Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=O.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(O)(=O)C.[Na].C(=O)([O-])O.[Na+]>ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH2:7][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Fc1ccc(Br)cc1CN1CCOCC1
Reaction time: 0.5 h

Procedure:
5-Bromo-2-fluorobenzaldehyde (2.5 g, 12.3 mmol) and morpholine (1.62 g, 18.5 mmol) are dissolved in 50 mL DCE and stirred for 0.5 h. Acetic acid (0.42 mL, 7.4 mmol) and sodium trisacetoxyboronhydride (3.92 g, 18.5 mmol) are added and the reaction mixture is stirred for 2 h. Then 50 mL of a saturated aqueous solution of sodium hydrogencarbonate is added and the reaction mixture is stirred for another 0.5 h. The reaction mixture is extracted with DCM and the combined organic phases are dried over MgSO4 and concentrated in vacuo. Yield: 3.02 g.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+]>CO>[Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CCl)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CCl)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Chloroacetophenone (5.0 g, 32 mmol) was dissolved in methanol (25 mL) and cooled to 0° C. Sodium borohydride (1.2 g, 32 mmol) was added and stirred at 0° C. for 30 minutes. The reaction mixture was neutralized by adding conc. HCI to pH 7.0 and evaporated to dryness. The residue was dissolved in ethanol (30 mL) and filtered, washed with ethanol. The ethanol was evaporated to dryness. The residue was dissolved in methylene chloride (20 mL) and dried over sodium sulfate. The methylene chloride solution was filtered and evaporated to give the desired product as an oil; yield 4.84 g (5.6%).
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[CH2:13][CH2:14][NH2:15])=[CH:5][CH:4]=1.[C:16](Cl)(=[O:18])[CH3:17]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2cccc(CCN)c2c1
Solvent: c1ccncc1
Product: COc1ccc2cccc(CCNC(C)=O)c2c1

Procedure:
0.01 ml of 2-(7-methoxynaphth-1-yl)ethylamine is dissolved in 6 ml of pyridine. The mixture is cooled in an ice bath with agitation, and 0.012 mol of acetyl chloride is added dropwise.
Reaction SMILES: [C:1](O)(=O)/[C:2](=[C:4](\[CH:6]=[O:7])/[Br:5])/[Br:3].Cl.Cl.[CH2:12]([NH:19][NH2:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C(O)C>[CH2:12]([N:19]1[C:6](=[O:7])[C:4]([Br:5])=[C:2]([Br:3])[CH:1]=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=c1c(Br)c(Br)cnn1Cc1ccccc1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
Alternatively, a suspension of mucobromic acid (80 g., 310 mmol.) and benzylhydrazine dihydrochloride (60 g., 310 mmol.) in ethanol was heated to reflux for 16 hours. It was cooled to r.t. and under vigourous stirring water (50 mL) was added. The suspension was cooled in an ice bath and then filtered. The solid was washed with 95% aqueous ethanol and air dried. It was swished in hexanes (200 mL) and diethyl ether (25 mL), filtered and air dried to yield the title compound(58 g.).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[NH:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:21]([O:27][CH2:28]Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH2:28][O:27][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=O)c2c(ncn2Cc2ccccc2)[nH]1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Benzylxanthine (8.66 g) was dissolved in N,N-dimethylformamide (300 ml); sodium hydride (1.57 g) and chloromethyl pivalate (7.7 ml) were added to the solution; and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and washed with water and 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then, the solvent was removed by distillation. The residue was purified by silica gel column chromatography to give 2.66 g of the title compound from the elution fraction of hexane-ethyl acetate 1:1.
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[CH2:18]([NH:25][CH2:26][CH2:27][O:28][C:29]1[CH:37]=[C:33]([C:34]([NH2:36])=[O:35])[C:32]([OH:38])=[CH:31][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)(C)C>[CH2:18]([N:25]([CH2:26][CH2:27][O:28][C:29]1[CH:30]=[CH:31][C:32]([OH:38])=[C:33]([C:34](=[O:35])[NH2:36])[CH:37]=1)[CH2:17][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC(=O)c1cc(OCCNCc2ccccc2)ccc1O
Reactant: c1ccc(-c2ccc(OCC3CO3)cc2)cc1
Solvent: CC(C)O
Product: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)COc2ccc(-c3ccccc3)cc2)ccc1O

