Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](=O)[CH3:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[OH:19][CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)[CH2:21][NH2:22].O>C1C=CC=CC=1>[Cl:29][C:25]1[CH:24]=[C:23]([CH:20]([CH2:21][NH:22][CH:16]([CH3:17])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[CH:10][CH:11]=2)[OH:19])[CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)Cc1ccc(OCc2ccncc2)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Solvent: O
Solvent: c1ccccc1
Product: CC(Cc1ccc(OCc2ccncc2)cc1)NCC(O)c1cccc(Cl)c1
Reaction time: 1 h

Procedure:
A mixture of 1-[4-(4-pyridylmethyloxy)phenyl)propan-2-one (2.5 g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (1.78 g) in benzene (100 ml) was boiled under reflux with azeotropic removal of water until the reaction was complete. The solvent was evaporated, the residue dissolved in methanol (150 ml), cooled in an ice bath and treated with sodium borohydride (1.0 g). After stirring for 1 hour the methanol was evaporated, the residue partitioned between ethyl acetate and water, the washed organic phase dried and evaporated to give an oil which was chromatographed on Kieselgel 60. Elution with 4% methanol in chloroform gave 3-chloro-α-[[[2-[4-[4-pyridylmethyloxy)phenyl]-1-methylethyl]amino]methyl]benzenemethanol m.p. 85°-110° C. (ethylacetate-ether) as a 45:55 mixture of diastereoisomers.
Reaction SMILES: [C:1]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[N:12]([CH3:25])[C:11]2=[O:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Br[C:36]1([C:42]([O:44]C)=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>CC(O)(C)C>[C:1]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:36]4([C:42]([OH:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:22][CH:23]=3)[N:12]([CH3:25])[C:11]2=[O:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1C(=O)N(Cc2ccc(C(C)(C)C)cc2)CC1CCCc1ccc(O)cc1
Reactant: COC(=O)C1(Br)CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CN1C(=O)N(Cc2ccc(C(C)(C)C)cc2)CC1CCCc1ccc(OC2(C(=O)O)CCCCC2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A mixture of 1-(4-tert-butyl-benzyl)-4-[3-(4-hydroxy-phenyl)-propyl]-3-methyl-imidazolidin-2-one (0.074 g, 0.194 mmol) and potassium tert-butoxide (0.044 g, 0.392 nmol) in 2-methyl-2-propanol (8 mL) was heated to 60° C. under N2 and then and methyl 1-bromocyclohexanecarboxylate (0.274 g, 1.16 mmol) was added dropwise to the to 60° C. solution. Additional potassium tert-butoxide (0.044 g, 0.392 mmol) and methyl 1-bromocyclohexanecarboxylate (0.274 g, 1.16 mmol) was added to the reaction and it was stirred for 2 h. The reaction mixture was cooled and quenched with 1 N HCl. The mixture was then diluted with water and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford 0.400 g of crude product that was purified by preparative HPLC to give 0.059 g (60%) 1-(4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-cyclohexanecarboxylic acid. 1H NMR. HRMS (ES+) m/z exact mass calcd for C31H43N2O4 [M+1] 507.3223, found 507.3237.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[N:24]=2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ccnc(Cl)n2)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(c2nccc(-c3ccc(C(=O)Nc4ccccc4NC(=O)OC(C)(C)C)cc3)n2)CC1
Yield: 70.2 %

