Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19].C(=O)([O-])O.[Na+].[OH-].[Na+]>C(O)(=O)C>[N+:18]([C:4]1[CH:5]=[CH:6][C:1]([CH:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)=[CH:2][CH:3]=1)([O-:20])=[O:19]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Temperature: 25 °C

Procedure:
4-Phenylpiperidine (8 g, 49 mmol) was dissolved in 40 mL acetic acid and stirred with cooling below 25° C. while adding a solution of 2.64 mL sulphuric acid in 40 mL acetic acid. The solution was stirred at 20° C. while adding a solution of 2.08 mL 99% nitric acid in 20 mL acetic acid. Sulphuric acid (40 mL) was added without cooling, the temperature peaking at 58° C. When the solution had cooled to 25° C. it was added to 100 g ice/water and basified with a total of 150 g sodium hydrogen carbonate at 40° C. The mixture was then brought to pH 14 with 5M-sodium hydroxide solution. The mixture was extracted with dichloromethane (3×150 mL), dried with sodium sulphate and evaporated giving a pale yellow solid. Recrystallisation from a total of 180 mL cyclohexane (hot filtration) gave the product as pale beige solid. NMR δ 8.18(d,2H), 7.40(d,2H), 3.21(m,2H), 2.77(m,3H), 1.82(m,3H), 1.68(m,2H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C=O)C>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.6 %

Procedure:
To a solution of 4-phenylimidazole (500 mg, 3.47 mmol) in 5 mL DMF, were added TEA (508 μL, 3.64 mmol) and trityl chloride (1.06 g, 3.82 mmol). The mixture was stirred at rt for 15 h, then was poured into 50 mL H2O. The precipitate was collected by filtration and sucked dry, then was suspended in 20 mL Et2O. The suspension was filtered, rinsed with 5 mL Et2O, then vacuum dried to afford 974 mg of Intermediate 8.1 as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:15]1[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 18 h
Yield: 62 %

Procedure:
4.65 g (3.10 mmol) of 2-fluoro-5-nitrotoluene, 6.71 g (3.60 mmol) of tert-butyl 1-piperazinecarboxylate and 10.4 g (7.50 mmol) of potassium carbonate are solubilized under an argon atmosphere, in dry DMF (50 ml), then the reaction medium is taken to 80° C. for 18 hours. The reaction medium is then cooled down using an ice bath then poured into ice-cold water. The product is extracted using 3 times 50 ml of ethyl acetate. The organic solution is dried over magnesium sulphate, followed by filtration and concentration under vacuum. Purification is then carried out by crystallization from diisopropyl ether and the solid obtained is filtered and rinsed with isopentane in order to obtain, after drying, 5.9 g of a yellow solid product (yield 62%). Melting point: 121.8-123.4° C.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18]CC1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>O>[NH:13]([CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[CH2:12][CH2:11][CH2:10][CH2:9][OH:8]
Reactant: c1ccc(COCCCCNCCCCOCc2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: OCCCCNCCCCO
Reaction time: 18 h

Procedure:
To a solution of bis(4-(benzyloxy)butyl)amine (300 mg, 0.879 mmol) was in a mixed solvent of Dioxane (5 ml)/Water (5 mL), was added PdOH2 (30.8 mg, 0.044 mmol). The reaction was stirred under H2 at 40 PSI for 18 h. LC-MS showed no starting material and formation of desired product. The mixture was filtered through a pad of celite, washed with dioxane/water (10 mL, 1/1). The filtrate was concentrated and dried over high vacuum pump to give the titled compound (130 mg, 0.806 mmol, 92% yield). LC-MS Method A: m/e=162.01 [M+1]; Rt=0.18 min.
Reaction SMILES: [CH2:1]([OH:20])[CH:2]([OH:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1.C([O-])(O)=O.[Na+]>ClCCl>[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:20][CH2:1][CH:2]([OH:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCC(O)CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCC(O)COC1CCCCO1
Temperature: 25 °C
Yield: 28.9 %

