Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][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].Cl.[CH3:17][O:18][NH2:19].[OH-].[Na+].O>C(O)C>[CH3:17][O:18][N:19]=[C:2]([CH3:15])[CH2:3][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]
Reactant: CON
Reactant: CC(=O)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CON=C(C)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.7 %

Procedure:
1.33 g (6.55 mmol) of N-(2-oxopropyl)phthalimide was dissolved in 30 ml of ethanol and to the solution was added 1.64 g (19.7 mmol) of O-methylhydroxylamine hydrochloride. To this suspension was added 20 ml of 2N aqueous sodium hydroxide solution, followed by being stirred at room temperature for 12 hours. The reaction mixture was poured into 100 ml of water and extracted with chloroform (30 ml×3), and the combined organic layer was dried over magnesium sulfate. Chloroform was distilled off and the residual solids were washed with hexane to give 1.03 g (yield 68%) of the titled compound as colorless crystals.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[C:24]([CH3:33])([CH3:32])[CH2:23]3)[CH:16]=2)[CH2:11][C@H:10]1[CH2:34][OH:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[S:37]([NH2:40])(=[O:39])=[O:38].CCOC(C)=O.CCN(CC)CC>CC(N(C)C)=O.C(#N)C>[S:37](=[O:39])(=[O:38])([O:35][CH2:34][C@@H:10]1[CH2:11][C@@H:12]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[C:24]([CH3:33])([CH3:32])[CH2:23]3)[CH:16]=2)[CH2:13][C@@H:9]1[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[NH2:40]
Reactant: CC1(C)C[C@H](Nc2cc(O[C@@H]3C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)C3)ccn2)c2ccc(Cl)cc21
Reactant: NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: CC1(C)C[C@H](Nc2cc(O[C@@H]3C[C@@H](COS(N)(=O)=O)[C@@H](O[Si](C)(C)C(C)(C)C)C3)ccn2)c2ccc(Cl)cc21
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To a solution of {(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(2-{[(1S)-5-chloro-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}pyridin-4-yl)oxy]cyclopentyl}-methanol (28.1 mg, 0.0000543 mol) in DMA (1.00 mL) was added chlorosulfonamide (0.0251 g, 0.000217 mol) in 0.50 ml acetonitrile. The mixture was stirred for 30 min then poured into 50 ml EtOAc and 1.00 ml Et3N. The layers were separated and the organic layer was washed (water) and concentrated. The residue was purified by preparative plate chromatography (85% EtOAc/hexanes) to afford the title compound (28.7 mg, 89%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:10])[CH3:9]
Reactant: CC(=O)c1ccccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccccc1Br
Reaction time: 24 h

Procedure:
To a stirred solution of 1-(2-bromophenyl)ethanone (5 g, 25.1 mmol) in methanol (50 mL) was added sodium borohydride (1.43 g, 37.7 mmol) at room temperature and the mixture was stirred for 24 h at the same temperature. The reaction mixture was quenched by the addition of water, and concentrated to give a colorless residue. The crude material was partitioned between diethyl ether and water, and then the organic layer washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (100 g) eluting with hexane/ethyl acetate (5/1) to afford 5.4 g (quant.) of the title compound as a colorless oil:
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[CH3:33][N:30]1[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:32][CH2:31]1
Reactant: CN1CCN(CCc2nnc3ccc(F)cn23)CC1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(CCc2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 42.3 %