Procedure:
Using an analogous procedure to that described in Method 41, the N-(2-t-butoxycarbonylaminophenyl)-4-(2-chloropyrimidin-4-yl)benzamide (Method 52, 59 mg, 0.14 mmol) was reacted with 1-methylpiperazine (77 mg, 0.69 mmol) and residue purified by flash chromatography eluting with methanol/dichloromethane (0-20%) to give the title compound (48 mg, 71%); Mass Spectrum: M+H+ 489.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=[O:3].[CH2:11](O)[CH2:12][OH:13]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2([CH3:1])[O:13][CH2:12][CH2:11][O:3]2)=[CH:5][CH:6]=1
Reactant: OCCO
Reactant: CC(=O)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(c2ccc(Br)cc2)OCCO1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
A mixture of 4-bromoacetophenone (1 Scheme 19, 20.0 g, 0.1 mol) and ethylene glycol (12.5 g, 0.2 mol) and p-toluenesulfonic acid (200 mg) in benzene (400 mL) was refluxed in a Dean Stark apparatus for 6 h. The reaction mixture was cooled to room temperature, and the solution was extracted with H2O/ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), and concentrated to give a colorless oil (23 g, 96%); 1H NMR (300 MHz, CDCl3) δ 1.63 (s, 3 H), 3.76 (m, 2 H), 4.04 (m, 2 H), 7.37 (d, J=8.40 Hz, 2 H), 7.47 (d, J=8.40 Hz, 2 H); 13C NMR (75 MHz, CDCl3) 27.6, 64.5 (2C), 108.4, 121.9, 127.2 (2C), 131.4 (2C), 142.5
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5](O)=[O:6].C[N:13](C=O)C>S(Cl)(Cl)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([NH2:13])=[O:6]
Reactant: Cc1cc(C)cc(C(=O)O)c1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1cc(C)cc(C(N)=O)c1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
3,5-Dimethylbenzoic acid (50 g, 0.33 M, Aldrich) was suspended in thionyl chloride (150 mL) and DMF (0.5 mL) was added. The mixture was then refluxed for 2.5 hr. Excess thionyl chloride was evaporated in vacuo and the residue was added dropwise to ammonium hydroxide solution (ACS, 250 ml) cooled in an ice bath. The mixture was stirred for further 30 min. The white precipitate was then filtered, washed with water several times, and dried by standing on air. The crude product was dissolved in MC, washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to afford 42 g (85%) of 3,5-dimethylbenzamide as a white solid. m.p. 148-149° C. 1H NMR (200 MHz, CDCl3) δ 2.35 (6H, s), 6.01 (2H, br. s), 7.15 (1H, s), 7.42 (2H, s).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][OH:13])[CH:6]=1)=[O:4].[CH3:14][N:15]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:16]1C=C[CH:19]=[C:18]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=1>CC(=O)CC>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:22]([CH:18]([CH3:19])[CH2:17][CH2:16][N:15]([CH3:14])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:6][C:7]=1[CH2:12][OH:13]
Reactant: CN(c1ccccc1)c1cccc(NCc2ccccc2)c1
Reactant: O=C(CBr)c1ccc(O)c(CO)c1
Solvent: CCC(C)=O
Product: CC(CCN(C)c1ccccc1)N(CC(=O)c1ccc(O)c(CO)c1)Cc1ccccc1
Yield: 66.6 %

Procedure:
A solution of 2-bromo-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanone (9.1 g) and N-methyl-N-phenyl-N'-(phenylmethyl)-1,3-benzenediamine (16.6 g) in butanone (200 ml) was heated under reflux for 4 hours. The mixture was cooled at 0° and the amine hydrobromide was filtered off. The filtrate was evaporated and a solution of the residue in 2 N hydrochloric acid (200 ml) was extracted with ethyl acetate. The acidic solution was basified with solid sodium bicarbonate and then extracted with ethyl acetate. The solvents were evaporated to give a brown gum (10.7 g). The crude product in ethyl acetate was filtered through a column of silica (100 g) to yield a light brown gum (7.9 g).
Reaction SMILES: [H-].[Na+].I[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C.[CH3:11][C:12]1([CH3:37])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=3)[CH:20]=2)[N:15]=[C:14]([S:35][CH3:36])[CH2:13]1>C1COCC1>[CH3:37][C:12]1([CH3:11])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=3)[CH:20]=2)[N:15]=[C:14]([S:35][CH2:36][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:13]1
Reactant: CCCCCCCI
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(SC)=N3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCSC1=Nc2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc2C(C)(C)C1

