Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:40])([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][CH:21]=3)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]3[N:37]=[CH:38][N:39]=[C:13]23)=[CH:8][CH:7]=1)[CH:3]=[O:4].[CH3:41][Mg]Br.C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[OH:4][CH:3]([CH3:41])[C:2]([CH3:1])([CH3:40])[O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][CH:21]=3)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]3[N:37]=[CH:38][N:39]=[C:13]23)=[CH:8][CH:7]=1
Reactant: C[Mg]Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)(C)C=O)cc2)c2ncnn12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)(C)C(C)O)cc2)c2ncnn12
Reaction time: 3 h
Yield: 72 %

Procedure:
To a solution of 4′-({4-[4-(1,1-dimethyl-2-oxoethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.97 g) in tetrahydrofuran (10 mL) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 0.91 mL) at 0° C., and the mixture was stirred for 3 hr. Ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.72 g, 72%).
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=2)[CH2:9]1)(=[O:5])[CH2:2][CH2:3][CH3:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(C)=O>[C:1]([O:6][CH2:7][C@H:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=2)[CH2:9]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OCC1CC(c2ccc(Br)cn2)=NO1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCC(=O)OC[C@@H]1CC(c2ccc(Br)cn2)=NO1

Procedure:
Racemic [3-(5-bromopyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methyl butyrate (Intermediate 9, 80 g, 0.244 mol) was dissolved in acetone (4 L), and 0.1 M potassium phosphate buffer (pH˜7) (4 L) was added with vigorous stirring to give a clear yellow solution. PS-lipase (1.45 g, Sigma cat no L-9156) was added and the mixture was gently stirred at ambient temp. for 42 hrs. The solution was divided into 3 equal volumes of ˜2.6 L and each was extracted with dichloromethane (2×1 L), the pooled organic phases were dried over sodium sulfate and evaporated. The unreacted [(5S)-3-(5-bromopyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methyl butyrate was isolated via flash column chromatography (9:1 hexane:ethyl acetate) as a clear yellow oil, 36.4 g (45.5%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[Li]CCCC.CC([O:24][B:25](OC(C)C)[O:26]C(C)C)C>O1CCCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([B:25]([OH:26])[OH:24])=[CH:7][CH:6]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccccc1Oc1ccc(I)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(Oc2ccccc2F)cc1
Temperature: -78 °C
Yield: 90.2 %

Procedure:
Into a 100 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of 1-(2-fluorophenoxy)-4-iodobenzene (3.3 g, 10.51 mmol, 1.00 equiv) in tetrahydrofuran (50 mL). n-BuLi (4.4 mL) was added dropwise with stirring at −78° C. The resulting solution was stirred for 10 mins at −78° C. and then tris(propan-2-yl)borate (2.1 g, 11.17 mmol, 1.06 equiv) was added dropwise with stirring at −78° C. over 10 min. The resulting solution was stirred while the temperature warmed from −78° C. to room temperature. The reaction was then quenched by the addition of saturated aqueous NH4Cl and concentrated under vacuum. The resulting solution was diluted with 10% aquious potassium hydroxide and then washed with ether. The pH of the aqueous was adjusted to 2-4 with hydrogen chloride (37%). The resulting solution was extracted with ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 2.2 g (90%) of [4-(2-fluorophenoxy)phenyl]boronic acid as a white solid
Reaction SMILES: [N:1]1[CH:6]=CC=C(CNC(C2C=CC3NC(C4C(C(=O)NC(C)C)=CNN=4)=NC=3C=2)=O)[CH:2]=1.[CH3:31][C:32]1[C:52]([CH3:53])=[CH:51][C:35]2[NH:36][C:37]([C:39]3[C:47]4[C:42](=[CH:43][CH:44]=[C:45]([C:48]([OH:50])=O)[CH:46]=4)[NH:41][N:40]=3)=[N:38][C:34]=2[CH:33]=1.[ClH:54].CNC>>[ClH:54].[ClH:54].[CH3:2][N:1]([CH3:6])[C:48]([C:45]1[CH:46]=[C:47]2[C:42](=[CH:43][CH:44]=1)[NH:41][N:40]=[C:39]2[C:37]1[NH:38][C:34]2[CH:33]=[C:32]([CH3:31])[C:52]([CH3:53])=[CH:51][C:35]=2[N:36]=1)=[O:50]
Reactant: Cc1cc2nc(-c3n[nH]c4ccc(C(=O)O)cc34)[nH]c2cc1C
Reactant: CC(C)NC(=O)c1c[nH]nc1-c1nc2cc(C(=O)NCc3cccnc3)ccc2[nH]1
Agent: CNC
Agent: Cl
Product: Cc1cc2nc(-c3n[nH]c4ccc(C(=O)N(C)C)cc34)[nH]c2cc1C