Procedure:
A 1-liter flask equipped with a stirrer and dropping funnel was charged with 20 g (70 mmol) of octadecane-1,2-diol, 0.7 g (3.5 mmol) of p-toluenesulfonic acid and 350 ml of dichloromethane. While stirring the contents at room temperature, 5.9 g (70 mmol) of dihydropyran were added dropwise. After stirring the mixture at room temperature for 30 minutes, it was neutralized with NaHCO3 and concentrated under reduced pressure, and the resultant residue was then purified by column chromatography on silica gel, thereby obtaining 7.5 g (yield[: 29%) of 1-(2-tetrahydropyranyloxy)-2-octadecanol. This compound was charged into a 200-ml flask equipped with a stirrer, to which 5.1 g (50 mmol) of triethylamine and 50 ml of dichloromethane were added. Further, 3.8 g (33 mmol) of methanesulfonyl chloride were added at room temperature with stirring. After the resultant mixture was stirred at room temperature for 14 hours, the reaction mixture was added with water and subjected to extraction with dichloromethane, and the solvent was distilled off under reduced pressure. The resultant residue and 15 ml of dimethylformamide was charged into a 100-ml flask equipped with a stirrer, to which 5.5 g (83 mmol) of NaN3 were added. The contents were stirred at 90° C. for 1.5 hours. After cooling the reaction mixture to room temperature, it was added with water and subjected to extraction with chloroform, followed by concentration under reduced pressure. Thereafter, the resultant residue was purified by column chromatography on silica gel, thereby obtaining 7.1 g (yield: 90%) of an azide intermediate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[CH3:13]N(N=O)C(N)=O.[OH-].[K+]>COCCOC.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([O:9][CH3:13])=[O:8])([O-:3])=[O:2]
Reactant: CN(N=O)C(N)=O
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cccc([N+](=O)[O-])c1
Yield: 149.5 %

Procedure:
1.00 grams (6 millimoles) of m-nitrobenzoic acid and 2.4 grams (2.4 millimoles) of N-methyl,N-nitrosourea were dissolved in 25 milliliters of a 5:1 mixture of 1,2-dimethoxyethane and water. 40 milliliters of 0.6 N potassium hydroxide was added in a dropwise manner while the mixture was held at 0°C. in an ice bath. The solution was extracted with ether (4×50 milliliters) and the water layer (pH 10) was saved. The ether layer was dried (MgSO4) and workup gave 0.65 grams of methyl m-nitrobenzoate, melting point 71°-72°C. The water layer gave 0.25 grams of unreacted acid. Yield, based on consumed acid, was approximately 85 percent.
Reaction SMILES: O=C1CCC(=O)N1[C:8](=[O:20])[C:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH3:10].[CH:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C@@H:29]([NH2:33])[C:30]([OH:32])=[O:31])=[CH:23][CH:22]=1.O.C(N(CC)CC)C>C1COCC1>[C:15]([O:14][C:13]([NH:12][C:9]([CH3:11])([CH3:10])[C:8]([NH:33][C@H:29]([CH2:28][CH2:27][C:24]1[CH:23]=[CH:22][CH:21]=[CH:26][CH:25]=1)[C:30]([OH:32])=[O:31])=[O:20])=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1C(=O)CCC1=O
Reactant: N[C@H](CCc1ccccc1)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](CCc1ccccc1)C(=O)O
Temperature: 50 °C
Reaction time: 9 h

