Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([S:8]([O-:10])=[O:9])[CH:7]=1.[Na+].I[CH3:15]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([S:8]([CH3:15])(=[O:10])=[O:9])[CH:7]=1
Reactant: CI
Reactant: COc1ccc(Br)cc1S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium 5-bromo-2-methoxybenzenesulfinate (1.99 g) in DMF (873 ml) was added iodomethane (32 ml). The reaction mixture turned yellow and was stirred at room temperature for 2 hours. The reaction was quenched by the addition of water (ca. 5 ml). The mixture was diluted with EtOAc and extracted with 5% LiCl (3×) and brine (1×). The organic layer was dried (Na2SO4/MgSO4) and filtered. The filtrate was concentrated and purified by silica gel column chromatography to give 1.62 g 4-bromo-1-methoxy-2-(methylsulfonyl)benzene as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:36])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:37]([OH:39])=[O:38].C[O-].[Na+:42]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:36])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:24]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:37]([O-:39])=[O:38].[Na+:42]
Reactant: O=C(NCCc1cccc(Oc2ccccc2)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1cccc(Oc2ccccc2)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 0.33 h
Yield: 98.1 %

Procedure:
6-Chloro-7-(4-(3-phenoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (56.4 mg, 0.104 mmol), 0.1 molar in tetrahydrofuran, was treated with sodium methanolate (207 μl, 0.104 mmol) at ambient temperature. After 20 minutes, the solvent was removed in vacuo. The resulting solid was taken up in ethyl acetate and concentrated in vacuo. The solid was taken up in 4:1 dichloromethane-hexanes and concentrated in vacuo and dried under high vacuum to provide sodium 6-chloro-7-(4-(3-phenoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate (58.0 mg, 0.102 mmol, 98.8% yield) as a solid. MS (apci) m/z=543.9 (M+2H—Na).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][C@@H:15]([CH3:17])[NH:14][CH2:13][C@@H:12]1[CH3:18].FC1C=CC([N+]([O-])=O)=CC=1.C[C@H]1CN[C@H](C)CN1>>[CH3:18][C@H:12]1[CH2:13][NH:14][C@H:15]([CH3:17])[CH2:16][N:11]1[C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][CH:2]=1
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)[C@@H](C)CN1
Agent: C[C@@H]1CN[C@@H](C)CN1
Agent: O=[N+]([O-])c1ccc(F)cc1
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)[C@@H](C)CN1
Yield: 31 %

Procedure:
Racemic-[trans-2,5-dimethyl-1-(4-nitrophenyl)piperazine] (6.34 g, 31%) is prepared according to the method described above for the synthesis of racemic-1-(2-fluoro-4-nitrophenyl)-trans-2,5-dimethylpiperazine by treatment of 1-fluoro-4-nitrobenzene (12.3 g, 87.5 mmol) with trans-2,5-dimethylpiperazine (10.0 g, 87.5 mmol). LCMS-ESI (m/z): calcd for C12H17N3O2, [M+H]+235; found, 236.
Reaction SMILES: [N:1]1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[I-].[I-].[Sm+2].[CH3:18][C@@H:19]1[C:24](=[O:25])[CH2:23][C@:22]2([CH:26]([CH3:28])[CH3:27])[C@H:20]1[CH2:21]2>C1COCC1>[OH:25][C@@:24]1([C:2]2[CH:3]=[CH:4][C:5]3[C:14](=[C:13]4[C:8](=[CH:7][CH:6]=3)[CH:9]=[CH:10][CH:11]=[N:12]4)[N:1]=2)[C@@H:19]([CH3:18])[C@@H:20]2[C@@:22]([CH:26]([CH3:28])[CH3:27])([CH2:21]2)[CH2:23]1
Reactant: CC(C)[C@@]12CC(=O)[C@@H](C)[C@@H]1C2
Reactant: c1cnc2c(c1)ccc1cccnc12
Agent: [I-]
Agent: [Sm+2]
Solvent: C1CCOC1
Product: CC(C)[C@@]12C[C@@H]1[C@H](C)[C@@](O)(c1ccc3ccc4cccnc4c3n1)C2