Procedure:
A solution of 5.97 g of 4-(2,3-epoxypropoxy)-biphenyl and 6.87 g of 5-[2-(benzylamino)-ethoxy]-salicylamide in 140 ml of isopropanol is heated under reflux for 15 hours and the solvent is then removed in a rotary evaporator. The residue is recrystallised from diethyl ether, yielding 1-[N-benzyl-2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-(4-biphenyloxy)-2-propanol having a melting point of 135°-138°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([O:13][CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CCN(C)C(=O)OC(C)(C)C
Yield: 99.2 %

Procedure:
To a solution of 3-(tert-butoxycarbonyl(methyl)amino)propanoic acid (7.0 g, 0.032 mol) and K2CO3 (13.3 g, 0.096 mol) in DMF (100 mL) was added MeI (9.0 g, 0.064 mol) at rt. The resultant solution was stirred at rt for 3 hrs. The reaction mixture was quenched with ice water and extracted with ethyl acetate (2×). The combined organic layer was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution 0%˜10% EtOAc/petroleum ether) to afford methyl 3-(tert-butoxycarbonyl(methyl)amino)propanoate (6.9 g, 92%) as a white solid. ESI-MS (EI+, m/z): 118 [M−100+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[CH2:19][O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH:30](O)([CH3:32])[CH3:31]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[CH2:19][O:20][CH2:21][C:22]([O:24][CH:30]([CH3:32])[CH3:31])=[O:23])=[CH:4][CH:3]=1
Reactant: O=C(O)COCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)COCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
0.155 g (0.478 mmol) of 2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl) methoxy)acetic acid were solubilized with magnetic stirring in 5 ml of isopropanol and a drop of sulfuric acid was added. The mixture was stirred at 60° C. for 3 h. The reaction medium was washed with 2×10 ml of water, and then extracted with 2×30 ml of ethyl acetate. The combined organic phases were washed with 30 ml of a saturated NaCl aqueous solution, dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. 0.162 mg (yield=91%) of isopropyl 2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)-methoxy)acetate were obtained as a brown oil. LC-MS: m/z=367 (MH+); UV purity at 254 nm=98%. 1H NMR (300 MHz, DMSO) δ 8.62 (d, J=6.8 Hz, 1H), 7.74 (dd, J=8.7, 5.5 Hz, 2H), 7.67 (d, J=9.0 Hz, 1H), 7.45 (d, J=7.0 Hz, 1H), 7.33 (t, J=8.9 Hz, 2H), 7.12 (t, J=6.5 Hz, 1H), 4.93 (dt, J=12.5, 6.3 Hz, 1H), 4.78 (s, 2H), 4.19 (s, 2H), 1.15 (d, J=6.3 Hz, 6H).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7]([CH:22]=[CH:23][CH:24]=1)[CH2:8][CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:12]C(=O)[NH:10]1)([F:4])[CH3:3].[OH-].[Na+]>C(O)C.O>[NH2:10][CH:9]([CH2:8][C:7]1[CH:22]=[CH:23][CH:24]=[C:5]([C:2]([F:4])([F:1])[CH3:3])[CH:6]=1)[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[OH:12]
Reactant: CC(F)(F)c1cccc(CC2NC(=O)OC2c2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(F)(F)c1cccc(CC(N)C(O)c2ccc(F)cc2)c1
Yield: 79.7 %

Procedure:
To a solution of (4RS,5SR)-4-[3-(1,1-difluoroethyl)benzyl]-5-(4-fluorophenyl)-1,3-oxazolidin-2-one (3.83 g, 12.5 mmol) in ethanol (100 ml) was added 8N aqueous sodium hydroxide solution (7.8 ml, 39.0 mmol), and the mixture was heated under reflux for 5 hrs. After completion of the reaction, the mixture was diluted with water, and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from (hexane-ethyl acetate) to give (1RS,2SR)-2-amino-3-[3-(1,1-difluoroethyl)phenyl]-1-(4-fluorophenyl)-1-propanol (3.08 g, 88%) as colorless crystals.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].[ClH:39]>CO.[H][H]>[NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:15][CH:16]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].[ClH:39]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: Cl
Solvent: CO
Product: CC(C)[C@H](N)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)OC(C)(C)C

