Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[F:24])[N:14]=[C:13]3[O:25][N:26]=[C:27]([CH3:28])[C:12]=23)=[CH:8][CH:7]=[N:6][CH:5]=1.[OH-].[Na+]>CO>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]([F:24])=[C:17]([C:15]2[N:14]=[C:13]3[O:25][N:26]=[C:27]([CH3:28])[C:12]3=[C:11]([NH:10][C:9]3[C:4]([C:3]([OH:29])=[O:2])=[CH:5][N:6]=[CH:7][CH:8]=3)[N:16]=2)[CH:22]=1
Reactant: COC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2onc(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1noc2nc(-c3cc(Cl)ccc3F)nc(Nc3ccncc3C(=O)O)c12
Temperature: 70 °C
Yield: 27 %

Procedure:
4-[6-(5-Chloro-2-fluoro-phenyl)-3-methyl-isoxazolo[5,4-d]pyrimidin-4-ylamino]-nicotinic acid methyl ester (525 mg) was suspended in methanol (4 ml), 1M sodium hydroxide solution (4 ml) was added, and then heated to 70° C. for 30 min. The methanol was removed under vacuum and the solution was acidified to pH 4 with 6 M hydrochloric acid. The solid was filtered, washed with water and dried in the oven to give 137 mg product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl.Cl[CH2:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH2:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1
Reactant: Cn1ccc(CCl)n1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: Cn1ccc(COc2ccc([N+](=O)[O-])c(F)c2)n1
Temperature: 25 °C
Yield: 90.8 %

Procedure:
A solution of 3-fluoro-4-nitrophenol (50.0 g, 0.31 mol), 3-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride (52.1 g, 0.31 mol), powdered potassium carbonate (53.3 g, 0.38 mol), potassium iodide (52.8 g, 0.32 mol), and acetonitrile (900 mL) was stirred at 60° Celsius for 8 h. The reaction was cooled to RT and concentrated to dryness. The residue was partitioned between H2O (500 mL), sat. NaHCO3 (200 mL), and ethyl acetate (900 mL). The organic layer was separated, dried with MgSO4, filtered and concentrated to dryness. The resulting residue was recrystallized from ethanol (250 mL) and H2O (250 mL). The solid was collected by filtration and rinsed with a H2O/ethanol (2:1, 225 mL) followed by hexanes (250 mL) yielding the title compound as a tan solid (70.7 g, 90.2%). MS (ESI): mass calcd. for C11H10FN3O3, 251.1; m/z found, 252.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.13-8.03 (m, 1H), 7.42-7.32 (d, J=2.2, 1H), 6.93-6.87 (m, 1H), 6.87-6.84 (d, J=1.6, 1H), 6.36-6.29 (d, J=2.2, 1H), 5.18-5.10 (s, 2H), 4.00-3.87 (s, 3H).
Reaction SMILES: O=[C:2]([CH3:21])[CH2:3][C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:13]=[C:12]1[CH3:20])=[O:5].[NH3:22]>C(O)C>[NH2:22][C:2]([CH3:21])=[CH:3][C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:13]=[C:12]1[CH3:20])=[O:5]
Reactant: CC(=O)CC(=O)OCCCCn1c(C)nc2cnccc21
Reactant: N
Solvent: CCO
Product: CC(N)=CC(=O)OCCCCn1c(C)nc2cnccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(2-Methylimidazo[4,5-c]pyrid-1-yl)butyl 3-oxobutanoate (1.52 g) (see Preparation 6) was dissolved in ethanol (50 ml) containing dry silica gel (2.5 g) and gaseous ammonia was then bubbled through the mixture for 20 minutes. The mixture was stirred at room temperature for a further 11/2 hours and then filtered and evaporated to dryness leaving the crude title compound (1.54 g) which was used directly.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[CH:13]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCCC1ON(C(=O)OCc2ccccc2)CC1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CN(C(=O)OCc2ccccc2)OC1CCCCO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 104.2 %

