Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=4)=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[O:8]C.[Br-].[Li+].N1CCNCC1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=4)=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[OH:8]
Reactant: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4cccc([N+](=O)[O-])c4)cc32)cc1Br
Agent: C1CNCCN1
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2ncc(-c3cccc([N+](=O)[O-])c3)cc21

Procedure:
By the same method as in the step f) of Example 22, (3,5-dibromo-4-methoxy-phenyl)-[7-(3-nitro-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone (101 mg, 0.18 mmol), lithium bromide (32 mg, 0.36 mmol), and piperazine (24 mg, 0.28 mmol) were dissolved in N,N-dimethyl formamide (3 ml), and reacted at 100□ to obtain the target compound 50, i.e., (3,5-dibromo-4-hydroxy-phenyl)-[7-(3-nitro-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone, as pale-brown solid (24 mg, 25%).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[SH:13].Cl[Sn:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[S:13][Sn:15]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cn1c(S)nc2ccccc2c1=O
Reactant: Cl[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(S[Sn](c2ccccc2)(c2ccccc2)c2ccccc2)nc2ccccc2c1=O
Yield: 61.6 %

Procedure:
A mixture of 11.6 g (0.06 mole) 3-methyl-2-mercapto-4(3H)-quinazolinone, 23.2 g (0.06 mole) chlorotriphenyl tin and 6.1 g (0.06 mole) triethylamine in methylene chloride (about 200 ml) were stirred together, then refluxed for four hours and stirred overnight. The reaction mixture was washed with water, dried and stripped. After trituration with ether, 20.0 g of the above-identified product as a white solid, melting point 155°-157° C. was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]([F:17])([F:16])[F:15])([O-])=O.[H][H]>[Ru].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:6][C:5]=1[C:14]([F:17])([F:15])[F:16]
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Ru]
Solvent: CCO
Product: Nc1ccc(S(N)(=O)=O)cc1C(F)(F)F

Procedure:
1.0 G. of 4-nitro-3-trifluoromethylbenzenesulfonamide is hydrogenated over 5% Ruthenium on charcoal in 20 ml. of absolute ethanol at room temperature under 40 lbs. of hydrogen for 5 hours. The hydrogen uptake is 100% of theory. The mixture is filtered, evaporated and dried affording 0.87 g. of crude solid. This material is recrystallized from toluene affording 0.75 g. of 4-amino-3-trifluoromethylbenzenesulfonamide, m.p. 150° to 151° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:11][N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17](O)=[O:18].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([NH:8][NH:9][C:17]([C@@H:13]2[CH2:14][CH2:15][CH2:16][N:12]2[CH3:11])=[O:18])=[N:6][CH:7]=1
Reactant: Cc1cc(F)cnc1NN
Reactant: CN1CCC[C@H]1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cc(F)cnc1NNC(=O)[C@@H]1CCCN1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.1 %

Procedure:
A solution of Intermediate 105b (76 mg, 0.537 mmol), (S)-1-methyl-pyrrolidine-2-carboxylic acid (55 mg, 0.72 mmol) and HOBT (8 mg, 0.72 mmol) in anhydrous DCM (5 mL) was treated with EDC (138 mg, 0.717 mmol) and stirred at RT under a nitrogen atmosphere for 18 h. The reaction mixture was diluted with DCM and washed with brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 1-10% MeOH in DCM, to afford the title compound (76 mg, 56%). 1H NMR (400 MHz, CDCl3): 1.74-2.05 (3H, m), 2.15-2.33 (4H, m), 2.34-2.46 (1H, m), 2.52 (3H, s), 3.02-3.12 (1H, m), 3.15-3.25 (1H, m), 6.70 (1H, s), 7.08-7.18 (1H, m), 7.90 (1H, d, J=2.8 Hz), 9.52 (1H, br s).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH3:11])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12]Br.O.[OH-].[K+]>C(O)(=O)C>[Br:12][C:9]1[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]([CH3:11])[C:8]=1[NH2:10]
Reactant: Cn1nc(C(C)(C)C)cc1N
Reactant: BrBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cn1nc(C(C)(C)C)c(Br)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a solution of 3-tert-butyl-1-methyl-1H-pyrazol-5-amine (10 g, 65.3 mmol) in acetic acid (90 mL) was added bromine (10.4 g, 65.26 mmol) in acetic acid (10 mL). The solution was stirred at rt for 30 min, and then water (100 mL) was added. The reaction mixture was basified to pH 9 using KOH (1.0 M ice cold solution). The resulting brown solid was filtered, collected, and purified by silica gel flash chromatography using 10 to 30% ethyl acetate in hexanes to afford 13.2 g (87%) of the title compound (white solid).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:13]=[O:14])[C:9](F)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1.[CH3:15][C@H:16]1[O:21][C@H:20]([CH3:22])[CH2:19][NH:18][CH2:17]1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:13]=[O:14])[C:9]([N:18]3[CH2:17][C@@H:16]([CH3:15])[O:21][C@H:20]([CH3:22])[CH2:19]3)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1
Reactant: C[C@@H]1CNC[C@@H](C)O1
Reactant: O=Cc1cc2c(Cl)noc2c(F)c1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2c(C=O)cc3c(Cl)noc3c2F)C[C@@H](C)O1
Temperature: 25 °C

