Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2.[B:12]([O-])([O-:14])[O-:13].Cl.O>CCCCCC.C1COCC1>[CH2:8]1[C:9]2[C:4](=[CH:3][C:2]([B:12]([OH:14])[OH:13])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: [O-]B([O-])[O-]
Reactant: Brc1ccc2c(c1)CCCC2
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: OB(O)c1ccc2c(c1)CCCC2
Temperature: -69 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
In a 5 liter three-necked flask, 67.55 g of 6-bromo-1,2,3,4-tetrahydronaphthalene and 1480 ml of dry tetrahydrofurah (THF) were placed and cooled to −70 to −68° C. on a dry ice-acetone bath in a dry nitrogen gas atmosphere. At that temperature, to the mixture, 200 ml of 1.6 M-butyllithium solution in hexane was added dropwise, followed by stirring for 2 hours at −67° C. or below. To borate in 435 ml of dry THF was added dropwise at −70 to −68° C., followed by stirring for 2 hours at −67° C. or below. The reaction mixture was gradually warmed to room temperature and left standing overnight. The resultant reaction mixture was gradually added dropwise to a mixture of 108 ml of HCl and 438 ml of water kept at 10° C. or below, followed by stirring for 1 hour at that temperature. Thereafter, the mixture was subjected to extraction with toluene. The organic layer was washed with water, followed by distilling-off of the solvent under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=2/1) and recrystallized from hexane to obtain 30.4 g of 1,2,3,4-tetrahydronaphthalene-6-boronic acid (Yield: 54.0%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25])([O-:17])=[O:16]>ClCCl>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][S:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N+:15]([O-:17])=[O:16])(=[O:25])=[O:26]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CN(C)CCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of N,N-dimethyl-1,3-diaminopropane (0.92 g) and triethylamine (0.95 mL) in dichloromethane (10 mL) was added 2-nitrobenzenesulfonyl chloride (1 g), and the mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (1.26 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[CH2:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.[C:21](N=C(N(C)C)N(C)C)([CH3:24])([CH3:23])[CH3:22].BrCC(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([N:8]([CH2:22][CH:21]([CH3:24])[CH3:23])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[CH2:19])=[CH:14][CH:13]=2)(=[O:10])=[O:11])[CH:7]=1
Reactant: C=Cc1ccc(S(=O)(=O)Nc2cc(Cl)ccc2F)cc1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Solvent: CC(C)CBr
Product: C=Cc1ccc(S(=O)(=O)N(CC(C)C)c2cc(Cl)ccc2F)cc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of N-(5-chloro-2-fluorophenyl)-4-vinylbenzenesulfonamide (822 mg, 2.64 mmol) in acetonitrile (10 mL) stirred in air at 20° C., was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (903 mg, 5.27 mmol). The reaction mixture was stirred at 20° C. for 2 hours. 1-bromo-2-methylpropane (0.573 mL, 5.27 mmol) was then added and the reaction vessel sealed and heated by microwaves (Emrys Optimiser) to 150° C. for 30 minutes. After cooling, the reaction mixture was concentrated in vacuo and redissolved in ethyl acetate. The organic phase was washed with water (10 mL), dried using a hydrophobic frit and evaporated in vacuo to give the crude product as a yellow oil which solidified. The crude was purified by silica (Si) chromatography using a 0-50% ethyl acetate-cyclohexane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product, 824 mg as a colourless oil. LCMS [LCMS2] Rt 1.46 min, m/z (ES+) 368 (M+H).
Reaction SMILES: CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.[CH2:26](O)[CH2:27][C:28]#[CH:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:29]([N:18]1[N:19]=[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]2=[N:17]1)[CH2:28][C:27]#[CH:26]
Reactant: c1ccc2[nH]nnc2c1
Reactant: C#CCCO
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C#CCCn1nc2ccccc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 222 %