Procedure:
To a solution of 4-(N-benzyloxycarbonyl-4-oxo-isoxazol-5-yl)butyric acid (327 mg, 1.06 mmol), from Step b, in 10 mL of THF at 0° C. was added 1.1 mL (2.13 mmol) of a 2M solution of borane-methyl sulfide complex in THF. The reaction mixture was stirred at ambient temperature for 1.5 hours, diluted with ethyl acetate and extracted with water. The aqueous layer was acidified with potassium hydrogen sulfate and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 324 mg of the title compound. MS (DCl/NH3) m/e 294 (M+H)+, 311 (M+NH4)+.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]([NH2:16])([C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:9])[CH:5]([CH3:7])[CH3:6].C1COCC1.[Li+].[OH-]>CO.O>[CH3:6][CH:5]([CH3:7])[C:4]([NH2:16])([C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:9])[C:3]([OH:17])=[O:2]
Reactant: COC(=O)C(N)(C(=O)c1cccnc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(N)(C(=O)O)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a solution of 3-methyl-2-[pyridine-3-carbonyl]-amino-butyric acid methyl ester (1.5 g, 6.3 mmol), in methanol (15 mL), THF (9 mL) was added LiOH (1.3 g, 31.7 mmol) dissolved in water (3 mL). The mixture was allowed to stir at room temperature (25° C.) over 2 h. Solvent was evaporated from reaction mixture, dissolved in water (15 mL), acidified with 1.5N HCl extracted with ethyl acetate (150 mL), dried over sodium sulphate and concentrated to obtain product as yellow colour solid (1.38 g, 99%).
Reaction SMILES: [CH3:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[C:16]3[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH2:27][C:28]#[CH:29])=[O:24])[CH2:19][C:17]=3[S:18][C:5]=2[NH:4][C:3]1=O.C(=O)([O-])O.[Na+].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:37].ClCCl>C(COC)OC.CO>[CH3:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[C:16]3[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH2:27][C:28]#[CH:29])=[O:24])[CH2:19][C:17]=3[S:18][C:5]=2[NH:4][C:3]1=[S:37]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: C#CCCOC(=O)N1CCc2c(sc3c2C(c2ccccc2Cl)=NC(C)C(=O)N3)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: COCCOC
Product: C#CCCOC(=O)N1CCc2c(sc3c2C(c2ccccc2Cl)=NC(C)C(=S)N3)C1
Temperature: 80 °C
Yield: 68.9 %

Procedure:
0.21 g of 3-methyl-5-(2-chlorophenyl)-8-(3-butynyloxycarbonyl)-6,7,8,9-tetrahydro-1H,3H-pyrido[4',3':4,5]thieno[3,2-f][1,4]diazepin-2-one was dissolved in 10 ml of dimethoxyethane, to which 0.11 g of sodium hydrogencarbonate and 0.22 g of phosphorus pentasulfide were added, followed by heating at 80° C. for 3 hours. After completion of the reaction, dichloromethane and methanol were added, and the mixture was filtered, followed by addition of silica gel to the resultant filtrate and evaporating the solvent to dryness. Silica gel column chromatography (elution solvent: dichloromethane:methanol=99:1) was used for purification, thereby obtaining 0.15 g of the intended compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[N:10][OH:11])[NH2:9])=[CH:6][N:5]=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18](Cl)=O>>[NH2:1][C:2]1[C:7]([C:8]2[N:9]=[C:18]([C:14]3[S:15][CH:16]=[CH:17][C:13]=3[Cl:12])[O:11][N:10]=2)=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: NC(=NO)c1cncnc1N
Reactant: O=C(Cl)c1sccc1Cl
Product: Nc1ncncc1-c1noc(-c2sccc2Cl)n1

Procedure:
The title compound was prepared from 4-amino-pyrimidine-5-amidoxime (50 mg, 0.33 mmol) and 3-chloro-thiophene-2-carbonyl chloride (59 mg, 0.33 mmol), similar to Example 16, and yielded 25 mg (27%) of yellow solid. 1H NMR (CDCl3): 9.18 (s, 1H), 8.69 (s, 1H), 7.66 (d, J=5.22 Hz, 1H), 7.16 (d, J=5.22 Hz, 1H), 5.85 (s, 1H), 3.51 (s, 1H).
Reaction SMILES: CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:20]1([NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26].[Br:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](O)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[Br:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]1[NH:27][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1ccccc1Br
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: Brc1ccccc1-c1nc2ccccc2[nH]1
Temperature: 0 °C
Yield: 56.7 %

