Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:27])[CH:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)=[CH:18][CH:17]=1)[C:12](=O)[CH3:13].CS(O)(=O)=O.C([O-])(=O)C.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]2[C:3]=1[NH:9][C:10](=[O:27])[C:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][CH:17]=1)=[C:12]2[CH3:13]
Reactant: CC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)Nc1cc(O)ccc1Cl
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)c(=O)[nH]c2c(Cl)ccc(O)c12
Temperature: 100 °C
Yield: 65.4 %

Procedure:
A mixture of N-(2-chloro-5-hydroxyphenyl)-3-oxo-2-(4-pyrazol-1-ylbenzyl)butyramide (1.3 g) and methanesulfonic acid (7.0 mL) was heated at 100° C. for 10 minutes. The mixture was cooled to room temperature and then poured into a saturated aqueous solution of sodium acetate. The resulting precipitate was collected by filtration, washed with water and dried to afford title compound as a beige solid (0.81 g).
Reaction SMILES: [NH2:1][CH:2]1[C:16]2=[N:17][CH:18]=[C:19]([C:20]([OH:23])([CH3:22])[CH3:21])[N:15]2[CH2:14][C:5]2[C:6]3[CH:7]=[N:8][NH:9][C:10]=3[C:11]([Cl:13])=[CH:12][C:4]=2[CH2:3]1.[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[C:26]21[CH2:41][C:40]1[C:35](=[CH:36][CH:37]=[C:38]([C:42](O)=[O:43])[CH:39]=1)[CH2:34]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:13][C:11]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:14][N:15]3[C:19]([C:20]([OH:23])([CH3:21])[CH3:22])=[CH:18][N:17]=[C:16]3[C@H:2]([NH:1][C:42]([C:38]3[CH:39]=[C:40]4[C:35](=[CH:36][CH:37]=3)[CH2:34][C:26]3([C:27]5[C:28](=[N:29][CH:30]=[CH:31][CH:32]=5)[NH:33][C:25]3=[O:24])[CH2:41]4)=[O:43])[CH2:3][C:4]=2[CH:12]=1
Reactant: O=C(O)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: CC(C)(O)c1cnc2n1Cc1c(cc(Cl)c3[nH]ncc13)CC2N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(O)c1cnc2n1Cc1c(cc(Cl)c3[nH]ncc13)C[C@H]2NC(=O)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21

Procedure:
A solution of 2-[7-amino-4-chloro-3,6,7,12-tetrahydroimidazo[1′,2′:1,7]azepino[3,4-e]indazol-10-yl]propan-2-ol (100 mg, 0.3 mmole) and (±)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylic acid (78 mg, 0.28 mmol) [Bell et al. WO 2006/031606], HOBT (43 mg, 0.28 mmol), and EDC (54 mg, 0.28 mmol) in DMF (2 mL) was stirred at ambient temperature for 1 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and made basic with saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc (2×20 mL), and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound as an off white solid. MS: m/z=594 (M+1)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH3:30][O:31][C:32](=[O:42])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=1>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:40][C:37]1[CH:38]=[CH:39][C:34]([CH:33]([CH2:40][C:37]3[CH:36]=[CH:35][C:34]([CH2:33][C:32]([O:31][CH3:30])=[O:42])=[CH:39][CH:38]=3)[C:32]([O:31][CH3:30])=[O:42])=[CH:35][CH:36]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: COC(=O)Cc1ccc(CC(C(=O)OC)c2ccc(COc3cccc(-c4c(C(=O)c5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc2)cc1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and (4-bromomethyl-phenyl)-acetic acid methyl ester according to the procedure of Example 41. MS (ESI) m/z 718; HRMS: calcd for C43H34F3NO6+H+, 718.24110; found (ESI, [M+H]+), 718.2444.
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[CH:3]1[N:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[C:5](=[O:11])[O:4]1.[Li+].[CH3:15]C([N-]C(C)C)C.C1COCC1.CCCCCCC.ICI>C1COCC1>[CH3:15][C:6]12[CH2:10][CH2:9][CH2:8][N:7]1[CH:3]([C:2]([Cl:1])([Cl:12])[Cl:13])[O:4][C:5]2=[O:11]
Reactant: O=C1OC(C(Cl)(Cl)Cl)N2CCC[C@H]12
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: ICI
Product: CC12CCCN1C(C(Cl)(Cl)Cl)OC2=O
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of (7aR)-3-(trichloromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one (D48) (0.2 g, 0.82 mol) in THF (10 ml) cooled at −78° C. LDA 2M sol in THF/heptane (0.58 ml, 1.17 mol) was added and the mixture stirred 30 min. Diiodomethane (0.185 ml, 2.97 mol) was added and the temperature was allowed to warm to −40° C. over a period of 2 hrs then left at this temperature for an additional hour. The resulting mixture was partitioned between DCM and H2O. The aqueous phase was extracted with DCM (2×10 ml); the organic phases were collected, dried over Na2SO4 and evaporated in vacuo. The residue was purified by SPE-Si cartridge (25 g) eluting with DCM. Collected fractions after solvent evaporation afforded title compound (D49) in mixture (4:1) with starting material (110 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1)=[O:2].CN1CCCCC1.C(C1C=C(C=CC=1)OC[C:28]([N:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1)=O)=O>>[CH3:28][N:30]1[CH2:35][CH2:34][N:33]([C:9](=[O:11])[CH2:8][O:7][C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:13][CH:12]=2)[CH2:32][CH2:31]1
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)COc2cccc(C=O)c2)CC1
Solvent: CN1CCCCC1
Product: CN1CCN(C(=O)COc2ccc(C=O)cc2)CC1
Yield: 66 %