Procedure:
A solution of 3-chloro-6,7-difluorobenzo[d]isoxazole-5-carbaldehyde (Intermediate 532, 3.32 g, 10.6 mmol), (2R,6R)-2,6-dimethylmorpholine (Purchased from BASF®, 2.64 g, 22.9 mmol) and DIEA (4 ml, 22.9 mmol) in acetonitrile (20 ml) was heated at reflux for 3 hours. The mixture was cooled to room temperature before being partitioned between EtOAc and 1N HCl. The EtOAc was separated and washed with brine. The combined aqueous layers were extracted with EtOAc, which was washed with brine. The combined EtOAc was dried (MgSO4) and concentrated to give an oil that was chromatographed on silica gel (50% hexanes in CH2Cl2 followed by gradient elution to 100% CH2Cl2 followed by gradient elution to 5% EtOAc in CH2Cl2) to give 2 materials in order of elution: the first material (265 mg) is consistent with starting material and the second (3.33 g) with desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2Cl.[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1.O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[NH:24][C:21]1[CH:22]=[N:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1
Reactant: COc1ccc(N)cn1
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Nc2c([N+](=O)[O-])cnc3ccc(Br)cc23)cn1
Reaction time: 8 h

Procedure:
6-Bromo-4-chloro-3-nitroquinoline (compound of step 1, 5.2 mmol) and 6-methoxypyridin-3-amine (commercially available, 5.2 mmol) was dissolved in acetic acid (5 mL) and the mixture was stirred overnight. Water was added and the yellow precipitate was filtered off. The precipitate was washed with water and dried. The solid obtained was partitioned and extracted with EtOAc and THF, washed with saturated aqueous NaHCO3. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the title compound. 1H NMR (DMSO-d6, 300 MHz): 10.03 (s, 1H), 9.01 (s, 1H), 8.72 (d, J=1.5 Hz, 1H), 8.04-7.90 (m, 3H), 7.50 (dd, J=2.4, 8.7 Hz, 1H), 6.82 (d, J=9.0 Hz, 1H), 3.85 (s, 3H); MS (m/z): 377.0 (M+1)+.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[F:12][C:13]([F:44])([F:43])[C:14]1[CH:15]=[C:16]([CH:40]=[CH:41][CH:42]=1)[CH2:17][NH:18][C:19](=[O:39])[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]2[CH:31]=[C:30]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:29]=[CH:28][C:27]=2[NH2:38])[CH:21]=1.ClCC1C=C(C=CC=1)C(NC1C=CC(N2CCCCC2)=CC=1C1C=C(C=CN=1)C(NCC1C=CC=C(C(F)(F)F)C=1)=O)=O>>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:38][C:27]1[CH:28]=[CH:29][C:30]([N:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:31][C:26]=1[C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][N:23]=1)[C:19]([NH:18][CH2:17][C:16]1[CH:40]=[CH:41][CH:42]=[C:14]([C:13]([F:44])([F:12])[F:43])[CH:15]=1)=[O:39])=[O:7]
Reactant: O=C(Cl)c1cccc(CBr)c1
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Agent: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CCl)c2)c1
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CBr)c2)c1