Procedure:
Pd-on-charcoal catalyst is added to a solution of 31 g (58.8 mmoles) of Z-Val-Tyr(But)-OBut in 300 ml of methanol and hydrogen is passed through the solution at pH 4.5 (autotitrator) while stirring and adding approx. 2 N methanolic hydrochloric acid, until no further methanolic hydrochloric acid is taken up. The catalyst is then filtered off and the filtrate is concentrated. The residue is triturated with ether, filtered off and dried. Yield 23.6 g (94%), melting point 159°-161°, [α]D20 =+19.4° (c=1, methanol).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.Cl.[NH2:11][CH2:12][CH2:13][C:14]1[N:15]=[CH:16][N:17]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)([CH3:25])[CH3:24])[CH:18]=1.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]([NH:22][CH2:21][CH2:20][CH2:19][N:17]2[CH:18]=[C:14]([CH2:13][CH2:12][NH:11][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:15]=[CH:16]2)([CH3:25])[CH3:24])=[CH:27][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(NCCCn1cnc(CCN)c1)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NCCCn1cnc(CCNC(=O)c2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
Triethylamine (0.46 g) was added to a stirred suspension of 3-[4-(2-aminoethyl)imidazol-1-yl]-N-[1-(4-chlorophenyl)-1-methylethyl]propylamine trihydrochloride, (0.65 g) in dichloromethane (25 ml) and the resulting solution cooled to 0° C. A solution of benzoyl chloride (0.21 g) in dichloromethane (10 ml) was added over 20 minutes at 0-5° C. with stirring. The mixture was stirred at ambient temperature for 2.5 hours. The solution was washed with sodium bicarbonate solution, then water, then dried, filtered and evaporated to give N-[2-(1-{3-[1-(4-chlorophenyl)-1-methylethylamino]propyl}imidazol-4-yl)ethyl]benzamide as an oil.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:12][NH2:13]>C(O)CO>[F:10][C:7]1[CH:6]=[C:3]2[C:4]([NH2:5])=[N:13][NH:12][C:2]2=[N:9][CH:8]=1
Reactant: N#Cc1cc(F)cnc1Cl
Reactant: NN
Solvent: O
Solvent: OCCO
Product: Nc1n[nH]c2ncc(F)cc12
Reaction time: 4 h

Procedure:
A suspension of 38.5 g (245.93 mmol) of 2-chloro-5-fluoronicotinonitrile was initially charged in 1,2-ethanediol (380 ml), and hydrazine hydrate (119.6 ml, 2.459 mol) was then added. The mixture was heated under reflux with stirring for 4 h. The product precipitated on cooling. Water (380 ml) was added to the yellow crystals, and the mixture was subjected to extractive stirring at RT for 10 min. The suspension was then filtered with suction over a frit, and the filter product was washed with water (200 ml) and with −10° C. cold THF (200 ml). The residue was dried under high vacuum over phosphorus pentoxide.
Reaction SMILES: [CH3:1][C:2]12[CH2:22][CH:6]([N:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:12]=3)=[O:10])[CH2:8]1)[CH2:5][C:4]([CH3:24])([CH3:23])[CH2:3]2.[H-].[Na+].[CH2:27](I)[CH3:28]>CN(C=O)C>[CH2:27]([N:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]([N:7]2[CH2:8][C:2]3([CH3:1])[CH2:22][CH:6]2[CH2:5][C:4]([CH3:24])([CH3:23])[CH2:3]3)=[O:10])=[CH:12][CH:13]=1)[S:18]([CH3:21])(=[O:19])=[O:20])[CH3:28]
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NS(C)(=O)=O)cc2)C1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(c1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1)S(C)(=O)=O
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of N-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-methanesulfonamide (300 mg, 0.86 mmol) in dry DMF (25 ml) was added sodium hydride (42 mg, 1.73 mmol in 60% mineral oil) and the mixture was stirred for 1 hr. Ethyl iodide (83 μl, 1.03 mmol) was added and the stirring was continued for an additional 16 hrs. The reaction was quenched by addition of water (25 ml) and extracted with diethyl ether (2×50 ml). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (silica gel) using EtOAc-Heptane (1:1) as eluent. Pure fractions were collected and evaporated to dryness affording a slowly crystallizing oil which was suspended in diethyl ether and the solid filtered off affording 140 mg (43%) of the title compound as a solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].Cl.[Cl:19][C:20]1[CH:21]=[C:22]([C@H:26]2[C@@H:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:30][CH2:29][NH:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:6]([N:28]2[CH2:29][CH2:30][C@H:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)[CH2:27]2)=[O:7])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: Clc1cccc([C@@H]2CNCC[C@@H]2c2ccccc2)c1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccccc2)[C@H](c2cccc(Cl)c2)C1