Procedure:
2-(4-Formylphenoxy)acetic acid (53) was treated with 1-methylpiperidine in an analogous manner to Compound 49 to afford the desired product (66%) as a colorless oil. LCMS: 99.0% (M++1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:36])[C:22]([C:24]4[NH:25][C:26](=[N:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[S:27][CH:28]=4)=[O:23])[C:18](=[O:37])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1.CO.[OH-].[Na+].[BH4-].[Na+]>C(O)C>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:36])[CH:22]([OH:23])[C:24]4[N:25]=[C:26]([NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[S:27][CH:28]=4)[C:18](=[O:37])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1
Reactant: CCCS(=O)(=O)N=c1[nH]c(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4C)CS[C@H]23)cs1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CCCS(=O)(=O)Nc1nc(C(O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4C)CS[C@H]23)cs1

Procedure:
To a mixture of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-propanolsulfonylamino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-propanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (8.0 g.), methanol (160 ml.) and 1 N sodium hydroxide aqueous solution (13.6 ml.) was dropwise added a mixture of sodium borohydride (0.26 g.) and ethanol (15 ml.) over 20 minutes under stirring and ice-cooling. The mixture was further stirred for 1 hour, and then methanol was distilled off. The residue was dissolved in water, and the solution was washed with ethyl acetate. To the aqueous solution was added ethyl acetate, and the mixture was adjusted to pH 2 with 10% hydrochloric acid, and then the ethyl acetate layer was separated from the mixture. The remaining aqueous layer was saturated with sodium chloride and then extracted with ethyl acetate. The ethyl acetate extract was combined with the separated ethyl acetate layer, washed with a saturated aqueous solution of sodium chloride and then dried. The solvent was distilled off, and the residue was washed with diethyl ether and then dried to give 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-propanesulfonylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-propanesulfonylimino-1,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (5.5 g.), mp. 160° to 170° C. (dec.).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.[Cl:22][C:23]1[N:28]=[C:27](Cl)[N:26]=[C:25]([NH2:30])[N:24]=1.CCN(C(C)C)C(C)C>CC(O)C>[Cl:22][C:23]1[N:28]=[C:27]([NH:14][C@H:12]([C:10]2[N:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]3[CH:21]=[C:4]([F:3])[CH:5]=[CH:6][C:7]=3[N:11]=2)[CH3:13])[N:26]=[C:25]([NH2:30])[N:24]=1
Reactant: Nc1nc(Cl)nc(Cl)n1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1nc(N)nc(Cl)n1)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
To an ice-cooled mixture of (5)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (226 mg, 0.69 mmol), 4,6-dichloro-[1,3,5]triazin-2-ylamine (125 mg, 0.76 mmol) and IPA (5 mL) was added DIPEA (0.59 mL, 3.45 mmol). The reaction mixture was stirred at RT (room temperature) for 64 h. The solvent was removed under reduced pressure and the resulting residue was partitioned between EtOAc and aqueous Na2CO3. The aqueous phase was extracted with EtOAc and the combined organic fractions washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant EtOAc) affording the title compound as a colourless foam (quantitative). A portion (50 mg) was further purified by column chromatography (Si—PCC, eluant EtOAc) affording 269 after evaporation from acetone as a colourless foam (31.8 mg). LCMS (Method K): RT 4.06 min [M+H]+ 384.0/385.9. 1H NMR (DMSO-d6, 400 MHz, 80° C.): δ 7.69 (1H, bs), 7.66 (1H, dd, J=8.8, 4.9 Hz), 7.60-7.50 (5H, m), 7.07-7.02 (1H, m), 6.78 (2H, bs), 6.77 (1H, dd, J=8.9, 2.4 Hz), 5.21 (1H, quintet, J=7.1 Hz), 1.46 (3H, d, J=6.9 Hz)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=4)[N:11]=3)[CH:8]=2)[CH:3]=[N:2]1.O[Li].O.Cl>O1CCCC1.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=4)[N:11]=3)[CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4cn[nH]c4c3)c(N(C)C(C)C)nc2c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
To a solution of methyl 2-(1H-indazol-6-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (195.0 mg, 0.52 mmol) in tetrahydrofuran (20 mL) was added LiOH.H2O (25.0 mg, 1.04 mmol) and water (1 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (30 mL) and adjusted to pH 6 with hydrochloric acid (3N) and filtered to give 2-(1H-indazol-6-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (121.5 mg, 65%).
Reaction SMILES: [CH:1]1([C:7]2[C:16]3[C:11](=[C:12]([CH2:17]Cl)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C-:19]#[N:20].[Na+]>>[CH:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([CH2:17][C:19]#[N:20])[C:11]=3[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [C-]#N
Reactant: ClCc1cccc2c(C3CCCCC3)nccc12
Agent: [Na+]
Product: N#CCc1cccc2c(C3CCCCC3)nccc12