Procedure:
0.025 g (0.694 mmol) of sodium hydride in 2 ml of THF, 0.229 g (0.631 mmol) of ethyl 4-[(4,4-dimethyl-2-thio-1,2,3,4-tetrahydro-6-quinolinyl)ethynyl]benzoate (Compound 8) in 2 ml of THF and 1.03 ml (6.31 mmol) of iodoheptane were reacted substantially in accordance with the procedure used for the preparation of ethyl 4-[(4,4-dimethyl-2-methylthio-3,4-dihydro-6-quinolinyl)ethynyl]benzoate (Compound 9). Purification by flash chromatography (silica gel, 10% ethyl acetate in hexane) yielded the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C1CCC(O)(c2ccc(Br)cn2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(Br)cn3)CC2)C1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-(5-bromo-pyridin-2-yl)-4-hydroxy-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([N:13]([CH3:38])[C@H:14]([C:18]([N:20]([CH3:37])[C@H:21]([C:34]([NH2:36])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1)=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH:5]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]([C:11]([N:13]([CH3:38])[C@H:14]([C:18]([N:20]([CH3:37])[C@H:21]([C:34]([NH2:36])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:31])([CH3:32])[CH3:33])[CH:24]=1)=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH:5]=1
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1cccc(F)c1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@@H](N)Cc1cccc(F)c1
Reaction time: 0.25 h
Yield: 86.8 %

Procedure:
To a solution of Boc-Phe(3-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.33 g, 0.525 mmol) in methylene chloride (3 ml), TFA (1.5 ml) was added, stirred for 15 min. and then evaporated to remove the solvent under reduced pressure. The residue was mixed with methylene chloride, washed with a saturated aqueous NaHCO3 solution, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:aqueous ammonia=40:1:0.1) to give Phe(3-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (241 mg, 87%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:9]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17](O)=[O:18])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br.Br.[S:37]1[C:41]2[CH2:42][CH:43]([NH2:46])[CH2:44][CH2:45][C:40]=2[N:39]=[C:38]1[NH2:47]>>[NH2:47][C:38]1[S:37][C:41]2[CH2:42][CH:43]([NH:46][C:17]([C@@H:13]3[CH2:14][CH2:15][CH2:16][N:12]3[C:10](=[O:11])[C@H:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:18])[CH2:44][CH2:45][C:40]=2[N:39]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)[C@H](CC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: Nc1nc2c(s1)CC(N)CC2
Agent: Br
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)[C@H](CC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)NC1CCc2nc(N)sc2C1
Yield: 65 %

Procedure:
The title compound was prepared from (2S)-1-((2R)-2-{(tert-butoxycarbonyl)[2-(tert-butoxy)-2-oxoethyl]amino}-3-cyclohexylpropanoyl)-2-pyrrolidinecarboxylic acid and 4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine dihydrobromide according to the procedure of EXAMPLE 25, and was obtained as a white solid.
Reaction SMILES: Cl[CH:2]1[NH:6][C:5]2=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][C:10]([F:11])=[C:4]2[O:3]1.[N+:16](C1C=CC=CC=1O)([O-])=O.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[NH2:16][C:2]1[O:3][C:4]2[C:5](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][C:10]=2[F:11])[N:6]=1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: COC(=O)c1ccc(F)c2c1NC(Cl)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)c2oc(N)nc12
Yield: 26.2 %