Procedure:
This compound was prepared from 3-(bromomethyl)benzoyl chloride and Intermediate 4.1c using the procedure described for the synthesis of 2-(2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide 8.1a.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[OH:29])([CH3:22])[CH3:21])[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:49][C@@H:50]2[CH2:54][O:53][C:52](=[O:55])[NH:51]2)(=O)=O)=CC=1>C(#N)C.O>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([CH3:22])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:49][C@H:50]4[CH2:54][O:53][C:52](=[O:55])[NH:51]4)[CH3:21])[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(=O)N2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OC[C@H]2COC(=O)N2)c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 97.1 %

Procedure:
A solution of N-cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide (Example 134, 0.5 g) in acetonitrile (10 mL) was treated with potassium carbonate (0.495 g) and (S)-(2-oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate (0.324 g) under nitrogen. The resulting mixture was stirred at 80° C. for 16 h. The reaction mixture was diluted with water, and extracted with DCM. The organic layer was dried (MgSO4), filtered and evaporated to afford the subtitle compound as a solid (0.6 g).
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[F:14][C:15]1[CH:35]=[N:34][C:18]2[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)C(=O)[O:21][C:22](=O)[C:17]=2[CH:16]=1.Cl>CC(N(C)C)=O>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[N:19]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:18]2[C:17]([C:22]=1[OH:21])=[CH:16][C:15]([F:14])=[CH:35][N:34]=2)=[O:4])[CH3:7]
Reactant: COc1ccc(Cn2c(=O)oc(=O)c3cc(F)cnc32)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(O)c2cc(F)cnc2n(Cc2ccc(OC)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Diethyl malonate (10.79 mL, 71.38 mmol) was added slowly to a suspension of NaH (60% in mineral oil, 3.13 g, 78.24 mmol) in dimethylacetamide (200 mL) and stirred at room temperature for 0.5 h under inert atmosphere. 6-Fluoro-1-(4-methoxy-benzyl)-1H-pyrido-[2,3-d]-[1,3]-oxazine-2,4-dione (69) (21.5 g, 71.31 mmol) was added to the solution and heated at 110° C. for 4 h (TLC control). The solution was cooled and poured into ice water. The pH of the solution was adjusted to 3 by cold 10% HCl. The solids formed were filtered, washed by excess water, and dried in a vacuum oven to yield 26.01 g (98%) of 6-fluoro-4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (74) as pale yellow solids. MP: 163° C.; 1H-NMR (DMSO-d6): δ 1.27 (t, J=7.2 Hz, 3H), 3.68 (s, 3H), 4.27 (q, J=7.0 Hz, 2H), 5.43 (s, 2H), 6.81 (m, Hz, 2H), 7.19 (m, 2H), 8.26 (dd, J=2.8, 8.0 Hz, 1H), 8.74 (d, J=2.8 Hz, 1H), 13.00 (br. S, 1H); EIMS: 373 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.Cl.[NH2:10][OH:11].C([O-])(=O)C.[Na+]>CCO.O>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=[N:10][OH:11])[CH2:4][CH2:3]1
Reactant: CC1CCC(=O)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1CCC(=NO)CC1