Procedure:
1-Cyclohexyl-5-chloromethylisoquinoline and sodium cyanide were reacted in the same way as in step (h) of Example 13 to afford 1-cyclohexylisoquinoline-5-acetonitrile having a melting point of 85.3° to 85.6° C.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH2:6].Br[C:8](=[CH:11]OC(C)C)[CH:9]=[O:10].C1(N2C(C=O)=CN=C2C)CC1>>[S:1]1[CH2:5][CH2:4][N:3]2[C:8]([CH:9]=[O:10])=[CH:11][N:6]=[C:2]12
Reactant: NC1=NCCS1
Reactant: CC(C)OC=C(Br)C=O
Agent: Cc1ncc(C=O)n1C1CC1
Product: O=Cc1cnc2n1CCS2

Procedure:
2,3-Dihydro-imidazo[2,1-b]thiazole-5-carbaldehyde was prepared from 4,5-dihydro-thiazol-2-ylamine and and 2-bromo-3-isopropoxy-propenal in the same manner as cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde (Example 45).
Reaction SMILES: C(N(C1C=CC=CC=1)N=[CH:10][C@H:11]([C@H:13]([C@@H:15]([C@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14])[OH:12])C1C=CC=CC=1.O.C(=[O:35])C1C=CC=CC=1.C(O)(=O)C1C=CC=CC=1>C(O)C>[O:20]=[CH:19][C@H:17]([C@H:15]([C@@H:13]([C@H:11]([CH2:10][OH:35])[OH:12])[OH:14])[OH:16])[OH:18]
Reactant: OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C=NN(Cc1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: O=C(O)c1ccccc1
Solvent: O
Solvent: CCO
Product: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
The L-gulose benzylphenylhydrazone was refluxed for three hours with 100 ml. of water and 20 ml. of ethanol containing 7.5 ml. of benzaldehyde and 0.8 grams of benzoic acid. After cooling, the solution was decanted from the crystals of benzaldehyde benzylphenylhydrazone and extracted several times with ether to remove the benzaldehyde and benzoic acid. The solution was then decolorized with activated carbon and concentrated under reduced pressure to a colorless syrup to yield 3.4 grams of syrupy L-gulose.
Reaction SMILES: [O:1]=[C:2]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:19]1)[CH2:3][NH:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:46])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[Cl:45]>C(Cl)Cl>[F:13][C:12]([F:15])([F:14])[C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:5]([NH:4][CH2:3][C:2]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH:23]2[CH2:24][CH2:25][N:26]([C:36]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:45])=[O:46])[CH2:27][CH2:28]2)[CH2:19]1)=[O:1])=[O:16]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCNCC2)C1
Reactant: O=C(Cl)OCc1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(C(=O)OCc3ccccc3Cl)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
To a solution of N-(2-oxo-2-{[(3R)-1-piperidin-4-ylpyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide (50 mg, 0.16 mmol) in CH2Cl2 (5 mL) was added triethylamine (24 mg, 0.24 mmol) followed by 2-chlorobenzyl carbonochloridate (49 uL, 0.24 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, then to the slurry was added NaHCO3 (sat. aq., 10 mL) and ethyl acetate (10 mL). The aqueous layer was separated and the organic layer was washed with brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford 2-Chlorobenzyl 4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}piperidine-1-carboxylate (35 mg, 38%) as a white solid. 