])[CH2:4][CH3:5])=[C:8]([CH3:15])[CH:9]=3)[O:14][N:22]=2)[CH:25]=[C:26]([CH3:27])[C:17]=1[OH:16]
Reactant: Cc1cc(C(=N)NO)cc(Cl)c1O
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Product: CCN(CC)Cc1sc(-c2nc(-c3cc(C)c(O)c(Cl)c3)no2)cc1C
Yield: 24 %

Procedure:
The title compound (11 mg) is prepared starting from 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (30 mg, 130 μmol) and 4,N-dihydroxy-3-chloro-5-methyl-benzamidine (23 mg, 117 μmol) according to Method A; LC-MS: tR=0.60 min; [M+1]+=392.12.
Reaction SMILES: [P:1]([CH2:5][C:6]([OH:8])=[O:7])([OH:4])([OH:3])=[O:2].[CH3:9]O>>[P:1]([CH2:5][C:6]([O:8][CH3:9])=[O:7])([OH:4])([OH:3])=[O:2]
Reactant: O=C(O)CP(=O)(O)O
Reactant: CO
Product: COC(=O)CP(=O)(O)O

Procedure:
Phosphonoacetic acid, 5 g., was dissolved in 25 ml. methyl alcohol. Dry hydrogen chloride was bubbled through the solution for 30 minutes at O° C. The solution was refluxed for 4 hours. Evaporation of the solvent left an oil which was dried in vacuo over P2O5 and NaOH.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14](O)=[S:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([Cl:21])=[S:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OC(=S)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: c1ccccc1
Product: S=C(Cl)Cc1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 17.5 g (0.0595 mol) of p-(p-chlorophenoxy)-phenylthio-acetic acid (Code No. CRL 40,271) and of 21.6 ml (0.3000 mol) of thionyl chloride is heated under reflux for 30 minutes. After having taken up the reaction mixture in benzene, filtered the solution in the presence of charcoal and evaporated the solvent, 18.5 g of a limpid orange-yellow oil are obtained.
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.O[Li].O.[O:20]=[C:21]1[O:25][C@H:24]2[CH2:26][C@@H:27]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:28]([CH:29]=O)[C@H:23]2[CH2:22]1.[NH4+].[Cl-]>CC(OC)(C)C.ClCCl.O>[F:15][C:9]([F:14])([CH2:10][CH2:11][CH2:12][CH3:13])[C:8](=[O:16])/[CH:7]=[CH:29]/[C@@H:28]1[C@@H:23]2[C@@H:24]([O:25][C:21](=[O:20])[CH2:22]2)[CH2:26][C@H:27]1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OCc1ccccc1
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [Cl-]
Agent: [Li]O
Agent: [NH4+]
Solvent: ClCCl
Solvent: COC(C)(C)C
Solvent: O
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of dimethyl(3,3-difluoro-2-oxoheptyl)phosphonate (6.9 g, 26.5 mmoL) in MTBE (30 mL) was added LiOH.H2O (1.11 g, 26.5 mmoL) and the mixture was stirred under nitrogen for 1 h. A solution of (3aR,4R,5R,6aS)-hexahydro-2-oxo-5-(phenylmethoxy)-2H-cyclopenta[b]furan-4-carboxaldehyde (6, R1 is phenyl, and R2 and R3 are H, 6 g, 23.1 mmoL) in dichloromethane (30 mL) was added followed by NH4Cl (370 mg, 6.93 mmoL), 0.2 mL water and then the mixture was stirred for 12 h. After completion of the reaction, the reaction was then quenched with a saturated NH4Cl solution (12 mL). The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated to dryness under vacuum. The crude material was further purified by column chromatography [25% ethyl acetate in heptanes] to yield (3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-oxo-1-octenyl)-2-oxo-5-(phenylmethoxy)hexahydro-2H-cyclopenta[b]furan (7, R1 is phenyl, and R2 and R3 are H) in 56% yield.
Reaction SMILES: [CH:1]([N:4]1[CH2:7][CH:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5]1)([CH3:3])[CH3:2].Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:1]([N:4]1[CH2:7][CH:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CC(COc2ccc(C3(CN)CCOCC3)cc2)C1
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)N1CC(COc2ccc(C3(CNc4ccccn4)CCOCC3)cc2)C1
Yield: 26 %