Procedure:
To a flask were added 80 g methanesulfonic acid and 8 g phosphorus pentoxide and the mixture was heated to 60 C under nitrogen until the solids had completely dissolved. To this solution was added 2.7 g 1,2-phenylene diamine and 5.0 g 2-bromobenzoic acid and the mixture was heated to 100 C for 30 minutes. The mixture was poured onto 300 ml ice water and basified with the addition of small portions of sodium carbonate. Following filtration of the solid and washing with water, the crude product was dissolved in 85 ml hot ethanol, filtered and 9 ml of water was added. After cooling to 5 C, the product was filtered and washed with 50% ethanol and dried, giving 3.85 g off-white solid.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:30]C)=[C:13]([NH:15][S:16]([C:19]3[S:20][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH:14]=2)[CH2:3]1.B(Br)(Br)Br.O.C(=O)(O)[O-].[Na+]>ClCCl.CO>[CH3:8][C@H:6]1[NH:7][C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:10]=[CH:11][C:12]([OH:30])=[C:13]([NH:15][S:16]([C:19]3[S:20][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH:14]=2)[CH2:5]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccccn2)s1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(O)c(NS(=O)(=O)c3ccc(-c4ccccn4)s3)c2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[5-(cis-3,5-Dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-5-(2-pyridinyl)-2-thiophenesulfonamide (E13) (277 mg, 0.66 mmol) was dissolved in dichloromethane (5 ml) and treated with 1M boron tribromide in dichloromethane (1.8 ml, 1.8 mol) for 4.5 hours. Further 1M boron tribromide in dichloromethane (3 ml, 3 mmol) was added and the mixture stirred at room temperature overnight. Water and methanol were cautiously added and the solution basified to pH9 with saturated aqueous sodium bicarbonate solution. The precipitated solids were filtered, washed with ether and purified by mass directed autoprep HPLC to afford the title compound (E120). MS (ES+) m/e 445 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27](O)=O)=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>O1CCCC1>[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27]3[O:13][C:12](=[O:14])[C:11]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][N:9]=5)[CH:4]=[CH:3][C:2]=4[N:1]=3)=[CH:25][C:24]([C:30]([F:33])([F:31])[F:32])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Nc1ccc2cccnc2c1C(=O)O
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ccc3cccnc3c12
Temperature: 0 °C
Reaction time: 48 h
Yield: 15.2 %

Procedure:
To a suspension of 500 mg (2.66 mmol) of 7-amino-quinoline-8-carboxylic acid in 20 mL of anhydrous tetrahydrofuran at 10° C., is added 775 mg (2.66 mmol) of 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid followed by 1.07 mL (13.28 mmol) of pyridine. Then the suspension is cooled to 0° C. and 830 μL (10.63 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at ambient temperature for 48 hours. Then the solvent is evaporated and the residue is precipitated with a minimum of water. The filtration gave 180 mg of product after drying on high vacuum pump. The filtrate is evaporated and the residue obtained is purified by flash chromatography to afford 100 mg more of product as a solid. The overall yield is 24%; LC/MS:444/446 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20](=[O:31])[C@H:21]([C:27]([CH3:30])([CH3:29])[CH3:28])[NH:22][C:23]([O:25][CH3:26])=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][C:42]([NH:44][C@@H:45]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:46](O)=[O:47])=[O:43].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:40][O:41][C:42](=[O:43])[NH:44][C@@H:45]([C:49]([CH3:51])([CH3:50])[CH3:52])[C:46](=[O:47])[NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=1)[NH:19][C:20](=[O:31])[C@H:21]([C:27]([CH3:30])([CH3:29])[CH3:28])[NH:22][C:23](=[O:24])[O:25][CH3:26]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2cccnc2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2cccnc2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.8 %

Procedure:
To a solution containing the product from Example 148E (0.17 mmol) in tetrahydrofuran (1.7 mL) were added the product from Example 1F (0.036 g, 0.190 mmol), DEPBT (0.077 g, 0.258 mmol), and N,N-diisopropylethylamine (0.15 mL, 0.861 mmol) and the mixture was stirred at room temperature for 18 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic was washed with additional 10% Na2CO3 solution and then brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on reverse phase HPLC on C18 column eluting with a gradient starting with water and ending with methanol to give the product (0.044 g, 37% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (s, 9 H), 0.82 (s, 9 H), 1.42-1.59 (m, 2 H), 2.67-2.79 (m, 3 H), 3.47 (s, 3 H), 3.59-3.67 (m, 1 H), 3.81 (d, J=9.6 Hz, 1 H), 3.91 (d, J=9.6 Hz, 1 H), 4.02-4.21 (m, 2 H), 4.87 (d, J=5.2 Hz, 1 H), 6.65 (d, J=9.6 Hz, 1 H), 6.80 (d, J=9.9 Hz, 1 H), 7.12-7.23 (m, 8 H), 7.45-7.55 (m, 4 H), 7.80 (d, J=8.5 Hz, 1 H), 8.01 (d, J=8.1 Hz, 1 H), 8.54 (d, J=4.8 Hz, 1 H), 8.83 (d, J=1.8 Hz, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10]COC.Cl[C:15]1[CH:16]=[C:17]([B:21]2C3C=CC(F)=CC=3CO2)[CH:18]=[CH:19][CH:20]=1>>[C:17]1([B:21]2[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[CH2:8][CH2:9][O:10]2)[CH:18]=[CH:19][CH:20]=[CH:15][CH:16]=1
Reactant: Fc1ccc2c(c1)COB2c1cccc(Cl)c1
Reactant: COCOCCc1ccccc1Br
Product: c1ccc(B2OCCc3ccccc32)cc1

