Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4](C(OCC)=O)[CH:3]=1.[CH3:12][Mg]Br.C([O:17][CH2:18][CH3:19])C>C1COCC1>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:18]([OH:17])([CH3:19])[CH3:12])[CH:3]=1
Reactant: C[Mg]Br
Reactant: CCOCC
Reactant: CCOC(=O)c1csc(Br)c1
Solvent: C1CCOC1
Product: CC(C)(O)c1csc(Br)c1
Reaction time: 0.33 h
Yield: 64 %

Procedure:
To a stirred and cooled (0° C.) solution of ethyl 5-bromothiophene-3-carboxylate (13.30 g, 56.57 mmol) in THF (100 mL) was added a solution of methylmagnesium bromide in diethyl ether [3.0 M] (55.0 mL, 165 mmol), dropwise over 20 minutes. After 2 hours, the reaction solution was concentrated. The residue was taken up in aqueous NH4Cl (200 mL) and extracted with ethyl acetate (2×100 mL). The combined extracts were dried (Na2SO4) and concentrated. The resulting amber oil was purified by flash chromatography using a hexane/ethyl acetate gradient to afford 2-(5-bromothiophen-3-yl)propan-2-ol as a pale amber oil (8.05 g, 64%).
Reaction SMILES: [H-].[Na+].[NH:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[NH:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Br[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1>C1COCC1>[CH3:16][C:15]([O:14][C:12]([N:3]([CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[NH:4][C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])=[O:13])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.7 %

Procedure:
NaH (362 mg, 9.04 mmol) was added to a stirred solution of Di-Tert-Butyl Hydrazodicarboxylate (2 g, 8.61 mmol) in anhydrous THF (50 ml). The reaction was stirred at ambient temperature for 10 minutes then treated with a solution of Methy 4-(Bromomethyl)Benzoate (1.98 g, 8.61 mmol) in anhydrous THF (20 ml). The reaction was stirred at ambient temperature for 4 hours. The reaction was partitioned between ether (˜100 ml) and water (˜100 ml). The layers were separated and the aqueous layer was re-extracted with ether (˜50 ml). The ether layers were combined, washed with brine (˜50 ml), dried (MgSO4), filtered and evaporated to yield the title compound (3.3 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:16](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.O>[CH3:16][O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)c1c(O)cnc2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: O
Product: COC(=O)c1c(OC)cnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3-hydroxycinchoninate, (J. Org. Chem. 1953, 18, 552) (1.53 g, 7.54 mmol), potassium carbonate (1.15 g, 8.29 mmol) in acetone (11 ml) was treated with methyl iodide (470 uL, 7.54 mmol) was stirred at RT under nitrogen overnight. The mixture diluted with water and extracted into DCM and washed with satd. sodium thiosulfate solution. The organics were dried over Na2SO4 and concentrated. Material purified by SGC (Combi flash, 10-50% EtOAc-hexanes over 40 minutes) gave methyl 3-methoxycinchoninate. 1H NMR (CDCl3) δ 8.85 (s, 1H), 8.07 (d, 1H), 7.72 (d, 1H), 7.61 (m, 2H), 4.08 (s, 3H), 4.03 (s, 1H). MS (ESI+) for m/z 218 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:44][C:45]([C:47]1[N:48]([CH3:53])[CH:49]=[C:50]([NH2:52])[CH:51]=1)=[O:46]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:52][C:50]3[CH:51]=[C:47]([C:45]([OH:46])=[O:44])[N:48]([CH3:53])[CH:49]=3)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)O)cc2)cc1
Reactant: COC(=O)c1cc(N)cn1C
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)Nc3cc(C(=O)O)n(C)c3)cc2)cc1

Procedure:
The product from Example 233 and 4-amino-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ11.89-12.33 (br.s, 1 H), 9.81 (s, 1 H), 8.94 (s, 1 H), 7.24 (m, 8 H), 6.98 (m, 7 H), 6.82 (d, 2 H), 6.65 (d, 1 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.97 (t, 2 H), 3.79 (s, 3 H), 2.91 (s, 3 H), 2.38 (m, 5 H), 1.99 (m, 2 H); MS (ESI+) m/z 697 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[S:10])=[CH:4][CH:3]=1.[Br:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29].C(N(CC)CC)C>C(Cl)Cl>[Br:24][CH2:25][CH2:26][CH2:27][C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:14]=[CH:15][C:16]([C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:17][CH:18]=2)=[S:10])=[CH:4][CH:3]=1)=[O:29]
Reactant: O=C(Cl)CCCBr
Reactant: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(N)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(NC(=O)CCCBr)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.5 %