Procedure:
1-(4-{4-[(1-isopropylazetidin-3-yl)methoxy]phenyl}tetrahydro-2H-pyran-4-yl)methanamine was stirred with 2-bromopyridine (60 μl, 0.63 mmol), tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.018 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (19 mg, 0.036 mmol) and sodium tert-butoxide (90 mg, 0.94 mmol) and heated at 80° C. in toluene (5 ml) for 3 hours under nitrogen. The reaction mixture was partitioned between aqueous sodium hydroxide (50 ml) and ethyl acetate (80 ml). The organics were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (97:3:0.3 to 90:10:1 by volume) to give the product which required further purification by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4 to 94:6:0.6 by volume) to give a pale yellow oil which crystallized on standing, this was triturated with diethyl ether (2 ml) to give the title compound as a pale yellow powder (65 mg, 26%). 1H NMR (400 MHz, CDCl3) δ 8.02 (d, 1H), 7.31 (t, 1H), 7.25 (d, 2H), 6.91 (d, 2H), 6.50 (t, 1H), 6.20 (d, 1H), 4.09 (d, 2H), 3.99 (t, 1H), 3.82 (m, 2H), 3.59 (m, 2H), 3.48 (d, 2H), 3.45 (m, 2H), 3.03 (m, 2H), 2.88 (m, 1H), 2.33 (m, 1H), 2.13 (m, 2H), 1.92 (m, 2H), 0.93 (d, 6H). LRMS ESI+ m/z 396 [M+H]+. HRMS ESI+ m/z 396.2639 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].CC(C)([O-])C.[K+].[Cl:12]C1C(C)=CC=C(Cl)C=1NC1C=CC=CC=1[C:28]1[N:32]=[C:31](S(C2C=CC(C)=CC=2)(=O)=O)[S:30][N:29]=1.CCOCC>C(O)(C)(C)C>[ClH:12].[S:30]1[C:31]([NH:4][C:3]([NH2:5])=[NH:2])=[N:32][CH:28]=[N:29]1
Reactant: N=C(N)N
Reactant: Cc1ccc(S(=O)(=O)c2nc(-c3ccccc3Nc3c(Cl)ccc(C)c3Cl)ns2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: N=C(N)Nc1ncns1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
A suspension of guanidine hydrochloride (197 mg, 2.06 mmols) and potassium t-butoxide (150 mg, 1.33 mmols) in 10 mL of t-butanol is heated to 40° C. 2,6-Dichloro-3-methyl-N-[2-[5-[(4-methylphenyl)-sulfonyl]-1,2,4-thiadiazol-3-yl]phenyl]benzenamine (200 mg, 0.41 mmols), prepared as described in Example 2, is added and heating is continued at 55° C. for 10 minutes. The solution is cooled to room temperature, poured into ether, and washed with water followed by brine. The organic layer is dried over magnesium sulfate, filtered, and concentrated to 10 mL. A few drops of methanol saturated with HCl are added. The resultant precipitate is collected by filtration, providing 84 mg (48%) of 3-[2-[2,6-dichloro-3-methylphenyl)amino]phenyl]-1,2,4-thiadiazol-5-yl guanidine, monohydrochloride as a white solid; mp 268°-277° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[N:15][C:14]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[N:12]=1)=[O:10].COC(C1C(C(F)(F)F)=NC(Br)=C(C2C=CC([Cl:56])=C(Cl)C=2)N=1)=O>>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:16]([C:17]([F:20])([F:18])[F:19])=[N:15][C:14]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([Cl:56])=[C:30]([Cl:34])[CH:29]=2)[N:12]=1)=[O:10]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(Cl)c2)c(Br)nc1C(F)(F)F
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2cccc(Cl)c2)c(Oc2ccccc2)nc1C(F)(F)F
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2ccc(Cl)c(Cl)c2)c(Oc2ccccc2)nc1C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 8 (6-(3-chloro-phenyl)-5-phenoxy-3-trifluoromethyl-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide) by substituting 5-bromo-6-(3-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid methyl ester with 5-bromo-6-(3,4-dichloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11]([NH2:14])(=[O:13])=[O:12].[Br:15][CH:16]([CH3:20])[C:17](Cl)=[O:18]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11]([NH:14][C:17](=[O:18])[CH:16]([Br:15])[CH3:20])(=[O:13])=[O:12]
Reactant: CC(Br)C(=O)Cl
Reactant: COc1ccc(OC)c(S(N)(=O)=O)c1
Product: COc1ccc(OC)c(S(=O)(=O)NC(=O)C(C)Br)c1
Temperature: 25 °C

Procedure:
A stirred mixture of 7.0 g (0.032 mole) of 2,5-dimethoxyphenylsulfonamide in 10 mL of 2-bromopropionyl chloride was heated at reflux for 40 minutes then allowed to cool to room temperature. The resultant solution was poured into petroleum ether. Crystals formed after scratching the sides of the flask and were collected by filtration. The filter cake was washed four times with fresh petroleum ether to yield 10.3 g of N-(2,5-dimethoxyphenylsulfonyl)-2-bromopropionamide (mp 116°-118° C.).