1H-NMR (CDCl3) δ: 1.30-1.43 (m, 2H), 1.56-1.64 (m, 1H), 1.69-1.74 (b, 2H), 2.14-2.35 (m, 3H), 2.56-2.68 (m, 2H), 2.86-2.88 (m, 3H), 4.01-4.06 (m, 4H), 4.40-4.42 (m, 1H), 5.16 (s, 2H), 6.50 (d, J=7.5 Hz, 2H), 7.18-7.22 (m, 4H), 7.30-7.34 (r, 2H), 7.50 (t, J=8.1 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 8.03 (s, 1H). MS m/z: 567 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Br[CH:14](C(OC)=O)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[N+:10]([C:9]1[C:2]2[O:1][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:4][C:3]=2[CH:6]=[CH:7][CH:8]=1)([O-:12])=[O:11]
Reactant: COC(=O)C(Br)C(=O)OC
Reactant: O=Cc1cccc([N+](=O)[O-])c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cccc([N+](=O)[O-])c2o1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A mixture of 2-hydroxy-3-nitrobenzaldehyde (4.3 g, 25.7 mmol), dimethyl 2-bromomalonate (5.95 g, 28.3 mmol), potassium carbonate (5.32 g, 38.6 mmol) and tetra-n-butylammonium bromide (0.8 g, 2.5 mmol) in toluene (100 mL) was heated at reflux with a Dean-Start trap for 5 hours. After cooling to room temperature, the mixture was evaporated and purified by silica gel chromatography (dichloromethane) to afford the product methyl 7-nitrobenzofuran-2-carboxylate (4.6 g, yield 81%). 1H NMR (400 MHz, CDCl3) δ ppm 8.31-8.33 (dd, 1H, J=1.2 Hz, 8.0 Hz), 8.02-8.04 (dd, 1H, J=1.2 Hz, 8.0 Hz), 7.66 (s, 1H), 7.46-7.50 (t, 1H, J=8.0 Hz), 4.03 (s, 3H).
Reaction SMILES: C(O[C:6](=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.[OH-].[Na+]>O>[CH3:6][NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CNC1CCC(N)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.4 %

Procedure:
Amine 1 (15.0 g, 0.7 mol) was added slowly over 45 min to a 1N solution of lithium aluminium hydride in THF (450 mL, 0.36 mol) under nitrogen. The mixture was stirred for 30 min at room temperature, then heated at reflux for 5-6 hours under nitrogen. Water (13.2 mL) was added to the mixture followed by 15% aqueous sodium hydroxide (13.2 mL), and water (39.7 mL). The mixture was then stirred for 15-30 min. The solid was filtered off and washed with t-butylmethyl ether (200 mL), dichloromethane (200 mL), and t-butylmethyl ether (200 mL). The organic extracts were collected, dried (MgSO4), and filtered. The drying agent was then washed with dichloromethane and the organic extracts combined and concentrated in vacuo to give the title compound 2 (7.52 g, 84%) as a pale yellow solid: δH (360 MHz: CDCl3) 1.04-1.20 (q, 4H), 1.51 (br s, 3H), 1.80-1.96 (m, 4H), 2.25-2.35 (m, 1H), 2.41 (s, 3H), 2.61-2.72 (m, 1H).
Reaction SMILES: [F:1][CH:2]([C:8](=O)C1C=CC=CC=1)[C:3](OCC)=[O:4].[C:16]1([NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22].C(O)(=O)C>C(O)C>[F:1][C:2]1[C:3](=[O:4])[N:23]=[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]2=[N:22][CH:8]=1
Reactant: CCOC(=O)C(F)C(=O)c1ccccc1
Reactant: Nc1ccccc1N
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1nc2ccccc2ncc1F