Procedure:
A mixture of methyl 2-chloro-7-fluoro-2,3-dihydrobenzoxazole-4-carboxylate (720 mg, 3.14 mmol), o-nitrophenol (660 mg, 4.71 mmol) and K2CO3 (0.96 g, 7.0 mmol), in THF (10 mL), was stirred at ambient for 2.5 h. The reaction mixture was filtered and gaseous ammonia was bubbled through the mother liquor for 10 min. The precipitate formed was filtered and washed with THF (20 mL). The combined THF fractions were concentrated, and the resulting residue crystallized from methanol to afford methyl 2-amino-7-fluorobenzoxazole-4-carboxylate (173 mg, 26%) as a pale yellow solid. 1H NMR and MS consistent.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].C(O[CH2:20][C:21]([F:37])=[CH:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=2[F:36])[CH2:25][CH2:24]1)(=O)C>O1CCCC1>[F:37][C:21]([CH2:20][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)=[CH:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][C:27]=2[F:36])[CH2:24][CH2:25]1
Reactant: Brc1cccc(Oc2ccccc2)c1
Reactant: CC(=O)OCC(F)=CC1(c2ccc(C(F)(F)F)cc2F)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(=CC1(c2ccc(C(F)(F)F)cc2F)CC1)Cc1cccc(Oc2ccccc2)c1
Yield: 28.3 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 3-phenoxyphenyl bromide (0.26 g), tetrahydrofuran (2 ml) and magnesium (22 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(2-fluoro-4-trifluoromethylphenyl)cyclopropane (Example 21) (0.1 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: C8; solvent: methanol; flow rate: 2 ml/min) to afford 1-(2-fluoro-3-(3-phenoxyphenyl) prop-1-enyl)-1-(2-fluoro-4-trifluoromethylphenyl)cyclopropane (38 mg, 27%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Li]CCCC.N1([CH:25]=[O:26])CCCCC1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[N:7]1[C:2]([CH:25]=[O:26])=[CH:3][CH:4]=[CH:5][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Brc1cccc(-c2ccccn2)n1
Reactant: O=CN1CCCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1cccc(-c2ccccn2)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A cooled (−78° C.) solution of commercially available 6-bromo-2,2′-bipyridine (600 mg; 2.55 mmol) in anh. THF (10 ml) was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (1.60 ml; 2.56 mmol), and the resulting mixture was further stirred at −78° C., under nitrogen, for 30 min. Piperidine-1-carbaldehyde (577 mg; 5.10 mmol) was added dropwise to the cooled (−78° C.) reaction mixture, and stirring was continued at −78° C. for 30 min. Aq. sat. NH4Cl (25 ml) and AcOEt (50 ml) were added, and the separated organic layer was further washed with brine (20 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (toluene/AcOEt=8/2) afforded [2,2′-bipyridine]-6-carbaldehyde as a dark-purple solid. LC-MS (conditions C): tR=0.75 min.; [M+H]+: 185.24 g/mol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[C:24]([N+:26]([O-])=O)[CH:25]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)=[O:8])([O-])=O.O1CCOCC1>Cl>[NH2:1][C:4]1[CH:5]=[C:6]([CH:23]=[C:24]([NH2:26])[CH:25]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(c1ccc(C#Cc2ccccc2)cc1)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cc(N)cc(C(=O)c2ccc(C#Cc3ccccc3)cc2)c1
Temperature: 25 °C
Yield: 79.1 %

Procedure:
To a 1 L Erlenmeyer flask equipped with a magnetic stirrer was charged 3,5-dinitro-4'-phenylethynylbenzophenone (19.6 g, 0.053 mol) and 1,4-dioxane (450 mL). The orange solution was cooled to ~10°-15° C. by means of an ice bath. A cooled solution (~10° C.) of stannous chloride dihydrate (78.4 g, 0.35 mol) in concentrated hydrochloric acid (300 mL) was added dropwise while maintaining the temperature between 10°-20° C. After the addition, the ice bath was removed and the reaction mixture allowed to warm to room temperature. The mixture was stirred at room temperature for ~16 h. During this time the product precipitated from solution. The solid was collected, placed in distilled water and neutralized with aqueous ammonium hydroxide. The crude material was collected by filtration, washed in water and dried at 65° C. for 1 h in flowing air to afford 16.0 g (98%) of a crude solid. The crude product was recrystallized form toluene to afford 13.1 g (80%) of a yellow powder, mp (DSC, 10° C./min) 156° C. Anal. calcd. for C21H16N2O: C, 80.74%; H, 5.16%; N, 8.97%; Found: C, 80.73%; H, 5.10%; N 8.98%.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1>CO.[OH-].[Na+]>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:16])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(-c2ccccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2ccccn2)cc1

