Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH:13]([OH:14])[CH2:12][C:11]([CH3:16])([CH3:15])[NH:10][C:9]1([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]=O.[OH-].[Na+]>O1CCOCC1>[CH2:1]([CH:8]1[CH:13]([OH:14])[CH2:12][C:11]([CH3:16])([CH3:15])[N:10]([CH3:19])[C:9]1([CH3:18])[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: CC1(C)CC(O)C(Cc2ccccc2)C(C)(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN1C(C)(C)CC(O)C(Cc2ccccc2)C1(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
Into a 100 ml-flask equipped with a thermometer, a cooling tube, a dropping funnel and a magnetic stirrer were added 3.7 g of 3-benzyl-2,2,6,6-tetramethyl-4-piperidinol prepared in Example A1 above, 30 ml of dioxane and 0.78 g of fumic acid, and the content in the flask was heated to 80° C. When the temperature of the content was at a constant level, 2.44 g of 37% aqueous formaldehyde in which 10 ml of dioxane had been dissolved was introduced gradually through the dropping funnel, and the content of the flask was heated at the same temperature under agitation for 8 hours. The temperature was then lowered to room temperature, 10% aqueous NaOH was added so that the pH became to 7, and the solution was subjected to extraction with 150 ml of diethylether. The extract obtained was washed three times with 30 ml of water, 10 g of magnesium sulfate and the solution was kept standing for 2 hours, and the solution was filtered and concentrated to give 3.3 g (yield: 83%) of the title compound as a white solid product.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH2:16](O)[CH2:17][OH:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]([CH:12]2[O:18][CH2:17][CH2:16][O:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2nc(Cl)c(C3OCCO3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 2-chloro-6-methoxyquinoline-3-carbaldehyde (4.01 g, 18.10 mmol) in toluene (200 mL) in a 500 mL round-bottomed flask equipped with a magnetic stirrer under N2 was added ethylene glycol (1.20 mL, 21.52 mmol) followed by p-toluenesulfonic acid monohydrate (348 mg, 1.83 mmol). The mixture was stirred overnight under reflux using a Dean-Stark apparatus. After cooling to RT, the mixture was concentrated at 40° C. under vacuum, then the residue was diluted with saturated aqueous NaHCO3 solution (40 mL) before extraction with CH2Cl2 (100 mL). The organic phase was isolated, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 92:8 to 75:25) gave 2-chloro-3-(1,3-dioxolan-2-yl)-6-methoxyquinoline SMA 44002 as a white solid (4.39 g, 91% yield).
Reaction SMILES: [CH2:1](S([O-])(=O)=O)[CH2:2][CH3:3].[NH2:8][C:9]1[S:10][C:11]2[CH2:17][CH:16]([NH2:18])[CH2:15][CH2:14][C:12]=2[N:13]=1>>[NH2:8][C:9]1[S:10][C:11]2[CH2:17][CH:16]([NH:18][CH2:1][CH2:2][CH3:3])[CH2:15][CH2:14][C:12]=2[N:13]=1
Reactant: Nc1nc2c(s1)CC(N)CC2
Reactant: CCCS(=O)(=O)[O-]
Product: CCCNC1CCc2nc(N)sc2C1

Procedure:
In some embodiments, step one of the process may include the additional steps of heating a diamine to form a solution or melt in a heating step and adding the n-propyl halide or n-propyl sulfonate slowly over a period of time from, for example, about 0.5 hours to about 5 hours, in an additional step. In other embodiments, after the n-propyl halide or n-propyl sulfonate has been completely added to the 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole, the reaction may continue under heating for an additional period of time ranging from, for example, about 1 hour to about 12 hours, in a reaction step. In certain embodiments, the reaction mixture may be mixed by, for example, stirring for one or more of the steps above or the reaction mixture may be continually stirred from the heating step to the reaction step. Following the reaction step, the reaction mixture may be cooled and the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be isolated and purified.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[Cl:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[CH:35][CH:36]=[C:37]2[CH2:40]O)=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[N:15]([CH2:40][C:37]1[C:38]2[C:33](=[CH:32][CH:31]=[C:30]([Cl:29])[CH:39]=2)[CH:34]=[CH:35][CH:36]=1)=[N+:16]=[N-:17]