Procedure:
A solution of di-tert-butylazodicarboxylate (3.15 g, 13.4 mmol) in DCM (3 mL) was added dropwise over 30 min at 0° C. to a suspension of benzotriazole (2.40 g, 1.50 mmol), but-3-yn-1-ol (940 mg, 13.4 mmol) and polymer bounded triphenylphosphine (4.40 g, 16.8 mmol, 0.3 mmol/g) in DCM (3 mL). The reaction mixture was stirred at room temperature with a polymix agitation for 2 days and filtered through celite. The organic phase was washed with NH4OH, brine, dried over MgSO4, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 571 mg (3.33 mmol, 25%) of 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:34]=[CH:33][C:20]([C:21]([N:23]([CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]#[N:31])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C[Sn]([N:39]=[N+:40]=[N-:41])(C)C>C1(C)C(C)=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[NH:41][N:40]=[N:39][N:31]=4)=[O:22])=[CH:33][CH:34]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3C#N)cc2)cc1
Solvent: Cc1ccccc1C
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3-c3nnn[nH]3)cc2)cc1
Temperature: 120 °C
Yield: 60.7 %

Procedure:
A mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-cyanophenyl)benzamide (350 mg) and trimethyltin azide (453 mg) in xylene (15 ml) heated at 120° C. for 2 days and cooled to ambient temperature. The solution was directly applied to silica gel column (the column was pre-packed with chloroform as a solvent). The column was eluted with 2% methanol in chloroform and the solvent was evaporated in vacuo. The residue was solidified with diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(tetrazol-5-yl)phenyl]benzamide (233 mg) as a white powder.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].F[C:9]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]>C1COCC1.CN(C=O)C>[F:17][C:15]1[CH:16]=[CH:9][C:10]([C:11]#[N:12])=[C:13]([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)[CH:14]=1
Reactant: N#Cc1ccc(F)cc1F
Reactant: c1c[nH]nn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)cc1-n1nccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.6 %

Procedure:
To a solution of 1H-1,2,3-triazole (3.5 g, 50.7 mmol) in THF (10 mL) and DMF (20 mL) was added portionwise, NaH (1.3 g, 51 mmol, 95%). The mixture was stirred at room temp for 30 min. Added to this was 2,4-difluorobenzonitrile (7.6 g, 55 mmol) and the mixture was stirred at 85° C. for 3 h. The white mixture was concentrated and purified by flash chromatography eluting with 0%-5%-10% EtOAc/hexane to give the title compound as white needles (0.34 g, 3% yield). 1H-NMR (300 MHz, CDCl3) δ: 7.92 (2H, s), 7.88-7.79 (2H, m), 7.19-7.12 (1H, m). LCMS [M+H]+ calcd for C9H6N4F: 189.05; found: 189.12.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[NH:13][C@H:12]([C:14]([OH:16])=[O:15])[CH2:11][S:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[C:17](Cl)(=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24].Cl>C(=O)([O-])[O-].[Na+].[Na+].O>[C:17]([N:13]1[C@H:12]([C:14]([OH:16])=[O:15])[CH2:11][S:10][CH:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1)(=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:13]1[C@H:12]([C:14]([OH:16])=[O:15])[CH2:11][S:10][CH:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1)=[O:24]
Reactant: N#Cc1cccc(C2N[C@H](C(=O)O)CS2)c1
Reactant: O=C(Cl)CCCCCC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1cccc(C2SC[C@@H](C(=O)O)N2C(=O)CCCCCC(=O)N2C(c3cccc(C#N)c3)SC[C@H]2C(=O)O)c1
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
To a stirred solution of (4R)-2-(3-cyanophenyl)-4-thiazolidinecarboxylic acid (4.7 g) in 1M sodium carbonate (30 ml), heptanedioyl dichloride (2.1 g) was added dropwise under ice-cooling. The reaction mixture was stirred for 30 minutes at the same temperature, and filtered to give the precipitates. The precipitates were dissolved in hot water (100 ml), and acidified with concentrated hydrochloric acid. The separated crystals were collected by filtration to give 3.5 g (59%) of the titled compound: mp 105°-112° C.; [α]D25 +115.0° (c=1.0, methanol). IR (nujol, cm-1): 2270 (CN), 1735 (COOH), 1640 (CON), 1610 (aromatic), 1195, 790 (aromatic). NMR (DMSO-d6) δ: 0.69-1.66 (6H, m, --CH2 --CH2)3CH2 --), 1.70-2.50 (4H, m, --CH2 --CH2)3CH2 --), 2.85-3.66 (4H, m, C5 --H), 4.69 (1H, dd, J=8.2, 6.0 Hz, C4 --H), 5.13 (1H, m, C4 --H), 6.16 (1H, s, C2 --H), 6.43 (1H, s, C2 -- H), 7.3-8.3 (8H, m, arom. H). TLC: Rf value* 0.33.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[N+:24]([O-])=O)[CH2:4][CH3:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1N
Yield: 98.2 %