Procedure:
12.85 g (60.2 mmol) of 4-(pyridin-2-yl)-benzoic acid methyl ester in 125 ml of methanol and 67 ml of 1N sodium hydroxide solution are stirred at room temperature for 6 hours. The resulting solution is partially concentrated by evaporation; the aqueous residue is extracted with ethyl acetate and acidified to pH≈1.5 with 2N HCl solution. The title compound precipitates out and can be filtered off and washed with water: TLC (ethyl acetate): Rf=0.35; FAB MS (M+H)+=200.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[S:8][C:7]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([S:18]([CH2:21][C:22]([O:24]C)=[O:23])(=[O:20])=[O:19])=[CH:17][C:11]=3[N:10]=2)=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[S:8][C:7]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([S:18]([CH2:21][C:22]([OH:24])=[O:23])(=[O:19])=[O:20])=[CH:17][C:11]=3[N:10]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)CS(=O)(=O)c1ccc2[nH]c(-c3ccc(Cl)s3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CS(=O)(=O)c1ccc2[nH]c(-c3ccc(Cl)s3)nc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
14.5 5 ml of aqueous 1 N sodium hydroxide solution are added to a solution of 1.04 g (2.81 mmol) of methyl [2-(5-chlorothiophen-2-yl)-1H-benzimidazole-5-sulfonyl]acetate in 50 ml of methanol, and the mixture is stirred at room temperature for 3 days. The reaction mixture is evaporated, and the residue is taken up in water. A pH of 2 is set by addition of conc. hydrochloric acid. The resultant precipitate is filtered off, washed with water and dried, giving [2-(5-chlorothiophen-2-yl)-1H-benzimidazole-5-sulfonyl]acetic acid as a brownish solid; ESI 357.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]=2[CH:17]=1.Cl.[N:19]([O-])=[O:20].[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([N:19]=[O:20])[CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]=2[CH:17]=1
Reactant: Cc1ccc2c(c1)OC(c1ccccc1)CN2
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)OC(c1ccccc1)CN2N=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7-Methyl-2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.4 g) was dissolved in ethanol (6.5 mL), and to it was added 1N HCl (6.5 mL). The reaction mixture was cooled to 0° C., and a solution of sodium nitrite (0.858 g) in water (23 mL) was added. After addition, the reaction mixture was stirred for 2 h at RT. The reaction was monitored by TLC. After completion of reaction, the mixture was evaporated and dried under high vacuum (1.5 g). The crude compound was carried forward to the next step without further purification.
Reaction SMILES: S(Cl)(Cl)=O.O[CH2:6][C:7]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:13]=1[CH3:21])([CH3:9])[CH3:8]>C(OCC)C>[CH3:9][C:7]1([CH3:8])[CH2:6][O:22][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:13]=2[CH3:21])=[N:10]1
Reactant: Cc1c(C(=O)NC(C)(C)CO)cccc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: Cc1c(C2=NC(C)(C)CO2)cccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Thionyl chloride, 37 ml, is added dropwise with stirring to 39.7 g (0.1575 mol) of N-(2-hydroxy-1,1-dimethylethyl)-2-methyl-3-nitrobenzamide. The mixture is allowed to stand overnight, poured into diethylether, filtered and the solvent evaporated to give 33.4 g of 4,5-dihydro-4,4-dimethyl-2-(2-methyl-3-nitrophenyl)oxazole as a pale yellow oil which crystallizes on cooling; mp 60°-61° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]32[CH2:12][CH2:11]3)=[CH:4][CH:3]=1.[O-:13][Mn](=O)(=O)=O.[K+]>CC(C)=O.[O-]S([O-])(=O)=O.[Mg+2]>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:13])[CH2:7][C:8]32[CH2:12][CH2:11]3)=[CH:4][CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Brc1ccc2c(c1)C1(CC2)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: O=C1CC2(CC2)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a solution of 6′-bromo-2′,3′-dihydrospiro[cyclopropane-1,1′-indene] (5.7 g, 25.6 mmol) in acetone (78 mL) and 1.5 M aq. MgSO4 (29 mL) was added KMnO4 (4.46 g, 28.2 mmol). The reaction was stirred overnight at room temperature. Upon completion, the reaction was filtered over celite and concentrated. The residue was partitioned between water (100 mL) and EtOAc (200 mL), and the layers were separated. The organic was washed with brine, dried over Na2SO4, then filtered and concentrated. 6′-bromospiro[cyclopropane-1,1′-inden]-3′(2′H)-one (2.11 g, 39% yield) was isolated as a white solid after flash chromatography over silica gel (5% EtOAc/hexane eluent). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.59 (d, J=8.3 Hz, 1H), 7.45 (dd, J=8.0, 1.5 Hz, 1H), 7.14 (d, J=1.3 Hz, 1H), 2.76 (s, 2H), 1.15-1.34 (m, 4H); MS (EI) m/z=238.1 [M+1]+.