Procedure:
The title compound, MS: m/e=512.2 (M+), was prepared in accordance with the general method of example 1 from 3,5-bis(trifluoromethyl)benzoyl chloride and rac-cis-3-(3-chloro-phenyl)-4-phenyl-piperidine hydrochloride.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[N:7]3[CH2:13][CH2:12][CH2:11][C@H:8]3[CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:17][O-:18].[Na+]>CN(C)C=O.O>[CH3:17][O:18][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[N:7]3[CH2:13][CH2:12][CH2:11][C@H:8]3[CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: O=C1c2ccc(F)cc2OC[C@@H]2CCCN12
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC[C@@H]1CCCN1C2=O
Temperature: 110 °C

Procedure:
A solution of (S)-8-fluoro-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c][1,4]-benzoxazepine-5-one (0.5 g; 2.14 mmol), prepared as described in Example 5A, and sodium methoxide (0.244 g; 4.52 mmol) in dimethylformamide (2 mL) was heated at 110° C. for 3 h. The reaction was diluted with water and extracted with ethyl acetate and the organic layer washed with water then dried (Na2SO4) and evaporated in vacuo. The crude product was purified by chromatography on silica (eluting with 5% methanol in dichloromethane) to give the title product, m.p. 104-106° C.; EIMS: m/z=234 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[N:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1>C(O)C>[OH:10][C:9]1[C:4]2[C:5](=[CH:11][CH:12]=[C:2]([CH3:1])[CH:3]=2)[C:6](=[O:8])[C:19]=1[C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Reactant: Cc1ccncc1
Solvent: CCO
Product: Cc1ccc2c(c1)C(O)=C(c1ccncc1)C2=O
Temperature: 165 °C

Procedure:
A mixture of 47.5 g (293 mmol) 4-methyl-phthalic anhydride and 28.6 ml (293 mmol) 4-pi-coline is heated to 165° C. for 18 h. The resulting material is stirred in 190 ml of boiling ethanol, filtered and washed with ethanol and diethyl ether, yielding the title compound: An. calc. (C15H11NO2) C, 75.94%; H, 4.67%; N, 5.90%; O, 13.49%; An. meas. C, 75.60%; H, 4.64%; N, 6.02%; O, 13.60%; 1H NMR (DMSO-d6) δ8.70 (d, 2H), 8.14 (d, 2H), 7.34 (m, 2H), 7.29 (s, 1H), 2.38 (s, 3H); FAB MS (M+H)+=238.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+].[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>O>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Cc1ccc(-c2ccccc2F)cc1

Procedure:
47.6 g (0.21 mol) of methyl 4-bromophenylacetate are introduced under argon into 400 ml of absolute tetrahydrofuran and, at room temperature, 320 ml of 1M sodium carbonate solution and 40 g (0.28 mol) of 2-fluorophenylboronic acid are added. Addition of 7.0 g (0.01 mol) of bis(triphenylphosphane)palladium(II) chloride is followed by heating under reflux for 18 h. Cooling is followed by dilution with 500 ml of water and extracted three times with 300 ml of ethyl acetate each time. The combined organic phases are washed with 400 ml each of saturated ammonium chloride solution, water and saturated sodium chloride solution, dried over magnesium sulfate and freed of solvent in vacuo. Example V is obtained after silica gel filtration (petroleum ether/ethyl acetate 10:1) as a colorless oil.
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17]Br.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH2:17]1[C:12]2[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][C:2]21[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:1]2=[O:8]
Reactant: BrCc1ccccc1CBr
Reactant: O=C1CCCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCCCCC12Cc1ccccc1C2
Temperature: 85 °C
Reaction time: 20 h