Procedure:
A mixture of (1-ethyl-propyl)-[6-methyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine (40 mg, 0.112 mmol) and 4 mg of 10% Pd/C in 10 ml of ethanol was hydrogenated at 50 psi overnight. The mixture was filtered through Celite™ and the filtrate was concentrated to dryness to give a light brown crystals which were purified through silica gel column chromatography using 1:1 chloroform:hexane as eluent to give the title compound as golden crystals (36 mg, 97%), mp 105–107° C. 1H NMR (CDCl3) δ 6.88 (s, 2H), 6.11 (s, 1H), 4.00 (brs, 1H), 3.28 (m, 1H), 3.10 (brs, 2H), 2.31 (s, 3H), 2.16 (s, 3H), 2.10 (s, 6H), 1.45–1.75 (m, 4H), 0.98 (t, 6H) ppm. The corresponding HCl salt was prepared as white solid, mp 174–178° C., 1H NMR(D2O) δ 7.09 (s, 2H), 6.63 (s, 1H), 3.65 (m, 1H), 2.31 (s, 3H), 2.25 (s, 3H), 2.11 (s, 6H), 1.45–1.80 (m, 4H), 0.91 (t, 6H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[CH:17]=O>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:22][C:20]2[CH:19]=[C:16]([CH3:17])[CH:15]=[C:14]([Br:13])[CH:21]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Cc1cc(Br)cc(C=O)c1
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Cc2cc(C)cc(Br)c2)cc1
Temperature: 25 °C
Yield: 41.9 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (8.3 g, 50.3 mmol) and 3-bromo-5-methyl-benzaldehyde (11.0 g, 50.3 mmol) in ethanol (100 mL) was prepared. The reaction mixture was heated to reflux for 2 hours. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(3-bromo-5-methyl-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (7.3 g, 50%) as a white solid: LC/MS m/e calcd for C17H16BrNO2 M+: 346.2, observed: 346.1.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[S:37])=[C:31]([CH3:39])[CH:30]=1.[C:40]([O-])(=[O:42])C.[Na+]>>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:40]([NH:24][CH2:23][CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=4)[N:11]=3)=[CH:16][CH:17]=2)=[O:42])=[S:37])=[C:31]([CH3:39])[CH:30]=1
Reactant: COc1ccc(NC(N)=S)c(C)c1
Reactant: NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Product: COc1ccc(NC(=S)NC(=O)NCCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c(C)c1

Procedure:
The title compound was prepared as described in Example 63 using 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (C60) and 1-(4-methoxy-2-methylphenyl)thiourea. Sodium acetate was used in place of sodium bicarbonate. The title compound was isolated as a white solid (0.119 g, 38%): 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 10.00 (s, 1H), 9.39 (s, 1H), 8.16-7.98 (m, 4H), 7.70-7.57 (m, 2H), 7.38 (dd, J=8.4, 1.9 Hz, 3H), 7.08 (t, J=5.7 Hz, 1H), 6.84 (d, J=2.9 Hz, 1H), 6.77 (dd, J=8.7, 3.0 Hz, 1H), 3.75 (s, 3H), 3.16 (q, J=6.5 Hz, 2H), 2.70 (dd, J=8.5, 6.7 Hz, 2H), 2.17 (s, 3H), 1.81 (p, J=7.2 Hz, 2H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 585 ([M+H]+), 583 ([M−H]−).
Reaction SMILES: [CH2:1]([CH2:5][C:6](=O)[CH3:7])[C:2]([CH3:4])=O.[N+:9]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])([O-:11])=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:4][C:2]1[N:14]([C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[N+:9]([O-:11])=[O:10])[C:6]([CH3:7])=[CH:5][CH:1]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccccc1[N+](=O)[O-]
Yield: 60.3 %

