Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:21][C:20]([CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:35])[CH2:9]2)=[C:4]([C:36]([F:39])([F:38])[F:37])[CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:21][C:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:35])[CH2:9]2)=[C:4]([C:36]([F:38])([F:37])[F:39])[CH:3]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(C2CCNCC2)s1
Yield: 60.3 %

Procedure:
Prepared according to the synthesis of Example 29EY in Step 4C from (R)-tert-butyl 4-(5-(4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)thiophen-2-yl)piperidine-1-carboxylate (150 mg, 0.253 mmol) in DCM (3 mL) and TFA (1 mL), purified by SiO2 column eluted with EtOAc/MeOH to give the titled compound as a white solid (75 mg, 60%). HRMS: calcd for C21H25F4N3O2S2+H+, 492.13970. found (ESI-FTMS, [M+H]1+), 492.14043.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]([CH3:10])=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]([CH3:10])=[N:4][C:3]=1[C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2nc(C)n(C(C)C)c2Cl)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nc(-c2ccc(O)cc2)c(Cl)n1C(C)C

Procedure:
This compound is prepared in a manner analogous to that of Step H of Example 1, using 2.6 grams (0.010 mole) of 5-chloro-1-(1-methylethyl)-4-(4-methoxyphenyl)-2-methylimidazole and 20 mL (0.020 mole) of 1M boron tribromide (in methylene chloride) in 50 mL of methylene chloride, yielding 4-[5-chloro-1-(1-methylethyl)-2-methylimidazol-4-yl]phenol.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.N1C=CC=CC=1>C(Cl)Cl>[N:8]1([C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: C1COCCN1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)N1CCOCC1

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (2.64 g, 2 mL, 18.5 mmol) was reacted with morpholine (1.69 g, 1.7 mL, 19.4 mmol) and pyridine (1.68 g, 1.72 mL, 21.2 mmol) in methylene chloride (25 mL) at room temperature overnight to give the crude product, 1-chloroethyl morpholine-4-carboxylate. A portion of 1-chloroethyl morpholine-4-carboxylate (670.1 mg, 3.46 mmol) was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (200.5 mg, 0.325 mmol) in the presence of cesium carbonate (1.094 g, 3.36 mmol) in dimethylformamide (7 mL) overnight to give, 1-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)ethyl morpholine-4-carboxylate as an off-white solid (186.5 mg, 74% yield). MS (ES+) m/z calcd. for C38H41Cl2F2N4O7: [(M+H)+]: 773, found: 773
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15](O)=[O:16])[O:12][C:13]=2[CH3:14])=[CH:3][CH:2]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH2:34])(=[O:33])=[O:32].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.O1CCCC1.C(#N)C>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:2]=[CH:3][C:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]([NH:34][S:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH3:24])(=[O:32])=[O:33])=[O:16])[O:12][C:13]=2[CH3:14])=[CH:5][CH:6]=1
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: Cc1oc(C(=O)O)cc1COc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1cc(COc2ccc(-c3ccccc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.7 %

Procedure:
A stirred solution of 4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (18) (50 mg, 0.162 mmoles), 2-methyl-benzenesulphonamide (42 mg, 0.243 mmoles) and 4-(N,N-dimethylamino)-pyridine (2.5 mg) in a mixture of tetrahydrofuran (8 ml) and acetonitrile (2 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38 mg, 0.194 mmoles). The mixture was stirred at room temperature for 16 hours under an argon atmosphere. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to afford compound 60 (20 mg) as a white solid. LC/MS System D; Rt=11.09 mins, m/z (ES+)=462 (M+H for C26H23NO5S).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[Br:26][C:27]1[C:28](B(O)O)=[CH:29][S:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[Br:26][C:27]1[C:28]([C:2]2[N:6]([S:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)=[CH:29][S:30][CH:31]=1
Reactant: OB(O)c1cscc1Br
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1cc(-c2cscc2Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), (4-bromo-3-thienyl)boronic acid (248 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (116 mg), the title compound was obtained as a pale-yellow oil (yield 470 mg, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1C1C=C(Cl)C=CC=1OCC1C=CC=CC=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:33]=2I)=[CH:26][CH:25]=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:33]1[CH:34]=[C:35]([C:38]([F:41])([F:40])[F:39])[CH:36]=[CH:37][C:32]=1[O:31][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=1
Reactant: Fc1ccc(COc2ccc(C(F)(F)F)cc2I)cc1
Reactant: Clc1ccc(OCc2ccccc2)c(-c2ccccc2Br)c1
Product: Fc1ccc(COc2ccc(C(F)(F)F)cc2-c2ccccc2Br)cc1