Procedure:
A mixture comprising of tert-Butyl 1-(2,5-dioxopyrrolidin-1-yl)-2-methyl-1-oxopropan-2-ylcarbamate (1 g, 3.52 mmol) (prepared according to the procedure described in EP1486498A1 page 20) and H-D-Homophe-OH (0.630 g, 3.52 mmol) in THF (16 ml)/water (4 ml) was treated with triethylamine (1.471 ml, 10.55 mmol). The reaction mixture was stirred at 50° C. for 9 hours. THF was removed in vacuo. The aqueous solution was further diluted with water and the pH adjusted to pH 2-3 using 1M HCl. The resulting aqueous phase was extracted with EtOAc. The organic portion was dried (MgSO4) and concentrated in vacuo to afford the title compound.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[C:42]1[CH:43]=[C:44]([CH2:53]OS(C)(=O)=O)[C:45](=[O:52])[N:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[N:47]=1.CN1CCNCC1>>[F:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[C:42]1[CH:43]=[C:44]([CH2:53][N:11]2[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]2)[C:45](=[O:52])[N:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[N:47]=1
Reactant: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(COS(C)(=O)=O)c1=O
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CN1CCNCC1
Product: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CN2CCN(C)CC2)c1=O
Yield: 94 %

Procedure:
Following the procedure of Example 1 (10), 6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a pale yellow oil (yield: 94.0%).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][CH2:16][CH2:17][C@@H:18]1[CH2:20][C@@H:19]1[CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:29][N:28]=2)[CH2:23][CH2:22]1.[N:37]1([C:41](=[O:51])[CH2:42][C:43]2[CH:48]=[CH:47][C:46](O)=[CH:45][C:44]=2[F:50])[CH2:40][CH2:39][CH2:38]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[N:37]1([C:41](=[O:51])[CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:15][CH2:16][CH2:17][C@@H:18]3[CH2:20][C@@H:19]3[CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:34])[CH3:35])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)=[CH:45][C:44]=2[F:50])[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(O)c1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Reactant: O=C(Cc1ccc(O)cc1F)N1CCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(O)c1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CCC4)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
DIAD (95 μL, 0.491 mmol) was slowly added to a solution of 2-(2-{4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidin-1-yl}pyrimidin-5-yl)propan-2-ol (100 mg, 0.327 mmol), 1-(azetidin-1-yl)-2-(2-fluoro-4-hydroxyphenyl)ethanone (72 mg, 0.344 mmol), and triphenylphosphine (129 mg, 0.491 mmol) in DCM (1.6 mL). The mixture was stirred at rt for 3 hrs. The mixture was diluted with DCM (8 mL) and washed with 2 N NaOH solution (5 mL×1). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC using 2×2000 micron silica preparative TLC plates (uv 254 active) which were developed using 100% EtOAc. The desired band (Rf=0.5 @ 100% EtOAc) was collected and extracted to give the title compound. 1H NMR (500 MHz, CD3CN) δ 8.41 (s, 2H), 7.17 (t, 1H), 6.72 (t, 2H), 4.68 (t, 2H), 4.19 (t, 2H), 4.06 (m, 2H), 3.91 (t, 211), 3.36 (s, 2H), 2.83 (t, 2H), 2.22 (m, 2H), 2.07 (m, 1H), 1.83 (m, 2H), 1.57 (m, 1H), 1.48 (s, 6H), 1.35-1.10 (m, 3H), 0.91 (m, 1H), 0.60 (m, 2H), −0.05 (m, 111). LC/MS (m/z): 497 (M+H)+, GPR119 Human EC50: 7.5 nM.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH:10]([C:21](O)=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:38]([C@H:45]1[CH2:49][O:48][C:47](=[O:50])[NH:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[Cl-].[Li+]>C1COCC1.C(OCC)(=O)C>[CH2:38]([C@H:45]1[CH2:49][O:48][C:47](=[O:50])[N:46]1[C:21]([C@@H:10]1[C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)=[O:22])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(O)C1CN(Cc2ccccc2)CC1c1ccc(F)c(F)c1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidine-3-carboxylic acid (25 g, 78.8 mmol) in THF (350 mL) at -20° C. were added triethylamine (27.45 mL, 197 mmol) and pivaloyl chloride (24.2 mL, 197 mmol) subsequently. Stirring was continued for two hours at the same temperature, and to this mixture were added (S)-4-Benzyl-oxazolidin-2-one (14.7 g, 82.7 mmol) and lithium chloride (3.67 g, 86.7 mmol). The reaction mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water two times and saturated sodiumbicarbonate. The separated organic phase was dried on Na2SO4 and concentrated under vacuo. The two diastereoisomeres were separated by column chromatography (SiO2, EtOAc/H, 15:85) to yield (S)-4-benzyl-3-[(3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidine-3-carbonyl]-oxazolidin-2-one 18 g (48%) as awhite solid. MS m/e: 477.1 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=3[C:19]=2[CH3:28])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.CO.O.[Li+].[OH-]>CC(O)C.C(Cl)Cl>[Cl:27][C:25]1[CH:24]=[CH:23][C:21]2[S:22][C:18]([C:16]([NH:15][C:6]3([C:4]([OH:5])=[O:3])[CH2:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:7]3)=[O:17])=[C:19]([CH3:28])[C:20]=2[CH:26]=1
Reactant: CCOC(=O)C1(NC(=O)c2sc3ccc(Cl)cc3c2C)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cc1c(C(=O)NC2(C(=O)O)Cc3ccccc3C2)sc2ccc(Cl)cc12
Reaction time: 36 h
Yield: 72.9 %