Procedure:
By proceeding in a manner similar to Example 246(j) above, but (i) using 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid [97 mg, Example 263] and dimethylamine hydrochloride (23 mg), (ii) carrying out the reaction at ambient temperature overnight, and (iii) subjecting the reaction product to flash column chromatography [eluting with ethyl acetate to ethyl acetate/methanol (97:3, v/v)] followed by treatment with 4M hydrogen chloride in 1,4-dioxane and trituration with dichloromethane and diethyl ether there was prepared 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid dimethylamide dihydrochloride (8 mg) as a white solid. LC-MS (METHOD M): RT=9.37 minutes, 320 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].I[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N+:12]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[O:1][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([O-:14])=[O:13]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: CCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 100.4 %

Procedure:
A slurry of methyl 3-hydroxy-4-nitrobenzoate (5.5 g, 0.028 mol), iodooctane (10.0 g, 0.042 mol) and potassium carbonate (20 g) in 100 mL DMF was stirred at 100° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with 500 mL H2O, then extracted with ether/ethyl acetate (9/1, 2×200 mL). The combined organic solution was washed with 400 mL H2O, dried over sodium sulfate, and concentrated to form methyl 4-nitro-3-octoxybenzoate as an off-white oil (8.7 g, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10].[N+](=[CH2:14])=[N-]>C(OCC)C>[C:7]([C:6]1[N:2]([CH3:1])[C:3]([N+:9]([O-:11])=[O:10])=[N:4][CH:5]=1)(=[O:8])[CH3:14]
Reactant: C=[N+]=[N-]
Reactant: Cn1c(C=O)cnc1[N+](=O)[O-]
Solvent: CCOCC
Product: CC(=O)c1cnc([N+](=O)[O-])n1C
Temperature: 0 °C
Reaction time: 168 h

Procedure:
To a solution of 0.70 g. of 1-methyl-2-nitro-5-imidazolecarboxaldehyde in 180 ml. of diethyl ether, a solution of 0.43 g. of diazomethane in 86 ml. of diethyl ether is added under cooling at about 0° C. After standing at room temperature for 7 days, the reaction mixture is filtered and then evaporated to dryness. The residue (0.60 g.), dissolved in 6 ml. of chloroform, is chromatographed on 6 plates of silica gel, eluting with a 9:1 (v/v) chloroform:methanol mixture, and TLC spots are visualized under U.V. light. The silica gel, which corresponds to an Rf value from 0.64 up to 0.76 is collected and extracted with methanol. From this solution, after filtration and concentration, 0.065 g. of 5-acetyl-1-methyl-2-nitroimidazole is obtained, m.p. 81°-83° C.
Reaction SMILES: Cl.[C:2]([O:5][CH2:6][C:7]1[C@H:12]([C:13]([OH:15])=[O:14])[N:11]2[C:16](=[O:19])[C@@H:17]([NH2:18])[C@H:10]2[S:9][CH:8]=1)(=[O:4])[CH3:3].C[Si](C)(C)N[Si](C)(C)C.[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:31]=1[C:32](Cl)=[O:33].C(C(CCCC)C([O-])=O)C.[Na+:50]>C(OCC)(=O)C.C(Cl)(Cl)Cl>[C:2]([O:5][CH2:6][C:7]1[C@H:12]([C:13]([O-:15])=[O:14])[N:11]2[C:16](=[O:19])[C@@H:17]([NH:18][C:32](=[O:33])[C:31]3[C:30]([Cl:29])=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:39])[C@H:10]2[S:9][CH:8]=1)(=[O:4])[CH3:3].[Na+:50]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CC(=O)OCC1=CS[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Agent: CCCCC(CC)C(=O)[O-]
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=CS[C@@H]2[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)N2[C@H]1C(=O)[O-]
Reaction time: 1 h