Procedure:
Another embodiment of the process comprises mixing a solution of 1,10-phenanthroline in THF with a solution of samarium diiodide in THF and adding to the mixed solutions a solution of the chiral bicyclic ketone, (−)-thujone, in THF. The chiral product, 2-{(1S,3R,4S,5R)-(3-hydroxy-1-isopropyl-4-methylbicyclo[3.1.0]hex-3-yl)}-1,10-phenanthroline, is isolated and purified as described above in the preceding embodiment. This embodiment is illustrated by the following reaction scheme.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][C:15]2=[O:20].C(Cl)Cl.O=O>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(N(CC)CC)C>[O:10]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][C:15]2=[O:20])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1CCc2c(O)cccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCc2c(Oc3ccccc3)cccc21
Yield: 72.7 %

Procedure:
To phenyl boronic acid (1.0 g) and 4-hydroxy-2,3-dihydro-1H-inden-1-one (1.0 g), methylene chloride (67 mL) was added and thereto, copper (II) acetate (1.4 g), molecular sieves 4A (1.9 g), and triethylamine (4.7 mL) were added, followed by stirring the resultant reaction mixture at room temperature in an oxygen atmosphere for 19 hours. The reaction mixture was filtered through a pad of Celite and the filtered substance was washed with ethyl acetate. To the resultant filtrate, a 1M aqueous solution of sodium hydroxide was added and the resultant mixture was filtered through a pad of Celite again. The resultant filtrate was phase-separated into an aqueous phase and an organic phase and the aqueous phase was extracted with ethyl acetate to combine the resultant organic phase with the above organic phase. The combined organic phase was washed with saturated saline and was dried over sodium sulfate anhydride. From the organic phase, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography to obtain the subject compound (1.1 g) as an orange solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:4]([C:9](=[O:11])[CH3:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[Br:14]Br>Br>[Br:14][CH2:10][C:9]([C:4]1[C:3]([C:2]([F:1])([F:12])[F:13])=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:11].[BrH:14]
Reactant: CC(=O)c1ncccc1C(F)(F)F
Reactant: BrBr
Agent: Br
Product: O=C(CBr)c1ncccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Dissolve 1-(3-trifluoromethyl-pyridin-2-yl)-ethanone (2.10 g, 11.1 mmol) in HBr (30% by wt in AcOH) (14 mL). Cool the mixture to 0° C. and add bromine (0.62 mL) drop wise. Allow the resulting solution to warm to room temperature and stir for 3 hours. Concentrate the reaction under reduced pressure to yield the title compound as its HBr salt.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:7]=[C:6]([C:26]2[CH:31]=[CH:30][C:29](Cl)=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=2)[C:3]=1[C:4]#[N:5].[CH2:36]([N:38](CC)[CH2:39]C)C.Cl.CNC>CN(C=O)C>[NH2:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:7]=[C:6]([C:26]2[CH:31]=[CH:30][C:29]([N:38]([CH3:39])[CH3:36])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=2)[C:3]=1[C:4]#[N:5]
Reactant: CCN(CC)CC
Reactant: COc1ccc(COc2ccccc2-c2cc(-c3ccc(Cl)c([N+](=O)[O-])c3)c(C#N)c(N)n2)cc1
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccccc2-c2cc(-c3ccc(N(C)C)c([N+](=O)[O-])c3)c(C#N)c(N)n2)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a stirred solution of 2-amino-4-(4-chloro-3-nitrophenyl)-6-{2-[(4-methoxybenzyl)oxy]phenyl}-nicotinonitrile (0.850 g, 1.746 mmol) in DMF (5 mL) including triethylamine (1.2 mL) was added dimethylamine hydrochloride (0.996 g, 12.220 mmol), and the mixture was stirred at 70° C. for 3 hrs. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was suspended in ethanol. The resulting solid was collected by filtration, washed with ethanol, and dried under reduced pressure to give 2-amino-4-[4-(dimethylamino)-3-nitrophenyl]-6-{2-[(4-methoxybenzyl)-oxy]phenyl}nicotinonitrile as an orange oil (0.820 g, yield 95%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=1.[CH:14]1([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([NH2:36])[CH:31]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.O=P(Cl)(Cl)Cl.O>CN(C=O)C>[CH:14]1([NH:20][C:21]([CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][C:30]3[CH:31]=[C:32]([NH:36][C:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:13])[F:12])[N:8]=4)=[O:11])[CH:33]=[CH:34][CH:35]=3)[CH2:27][CH2:28]2)=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=C(O)c1cccc(C(F)(F)F)n1
Reactant: Nc1cccc(CN2CCC(C(=O)NC3CCCCC3)CC2)c1
Solvent: O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Nc1cccc(CN2CCC(C(=O)NC3CCCCC3)CC2)c1)c1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-trifluoromethylpyridine-2-carboxylic acid (19.1 mg, 0.1 mmol) in DMF (0.5 mL) is treated successively with a solution of 1-(3-Amino-benzyl)-piperidine-4-carboxylic acid cyclohexylamide BB-1 (36.3 mg, 0.1 mmol) in DMF (0.5 mL) and with POCl3 (0.01 mL, 0.11 mmol) at RT. The resulting solution is stirred at RT for 30 min and heated at 80° C. for 1 h. The reaction mixture is treated with water (0.2 mL) and evaporated under HV. The title compound is obtained by prep. HPLC F as a colorless powder: LC-MS B: tR=1.21 min; [M+H]+=440.1. 1H-NMR (CDCl3): δ 1-1.3 (m, 6H), 1.5-2.1 (m, 12H), 2.3-2.4 (m, 1H), 3.0-3.1 (m, 2H), 3.4-3.5 (m, 1H) 5.4 (s broad, 1H), 7.16 (d, J=7, 1H), 7.37 (t, J=7, 1H), 7.67 (s, 1H), 7.79 (d, J=7.5, 1H), 7.90 (d, J=7.5, 1H), 8.15 (t, J=8, 1H), 8.53 (d, J=8, 1H) 9.81 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:36]=[CH:35][C:10]([C:11]([NH:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([N:30]4[CH:34]=[CH:33][CH:32]=[CH:31]4)[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=3)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([N:30]3[CH:34]=[CH:33][CH:32]=[CH:31]3)[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[O:12])=[CH:35][CH:36]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3)cc2)cc1)n1cccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCCOc1ccc(CC(C(=O)O)n2cccc2)cc1)c1ccc(-c2ccccc2)cc1