Procedure:
40 mL vial containing the 2-[(5-chloro-3-methyl-benzo[b]thiophene-2-carbonyl)-amino]-indane-2-carboxylic acid ethyl ester (0.53 g, 1.28 mmol) is charged with MeOH (7.5 mL) and a stirring bar is added. Stirring is initiated. After dissolution, water (3.8 mL) is added followed by the LiOH (134 mg, 3.20 mmol). After 36 h, tlc analysis (silica, 5% i-PrOH/DCM) indicates that the starting material is completely consumed. The pH of the reaction mixture is carefully adjusted to pH 2 by slowly adding dilute aqueous HCl (3%, ˜10 mL). The contents of the flask are poured into a reparatory funnel containing EtOAc (30 mL). The layers are separated. The aqueous layer is extracted with EtOAc (20 mL). The combined organic extracts are washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated to yield 360 mg of amorphous white solid.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11](F)[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH3:17]>C1COCC1>[NH2:17][C:11]1[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([F:1])[CH:12]=1
Reactant: N
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1F

Procedure:
Prepared analogously to example 659a from ethyl 2,4-difluoro-5-nitro-benzoate and ammonia in THF.
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:44]([C:60]([N:62]2[CH2:67][CH2:66][N:65]([C:68](=[NH:84])[N:69](C)[C:70](OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:64][CH2:63]2)=[O:61])[CH2:43]1>>[OH:38][C@@H:36]([C@H:35]1[C:34](=[O:39])[N:19]2[C:20]([C:21]([OH:23])=[O:22])=[C:16]([S:41][C@@H:42]3[CH2:46][NH:45][C@H:44]([C:60]([N:62]4[CH2:67][CH2:66][N:65]([C:68](=[NH:84])[NH:69][CH3:70])[CH2:64][CH2:63]4)=[O:61])[CH2:43]3)[C@H:17]([CH3:40])[C@H:18]12)[CH3:37]
Reactant: CN(C(=N)N1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Product: CNC(=N)N1CCN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2)CC1