Reactant: OCc1cccc2ccc(Cl)cc12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1cccc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.52 ml of Diphenylphosphoryl azide and 1.10 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene are added to 1.3 g of (7-Chloro-naphthalen-1-yl)-methanol in 18 ml of toluene. The mixture obtained is stirred at rt for 1 hour, washed with brine, the organic phase is dried and solvent is evaporated. The residue obtained is purified by flash chromatography on silica gel (eluent: cyclohexane/EtOAc 99/1) to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]1([NH2:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH:38]1([NH:44][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: NC1CCCCC1
Product: O=C(Nc1ccc(Oc2ccnc(NC3CCCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and cyclohexylamine according to conditions described in general procedure C. Mp: 118-120° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.00-1.23 (m, 6 H), 1.60-1.74 (m, 10 H), 3.10-3.29 (m, 5 H), 6.10-6.30 (m, 1 H), 6.97-7.00 (m, 2 H), 7.17 (d, J=8.8 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.55-7.62 (m, 3 H), 7.83 (d, J=8.0 Hz, 1 H), 7.99 (d, J=8.0 Hz, 1 H), 8.21 (s, 1 H), 10.47 (s, 1 H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[C:18]([OH:19])=[C:17]([Br:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:21]([N:24]([CH2:29][CH2:30][CH3:31])[C:25](=[O:28])[CH2:26]Cl)[CH2:22][CH3:23].O>CC(C)=O>[Br:7][C:8]1[C:18]([O:19][CH2:26][C:25]([N:24]([CH2:29][CH2:30][CH3:31])[CH2:21][CH2:22][CH3:23])=[O:28])=[C:17]([Br:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1ccc(Br)c(O)c1Br
Reactant: CCCN(CCC)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCN(CCC)C(=O)COc1c(Br)ccc(C(=O)OCC)c1Br

Procedure:
0.853 g of K2CO3, 0.154 g of KI and 1.000 g of ethyl 2,4-dibromo-3-hydroxybenzoate were introduced in 10 ml of acetone. At RT 0.783 g of N,N-di-n-propylchloroacetamide was added. The mixture was then heated at reflux for 4 hours. It was subsequently poured into water and extracted with diisopropyl ether. The organic phases were washed with water, dried over Na2SO4 and concentrated. Chromatography on silica gel (eluent: n-heptane/ethyl acetate) gave ethyl 2,4-dibromo-3-(N,N-di-n-propylaminocarbonylmethoxy)benzoate as brown oil.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Br[C:6]1[N:10]([C@H:11]2[O:17][C@@H:16]([CH3:18])[C@:14](C(=O)C)([OH:15])[C@:12]2(C(=O)C)[OH:13])[C:9]2[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:8]=2[N:7]=1.C(O)C>CN(C=O)C>[CH:1]([NH:4][C:6]1[N:10]([C@H:11]2[O:17][C@@H:16]([CH3:18])[C@H:14]([OH:15])[C@@H:12]2[OH:13])[C:9]2[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:8]=2[N:7]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)[C@@]1(O)[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)O[C@@H](C)[C@@]1(O)C(C)=O
Reactant: CC(C)N
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2n1[C@H]1O[C@@H](C)[C@H](O)[C@@H]1O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Isopropylamine (5 mL ) and 2-bromo-5,6-dichloro-1-(5-deoxy-2,3-diacetyl-beta-L-ribofuranosyl)-1H-benzimidazole (0.40 g, 0.86 mmol) were combined with absolute ethanol (20 mL) and stirred at 80° C. for 24 h. The reaction mixture was concentrated and purified by multiple cyclings on a chromatotron fitted with a 2 mm silica gel rotor, with 1:30 methanol:dichloromethane and 1:1 ethyl acetate:hexanes and 1:4 acetone:dichloromethane to give a white solid (0.18 g, 0.70, mmol, 60%); m.p. 103-105° C.; [α]20D=(+) 38.8 (c=0.5 DMF); UV λmax (ε): pH 7.0:303 nm (10,400), 276 (2,500), 260 (10,000); MS (CI): m/z (rel. intensity) 360 (14.26, M−); 1H NMR (DMSO-d6) d 7.39 (s, 1H, Ar—H), 7.31 (s, 1H, Ar—H), 6.57 (d, 1H, NH, J=7.6 Hz), 5.68 (d, 1H, H-1′, J=6.6 Hz), 5.23 (d, 1H, OH, J=4.8 Hz), 5.21 (d, 1H, OH, J=7.1 Hz), 4.31 (q, 1H, H-4′, J=6.7 Hz), 4.04-3.98 (m, 1H, isopropyl-CH), 3.95-3.87 (m, 1H), 3.81-3.76 (m, 1H), 1.36 (d, 3H, H-5′, J=6.5 Hz), 1.20 (d, 6H, cyclopentyl-CH2, J=6.6 Hz).