Procedure:
Thiourea 4 (200 mg, 0.61 mmol, 1 equiv.) was stirred in CH2Cl2 (10 mL) under N2 atmosphere. 4-Bromobutyryl chloride (169 mg, 0.92 mmol, 1.5 equiv.) was added, followed by triethylamine (85 μL, 0.61 mmol, 1 equiv.). The orange solution was stirred at rt for 1.5 h and diluted with CH2Cl2 (10 mL). The organic solution was washed with 1 M aqueous hydrochloric acid (1×10 mL), 10% aqueous sodium hydroxide (1×50 mL), and saturated brine (1×10 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The resulting pale yellow foam was purified by flash chromatography on silica (50% ethyl acetate/petroleum ether) to give 4-bromo-N-{4-[3-(4-tert-butyl-benzoyl)-thioureido]-phenyl}-butyramide (138 mg, 48%) as a yellow oil.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([O:21][CH3:22])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([O:21][CH3:22])[CH:12]=2)[C:8]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc([C@@H](CC2CCCC2)C(=O)O)ccc1S(C)(=O)=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
A solution of (R)-3-cyclopentyl-2-(4-methanesulfonyl-3-methoxy-phenyl)-propionic acid (60 mg, 0.18 mmol) was dissolved in methylene chloride (5 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 110 μL, 0.21 mmol) which produced gas evolution and it was then warmed to 25° C. and stirred for 1 h. After this time, the reaction was concentrated in vacuo to about 2 mL. In a separate round bottom flask was placed 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 31 mg, 0.20 mmol), 2,6-lutidine (32 μL, 0.28 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise the above solution acid chloride. The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 70% ethyl acetate/hexanes to 85% ethyl acetate/hexanes) afforded (R)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methanesulfonyl-3-methoxy-phenyl)-propionamide (61 mg, 73%) as a white foam: [α]28589=−26.0° (c=0.10, methanol); ES-HRMS m/e calcd for C23H33N3O5S (M+H)+ 464.2214, observed 464.2211; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.10 (m, 2H, CH2), 1.35-1.80 (m, 8H, 4×CH2), 2.11 (m, 1H, CH), 3.20 (s, 3H, SO2CH3), 3.86 (s, 2H, NCH2), 3.90 (br, 1H, ArCHCO), 3.95 (s, 3H, OCH3), 4.65 (s, 1H, OH), 6.46 (s, 1H, Ar), 7.15 (d, Jo=8.2 Hz, 1H, Ar), 7.27 (s, 1H, Ar), 7.50 (s, 1H, Ar), 7.74 (d, Jo=8.2 Hz, 1H, Ar), 10.73 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:5]([NH2:16])=[C:4]([F:17])[CH:3]=1.CC(C)([O-])C.[K+].O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([F:17])[CH:3]=1)[NH:16][C:9]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[CH:8]2
Reactant: Nc1c(F)cc(Cl)cc1C#Cc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1cc(Cl)cc2cc(-c3cccnc3)[nH]c12
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-2-fluoro-6-pyridin-3-ylethynyl-phenylamine (3.1 g, 12.57 mmol) in NMP (40 mL) is added potassium tert-butoxide (2.1 g, 18.85 mmol) and the mixture is stirred overnight. Water (1 mL) is added to quench the reaction and the mixture is poured into water (100 mL). The mixture is extracted with diethyl ether five times. The combined organic phase is partially concentrated, resulting in precipitation of the product, which is filtered through a glass sintered funnel and washed with dichloromethane to afford 5-chloro-7-fluoro-2-pyridin-3-yl-1H-indole as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.10-7.15 (m, 2H), 7.47-7.53 (m, 2H), 8.31 (dt, J=8.2, 1.9, 1.8 Hz, 1H), 8.55 (d, J=4.3 Hz, 1H), 9.16 (s, 1H), 12.23 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:19]=[CH:18][C:17]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH2:35][OH:36]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:19]=[CH:18][C:17]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:34][CH2:35][OH:36])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: OCCBr
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C4CCN(CCO)CC4)cn3)nc2n1C1CCCC1
Yield: 51.6 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (63 mg, 0.15 mmol) and 2-bromo ethanol (90 mg, 0.72 mmol) to give 7-cyclopentyl-2-[1′-(2-hydroxy-ethyl)-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (37 mg, 53%). MS (ESI) m/z 478.3 (M+H)+
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([C:14]3[CH:19]=[CH:18][N:17]4[C:20]([C:23]5[CH:24]=[C:25]([CH:29]=[C:30]([N+:32]([O-])=O)[CH:31]=5)[C:26]([NH2:28])=[O:27])=[CH:21][N:22]=[C:16]4[CH:15]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl>CCO.O.CO.[OH-].[OH-].[Pd+2]>[NH3:1].[CH3:3][OH:4].[NH2:32][C:30]1[CH:29]=[C:25]([CH:24]=[C:23]([C:20]2[N:17]3[CH:18]=[CH:19][C:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)[CH:9]=4)=[CH:15][C:16]3=[N:22][CH:21]=2)[CH:31]=1)[C:26]([NH2:28])=[O:27]
Reactant: NC(=O)c1cc(-c2cnc3cc(-c4cccc(CN5CCOCC5)c4)ccn23)cc([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCO
Product: N
Product: NC(=O)c1cc(N)cc(-c2cnc3cc(-c4cccc(CN5CCOCC5)c4)ccn23)c1
Temperature: 90 °C
Yield: 142.7 %