Procedure:
Ethyl 3-[4-[2-(4-phenylbenzoylamino)ethoxy]phenyl]-2-(pyrrole-1-yl)propionate, which is the product of Example 193, is hydrolyzed by sodium hydroxide in methanol to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](Cl)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.ClC1C=C(C(O)=O)C2C(=CC=CC=2)N=1.[N-:29]=[N+:30]=[N-:31].[Na+].CC(C)=O>O1CCOCC1.O>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([N:29]=[N+:30]=[N-:31])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C(Cl)c1cc(Cl)nc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: O=C(O)c1cc(Cl)nc2ccccc12
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NC(=O)c1cc(Cl)nc2ccccc12
Reaction time: 16 h

Procedure:
2-Chloro-4-chlorocarbonylquinoline (0.5 g), prepared by standard methods from 2-chloroquinoline-4-carboxylic acid, was added to sodium azide in aqueous dioxan (2.1 ml 1:3) at 0° C. Acetone was then added and the mixture stirred for 16 h. Water (10 ml) was added, the precipitated solid collected by filtration and air dried to give 2-chloroquinoline-4-carbonyl azide (0.455 g). The azide (0.232 g) in toluene (10 ml) was warmed from room temperature to 75° C. and then heating continued for 1 h. After cooling to room temperature 6-amino-2-methylbenzoxazole (0.148 g) in dichloromethane (15 ml) containing 4-N,N-dimethylaminopyridine (20 mg) was added and the mixture stirred for 16 h. The precipitated solid was separated by filtration to give a solid (0.25 g). Column chromatography (silica gel, dichloromethane/methanol/ammonia mixtures) gave the title compound (0.072 g). 1H NMR δ: 5 2.60 (3H, s), 7.25 (1H, d, J=8.5 Hz), 7.61 (1H, d, J=8.5 Hz), 7.73 (1H, t, J=7.0 Hz), 7.84 (1H, t, J=6.7 Hz), 7.91 (1H, d, J=8.0 Hz), 8.05 (1H, s), 8.20 (1H, d, J=8.25 Hz), 8.28 (1H, s), 9.49 (1H, s), 9.61 (1H, s). m/z (API+): 353, 355(MH+).
Reaction SMILES: O1CCOCC1.[OH-].[Na+:8].[C:9]1([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[C:17]([NH:24][C:25]([C:27]3[CH:28]=[N:29][C:30]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)=[CH:31][CH:32]=3)=[O:26])[CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO>[C:9]1([C:15]2[CH:23]=[CH:22][C:18]([C:19]([O-:21])=[O:20])=[C:17]([NH:24][C:25]([C:27]3[CH:28]=[N:29][C:30]([C:33]4[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=4)=[CH:31][CH:32]=3)=[O:26])[CH:16]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1.[Na+:8]
Reactant: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1ccc(-c2ccncc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)[O-])c1ccc(-c2ccncc2)nc1