Procedure:
Intermediate A (180 mg, 1.11 mmol) was added to a suspension of sodium hydride (60% in mineral oil, 133 mg, 3.33 mmol) in DMF (5 mL). The reaction was stirred for 20 min, then Intermediate 2b (310 mg, 1.11 mmol) was added in DMF (5 mL) and the resulting mixture heated to 60° C. for 3 h. After cooling, the reaction was quenched by dropwise addition of MeOH. The solution was loaded onto an SCX-2 cartridge, which was washed with MeOH and product eluted with 2M NH3 in MeOH. The residue was purified by FCC, using 2-20% [2M NH3 in MeOH] in DCM, to give the title compound (200 mg, 0.47 mmol, 43%). LCMS (Method 4): Rt 0.28 min, m/z 407 [MH+].
Reaction SMILES: [C:1]1([O:7][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([OH:17])C>>[C:1]1([O:7][C:8]([N:10]2[CH2:14][CH2:13][C@H:12]([OH:17])[CH2:11]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCO
Reactant: O=C(Oc1ccccc1)N1CCCC1
Product: O=C(Oc1ccccc1)N1CC[C@H](O)C1
Temperature: 21 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
Six Fernbach flasks, each containing 0.5 L of medium 2 as described in Example 2 were inoculated with spores of C. echinulata ATCC 8688b and incubated at 29° C. on a rotary shaker (220 rpm). After 24 hours, 5 mL of a 60 mg/mL ethanol solution of pyrrolidine-1-carboxylic acid phenylester (II) were added to each flask, and incubated for 16 more days. The bioconversion was monitored in two of the six flasks (flasks A and B) by removing samples of fermentation broth, extracting with ETOAc, and analyzing the extracts by reverse phase and chiral HPLC as described in Example 1. The results of these HPLC analyses are summarized in Table 3. The contents of all six flasks were pooled after the 16 days incubation and filtered through a triple-layer of cheesecloth to remove cells. The filtrate was then stirred with 50 g of Amberlite® XAD-16 resin (Rohm and Haas, Philadelphia, Pa.) for 4.5 hours at 21° C. The resin was collected onto filter paper and washed with 0.8 L of ETOAc. The ETOAc extract was washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to give 0.93 g of crude product. The crude product was applied to a 5 g silica Seppak® cartridge (Waters Corporation, Milford, Mass.) and eluted with mixtures of ETOAc and hexane, (2:3, 1:1) and the fractions containing the desired product were concentrated under reduced pressure to give 0.64 g (33% yield, 89% ee) of (S)-3-hydroxypyrrolidine-1-carboxylic acid phenylester (II).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)[C:10]([CH3:26])([CH3:25])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:25][C:10]1([CH3:26])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc([N+](=O)[O-])c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 97.1 %

Procedure:
A mixture of 3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2 g, 5.65 mmol) in methanol (15 mL) and tetrahydrofuran (30 mL), 30% sodium hydroxide in water (15 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.79 g, 97%) as a brown solid which was used for next step without further purification: LC/MS m/e calcd for C18H18N2O4 (M+H)+: 327.37, observed: 327.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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.O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2onc(-c3ccccc3)c2c1O
Reactant: OB(O)c1ccccc1
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
Product: CCOC(=O)c1nc(-c2ccccc2)c2onc(-c3ccccc3)c2c1O
Temperature: 25 °C
Yield: 49.9 %

Procedure:
A mixture of 7-bromo-4-hydroxy-3-phenyl-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (125.4 mg, 0.35 mmol), phenylboronic acid (85 mg, 0.69 mmol), cesium carbonate (339 mg, 1.04 mmol), tetrakis(triphenylphosphine)palladium (40 mg, 0.03 mmol), and dioxane (1.5 ml) was refluxed for 18 h before it was cooled to room temperature and quenched with water. It was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (63 mg): MS: (+) m/z 361.07 (M+1).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][NH2:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=O>C(O)(=O)C>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:12](=[O:17])[CH2:13][C:14]([CH3:16])=[N:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(C)=O
Reactant: NNc1ccc2c(c1)CCC2
Solvent: CC(=O)O
Product: CC1=NN(c2ccc3c(c2)CCC3)C(=O)C1
Temperature: 100 °C
Yield: 62.2 %

Procedure:
Indan-5-yl-hydrazine 1h (2.05 g, 13.8 mmol) was dissolved in 50 mL of acetic acid followed by addition of ethyl acetoacetate (1.76 mL, 13.8 mmol). The reaction mixture was heated at 100° C. overnight and the reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain the title compound 2-indan-5-yl-5-methyl-2,4-dihydro-pyrazol-3-one 1i (1.84 g, yield 62.3%) as a yellow solid.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ClC1C(O)=C(Cl)C(Cl)=C(Cl)C=1Cl.C([N+]#[C-])(C)C.Cl.[CH2:41]([O:43][C:44](=[O:47])[CH2:45][NH2:46])[CH3:42]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:41]([O:43][C:44](=[O:47])[CH2:45][NH:46][C:20](=[O:22])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH3:42]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [C-]#[N+]C(C)C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 50 °C
Yield: 82 %