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:41]1([O:50]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.NO>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12]([NH:41][OH:50])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (3R)-6-cyclohexyl-3-{3-[(dimethylamino)carbonyl]-1,2,4-oxadiazol-5-yl}hexanoic acid (Preparation 11) (60 mg, 0.18 mmol) and N,N-diisopropylethylamine (30 μl, 0.18 mmol) in N-N-dimethylformamide (3 ml) was treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (100 mg, 0.27 mmol) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Further N,N-diisopropylethylamine (90 μl, 0.52 mmol) was then added, followed by hydroxylamine hydrochloride (35 mg, 0.52 mmol) and the mixture was stirred at room temperature for 18 hours. The mixture was partitioned between ethyl acetate and pH 7 aqueous buffer. The layers were separated and the aqueous phase extracted with ethyl acetate (×2). The combined organic layers were washed sequentially with aqueous citric acid solution (5% w/v) and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:ethyl acetate (90:10 ) gradually changing to dichloromethane:ethyl acetate (50:50) then to dichloromethane: methanol (95:5). The residue was further purified by column chromatography on silica gel eluting with a gradient system of dichloromethane: methanol (99:1) gradually changing to dichloromethane:methanol (95:5) to afford the title compound as an oil which crystallised on standing (35 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[NH2:13].C(N(CC)CC)C.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[NH:13][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1N
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc([N+](=O)[O-])cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a solution of 2-amino-4-nitro-benzoic acid methyl ester (5.00 g, 25.5 mmol) in methylene chloride (75 mL) was added triethylamine (4.13 g, 40.8 mmol) followed by 4-trifluoromethoxy-benzoyl chloride (6.87 g, 30.6 mmol). This mixture was allowed to stir overnight at ambient temperature. The mixture was filtered, partitioned against brine, the layers were separated, and the aqueous layer was extracted with one portion of ethyl acetate. The organics were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was recrystallized from ethyl acetate (250 mL) to give 4-nitro-2-(4-trifluoromethoxy-benzoylamino)-benzoic acid methyl ester (6.83 g, 70%) as pale-yellow crystals. 1H NMR (500 MHz, DMSO-d6); δ 11.53 (s, 1H), 9.20 (d, 1H), 8.19 (d, 1H), 8.10 (d, 2H), 8.07 (dd, 1H), 7.63 (d, 2H), 3.91 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([CH3:48])([CH3:47])[C:44](O)=O)[CH2:10]2)=[CH:5][CH:4]=1.[Cl-].[NH4+].C([N:53](CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([CH3:47])([CH3:48])[C:44]#[N:53])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCN(CC)CC
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C#N)C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: -10 °C
Reaction time: 8 h

Procedure:
A suspension of 500 mg 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid (from example 65b), 111.2 mg ammonium chloride and 0.7 ml triethylamine in 5 ml tetrahydrofuran are cooled to −10° C. and 1.21 ml of a T3P® solution (50% in ethyl acetate) is added dropwise. The reaction mixture is warmed to room temperature and stirred for 8 hours. The resulting suspension is stirred at 70° C. for 2 days. During this time, the addition of 111.2 mg ammonium chloride, 0.7 ml triethylamine and 1.21 ml of a T3P® solution (50% in ethyl acetate) is repeated twice. The reaction mixture is quenched by addition of 5 ml of water and extracted with 50 ml ethyl acetate (3×). The combined organic layers are washed with brine and dried with sodium sulfate. The organic layer is filtered and evaporated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a colourless foam. Rf=0.12 (EtOAc-heptane 1:2); Rt=5.42.