Procedure:
4-Methylcyclohexanone (2.0 g, 17.8 mmol) was mixed with hydroxylamine hydrochloride (1.86 g, 26.8 mmol) and sodium acetate (2.63 g, 32.0 mmol) in a mixture of EtOH (20 mL) and water (12 mL). The mixture was refluxed for 5 h. All solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. After separation, the organic layer was washed with brine, dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][C:3]=1[O:14][CH3:15].Cl.[CH3:17][NH:18][O:19][CH3:20].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([N:18]([O:19][CH3:20])[CH3:17])=[O:11])=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: CNOC
Reactant: COc1cc(C(C)(C)C(=O)O)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C(C)(C)C(=O)N(C)OC)ccc1Cl
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a solution of 2-(4-chloro-3-methoxyphenyl)-2-methylpropanoic acid (15) (268 g, 1.17 mol) in CH2Cl2 (1.7 L) was added N,O-dimethylhydroxylamine hydrochloride (137 g, 1.4 mol), EDCl (270 g, 1.4 mol), and DMAP (172 g, 1.4 mol ). The resulting mixture was stirred for 3 h and washed with 10% citric acid solution (1.5 L), satd NaHCO3 (1.5 L), and brine(1.5 L) successfully. The organic phase was dried over MgSO4, filtered, and concentrated at reduced pressure to afford 2-(4-chloro-3-methoxyphenyl)-N-methoxy-N,2-dimethylpropanamide (16) as a brown solid (276 g, 96%). 1H NMR (400 MHz, CDCl3): δ 7.30-7.32 (d, 1H), 6.81-6.84 (m, 3H), 3.89 (s, 3H), 3.12 (s, 3H), 2.78 (s, 3H), 1.53 (s, 6H).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[O:8][N:7]=1)([CH3:5])[CH3:4])#[N:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[S:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39]>C1COCC1>[C:1]([C:3]([C:6]1[CH:10]=[C:9]([NH:11][C:12]([NH:39][C:38]2[CH:40]=[CH:41][CH:42]=[C:36]([S:35][C:26]3[C:25]4[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=4)[N:29]=[CH:28][N:27]=3)[CH:37]=2)=[O:20])[O:8][N:7]=1)([CH3:4])[CH3:5])#[N:2]
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C#N)c1cc(NC(=O)Oc2ccccc2)on1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C#N)no4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 32 %

Procedure:
A mixture of phenyl 3-(2-cyanopropan-2-yl)isoxazol-5-ylcarbamate (prepared as described in Example 125A steps 1 through 3) (95 mg, 0.35 mmol), 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described in Example 115B) (100 mg, 0.319 mmol) and N,N-4-(dimethylamino)pyridine (10 mg, 0.082 mmol) in THF (5 mL) was stirred at rt for 15 h. The reaction mixture was concentrated under reduced pressure to give the crude product which was partitioned between dichloromethane (10 mL) and water (10 mL). The organic layer was separated and dried over magnesium sulfate. Concentration under reduced pressure gave a solid which was triturated with methanol to afford 1-(3-(2-cyanopropan-2-yl)isoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (50 mg, 32%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.52 (brs, 1H), 9.14 (brs, 1H), 8.70 (s, 1H), 7.86 (s, 1H), 7.57 (m, 1H), 7.46 (m, 1H), 7.30-7.36 (m, 3H), 6.28 (s, 1H), 3.99 (s, 6H), 1.68 (s, 6H); LC-MS (ESI) m/z 491 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[CH:21]=[C:20]([OH:22])[C:19]2[C:18](=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[OH:24])[C:11](=[O:25])[C:10]=2[CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.Cl[C:34]([O:36][CH3:37])=[O:35]>O1CCCC1>[CH2:1]([O:5][C:6]([C:8]1[CH:21]=[C:20]([O:22][C:34]([O:36][CH3:37])=[O:35])[C:19]2[C:18](=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[O:24][C:6]([O:5][CH3:1])=[O:7])[C:11](=[O:25])[C:10]=2[CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)Cl
Reactant: CCCCOC(=O)c1cc(O)c2c(c1)C(=O)c1cccc(O)c1C2=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOC(=O)c1cc(OC(=O)OC)c2c(c1)C(=O)c1cccc(OC(=O)OC)c1C2=O
Reaction time: 3 h