Procedure:
A solution of 6.0 (20 mM) N-carbobenzoxy-L-phenylalanine, 5.3 g (20 mM) pentachlorophenol, and 2.0 g (30 mM) is isopropyl isonitrile in 40 ml chloroform was mixed with a solution of 2.8 g (20 mM) glycine ethyl ester hydrochloride and 2.02 g (20 mM) triethylamine in 30 ml chloroform. The mixture was heated at 50°C for 24 hours and evaporated. The residue was taken up in 150 ml ethyl acetate. The solution was washed sequentially with 100 ml water, 120 ml 1-N hydrochloric acid, four times 120 ml 5% sodium bicarbonate solution, and again with 100 ml water, then dried with desiccated sodium sulfate and evaporated. When the residue was crystallized from ethyl acetate and petroleum ether, 6.3 g N-carbobenzoxy-L-phenylalanyl-glycine ethyl ester was obtained (82 percent yield). Recrystallizing from ethyl acetate and petroleum ether reduced the yield to 5.4 g (70%). M.P. 107°-108.5°C. [ α]D25 = - 17.1° (C = 2, in ethanol).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][CH:8]1[N:16](CC2C=CC=CC=2Cl)[CH:15]=[CH:14][CH:13]=[C:9]1[C:10]([OH:12])=O)(=[O:3])[NH2:2].[Cl:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C>CN(C)C=O.O>[C:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:32][CH2:31][C:30]1[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=1[Cl:28])=[O:12])(=[O:3])[NH2:2]
Reactant: NCc1ccccc1Cl
Reactant: NC(=O)c1cccc(OC2C(C(=O)O)=CC=CN2Cc2ccccc2Cl)c1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccccc2Cl)c1
Yield: 50.1 %

Procedure:
To a stirred solution of 2-(3-Carbamoyl-phenoxy)-N-(2-chloro-benzyl)-nicotinic acid (0.300 grams, 1.25 mmole), o-chlorobenzylamine (0.195 grams, 1.375 mmole), and 1-hydroxybenzotriazole hydrate (0.203 grams, 1.50 mmole) in dry dimethylformamide (3 ml) was added 1-(3-dimethylamino)-propyl)-3-ethylcarbodiimide hydrochloride (0.311 grams, 1.63 mmole) and stirred over night. The mixture poured into 100 ml water and extracted with ethyl acetate. The combined extracts were washed with 1 N NaOH, water and brine, dried over Na2SO4, filtered and concentrated to give a white solid that was purified by chromatography on silica gel eluting with 7% methanollmethylene chloride. Recrystalization from ethyl acetate/hexane gave a white solid (0.239 g). M.P. 153-155° C.; Anal. calcd. for C20H16N3O3Cl: C, 62.91; H, 4.22; N, 11.01. Found: C, 62.92; H, 4.30; N, 11.09.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)([O-])=O.FC(F)(C1C=CC(N)=CC=1OCCN1CCCC1)C(F)(F)F>>[F:15][C:10]([C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1)([F:16])[C:11]([F:12])([F:14])[F:13]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)cc1
Agent: Nc1ccc(C(F)(F)C(F)(F)F)c(OCCN2CCCC2)c1
Product: Nc1ccc(C(F)(F)C(F)(F)F)cc1

Procedure:
4-(1,1,2,2,2-Pentafluoroethyl)phenylamine was prepared from 1-Nitro-4-(1,1,2,2,2-pentafluoroethyl)benzene similar to the procedure in preparation of 4-pentafluoroethyl-3-(2-pyrrolidin-1-yl-ethoxy)-phenylamine.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:19][CH:18]=2)=[CH:22][CH:23]=1
Reactant: COc1ccc(Oc2ccc(N3CCN(Cc4ccccc4)CC3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Oc2ccc(N3CCNCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.5 %