Reaction SMILES: [CH:1]1([NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([NH:27][S:28](=[O:41])(=[O:40])[NH:29][C:30]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[O:31])=[CH:26][C:20]=4[S:19](=[O:43])(=[O:42])[N:18]=3)[C:7]2=[O:44])[CH2:4][CH2:3][CH2:2]1.[CH3:45][Si](C=[N+]=[N-])(C)C>O1CCCC1.CO>[CH:1]1([NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([NH:27][S:28](=[O:41])(=[O:40])[N:29]([CH3:45])[C:30]([O:32][CH2:33][C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)=[O:31])=[CH:26][C:20]=4[S:19](=[O:43])(=[O:42])[N:18]=3)[C:7]2=[O:44])[CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(NS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NC3CCC3)c1=O)N2)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(=O)OCc1ccccc1)S(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NC3CCC3)c1=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
A solution of the product of Example 465 (0.045 g, 0.07 mmol) in 1:1 tetrahydrofuran/methanol (2 ml) at −10° C. was treated dropwise with trimethylsilyl diazomethane (2.0 M in hexanes, 70 μL, 0.14 mmol), stirred at 25° C. for 16 hours and concentrated under reduced pressure to provide the title compound (0.045 g, 98% yield).
Reaction SMILES: [CH3:1][C:2]([OH:13])([CH3:12])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1.CN(C)C=O.[CH2:19]([Si:21](Cl)([CH2:24][CH3:25])[CH2:22][CH3:23])[CH3:20].N1C=CN=C1>C(OCC)(=O)C>[CH3:12][C:2]([O:13][Si:21]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:19][CH3:20])([CH3:1])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1
Reactant: CC(C)(O)Cn1ccc([N+](=O)[O-])n1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC(C)(C)Cn1ccc([N+](=O)[O-])n1
Temperature: 0 °C
Yield: 71.5 %

Procedure:
In a round bottomed flask was placed 2-methyl-1-(3-nitro-pyrazol-1-yl)-propan-2-ol (170 mg, 0.92 mmol) and N,N-dimethylformamide (5 mL) and it was placed in an ice bath and cooled to 0° C. To this stirred solution was added triethylsilyl chloride (169 mL, 1.01 mmol) and imidazole (156 mg, 2.30 mmol) and it was stirred at 0° C. and slowly warmed to 25° C. and stirred for two days. The reaction was then diluted with ethyl acetate (15 mL) and washed with a saturated aqueous brine solution (10 mL). The aqueous layer was then extracted with ethyl acetate (2×15 mL). The organic layers were then combined and dried over sodium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix Intelliflash system (4 g column, 5% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) afforded 1-(2-methyl-2-triethylsilanyloxy-propyl)-3-nitro-1H-pyrazole (197 mg, 72%) as a clear colorless oil: ES-HRMS m/e calcd for C13H25N3O3Si (M+H)+ 300.1738, observed 300.1737; 1H NMR (300 MHz, CDCl3) δ ppm 0.58 (q, J=8.0 Hz, 6H, 3×SiCH2), 0.92 (t, J=8.0 Hz, 9H, 3×CH3), 1.26 (s, 6H, 2×CH3), 4.12 (s, 2H, NCH2), 6.89 (d, J=2.5 Hz, 1H, Ar), 7.56 (d, J=2.5 Hz, 1H, Ar).
Reaction SMILES: C(C1N=[CH:13][C:12]2[CH2:11][CH2:10][C:9]3[N:15]=[C:16]([NH:18][C:19]([N:21]4[CH:25]=[CH:24][N:23]=[CH:22]4)=[O:20])[S:17][C:8]=3[C:7]=2N=1)(C)(C)C.Cl.[F:27][C:28]([F:36])([F:35])[C:29]([CH3:34])([CH3:33])[C:30]([NH2:32])=[NH:31]>>[F:27][C:28]([F:36])([F:35])[C:29]([C:30]1[N:32]=[CH:13][C:12]2[CH2:11][CH2:10][C:9]3[N:15]=[C:16]([NH:18][C:19]([N:21]4[CH:25]=[CH:24][N:23]=[CH:22]4)=[O:20])[S:17][C:8]=3[C:7]=2[N:31]=1)([CH3:34])[CH3:33]
Reactant: CC(C)(C)c1ncc2c(n1)-c1sc(NC(=O)n3ccnc3)nc1CC2
Reactant: CC(C)(C(=N)N)C(F)(F)F
Agent: Cl
Product: CC(C)(c1ncc2c(n1)-c1sc(NC(=O)n3ccnc3)nc1CC2)C(F)(F)F

Procedure:
The title compound was prepared in analogy to the procedure described for Intermediate A but in Stage A.3 3,3,3-trifluoro-2,2-dimethyl-propionamidine hydrochloride (Stage 44.2) was used instead of tert-butylamidine hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:8]([C:9](=[O:26])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]3=[O:24])=[CH:13][C:12]=2[F:25])[CH:7]1[C:27](=[O:36])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)=[O:5])[CH3:2].[C:37](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH:8]([C:9](=[O:26])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:37])=[CH:19][C:18]3=[O:24])=[CH:13][C:12]=2[F:25])[CH:7]1[C:27](=[O:36])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(C(=O)Nc2ccc(Cl)cc2)C1C(=O)Nc1ccc(-n2ccc(O)cc2=O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)C1C(C(=O)Nc2ccc(Cl)cc2)C1C(=O)Nc1ccc(-n2ccc(OC)cc2=O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.5 %

Procedure:
A solution of 35 mg (0.07 mmol) of (1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(4-hydroxy-2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylic acid ethyl ester (example 142, step 2) in 5 ml of acetone was treated with 94 mg (0.6 mmol) of potassium carbonate and 8 ul (0.08 mmol) of dimethylsulfate. The mixture was stirred 2 hrs at RT and filtered. Evaporation of the solvent and chromatography on silica gel with AcOEt/methanol 95:5 gave 5 mg (13%) of (1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(4-methoxy-2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylic acid ethyl ester. Off-white solid. 526 (M−H)−.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.C1COCC1.[Cl:16][C:17]1[CH:18]=[C:19]([Mg]Br)[CH:20]=[CH:21][CH:22]=1.S(=O)(=O)(O)O>C(OCC)C>[CH2:9]([O:8][C:1](=[O:7])[C:2]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:16])[CH:22]=1)=[O:4])[CH3:10]
Reactant: Clc1cccc([Mg]Br)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1cccc(Cl)c1
Reaction time: 1.5 h
Yield: 101.2 %

Procedure:
Diethyl oxalate (4.4 g, 30.2 mmol) was dissolved in dry ethyl ether (30 mL) and freshly distilled THF (30 mL) and cooled to −78° C. with stirring, under a nitrogen atmosphere. Then added 3-chlorophenylmagnesium bromide (0.5 M in THF, 72.5 mL, 36.2 mmol) dropwise, via an addition funnel, while keeping the temperature between −75 to −78° C. The addition took approximately 90 minutes. After 3 hours, the reaction was quenched by the dropwise addition of 2N sulfuric acid (50 mL, 91 mmol) at −78° C. and upon completion of the addition, the mixture was allowed to return to room temperature. The mixture was extracted with ethyl ether (3×) and the combined ether extracts were washed with brine (2×), dried over magnesium sulfate, filtered, evaporated in vacuo and vacuum-dried to yield ethyl-(3-chlorophenyl)(oxo)acetate (6.5 g, HPLC RT=3.46 min, Method A; LCMS m/z=213).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([N:20]([CH2:25][C:26]([OH:28])=O)[CH2:21][C:22]([OH:24])=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)=O.[NH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:43][CH3:44])[CH:41]=2)[CH:36]=[CH:35][CH:34]=1>O1CCCC1.C(O)C>[CH3:44][O:43][C:40]1[CH:41]=[C:42]2[C:37]([CH:36]=[CH:35][CH:34]=[C:33]2[N:32]2[C:22](=[O:24])[CH2:21][N:20]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:25][C:26]2=[O:28])=[CH:38][CH:39]=1
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Reactant: COc1ccc2cccc(N)c2c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2cccc(N3C(=O)CN(Cc4ccccc4)CC3=O)c2c1
Yield: 82 %

Procedure:
126 mmol (2.2 equivalents) of carbonyldiimidazole are added to a suspension containing 58 mmol (1 equivalent) of N-benzyliminodiacetic acid in 200 ml of anhydrous tetrahydrofuran. The mixture is brought to reflux until the evolution of CO2 has ceased. A solution containing 58 mmol (1 equivalent) of 1-amino-7-methoxynaphthalene in 40 ml of anhydrous tetrahydrofuran is then added to the above mixture. The resulting mixture is brought to reflux for 20 hours, the solvent is evaporated off and the residue obtained is taken up with 300 ml of anhydrous ethanol. The precipitate formed is filtered off and then dissolved in 200 ml of dichloromethane. The insoluble matter is filtered off and the filtrate concentrated. The expected product is then obtained after taking up in isopropyl ether followed by filtration.