Procedure:
Refluxing of ethyl α-fluorobenzoylacetate (2.25 g, 10 mmol) with o-phenylenediamine (10 mmol) in the mixture of acetic acid and ethanol (25%) for 5 h gave 3-fluoro-1,5-benzodiazepin-2-one derivatives in good yields as follows. ##STR17## wherein X=H, 4-Me, 4-Cl or NO2. It is clear that the first step of this reaction is condensation of carbonyl ketone and amine by losing water and second step is cyclization of their ester with another amine by losing ethanol. When used p-CH3 or p-Cl o-phenylenediamine, these were condensed with α-fluorobenzoylacetate,
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:18]([N:20](CC)CC)C.COC(Cl)=O.CN>O.O1CCCC1>[OH:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:20][CH3:18])=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(Oc2ccc(O)cc2)cc1
Agent: CN
Agent: COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1ccc(Oc2ccc(O)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a mixture of 4-(4-Hydroxy-phenoxy)-benzoic acid (0.25 g, 1.09 mmol), triethylamine (0.15 mL, 1.07 mmol) and tetrahydrofuran (THF) (5.0 mL) at 0° C. was added methylchloroformate (0.084 mL, 0.10 g, 1.1 mmol). After stirring for 15 minutes, excess methylamine was added via a sparge tube, and stirring was continued for 10 minutes. The mixture was diluted with water, extracted three times with ethyl acetate, and the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo, affording 1 4-(4-Hydroxy-phenoxy)-N-methyl-benzamide as a colorless syrup.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([NH2:9])=[N:7][CH:8]=1)#[CH:2].[Si:10]([O:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=2[NH:34][C:35](=[O:44])[C:36]2[CH:41]=[C:40](I)[CH:39]=[CH:38][C:37]=2[F:43])[CH2:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:9][C:6]1[N:7]=[CH:8][C:3]([C:1]#[C:2][C:40]2[CH:39]=[CH:38][C:37]([F:43])=[C:36]([CH:41]=2)[C:35]([NH:34][C:25]2[CH:26]=[C:27]([C:30]([F:31])([F:32])[F:33])[CH:28]=[CH:29][C:24]=2[N:20]2[CH2:21][CH2:22][CH2:23][C@@H:18]([O:17][Si:10]([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:11])[CH3:12])[CH2:19]2)=[O:44])=[CH:4][N:5]=1
Reactant: C#Cc1cnc(N)nc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(I)ccc2F)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(C#Cc3cnc(N)nc3)ccc2F)C1
Temperature: 70 °C

Procedure:
In a 16×120 mm resealable pyrex tube, 5-ethynylpyrimidin-2-amine (0.080 g, 0.67 mmol), (R)-N-(2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)-2-fluoro-5-iodobenzamide (0.210 g, 0.34 mmol), Bis(triphenylphosphine)palladium(II) dichloride (0.012 g, 0.017 mmol), and Copper(I) iodide (0.0032 g, 0.017 mmol) were taken up in CH3CN and Triethylamine (0.71 ml, 5.1 mmol) was added, and the tube was flushed with nitrogen. The tube was sealed and the reaction heated to 70° C. overnight. The reaction was cooled, and transferred to a 50 mL RBF with EtOAc. The mixture was concentrated in vacuo, and the resulting solid was treated with 10% MeOH in CH2Cl2 and adsorbed onto 1.5 g silica gel and passed through a Redi-Sep®D pre-packed silica gel column (40 g) eluting with 0-60% EtOAc/hexane. The product-containing fractions were concentrated to afford (R)-5-(2-(2-aminopyrimidin-5-yl)ethynyl)-N-(2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][NH2:31])[CH:26]=[CH:27][CH:28]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:31][CH2:30][CH2:29][C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=4)[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Reactant: Cc1cccc(CCN)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cccc(CCNc2cc(-c3ccc4c(N)n[nH]c4c3)nc(N)n2)c1
Temperature: 160 °C
Yield: 35.1 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (300 mg, 0.99 mmol), 2-(3-methylphenyl)ethanamine (300 mg, 2.22 mmol), and Hunig's base (2 mL) in NMP (3 mL) was heated for 2 hours at 160° C. in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC to afford the title compound (125 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 2.03 (s, 3H), 2.79-2.82 (m, 2H), 3.49-3.51 (m, 2H), 5.35 (s, 2H), 5.99 (s, 2H), 6.28 (s, 1H), 6.92-7.10 (m, 4H), 7.41 (d, J=7.6 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.84 (s, 1H), 11.49 (s, 1H).