Procedure:
A solution of cycloheptanone (5.30 mL, 45.0 mmol) and 1,2-bis(bromomethyl)benzene (11.88 g, 45.0 mmol) in toluene (65 mL) was treated all at once with potassium tert-butoxide (10.10 g, 90 mmol). The reaction stirred for 20 hours at 85° C. After this time, the mixture was washed with 25 mL water and 65 mL of 15% HCl, then the aqueous washes were extracted three times with ether. The combined organics were washed with brine, dried over Na2SO4, and evaporated to a yellow oil, which was purified by chromatography on silica gel (93:7 to 85:15 EtOAc-hexane, eluant) to afford the title compound. 1H NMR (300 MHz, d6-DMSO) δ 7.09-7.18 (m, 4H), 3.26 (d, J=16.0 Hz, 2H), 2.75 (d, J=16.0, 2H), 2.59 (m, 2H), 1.84 (m, 2H), 1.57-1.66 (m, 4H), 1.47 (m, 2H). MS (DCI+) m/z 215 (M+H, 232 (M+NH4).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@@H:12]3[CH2:16][C@H:5]([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[C:3]=1[C:17](O)=O.[CH3:20][N:21]([CH3:40])[S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[CH2:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:24])=[O:23]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@@H:12]3[CH2:16][C@@:5]([CH2:4][N:37]4[CH2:38][CH2:39][CH:34]([CH2:33][C:26]5[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:25]=5[S:22](=[O:24])(=[O:23])[N:21]([CH3:20])[CH3:40])[CH2:35][CH2:36]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:17]=2[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N(C)C)c(CC2CCNCC2)c1
Reactant: O=C(O)c1c(Cl)ccc2c1[C@@H]1C[C@@H]2c2ccccc21
Product: COc1ccc(S(=O)(=O)N(C)C)c(CC2CCN(C[C@]34C[C@H](c5ccccc53)c3ccc(Cl)cc34)CC2)c1

Procedure:
Using a procedure similar to that described in Example 55a, except starting with (9R,10R)-2-chloro-9,10-dihydro-9,10-methanoanthracenecarboxylic acid, prepared as described in Example 2a, and 4-(2-dimethylsulfamoyl-5-methoxyphenylmethyl) piperidine, prepared as described in Example 58e, the title compound was obtained as a white solid (617 mg, 1.09 mmol, 57%)
Reaction SMILES: O=[C:2]1[CH:7]([CH2:8][C:9]([OH:11])=O)[CH2:6][S:5][C:4]2[S:12][CH:13]=[CH:14][C:3]1=2.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1>C(O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:9](=[O:11])[CH2:8][CH:7]3[CH2:6][S:5][C:4]4[S:12][CH:13]=[CH:14][C:3]=4[C:2]3=[N:23]2)=[CH:18][CH:17]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=C(O)CC1CSc2sccc2C1=O
Solvent: CCO
Product: O=C1CC2CSc3sccc3C2=NN1c1ccc(Cl)cc1
Yield: 73.3 %

Procedure:
A mixture of 4.0 g of 4-oxo-5,6-dihydro-4H-thieno-[2,3-b]thiopyran-5-acetic acid and 3.3 g of 4-chlorophenylhydrazine in 70 ml of ethanol is refluxed under heating for 6.5 hours. After cooling, the reaction mixture is concentrated under reduced pressure. The residue is dissolved in 50 ml of acetic acid and the solution is refluxed under heating for 2 hours. Then, the resultant mixture is concentrated under reduced pressure, the residue is subjected to chromatography on silica gel and eluted with chloroform. The crystals obtained from the fraction are recrystallized from a mixed solvent of chloroform and ethanol to give 4.3 g of 2-(4-chlorophenyl)-4a,5-dihydro-2H-thieno[2',3':2,3]thiopyrano[4,5-c]pyridazin-3(4H)-one as pale brown crystals, melting at 162°-164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCCC)[NH:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[C:33]([O:37][C:38]([N:40]1[CH2:43][CH:42]([NH:44][CH3:45])[CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([N:40]1[CH2:41][CH:42]([N:44]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][C:4]=3[C:29]([F:32])([F:30])[F:31])[N:8]=[CH:9]4)[C:18](=[O:26])[N:19]=2)[CH3:45])[CH2:43]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CCCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNC1CN(C(=O)OC(C)(C)C)C1
Product: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1)C1CN(C(=O)OC(C)(C)C)C1

Procedure:
3-({5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-azetidine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazolidin-4-one and 3-Methylamino-azetidine-1-carboxylic acid tert-butyl ester following General Procedure B.