Procedure:
The hydrochloride of 3-acetoxymethyl-7β-aminoceph-2-em-4α-carboxylic acid (1.5 g., 0.05 m.mol) was heated in refluxing dry chloroform (20 ml) containing hexamethyldisilazane (3.2 ml. 0.015 mol) for 1 hr. The excess silylating reagent and solvent were removed under high vacuum. The resulting gum was redissolved in dry ethyl acetate (20 ml) and 2,6-dichlorobenzoyl chloride (1.0 g 0.45 mmol) added. the reaction was carried out for 1 hr. at reflux. Treatment of the organic phase with dilute hydrochloric acid, water, drying and evaporation gave a gum. Addition of a solution of 10% sodium 2-ethylhexanoate in ethyl acetate precipitated a sodium salt, νmax (Nujol) 3300 (NH), 1760 (β-lactam), 1720 (acetate), 1660 (amide) and 1605 cm-1 (--CO2Na), RF (system 3) 0.53 (with an impurity, RF 0.19). These properties are consistent with the structure of the compound named in the title.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[C:28](O)(=[O:32])[CH:29]([CH3:31])[CH3:30]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: CC(C)C(=O)O
Agent: Cl
Product: CC(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (10 mg, 35%), MS (ISP) m/z=402.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and isobutyric acid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][C:15]([C:17]3[O:18][C:19]4[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:20]=4[N:21]=3)=[CH:16][C:4]=2[N:3]=1.[H][H]>[Pd].CO>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)[C:5]2[CH:13]=[CH:14][C:15]([C:17]3[O:18][C:19]4[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[CH:16][C:4]=2[N:3]=1
Reactant: Cc1nc2cc(-c3nc4ccc([N+](=O)[O-])cc4o3)ccc2n1C1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1nc2cc(-c3nc4ccc(N)cc4o3)ccc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 40.2 %

Procedure:
2-Methyl-5-(6-nitrobenzoxazol-2-yl)-1-(tetrahydropyran-4-yl)benzimidazole (see Working Example 47-2) (135 mg, 0.357 mmol) was added to methanol (20 mL) containing palladium/carbon (Pd: 10%, 0.06 g), hydrogen was substituted in by successively reducing the pressure and purging with hydrogen gas 3 times, and this was stirred at room temperature for 2.5 hours. After substituting in nitrogen, the insoluble material was filtered off through a Celite layer (20 mm thickness), and this same layer was washed with methanol (20 mL, 3 times). The filtrate was combined with the wash solutions and the solvent was distilled out at reduced pressure, the residue obtained was purified by silica gel column chromatography to yield the title compound (50 mg, 40.2% yield) as brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:19][CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1.S(Cl)(Cl)=O.C(N(CC)CC)C.[CH2:35]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)[C:36]1[CH:44]=[CH:43][C:42]2[O:41][CH2:40][O:39][C:38]=2[CH:37]=1>ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:19][CH2:20][C:21]([N:48]2[CH2:49][CH2:50][N:45]([CH2:35][C:36]3[CH:44]=[CH:43][C:42]4[O:41][CH2:40][O:39][C:38]=4[CH:37]=3)[CH2:46][CH2:47]2)=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: COc1cc(CCC(=O)O)ccc1Oc1ccc([N+](=O)[O-])cn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COc1cc(CCC(=O)N2CCN(Cc3ccc4c(c3)OCO4)CC2)ccc1Oc1ccc([N+](=O)[O-])cn1

Procedure:
3-[3-methoxy-4-(5-nitropyridin-2-yloxy)phenyl]propionic acid (3.18 g, 10 mmol) was dissolved in dichloromethane (30 mL). To the resulting solution were added thionyl chloride (0.88 mL, 12 mmol) and DMF (1 drop), and refluxed for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (20 mL). To the resulting solution were added triethylamine (1.67 mL, 12 mmol) and a solution of 1-piperonylpiperazine (2.20 g, 10 mmol) in dichloromethane (30 mL) under ice cooling, and the resulting solution was stirred for 1 hour at 0° C. The resulting reaction solution was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was recrystallized from ethyl acetate, to thereby yield 4.95 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:28])[CH3:27])[C:21]([C:29](O)=[O:30])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.Cl.C(N=C=NCCCN(C)C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:27])[CH3:28])[C:21]([C:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:30])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)n1c(C(=O)O)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(C)n1c(C(=O)N2CCOCC2)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21