Procedure:
A mixture of Pd(OH)2 (30 mg), 3-[7-(3-morpholin-4-ylmethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-5-nitro-benzamide (135 mg), 2N HCl (0.15 ml) and HCO2NH4 (150 mg, 2.4 mmol) in EtOH/H2O (4:1, 5 ml) was stirred and heated at 90° C. under N2 for 90 minutes. After cooling to RT the mixture was diluted with MeOH and loaded on to a SCX cartridge. This was washed with MeOH, then 2M NH3-MeOH, to give the title compound (90 mg, gum). MS: [M+H]+ 428.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10]([CH3:29])[CH2:11][CH2:12][N:13]([C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[OH:9][C:10]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:29])[CH2:11][CH2:12][N:13]([C@H:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:22])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(=O)CCN(C(=O)OC(C)(C)C)[C@@H](C)c1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N(CCC(C)(O)c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 14 h

Procedure:
A solution of phenylmagnesium bromide (1.0 M in THF, 1.0 mL) was added dropwise to a solution of (S)-tert-butyl 3-oxobutyl(1-phenylethyl)carbamate (0.0421 g, 0.144 mmol in THF (4 mL) under N2 at rt. After the solution was stirred for 14 h, the reaction was quenched with 10% aq Na2CO3 (0.5 mL) and diluted with CH2Cl2. The organic layer was dried over Na2SO4. After the solvents were evaporated, the crude product was directly used in the next step without further purification.
Reaction SMILES: C([O:4][CH:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:6]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=O)[CH:17]=2)[N:8]([CH3:24])[N:7]=1)(=O)C.[CH2:31]([NH2:37])[C:32]1[O:36][CH:35]=[CH:34][CH:33]=1.[BH4-].[Na+].O>C(O)C>[O:36]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:31][NH:37][CH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]1[N:8]([CH3:24])[N:7]=[C:6]([CH:5]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[OH:4])[N:10]=1
Reactant: NCc1ccco1
Reactant: CC(=O)OC(c1ccccc1)c1nc(NCCCOc2cccc(C=O)c2)n(C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1nc(C(O)c2ccccc2)nc1NCCCOc1cccc(CNCc2ccco2)c1
Reaction time: 16 h