Procedure:
This compound was synthesized from 22b and 7a in a similar manner to compound 9f: colorless oil; 1H NMR (300 MHz, DMSO-d6) δ (ppm) 2.94 (t, J=5.9 Hz, 2H), 4.21 (t, J=5.9 Hz, 2H), 7.28 (t, J=7.9 Hz, 2H), 7.3-7.5 (m, 4H), 7.66 (d, J=7.0 Hz, 1H), 7.75 (d, J=7.6 Hz, 2H); ESI-MS m/z not observed; HPLC purity 96.0%; Anal (C14H13BO) C. H.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([OH:14])[C:3]=1[C:15](=[O:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].Cl.[C:25](Cl)(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1.O>CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]2[C:3]=1[C:15](=[O:17])[CH:16]=[C:25]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[O:14]2
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(=O)c1c(O)cc(N2CCOCC2)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=c1cc(-c2cccnc2)oc2cc(N3CCOCC3)cc(O)c12
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 12 %

Procedure:
To a suspension of 1-(2,6-dihydroxy-4-morpholin-4-yl-phenyl)-ethanone (86 mg, 0.362 mmol) and K2CO3 (250 mg, 1.81 mmol) in acetone (3 mL) was added nicotinoyl chloride hydrochloride (0.71 mL, 0.399). The reaction vessel was sealed and heated to 85° C. for 24 h. After cooling to room temperature, water (about 2 mL) was added, and the mixture was allowed to stir for about 10 min. The contents were transferred to a separatory funnel containing water (5 mL) and extracted with EtOAc (3×15 mL). The organic layer was dried (MgSO4) and concentrated. The concentrate was purified via Biotage chromatography with gradient elution from 100% hexanes to 100% EtOAc to yield 14 mg (12%) of 5-hydroxy-7-morpholin-4-yl-2-pyridin-3-yl-chromen-4-one. Rf=0.22 (100% EtOAc).
Reaction SMILES: OC(C)(C)CN1C=C[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.NC1[S:60][N:59]=[C:58]([CH3:61])N=1>ClCCl>[CH3:61][C:58]1[N:5]=[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])[S:60][N:59]=1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Reactant: Cc1nsc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1nsc(NC(=O)[C@H](CC(C)C)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
To a solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 64, 67 mg, 0.21 mmol) in dichloromethane (1.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44 mg, 0.23 mmol) and 1-hydroxybenzotriazole (29 mg, 0.22 mmol). The resulting solution was stirred for 5 min before 5-amino-3-methyl-1,2,4-thiadiazole (50 mg, 0.43 mmol) was added and the resulting mixture stirred at 25° C. overnight. The mixture was washed with saturated ammonium chloride (1 mL), evaporated and the crude product purified by HPLC (Gilson semi-prep; Supelcosil ABZ+Plus 12 μM 25 cm×21.2 mm column 20-95% acetonitrile/water gradient) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (3-methyl-[1,2,4]thiadiazol-5-yl)-amide (37 mg, 43%) as a light yellow solid: HR-ES-MS m/z calculated for C19H21ClN4O3S [M+H]+ 421.1096, observed 421.1095; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.4 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 1.35-1.54 (m, 1H), 1.56-1.72 (m, 1H), 1.76-1.93 (m, 1H), 2.44 (s, 3H), 4.28 (d, J=18.4 Hz, 1H), 4.49 (d, J=18.4 Hz, 1H), 4.81 (s, 1H), 5.00 (dd, J=10.6, 4.2 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 13.24 (s, 1H).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Product: CCOC(=O)/C(=N\OCc1ccccc1)C(C)=O