Procedure:
The title compound was synthesized in analogy to Example 1, from 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylic acid, morpholine and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as a yellow solid (91%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:13])=[CH:5][C:6]=1[CH:7]1[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.Cl[C:15]1[CH:24]=[C:23]2[C:18]([C:19](=[O:30])[C:20]([C:27]([OH:29])=[O:28])=[CH:21][N:22]2[CH2:25][CH3:26])=[CH:17][C:16]=1[F:31]>N1C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH3:13])=[CH:5][C:6]=1[CH:7]1[NH:8][CH2:9][CH2:10][N:11]([C:15]2[CH:24]=[C:23]3[C:18]([C:19](=[O:30])[C:20]([C:27]([OH:29])=[O:28])=[CH:21][N:22]3[CH2:25][CH3:26])=[CH:17][C:16]=2[F:31])[CH2:12]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: Cc1cc(C2CNCCN2)c(C)s1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cc(C)sc4C)C3)cc21
Yield: 46.7 %

Procedure:
A mixture of 2.35 g of 2-(2,5-dimethyl-3-thienyl)piperazine and 1.076 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of pyridine was heated for 48 hours, then cooled and filtered. The filtrate was evaporated under reduced pressure and the residue triturated with chloroform:methanol (9:1),. giving 800 mg of the desired product, mp 248°-250° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:19]=2)[NH:16][C:15]([C:24]2[S:25][CH:26]([CH2:29][C:30]([OH:32])=O)[CH2:27][N:28]=2)=[CH:14]3)=[CH:6][CH:5]=1.Cl.C(N=C=N[CH2:39][CH2:40][CH2:41][N:42](C)C)C.ON1C2C=CC=CC=2N=N1.C1(N)CC1>O.CN(C)C=O>[CH:41]1([NH:42][C:30](=[O:32])[CH2:29][CH:26]2[S:25][C:24]([C:15]3[NH:16][C:17]4[C:13]([CH:14]=3)=[CH:12][C:11]([O:10][C:7]3[CH:8]=[N:9][C:4]([CH2:3][O:2][CH3:1])=[CH:5][CH:6]=3)=[CH:19][C:18]=4[O:20][CH:21]([CH3:23])[CH3:22])=[N:28][CH2:27]2)[CH2:39][CH2:40]1
Reactant: CCN=C=NCCCN(C)C
Reactant: COCc1ccc(Oc2cc(OC(C)C)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Agent: Cl
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COCc1ccc(Oc2cc(OC(C)C)c3[nH]c(C4=NCC(CC(=O)NC5CC5)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.2 %

Procedure:
A mixture of {2-[5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(1-methylethoxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (300 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (190 mg), 1-hydroxybenzotriazole (130 mg), cyclopropylamine (75 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give the title compound (170 mg, 52%) as pale yellow prisms. MS 495 (MH+). mp 100-101° C.
Reaction SMILES: [H-].[Na+].[OH:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[N+:15]([C:18]1[CH:23]=[CH:22][C:21](Cl)=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=1)([O-:17])=[O:16]>>[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([O:3][N:4]2[C:5](=[O:14])[C:6]3=[CH:13][CH:12]=[CH:11][CH:10]=[C:7]3[C:8]2=[O:9])=[C:20]([C:25]([F:26])([F:27])[F:28])[CH:19]=1)([O-:17])=[O:16]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Product: O=C1c2ccccc2C(=O)N1Oc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
11.5 g of sodium hydride as a 50% oil suspension were admixed at 20° C. with 300 ml of anhydrous diemthylformamide and after cooling the mixture to 5° to 10° C., 36.5 g of N-hydroxy-phthalimide were added thereto. The mixture was stirred at 20° C. for 30 minutes and 50 g of 4-nitro-2-trifluoromethyl-chloro benzene were added over 10 minutes. The suspension was heated at 80°-85° C. for one hour and was cooled to 20° C. and poured over ice. The mixture was stirred for one hour and was filtered. The solid product was washed with water and dried to obtain 60.7 g of N-(4-nitro-2-trifluoromethyl-phenoxy)-phthalimide melting at 190° C.
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].[CH3:7][C:8]1([CH3:24])[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[O:10][CH:9]1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)CC)C>O1CCCC1>[CH3:1][NH:2][S:3]([O:17][C:14]1[CH:15]=[CH:16][C:11]2[O:10][CH:9]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:8]([CH3:24])([CH3:7])[C:12]=2[CH:13]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)Cl
Reactant: CC1(C)c2cc(O)ccc2OC1N1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)Oc1ccc2c(c1)C(C)(C)C(N1CCOCC1)O2