Procedure:
A solution of 5-[[3-(3-formylphenoxy)propyl]amino]-1-methyl-α-phenyl-1H-1,2,4-triazole-3-methanol acetate (ester) (1.0 g) and furfurylamine (5 ml) in ethanol (30 ml) was stirred at 21° for 1.5 h before a suspension of sodium borohydride (1.3 g) in ethanol (10 ml) was added and stirring was continued for a further 16 h at 21°. Water (20 ml) was added, the mixture concentrated to remove ethanol and the aqueous residue extracted with 4-methylpentan-2-one. The extract was dried and evaporated to give an oil. Excess furfurylamine was removed in vacuo and the residue was dissolved in 2N hydrochloric acid, the acidic layer washed with ethyl acetate, basified (pH 9) with sodium carbonate, and extracted with 4-methylpentan-2-one. The extract was washed with water, dried and evaporated to give a brown gum (0.65 g) which was chromatographed on silica (Merck No. 7729) using System B as eluent to give the title compound (0.5 g) as a pale orange gum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH:17]([C:19](O)=[O:20])[CH3:18])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH:17]([C:19](=[O:20])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:18])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1ccccc1
Reactant: CC(C(=O)O)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: CC(C(=O)Nc1ccccc1)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 41 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-(1-carboxyethyl)-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (more polar) (100 mg, 0.28 mmol) and aniline (28 μL, 0.31 mmol) to give 50 mg of the title compound (41%): mp>300° C.; 1H NMR (270 MHz, DMSO-d6) δ11.92 (s, 1H), 9.46 (s, 1H), 7.32 (d, 2H, J=8 Hz), 7.23 (t, 1H, J=8 Hz), 7.21 (s, 1H), 7.19 (s, 1H), 6.99 (t, 1H, J=8 Hz), 5.13 (bd, 1H, J=9 Hz), 2.73~2.99 (m, 2H), 2.59 (qd, 1H, J=9, 7 Hz), 2.28 (dm, 1H, J=13.5 Hz), 1.72~1.92 (m, 1H), 1.13 (d, 3H, J=7 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:9][CH2:8][CH2:7][CH:6]2[N:3]1[C:4](=[O:13])[CH:5]2[N:10]=[N+]=[N-].[C:15]([O:18][CH2:19][CH3:20])(=[O:17])C>[Pd]>[CH3:1][C:2]1([CH3:14])[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:13])[C@@H:5]2[NH:10][C:15]([O:18][CH2:19][C:20]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:17]
Reactant: CCOC(C)=O
Reactant: CC1(C)OCCC2C(N=[N+]=[N-])C(=O)N21
Agent: [Pd]
Product: CC1(C)OCC[C@@H]2[C@@H](NC(=O)OCc3ccccc3)C(=O)N21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In 20 ml of ethyl acetate is dissolved 940 mg of 2,2-dimethyl-7-azido-1-aza-3-oxabicyclo[4,2,0]octan-8-one (1:4 cis-trans mixture) and catalytic reduction is carried out using 300 mg of 10% palladium-on-carbon (wet). The catalyst is then filtered off and washed with ethyl acetate. The filtrate and washings are combined and concentrated to about 20 ml. Then, 4 ml of propylene oxide and 0.9 ml of carbobenzoxy chloride are added and the mixture is stirred at room temperature for 1.5 hours and concentrated. The residue is subjected to column chromatography using silica gel (60 g), elution being carried out with chloroform-ethyl acetate (6:4) to give 388 mg of cis-(2,2-dimethyl-7-benzyloxyformamido-1-aza-3-oxabicyclo[4,2,0]octan-8-one) as the first product.
Reaction SMILES: [H-].[Na+].[P:3]([O-:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].Cl[CH:12]([F:14])[F:13]>C1COCC1.CCCCCC>[F:13][CH:12]([P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])[F:14]
Reactant: FC(F)Cl
Reactant: CCOP([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(F)F
Yield: 16.2 %

Procedure:
A sample of 6.82 g (171 mmol) of 60% NaH in mineral oil was washed twice with 30 ml of petroleum ether and was suspended in 130 ml of THF under argon. A solution of 22 ml (171 mmol) of diethyl phosphite was added dropwise over 45 minutes and the exotherm was controlled with a water bath. After stirring for an additional hour, 42 g (490 mmol) of chlorodifluoromethane was bubbled through the solution over 4.5 hours, while the internal temperature was maintained between 25° and 35° C. with a cool water bath. The white suspension was allowed to stir overnight, was diluted with hexane and filtered through Celite. The filtrate was evaporated to provide 27.6 g of a crude, pale yellow liquid. The crude material was fractionally distilled at 10 mm to provide 5.21 g (16%) of impure title compound (b.p. 82°-84° C.), followed by 20.66 g (64%) of title compound (b.p. 84°-86° C.) as a colorless liquid which contains a trace of impurity.
Reaction SMILES: [OH:1][CH:2]([CH:6]1[O:11][CH2:10][CH2:9][N:8]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:7]1)[C:3]([OH:5])=O.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[NH:29][O:30][C:31](=[O:33])[N:32]=2)=[CH:24][CH:23]=1.IC1C=C(C=CC=1)C(O)=O.FC1(F)CCNCC1>>[OH:1][CH:2]([CH:6]1[O:11][CH2:10][CH2:9][N:8]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:7]1)[C:3]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[NH:32][C:31](=[O:33])[O:30][N:29]=2)=[CH:26][CH:27]=1)=[O:5]
Reactant: Cc1ccc(C(=O)N2CCOC(C(O)C(=O)O)C2)cc1
Reactant: Nc1ccc(-c2nc(=O)o[nH]2)cc1
Agent: FC1(F)CCNCC1
Agent: O=C(O)c1cccc(I)c1
Product: Cc1ccc(C(=O)N2CCOC(C(O)C(=O)Nc3ccc(-c4noc(=O)[nH]4)cc3)C2)cc1
Yield: 64.6 %