Procedure:
Dioxane (2 mL), methanol (2 mL), and a 2 mol/L aqueous solution of sodium hydroxide (0.025 mL) were added to the obtained 4-phenyl-2-(6-(pyridin-4-yl)pyridine-3-carboxamido)benzoic acid (20 mg), and the solvent was evaporated under reduced pressure. Acetone was added to the obtained residue. The solid substance was collected by filtration to obtain 17 mg of sodium 4-phenyl-2-(6-(pyridin-4-yl)pyridine-3-carboxamido)benzoate as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22](Br)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1.B(O)(O)[C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=4)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(Br)ccc3C2=O)cc1
Reactant: OB(O)c1ccc2ccccc2c1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(-c4ccc5ccccc5c4)ccc3C2=O)cc1
Reaction time: 0.33 h
Yield: 61 %

Procedure:
The procedure of Example 2 was repeated except that N-(2-aminophenyl)-4-((5-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 56 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and naphthalen-2-yl-2-boronic acid instead of phenyl boronic acid were used, and the reaction was performed for 20 mins, to obtain the title compound (61%).
Reaction SMILES: [NH2:1][C:2]([CH3:32])([CH3:31])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([N:13]2[CH2:18][CH2:17][C@:16]([CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:15][C:14]2=[O:30])[CH3:12])=[CH:7][CH:6]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[OH:29][C:26]([CH3:27])([CH3:28])[CH2:25][C@@:16]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:15][C:14](=[O:30])[N:13]([C@H:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]#[C:3][C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])([CH3:31])[CH3:32])=[CH:6][CH:7]=2)[CH3:12])[CH2:18][CH2:17]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](c1ccc(C#CC(C)(C)N)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(C#CC(C)(C)NS(C)(=O)=O)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 15 using (S)-3-((S)-1-(4-(3-amino-3-methylbut-1-ynyl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and methanesulfonyl chloride. LC-MS Method 1 tR=1.53 min, m/z=513, 455; 1H NMR (CDCl3) 1.13 (s, 3H), 1.18 (s, 3H), 1.49 (d, 3H), 1.69 (s, 6H), 2.10-2.45 (5H), 2.83 (m, 1H), 3.14 (s, 3H), 5.66 (q, 1H), 6.92 (d, 2H), 7.17 (d, 2H), 7.30-7.40 (5H)
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:12]=[C:13]([CH:14]=[O:15])[C:8]=3[N:7]=[CH:6]2)[CH2:3][CH2:2]1.[CH3:20][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[C:11]([C:16]([F:18])([F:19])[F:17])[CH:12]=[C:13]([CH:14]([OH:15])[CH3:20])[C:8]=3[N:7]=[CH:6]2)[CH2:3][CH2:2]1
Reactant: C[Mg]Br
Reactant: O=Cc1cc(C(F)(F)F)cc2c1ncn2CC1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1cc(C(F)(F)F)cc2c1ncn2CC1CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 83.8 %

Procedure:
1-(Cyclopropylmethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole-4-carbaldehyde (0.323 g, 1.2 mmol) was dissolved in tetrahydrofuran (6 mL), cooled down to 0° C. and to it was added methylmagnesium bromide (1.0 M in dibutyl ether, 2.2 mL, 2.2 mmol) dropwise. After 1.5 h, saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate (3×30 mL). The organic layer was washed with water (20 mL), brine (20 mL) and dried (Na2SO4). The crude product obtained after evaporation of solvent was purified by flash chromatography on silica gel (2% MeOH/CH2Cl2) affording 286 mg (84%) of product as light yellow oil. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 8.11 (s, 1 H), 7.62 (s, 1 H), 7.46 (s, 1 H), 5.38-5.49 (m, 1 H), 4.16 (d, J=6.1 Hz, 1 H), 4.06 (d, J=7.0 Hz, 2 H), 1.70 (d, J=6.7 Hz, 3 H), 1.29-1.40 (m, 1 H), 0.69-0.80 (m, 2 H), 0.45 (q, J=5.2 Hz, 2 H). 308.17 (MNa)+.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:20]#[N:21])[C:10]([CH3:19])=[C:11]([N:14]4[CH:18]=[CH:17][CH:16]=[CH:15]4)[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:29][N:30]([CH3:36])[C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.C(=O)([O-])O.[Na+]>CS(C)=O.C(OCC)(=O)C>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:20]#[N:21])[C:10]([CH3:19])=[C:11]([N:14]4[CH:18]=[CH:17][CH:16]=[CH:15]4)[C:12]=3[N:33]3[CH2:34][CH2:35][C@H:31]([N:30]([CH3:36])[CH3:29])[CH2:32]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(-n2cccc2)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1c(-n2cccc2)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Temperature: 100 °C
Reaction time: 5.5 h
Yield: 70.6 %