Procedure:
Acetonylacetone (2.0 g, 17.5 mmol), o-nitroaniline (2.6 g, 18.8 mmol, 1.07 eq), and p-toluenesulfonic acid monohydrate (0.31 g, 1.63 mmol) in toluene (75 mL) were heated at reflux with azeotropic removal of water overnight. The crude product was purified by column chromatography over silica gel to give 2.28 g of 2,5-dimethyl-1-(2-nitrophenyl)-1H-pyrrole, which was reduced as in Example 64 to give 0.46 g of 2-(2,5-dimethyl-1H-pyrrol-1-yl)benzenamine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[CH:16]=[CH:15][S:14][C:13]=1[CH3:17])[NH:10][CH3:11].[C:18](O)(=O)[CH3:19].[CH2:22](OC(OCC)(OCC)CC)C>CCCCCC>[CH2:18]([C:11]1[N:10]([CH3:22])[CH:9]([C:12]2[CH:16]=[CH:15][S:14][C:13]=2[CH3:17])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[CH3:19]
Reactant: CNC(Cc1ccccc1N)c1ccsc1C
Reactant: CCOC(CC)(OCC)OCC
Reactant: CC(=O)O
Solvent: CCCCCC
Product: CCC1=Nc2ccccc2CC(c2ccsc2C)N1C

Procedure:
A solution of 3.95 g of 2-amino-N-methyl-α-(2-methyl-3-thienyl)benzeneethanamine, 5 ml of glacial acetic acid and 17.0 g of triethylorthopropionate was refluxed for 8 hours (under a nitrogen atmosphere). The solution was concentrated in vacuo at 80° C. and the residual oil dissolved in diethyl ether (50 ml) and acidified with 10% hydrochloric acid solution. The aqueous phase was washed with diethyl ether (50 ml), basified, and extracted with dichloromethane (2×100 ml). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The resultant oil was purified by preparative HPLC (Water's Associates Prep LC/System 500, silica gel, elution with methanol followed by 2% triethylamine in methanol). Concentration of the appropriate fractions afforded 2.26 g of 4,5-dihydro-2-ethyl-3-methyl-4-(2-methyl-3-thienyl)-3H-1,3-benzediazepine as an oil. Trituration with hexane afforded a solid which was combined with product obtained from previous run to afford the analytical sample, mp 82°-83.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:18][CH:19]([C:27]#[CH:28])[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].C(NC(C)C)(C)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:17][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:28]#[C:27][CH:19]([OH:18])[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C#CC(O)CCCC(=O)OC
Reactant: CCCCCCCCC(O)c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: CCCCCCCCC(O)c1ccccc1C#CC(O)CCCC(=O)OC
Yield: 129.2 %

Procedure:
Into a heavy walled pyrex test tube was added 130 mg (0.43 mmol) of 1-(0-bromophenyl)-1-nonanol, 67 mg (0.43 mmol) of methyl 5-hydroxy-6-heptynoate prepared according to the procedure of Nicolaou et al., J.A.C.S., 106, 2748 (1984), 25 mg (0.02 mmol, 5 mole%) of Pd(PPh3)4, and 4 ml (93.0 mg) of diisopropylamine. The reaction was run and worked up according to the procedure of Example 11 to yield 208 mg of a yellow-brown oil. The oil was chromatographed on a silica gel column which was eluted with 70% diethyl ether/hexane to produce the titled product as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C:13](=O)[CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.Cl.[NH2:21][OH:22].N1C=CC=CC=1.O>CO>[OH:22]/[N:21]=[C:13](/[C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][CH:9]=1)\[CH2:14][NH:15][C:16](=[O:18])[CH3:17]
Reactant: COc1ccc2cccc(C(=O)CNC(C)=O)c2c1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc2cccc(/C(CNC(C)=O)=N/O)c2c1