Procedure:
2.7 g (8 mmoles) of the product of Example 15 are dissolved in 100 ml of anhydrous tetrahydrofuran; the resulting solution is added first with 2.42 g (24 mmoles) of anhydrous triethylamine, then, after cooling to 0°-5° C., with 1.6 g (17 mmoles) of methyl chloroformate. The reaction is complete within 3 hours, keeping room temperature. After that, solvent is evaporated off under reduced pressure and the residue is washed with acidulated water, the product is filtered, washed and crystallized from ethyl ether. M.p. 200°-202° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Cl:14])[NH:6]1)=[O:4].[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:27][CH3:28])[C:24](O)=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N=C=NC(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Cl:14])[N:6]1[C:24](=[O:25])[C@@H:23]([NH:22][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:27][CH3:28])=[O:4]
Reactant: COC(=O)C1Cc2c(Cl)cccc2N1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2cccc(Cl)c2CC1C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-chloroindoline-2(R/S)-carboxylic acid methyl ester (0.41 g, 1.94 mmol) and N-t-butoxycarbonyl-2(S)-aminobutyric acid (0.47 g, 2.33 mmol) dissolved in dried dichloromethane(10 ml) under nitrogen at 10° C., was added diisopropylcarbodiimide (0.36 ml, 2.33 mmol). The mixture was stirred at room temperature for 24 hours, then filtered. The filtrate was evaporated under vacuum to afford a brown solid which was purified by column chromatography on silica gel using 20:1 dichloromethane: diethyl ether as eluent. A white foam was obtained which was the mixture of two diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[F:10][C:11]([F:15])([F:14])[CH2:12]I.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:12][C:11]([F:15])([F:14])[F:10])[CH:4]=1
Reactant: COc1cccc(O)c1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(OCC(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
A suspension of 5.00 g of 3-methoxy phenol, 10.0 g of 2,2,2-trifluoroethyl iodide and 20.0 g of cesium carbonate in DMF (15 ml) was stirred at 80° C. for two hours. The solution was added with water and extracted with Et2O; the organic layer was washed in saturated brine, then, was dried in MgSO4, the drying agent was separated by filtration and solvent was evaporated under reduced pressure obtained 6.60 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[CH2:25]([O:27][C:28](=[O:32])[CH:29]([CH3:31])[NH2:30])[CH3:26]>>[CH2:25]([O:27][C:28](=[O:32])[CH:29]([NH:30][C:19]([C:18]1[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:23][CH:22]=1)=[O:21])[CH3:31])[CH3:26]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CCOC(=O)C(C)N
Agent: Cl
Product: CCOC(=O)C(C)NC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Yield: 17 %

Procedure:
As described for example 15, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using DL-alanine ethylester hydrochloride instead of 3-methoxypropylamine, to the title compound (23 mg, 17%) which was obtained as a light yellow gum. MS: m/e=410.1 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)Cl
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: CS(=O)(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Yield: 57 %

Procedure:
The compound (0.15 g) obtained in Example 1 and methylsulfonyl chloride (0.040 ml) were reacted and treated in the same manner as in the method described in Example 2 to obtain the title compound as colorless oil (0.093 g, 57%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12]Cl.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(CC(C)C)=O.ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: COC(=O)c1ccccc1OCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)CC(C)C
Product: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
0.14 g (0.65 mmol) of 2-(2-chloro-ethoxy)-benzoic acid methyl ester were added to a mixture of 0.1 g (0.5 mmol) of 3-piperidin-4-yl-1H-indole, 0.10 g (0.75 mmol) of potassium carbonate and 0.06 g (0.37 mmol) of potassium iodide in 1.5 mL of isobutyl methyl ketone under nitrogen atmosphere and the reaction mixture was refluxed for 18 hours. After cooling at room temperature, 1.5 mL of dichloromethane and 0.08 g (0.1 mmol) of polystyrene methyl isocyanate were added and the mixture was stirred at this temperature for 3 hours. After filtering, the solution was placed directly onto a 500 mg Varian SCX ion exchange column. The columns were washed with 5 mL of methanol and the product was eluted with 5 mL of methanol/ammonia 20:1 affording, after removal of the solvent at reduced pressure, 0.113 g (60% yield) of 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][CH2:12][C:13]1([C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:25][CH:26]=2)[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][CH2:12][C:13]1([C:21]2[CH:26]=[N:25][C:24]([C:27]([OH:30])([CH3:28])[CH3:29])=[CH:23][CH:22]=2)[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CC(C)(O)c1ccc(C2(CN)CCC(F)(F)CC2)cn1
Product: CC(C)(O)c1ccc(C2(CNC(=O)c3ccccc3Cl)CCC(F)(F)CC2)cn1

Procedure:
From 2-chlorobenzoic acid and 2-[5-(1-aminomethyl-4,4-difluoro-cyclohexyl)-pyridin-2-yl]-propan-2-ol. LCMS (MH+): m/z=423.2, tR (minutes, Method F)=1.78