Procedure:
A mixture of the compound from step 2 (52 mg, 0.13 mmol), Pd(OH)2/C (20%, 5 mg) and methanol (3 mL) was stirred at ambient temperature under hydrogen (1 atm) for 24 h. The reaction mixture was filtered and the solvent was removed under vacuum to furnish the title compound (29 mg, 78.5%) as an off-white oil: MS (ESI) m/z 285 (M+H); 1H NMR (400 MHz, CDCl3) δ 2.31 (s, 3H), 3.12 (m, 4H), 3.16 (m, 4H), 6.85 (d, J=8.4 Hz, 2H), 6.89-6.95 (m, 4H), 7.11 (dd, J=0.8, 8.0 Hz, 2H).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].Cl[CH2:17][C:18]1[N:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:21][C:22]=1[CH3:23].O>CN(C)C=O>[CH3:23][C:22]1[O:21][C:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:19][C:18]=1[CH2:17][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1ccn2Cc1nc(-c2ccccc2)oc1C
Reaction time: 0.5 h

Procedure:
Methyl indole-4-carboxylate (700 mg) was dissolved in 7 ml of dimethylformamide, then 160 mg of sodium hydride (content 60%) was added to the resulting solution at room temperature and the mixture was stirred for 30 minutes. After adding 830 mg of 4-chloromethyl-5-methyl-2-phenyloxazole to the mixture and stirring them for 2 hours, the reaction solution was added to 70 ml of water and extracted with ethyl acetate (50 ml×2). The resulting organic phase was washed with, in order, water (50 ml×2) and 50 ml of a saturated common salt aqueous solution and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, the residue was crystallized in 50 ml of hexane to thus give 1.18 g of methyl 1-[(5-methyl-2-phenyloxazol-4-yl)methyl]indole-4-carboxylate as pale brown crystals. The yield thereof was found to be 85%.
Reaction SMILES: C([NH:4][C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([N:12]([CH3:14])[CH3:13])[N:6]=1)(=O)C.Cl.[CH3:16][C:17]([N:21]([CH3:23])[CH3:22])([CH3:20])[CH2:18]Cl>>[CH3:16][C:17]([N:21]([CH3:23])[CH3:22])([CH3:20])[CH2:18][NH:4][C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([N:12]([CH3:13])[CH3:14])[N:6]=1
Reactant: CN(C)C(C)(C)CCl
Reactant: CC(=O)Nc1nc(C)cc(N(C)C)n1
Agent: Cl
Product: Cc1cc(N(C)C)nc(NCC(C)(C)N(C)C)n1

Procedure:
Following the procedure of Example 1 part A using 2-acetamido-4-methyl-6-dimethylaminopyrimidine and 2-methyl-2-dimethylaminopropyl chloride hydrochloride, there is obtained 2-(2-methyl-2-dimethylaminopropylamino)-4-methyl-6-dimethyl minopyrimidine.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.O[C:17]1[CH:22]=[C:21]([N:23]2[CH:27]=[CH:26][CH:25]=[CH:24]2)[C:20]([CH3:28])=[CH:19][C:18]=1[CH:29]([CH3:33])[C:30]([OH:32])=[O:31]>C(Cl)Cl>[CH3:33][CH:29]1[C:18]2[CH:19]=[C:20]([CH3:28])[C:21]([N:23]3[CH:27]=[CH:26][CH:25]=[CH:24]3)=[CH:22][C:17]=2[O:31][C:30]1=[O:32]
Reactant: Cc1cc(C(C)C(=O)O)c(O)cc1-n1cccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1cc2c(cc1-n1cccc1)OC(=O)C2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.27 g (11 mmoles) of dicyclohexylcarbodiimide in 20 ml of absolute methylene chloride are added at room temperature to a solution of 2.5 g (10 mmoles) of 2-[2-hydroxy-5-methyl-4-(pyrrol-1-yl)-phenyl]-propionic acid in 30 ml of absolute methylene chloride. The reaction mixture is stirred for approximately 30 minutes at room temperature, the precipitate is filtered off and the filtrate is concentrated in a vacuum rotary evaporator. Distillation yields 3,5-dimethyl-6-(pyrrol-1-yl)-benzofuran-2(3H)-one, b.p. 180°/0.005 torr, m.p. 61°-63°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][CH:6]=[C:5]2Cl.O.[NH2:14][NH2:15]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][CH:6]=[C:5]2[NH:14][NH2:15]
Reactant: NN
Reactant: Clc1cnnc2ccc(Br)cc12
Solvent: CCO
Solvent: O
Product: NNc1cnnc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
A solution of Example 34D (2.6 g, 10.6 mmol) in ethanol (70 mL) was treated with hydrazine monohydrate (3 mL, 90% solution), stirred at room temperature for 3 days, and filtered. The solid washed with water (50 mL) and diethyl ether (50 mL) and dried under vacuum to provide the desired product (2.5 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[Cl:11].[Br-:13].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.CO>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([Br:13])=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[Cl:11]
Reactant: [Br-]
Reactant: COC(=O)c1cc(N)ccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1c(Cl)ccc(N)c1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28 %