Procedure:
In a 100-ml round-bottom flask, the compound obtained in Step G (4.2 mmol) is dissolved in 25 ml of methanol. Hydroxylamine hydrochloride (16.8 mmol) and pyridine (21.1 mmol) are added and then the reaction mixture is heated at reflux, with magnetic stirring, for 3 hours. After cooling, the reaction mixture is poured into 50 ml of water. The precipitate formed is filtered off under suction, washed with water and recrystallised from toluene to yield the title product in the form of a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)=[N:15][C:14]=3[CH:31]=2)=[CH:6][C:5]=1[F:32])(=[O:3])[NH2:2].[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>C(Cl)Cl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[F:32][C:5]1[CH:6]=[C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[CH:31]=2)[CH:8]=[CH:9][C:4]=1[C:1]([NH2:2])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C(N)=O)c(F)c4)ccc3o2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc(-c2ccc3oc(C4CCNCC4)nc3c2)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-butyl 4-[5-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate (140 mg, 0.32 mmol) dissolved in DCM (25 ml) and added trifluoroacetic acid (1 ml). This mixture stirred at rt for 3 h. After completion of the reaction, DCM removed on rotavapour and residue was co-distilled with ether to obtain 2-fluoro-4-(2-(piperidin-4-yl)-benzo[d]oxazol-5-yl)-benzamide 2,2,2-trifluoroacetate (140 mg). 2-Fluoro-4-(2-(piperidin-4-yl)-benzo[d]oxazol-5-yl)-benzamide 2,2,2-trifluoroacetate (140 mg, 0.31 mmol) was dissolved in DMF (5 ml) and added isovaleric acid (34.6 mg, 0.34 mmol), EDC.HCl (147 mg, 0.77 mmol), HOBt (50 mg, 0.37 mmol) and TEA (0.4 ml, 2.47 mmol). After completion of the reaction, water added to the reaction mixture to obtain solid. Solid was filtered and washed with ether to obtain the titled compound (20 mg) as a brown solid. M.P.: 186-190° C. MS (m/z): 424.1 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[C:9]1([P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[Br-:1].[CH3:7][CH:6]([CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2][P+:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)CCCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 81 %

Procedure:
A solution of 25 (2.30 g; 12.8 mmol) and triphenylphosphine (3.70 g; 14.1 mmol) was refluxed in toluene (12 mL) for 20 h. Then solvent was removed and the resulting crystal was washed with toluene (3 mL) and diethyl ether (3 mL) to give 4.57 g (10.4 mmol; 81% yield) of 10. m.p. 227-228° C.; 1H NMR (500 MHz, CD3CN) δ 0.82 (6H, d, J=6.6 Hz), 1.16 (2H, m), 1.42-1.52 (3H, m), 1.59 (2H, m), 3.30 (2H, m), 7.72 (12H, m), 7.85 (3H, m); 13C NMR (125 MHz, CD3CN) δ 22.7, 23.2, 28.4, 28.8, 28.9, 38.6, 131.2, 131.3, 134.7, 134.7, 136.0.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH2:10]([Mg]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCC)C>O1CCCC1>[CH2:10]([C:6]1[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([Cl:9])[CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Clc1cc(Cc2ccccc2)nc(Cl)n1
Temperature: 20 °C
Yield: 65 %

Procedure:
To a solution of 2,4,6-trichloropyrimidine (936 mg, 5.0 mmol) in tetrahydrofuran (50 mL) was added at −78° C. under an atmosphere of nitrogen and stirring drop wise 1 M benzylmagnesium chloride solution in diethyl ether (5 mL, 5.0 mmol). The reaction was let to warm up to 20° C. over 16 h. The solvent was removed under reduced pressure and the residue was dissolved in water. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed once with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using heptane and then heptane/ethyl acetate (9:1 v/v) as eluent to yield the title compound (778 mg, 65%) as a pale-yellow viscous oil.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=2[F:25])[NH:8][CH:7]=1)=[O:5].C1COCC1.CO.[Cl-].[NH4+]>CCOC(C)=O.[Zn]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:13]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:8][CH:7]=[C:6]([C:4](=[O:5])[CH2:3][N:2]([CH3:26])[CH3:1])[C:14]=23)=[C:17]([F:25])[CH:18]=1
Reactant: CN(C)CC(=O)c1c[nH]c2nccc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)CC(=O)c1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(dimethylamino)-1-(4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone (80 mg, 0.22 mmol) in a mixed solvent (5 mL of THF and 5 mL of MeOH) were added ammonium chloride (64.2 mg, 1.2 mmol, EMD) and Zn dust (78.4 mg, 1.2 mmol, Aldrich). The reaction mixture was stirred at room temperature overnight, diluted with 30 mL of EtOAc and filtered through a pad of Celite®. The filtrate was concentrated in vacuo and the resulting residue was purified by preparative HPLC. The desired fractions were combined, neutralized with saturated aq. NaHCO3 solution, and concentrated in vacuo. The solid that formed was collected by filtration (51 mg, 71%). MS(ESI+) m/z 328.1 (M+H)+.