Procedure:
A procedure similar to that described in Example 101 was repeated, but using 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 123) and (2S,4S)-4-mercapto-2-[4-(methyl-4-nitrobenzyloxycarbonylamidino)piperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 104 as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[NH:34]1[CH:38]=[CH:37][N:36]=[CH:35]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[N:34]1([CH2:6][C@H:7]2[CH2:12][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]2[C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:29])[F:30])=[CH:23][CH:22]=2)[CH:38]=[CH:37][N:36]=[CH:35]1
Reactant: c1c[nH]cn1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2Cn2ccnc2)cc1)C(F)(F)F
Temperature: 80 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
To a 50-mL round-bottomed flask was added ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (38 mg, 0.072 mmol, Intermediate B), imidazole (7 mg, 0.11 mmol, Aldrich, St. Louis, Mo.) and cesium carbonate (46 mg, 0.14 mmol) in acetonitrile (2 mL). The reaction mixture was stirred at 80° C. for 18 h. The reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2 (2×40 mL). The organic extracts were washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an off-white glass. The crude product was purified by silica gel chromatography, eluting with 5% MeOH in EtOAc to give 2-(4-((S)-2-((1H-imidazol-1-yl)methyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1-trifluoro-2-propanol (28 mg) as a white solid.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[K+]>C(O)C>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][CH:11]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2c[nH]c3ccccc23)cc1OC
Temperature: 120 °C

Procedure:
1-Benzenesulfonyl-3-(3,4-dimethoxy-phenyl)-indole (350 mg, 0.89 mmol) 19 was dissolved in ethanol (3 mL) and potassium hydroxide pellets (385 mg, 6.9 mmol) were added. The reaction mixture was heated in a CEM Discover microwave instrument at 120° C. for 10 minutes. The reaction mixture was concentrated to dryness and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic portion was dried with anhydrous magnesium sulfate, filtered and the filtrate concentrated to provide the desired product 22, which was used without further purification (208 mg, 92%)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:22])[C:13](=[O:21])[N:14]([C@H:15]4[CH2:18][C@@H:17]([O:19][CH3:20])[CH2:16]4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:23][N:24]([CH3:44])[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:44][N:24]([CH3:23])[CH2:25][CH2:26][CH2:27][O:28][C:29]1[N:30]=[CH:31][C:32]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:22])[C:13](=[O:21])[N:14]([C@H:15]5[CH2:18][C@@H:17]([O:19][CH3:20])[CH2:16]5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:33][CH:34]=1
Reactant: CN(C)CCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CO[C@H]1C[C@@H](n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CO[C@H]1C[C@@H](n2c(=O)n(C)c3cnc4ccc(-c5ccc(OCCCN(C)C)nc5)cc4c32)C1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Pd(Ph3P)4 (2.074 g, 1.79 mmol) was added to a mixture of 8-bromo-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one (13 g, 35.89 mmol), N,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine (13.15 g, 43.07 mmol) and cesium carbonate (23.39 g, 71.78 mmol) in 1,4-dioxane (200 mL) and water (40 mL) under nitrogen. The resulting mixture was stirred at 90° C. for 3 h before being allowed to cool. The reaction mixture was concentrated and diluted with EtOAc (750 mL), and washed sequentially with water (2×150 mL), and sat. brine (150 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by FCC, elation gradient 0 to 10% MeOH in DCM, to afford the desired material (12.50 g, 75%) as a white solid. NMR Spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.90 (2H, q), 2.16 (6H, s), 2.37 (2H, t), 2.72-2.92 (2H, m), 3.01 (2H, d), 3.21 (3H, s), 3.50 (3H, s), 3.79-3.95 (1H, m), 4.37 (2H, t), 5.12 (1H, t), 6.97 (1H, d), 7.82-7.98 (1H, m), 8.11 (1H, d), 8.19 (2H, dd), 8.42 (1H, s), 8.67 (1H, d), 8.87 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=462.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Cl:19][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: c1ccc(-c2cc3ccccc3cn2)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Clc1nc(-c2ccccc2)cc2ccccc12

Procedure:
3-Phenylisoquinoline (5 g) was dissolved in dry toluene (250 ml) and phosphorus oxychloride (16.52 g) was added and the mixture was heated at reflux for 48 hr, more phosphorus oxychloride (4 g) being added after 24 hr. The solvent was removed in vacuo to give 1-chloro-3-phenylisoquinoline as an oil which solidified on standing (4 g), characterised by its nmr spectrum. (A small portion was recrystallised from methanol, m.pt. 75°-77°).