Procedure:
To a solution of 5-amino-2-chloro-benzoic acid methyl ester (6.76 g, 36.4 mmol) in dichloromethane (100 mL) and methanol (50 mL) was added tetra-n-butylammonium tribromide (17.7 g, 36.4 mmol). The mixture was stirred at 25° C. for 90 minutes. Sodium thiosulfate (10% aqueous solution) was added and the mixture was extracted with dichloromethane. The combined extracts were washed with water, dried (Na2SO4), filtered, and concentrated to dryness under reduced pressure. The crude material was purified by flash column chromatography (hexane/acetone 8:2). Fractions with the desired product were concentrated to small volume. The resulting suspension was allowed to stand for two hours and was then filtered to obtain 5-amino-6-bromo-2-chloro-benzoic acid methyl ester as a white solid (2.7 g, 28%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]1[C:24](=[O:25])[CH2:23][CH2:22][CH:21]1[CH3:26].[BH4-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]1[CH:21]([CH3:26])[CH2:22][CH2:23][CH:24]1[OH:25]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2C(=O)CCC2C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2C(C)CCC2O)c1
Reaction time: 1 h

Procedure:
A 100 mL round bottom flask was charged with 66.56C (mixture of diastereomers) (0.59 g, 1.7 mmol) and 1:1 THF/MeOH (15 mL). To the solution was added sodium borohydride (0.063 g, 1.7 mmol) in one portion at room temperature. The mixture was stirred for 1 hour, quenched with 1 N HCl, and extracted with ether. The combined organic layers were dried (MgSO4) and concentrated to afford 66.56D (mixture of diastereomers) as a colorless oil. The product thus obtained was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=O)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C([O:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:26]=1[F:32])C.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([C:24]([OH:33])=[O:23])=[C:26]([F:32])[CH:27]=2)=[O:17])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N)cc1F
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2cccc(Cl)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(=O)O)c(F)c1)c1cccc(NS(=O)(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
A solution of 3-(3-chloro-benzenesulfonylamino)-benzoic acid (31.1 mg, 0.10 mmol) in DMF (0.5 ml) was added to 4-amino-2-fluoro-benzoic acid ethyl ester (20.1 mg, 0.11 mmol). Diisopropyl-ethyl-amine (0.035 ml) was added, followed by a solution of HATU (57.0 mg, 0.15 mmol) in DMF (0.5 ml). The mixture was shaken at room temperature overnight, then diluted with ethyl acetate (4.0 ml) and water (2.0 ml). The organic phase was separated and evaporated. The residue was dissolved in ethanol (0.60 ml) and treated with 3N KOH (0.40 ml). The mixture was shaken at room temperature overnight, then acidified to pH 2 with 3N HCl. Purification by preparative HPLC (ZORBAX Eclipse XDB-C18, 21.2×50 mm, 5 μm, gradient acetonitrile/water+0.1% formic acid) yielded the title compound (7.0 mg, 15%) as a white solid, MS (ISP): m/e=447.0 (M−H).