Procedure:
According to the Step 77-1 in synthetic method for EXAMPLE 77, compound 115-5 (74 mg) and 3-(4-aminophenyl)-1,2,4-oxadiazol-5(2H)-one (70.4 mg) were used instead of 3-iodobenzoic acid and 4,4-difluoropiperidine to obtain compound 115-6 (75.1 mg) as a pale yellow amorphous solid.
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[CH:7][C:6]=1[OH:13]>CN(C=O)C.O>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:1]#[N:2])=[CH:7][C:6]=1[OH:13]
Reactant: Oc1cc(CBr)ccc1Br
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(Br)c(O)c1
Temperature: 60 °C

Procedure:
A suspension of KCN (16.0 g, 238.3 mmol) in DMF (100 mL) was heated at 60° C. for 30 min. The slurry was cooled to room temperature and treated with a solution of 2-bromo-5-bromomethylphenol 72 (4.16 g, 15.7 mmol) in DMF (50 mL). The resultant mixture stirred at room temperature for 23 h, and then was diluted with water and extracted with ethyl acetate (5×). The organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (hexanes:EtOAc, 3:1) to afford impure (4-bromo-3-hydroxy-phenyl)acetonitrile 73. To a solution of KOH (26.5 mg) in MeOH (1.5 mL) was added (4-bromo-3-hydroxy-phenyl)-acetonitrile 73 (100.0 mg), the resulting mixture was stirred at room temperature for 10 min then conentrated in vacuo. DMSO (3 mL) and methanesulfonic acid 2-(1-methyl-pyrrolidin-2-yl)-ethyl ester, (prepared from 2-(1-methyl-pyrrolidin-2-yl)-ethanol, methane sulfonyl chloride in presence of triethylamine) were added. The reaction mixture was stirred at room temperature overnight. DCM (80 mL) was added and the organics washed with saturated aqueous NaHCO3 solution (20 mL) and brine (20 mL). The organic layer was dried with MgSO4. The residue was purified by silica gel column chromatography (eluent: DCM/MeOH, 4/1) to give 74. MS (EI) m/z (M+H+) 324.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOC(C)=O>[CH2:10]([O:17][C:18](=[O:19])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cc(N)ccc1O
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)OCc2ccccc2)ccc1O

Procedure:
4-Amino-2-methyl-phenol (717 mg, 5.8 mmol) and benzyloxycarbonyl chloride (1.09 g, 6.4 mmol) are stirred in a suspension of AcOEt/concentrated Na2CO3 solution (50 mL/50 mL) for 7 h. The organic phase is concentrated under reduced pressure and flash chromatographed (silica gel, 3.8×66 cm, AcOEt/hexane=1:3): M+H=257.9; HPLC (System 1): 5.43 min.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[N:15][C:16]([C:20]4[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=4)=[CH:17][CH:18]=3)[N:13]=[C:12]([CH2:30][O:31][CH3:32])[C:11]=2[C:33]([O:35]C)=[O:34])=[CH:5][CH:4]=1.O[Li].O.C1COCC1.O>C(O)(=O)C>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[N:15][C:16]([C:20]4[C:25]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=4)=[CH:17][CH:18]=3)[N:13]=[C:12]([CH2:30][O:31][CH3:32])[C:11]=2[C:33]([OH:35])=[O:34])=[CH:5][CH:4]=1
Reactant: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(Nc2ccc(C(F)(F)F)cc2)c1C(=O)OC
Agent: [Li]O
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(Nc2ccc(C(F)(F)F)cc2)c1C(=O)O

Procedure:
Stir a solution of methyl 4-[(4-trifluoromethylphenyl)amino]-7-(3-trifluoromethylpyridin-2-yl)-2-methoxymethyl-[1,8]naphthyridine-3-carboxylate (114 mg, 0.212 mmol), LiOH.H2O (45.0 mg, 1.06 mmol), THF (2 mL) and water (0.1 mL) for 18 hours at room temperature. Add water (20 mL) and acidify with acetic acid. Extract the solution with EtOAc (3×25 mL). Wash the combined organic extracts with brine and dry over Na2SO4. Remove the solvent under reduced pressure to yield the title compound. MS 523.18 (M+1). 1H NMR δ (CDCl3) 11.50 (1H, br s), 8.89 (1H, s), 8.19 (2H, d), 7.88 (1H, dd), 7.67 (2H, m), 7.59 (1H, dd), 7.51 (2H, d), 7.22 (1H, br s), 5.30 (2H, s), 3.65 (3H, s).