Procedure:
At 0° to 5°C and while stirring, 36 parts (by weight) of methylaminosulfonyl chloride was added to a solution of 48.8 parts of 2,3-dihydro-3,3-dimethyl-2-morpholino-5-hydroxybenzofuran and 27.3 parts of triethylamine in 130 parts of tetrahydrofuran. The reaction mixture was stirred for 1 hour at room temperature and then filtered. The filtrate was concentrated in vacuo and the residue dissolved in 250 parts of methanol. After addition of 100 parts of water and treatment of the solution with activated carbon, crystallization was initiated by cooling. The mush of crystals was suction filtered, washed with 50wt% aqueous methanol and dried in vacuo. The crude product melted at 125° to 128°C. Pure 2,3-dihydro-3,3-dimethyl-2-morpholinobenzofuran-5-yl methylaminosulfonate was obtained by recrystallizing a sample from 80% methanol.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([CH3:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Br[CH2:12][C:13]([N:15]1[CH2:19][C@@H:18]([F:20])[CH2:17][C@H:16]1[C:21]#[N:22])=[O:14]>>[CH3:10][C:5]12[CH2:8][CH2:9][C:2]([NH:1][CH2:12][C:13]([N:15]3[CH2:19][C@@H:18]([F:20])[CH2:17][C@H:16]3[C:21]#[N:22])=[O:14])([CH2:7][CH2:6]1)[CH2:3][CH2:4]2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Reactant: CC12CCC(N)(CC1)CC2
Product: CC12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 75.6 %

Procedure:
Using 4-amino-1-methylbicyclo[2,2,2]octane (56.0 mg) and (2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (95.0 mg), the same procedure was followed as in Example 1 to obtain (2S,4S)-1-[[N-(4-methylbicyclo[2,2,2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (89.2 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](C(O)=O)=[C:12]([C:17]#[N:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[N:10]2)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[C:12]([C:17]#[N:18])[C:11]([C:19]([F:22])([F:20])[F:21])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2nc(C(F)(F)F)c(C#N)c2C(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-n2cc(C#N)c(C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 170.1 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-3-(trifluoromethyl)-4-cyano-pyrazole-5-carboxylic acid (0.41 g, 1.32 mmol) in 20 mL of methylene chloride was added oxalyl chloride (0.17 mL, 1.98 mmol) and 2 drops of dimethylformamide. The reaction was stirred at ambient temperature for 6 h and then the volatiles were removed in vacuo. The residue was dissolved in 20 mL of methylene chloride and then there was added 4-dimethylaminopyridine (0.48 g, 3.96 mmol). The reaction was stirred for 10 min and then there was added (2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)amine hydrochloride (0.47 g, 1.45 mmol). The resulting mixture was allowed to stir at ambient temperature for 16 h. The reaction was diluted with ethyl acetate and the organics were washed with 10% aq HCl, sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated to afford 0.6 g (81%) of the title compound as a tan solid. LRMS (ES+): 581.3 (M+Na)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH2:17][OH:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH:17]=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H](CO)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CC1CCCN(C(=O)OCc2ccccc2)C1
Reaction time: 0.25 h

Procedure:
To a stirring, 0° C. solution of 0.303 g (1.20 mmol) of 3-hydroxymethyl-piperidine-1-carboxylic acid benzyl ester (8) in CH2Cl2 (4.0 mL) was added 0.630 g (1.44 mmol) of Dess-Martin periodinane, and the solution was stirred under N2. When the reaction was complete by TLC (about 30 min.), the reaction was concentrated, and then Et2O was added. After standing for about 15 min., the reaction was filtered through Celite wet with Et2O, rinsed with Et2O, and concentrated. The crude reaction was purified by column chromatography (florisil®, 100-200 mesh, 2:1 Hexane: EtOAc) to achieve pure 9.