Procedure:
2-Cyclopropyl-7-fluoro-5-methyl-6-(pyrrol-1-yl)-1,3-benzoxazole-4-carbonitrile (I-320) (28 mg, 0.10 mmol) was dissolved in dimethyl sulfoxide (2 ml), then at room temperature, triethylamine (18 μl, 0.13 mmol) and (3S)-3-(dimethylamino)pyrrolidine (17 μl, 0.13 mmol) were added, followed by stirring under nitrogen atmosphere at 100° C. for 5.5 hours. The reaction liquid was cooled to room temperature, then fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was roughly purified by preparative TLC (eluent, chloroform:methanol=92:8, v/v), and the obtained solid was further purified in slurry with diisopropyl ether. This was dried at 60° C. under reduced pressure for 12 hours to obtain the entitled compound (26.5 mg, 71%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C:9]([O:11]C)=O)[CH:2]=1.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1.C1CCN2C(=NCCC2)CC1>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C:9]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:22][CH:23]=2)=[O:11])[CH:2]=1
Reactant: COC(=O)COc1cccnc1
Reactant: NCc1ccc(C(=O)O)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: O=C(COc1cccnc1)NCc1ccc(C(=O)O)cc1
Reaction time: 24 h
Yield: 89.3 %

Procedure:
32 g (0.19 mole) of methyl 2-(pyridin-3-yloxy)-acetate, 27 g (0.18 mole) of 4-aminomethylbezoic acid and 59 g (0.39 mole) of DBU were added to ethanol (350 ml), and reaction was then carried out at room temperature for 24 hours. After the reaction mixture had been concentrated, partition was carried out between toluene and water. Concentrated hydrochloric acid was added to the resultant aqueous layer to accomplish neutralization, and a deposited solid was collected by filtration, washed with water and methanol, and then dried to obtain 46 g (yield: 89%) of 4-[N-(pyridin-3-yl)oxyacetylaminomethyl]benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.Cl[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>C1COCC1>[NH2:6][C:4]([C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[NH:1][C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5]
Reactant: CCOC(=O)C(=O)Cl
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Nc1ccc([N+](=O)[O-])cc1C(N)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.8 %

Procedure:
To a solution of 2-amino-5-nitrobenzamide (18.1 g) and triethylamine (15 mL) in THF (100 mL) was added dropwise a solution of ethyl chloroglyoxylate (14.4 g) in THF (20 mL) under ice-cooling, and the mixture was stirred at 0° C. for 1 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogencarbonate and saturated brine, dried, and concentrated. The obtained crude crystals were washed with diisopropyl ether to give ethyl {[2-(aminocarbonyl)-4-nitrophenyl]amino}(oxo)acetate (8.1 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21].O>CN(C=O)C.C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH:20]([CH3:22])[CH3:21])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)I
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(O)cc(OC(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of methyl 3,5-dihydroxybenzoate (0.1 mol) in DMF (180 mL) was added powdered potassium carbonate (0.2 mol) and 2-iodopropane (0.1 mol), and the resulting mixture stirred at ambient temperature for 16 hours. The reaction mixture was poured into water (1000 mL) and the mixture extracted with ether. The extracts were combined and washed sequentially with water (twice) and brine; the solution was dried (MgSO4), filtered and evaporated in vacuo to give the crude product as a pale yellow oil (12.6 g). This was treated with toluene (40 mL) and allowed to stand overnight. The insoluble material (starting phenol) was removed by filtration, and the filtrate evaporated in vacuo. The resulting oil was chromatographed (2×90 g Biotage silica cartridges), eluting with hexane containing ethyl acetate (10% increasing to 15% v/v). The title compound was obtained as an oil (25% yield), which was identical by tlc to a sample prepared by a similar procedure. 1H NMR δ (d6-DMSO): 1.2 (d, 6H), 3.8 (s, 3H), 4.5-4.6 (hept, 1H), 6.55 (m, 1H), 7.85 (m, 1H), 7.95 (m, 1H), 9.8 (s, 1H)