Procedure:
Ethyl (Z)-2-(hydroxyimino)-3-oxobutyrate (2.4 g) was alkylated with benzyl bromide as described in Example 4a, method 1, to give the title compound (2.94 g). (Found: M+, 249.0994. C13H15NO4 requires M 249.1001). νmax (film) 2980, 1740 and 1695 cm-1, δH (CDCl3) 1.28 (3H, t), 2.33 (3H, s), 4.26 (2H, q), 5.23 (2H, s), 7.27 (5H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11](=[N:18][C:19]2[C:28]3[O:27][CH2:26][CH2:25][O:24][C:23]=3[CH:22]=[CH:21][CH:20]=2)[NH:12][C:13]([O:15]CC)=O)[CH:10]=1)=[O:5])[CH3:2].ClCCCl>[Ti](Cl)(Cl)(Cl)Cl.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:12][C:13](=[O:15])[C:20]3[C:19](=[C:28]4[C:23](=[CH:22][CH:21]=3)[O:24][CH2:25][CH2:26][O:27]4)[N:18]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)NC(=Nc1cccc2c1OCCO2)n1cc(C(=O)OCC)cn1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc3c4c(ccc3c(=O)[nH]2)OCCO4)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
Titanium (IV) chloride (1.2 mL, 11 mmol) was carefully added to a solution of 1-[(2,3-dihydro-benzo[1,4]dioxin-5-ylimino)-ethoxycarbonylamino-methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (1.39 g, 3.58 mmol) and DCE (11 mL), and the resulting solution was heated to 110° C. for 2 h. The reaction mixture was cooled to room temperature and ethanol (60 mL) was added. The resulting slurry was stirred at room temperature for 30 min; the precipitate was then collected to yield the titled compound (0.970 g, 78% yield). MS (ESI/Cl): mass calcd. for C16H14N4O6, 342.1; m/z found, 343.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.78 (s, 1H), 8.90 (d, J=0.5 Hz, 1H), 8.31 (s, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 4.48-4.35 (m, 4H), 4.30 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH:18]=O.[NH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1.C([O-])(=O)C.[Na+]>ClC(Cl)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCC=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCN1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 103A (325 mg) and 1,2,3,4-tetrahydroquinoline (160 mg) in dichloroethane (10 mL) was added sodium acetate (310 mg). The mixture was stirred at ambient temperature overnight, diluted with ethyl acetate (200 mL) and washed with 1N NaOH, water, and brine. After drying over sodium sulfate and concentration, the concentrate was loaded on a silica gel cartridge and eluted with 5% ethyl acetate in hexane.
Reaction SMILES: ClC1C=CC(OC)=C(C=1)C(NC[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH2:22][CH3:23])[C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1)=O.CCC(C(O)=O)C1C=CC=CC=1.C=O.[ClH:41]>>[Cl:41][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH2:22][CH3:23])[C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1
Reactant: Cl
Reactant: CCC(C(=O)O)c1ccc(CCNC(=O)c2cc(Cl)ccc2OC)cc1
Agent: C=O
Agent: CCC(C(=O)O)c1ccccc1
Product: CCC(C(=O)O)c1ccc(CCl)cc1

Procedure:
The 2[4-(2-aminoethyl)-phenyl]-butyric acid hydrochloride used as starting material is prepared in the following manner: 2-phenylburyric acid is reacted with paraformaldehyde/hydrochloric acid to give 2-(4-chloromethylphenyl)-butyric acid (b.p. 173°-176° C./0.1 mm Hg). By the reaction thereof with potassium cyanide, there is obtained 2-(4-cyanomethylphenyl)-butyric acid (oil) which, after catalytic hydrogenation, gives 2-[4-(2-aminoethyl)-phenyl]-butyric acid hydrochloride; m.p. 128°-130° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C.O>[F:12][C:13]([F:22])([F:23])[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]1[NH:11][C:10]2[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=2[N:1]=1
Reactant: Nc1cccc(C(=O)O)c1N
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cccc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Temperature: 100 °C
Reaction time: 17 h
Yield: 74.2 %

Procedure:
2,3-diaminobenzoic acid (1; 50 mg, 0.33 mmol), 2-(trifluoromethyl)benzaldehyde (2; 57 mg, 0.33 mmol), and sodium metabisulfite (Na2S2O5, 82 mg, 0.43 mmol) were taken up in DMF (5 mL) and stirred at 100° C. for 17 h. The reaction mixture was cooled to room temperature and diluted with H2O. The resulting mixture was stirred at room temperature for 1 h and filtered. The collected solids were washed with water and dried to afford 2-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid 3 as a pale brown solid (75 mg, yield: 74%). MS (ESI) calcd for C15H9F3N2O2: 306.06; found: 307 [M+H].