Procedure:
Prepared as for 2′-bromo-5-chloro-2-[(phenylmethyl)oxy]biphenyl but using 1-{[(4-fluorophenyl)methyl]oxy}-2-iodo-4-(trifluoromethyl)benzene instead of 4-chloro-2-iodo-1-[(phenylmethyl)oxy]benzene.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]([O:14]C(C)(C)C)=O)=[CH:10][C:5]=2[CH2:4][O:3]1.[C:19](O)([C:21](F)(F)F)=O.C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C=O)C>[C:2]1(=[O:1])[C:6]2[CH:7]=[C:8]3[C:9](=[CH:10][C:5]=2[CH2:4][O:3]1)[CH2:11][C:12](=[O:14])[CH2:21][CH2:19]3
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Cc1ccc2c(c1)COC2=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C1CCc2cc3c(cc2C1)COC3=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a flask charged with tert-butyl (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetate (375 mg, 2.0 mmol) was added TFA (10 mL). The mixture was allowed to sit at RT for half an hour. LC at that point indicated complete cleavage of the tert-butyl group. The volatiles were removed under reduced pressure. The residue was pumped under high vacuum for 15 minutes before DCM (20 mL) was added to the flask, followed by addition of oxalyl chloride (0.22 mL, 2.5 mmol) and a drop of DMF. The mixture was stirred at RT for 1 hour, and then cooled to 0° C. with an ice bath. Aluminum chloride (780 mg, 5.9 mmol) was added into the reaction. After stirring the solution for 10 minutes, ethylene was bubbled through the reaction with a needle. TLC showed consumption of all material within 1 hour. The crude reaction was dumped into ice, and extracted with DCM (100 mL×3). The extractions were combined, washed with brine, dried over sodium sulfate, adsorbed onto silica gel, and purified by MPLC. The solvent was removed under reduced pressure to afford 7,8-dihydronaphtho[2,3-c]furan-1,6(3H,5H)-dione,
Reaction SMILES: C[O-].[Na+].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.O.Cl>CO>[NH:13]1[CH2:14][CH:15]=[C:16]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][CH:5]=2)[CH2:17][CH2:18]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C1=C(c2c[nH]c3ccccc23)CCNC1

Procedure:
To a solution of sodium methoxide (450 ml, 30% in methanol, 2.5 mol) in 1000 ml of methanol was added indole (50 g, 0.427 mol) and 4-piperidone.H2O.HCl (162 g, 1.05 mol). The mixture was heated under reflux for 18 h forming a yellow precipitate. The mixture was concentrated and water (1000 ml) was added. The precipitate was collected, washed with water and petroleum ether and then dried in a vacuum oven at 50° C. Yield 77 g (91%) of a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH:23]1([CH2:26][N:27]2[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[N:28]2)[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:20])([F:21])[F:22])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:33][CH2:32][C:29]2[CH:30]=[CH:31][N:27]([CH2:26][CH:23]3[CH2:25][CH2:24]3)[N:28]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: NCc1ccn(CC2CC2)n1
Product: O=C(NCc1ccn(CC2CC2)n1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CAN 1018782-82-5) and (1-(cyclopropylmethyl)-1H-pyrazol-3-yl)methanamine (example BW) as starting materials, MS (EI) 465.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH:10](C(OC)=O)[C:11]([O:13]C)=[O:12])[CH:5]=[C:4]([CH3:19])[CH:3]=1.[ClH:20]>>[ClH:20].[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:4]([CH3:19])[CH:3]=1
Reactant: COC(=O)C(CCc1cc(C)cc(N)n1)C(=O)OC
Agent: Cl
Product: Cc1cc(N)nc(CCCC(=O)O)c1
Temperature: 25 °C
Yield: 58 %

Procedure:
A mixture of dimethyl (2-(6-amino-4-methyl-2-pyridinyl)ethyl)malonate (34 mg, 0.13 mmol) in 2.0 mL of 2.0 N hydrochloric acid was refluxed for 8 h. After cooling to room temperature, the reaction was extracted with 2×15 mL of dichloromethane and the aqueous phase was concentrated in vacuo to give 17 mg (58% yield) of 4-(6-amino-4-methyl-2-pyridinyl)butanoic acid hydrochloride.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:29](=O)(O)[O-].[Na+]>CO.Cl>[OH:25][C@@H:23]1[CH2:22][CH2:21][C@@:20]2([CH3:26])[CH:19]([CH2:18][C@@H:17]([OH:27])[C@@H:16]3[C@@H:15]2[CH2:14][CH2:13][C@@:12]2([CH3:28])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]([O:7][CH3:29])=[O:6])[CH2:24]1
Reactant: O=C([O-])O
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 80 °C

Procedure:
CDCA (1.00 g, 2.50 mmol) was dissolved in methanol (43 mL), refluxed at 80° C., and then 12 drops of conc. hydrochloric acid (HCl) was added to this solution. The reaction mixture was heated at reflux for 2.5 h, cooled to room temperature, neutralized with a saturated solution of sodium bicarbonate, and the solvent was removed. 15 mL of water was added to the mixture, and the crude product was extracted with EtOAc (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated, and the crude product was chromatographed (SiO2, gradient, hexane/EtOAc 1:2 to EtOAc only) to give 1.08 g (2.64 mmol, >100%, less dry) of 25 as a white solid. Rf 0.40 (EtOAc); 1H NMR (400 MHz, CDCl3) 3.80 (m, 1H, H-3/H-7), 3.63 (s, 3H, CO2CH3), 3.40 (m, 1H, H-3/H-7), 2.35-0.93 (m, 28H), 0.89 (d, 3H, J=6.5 Hz, CH3), 0.87 (s, 3H, CH3), 0.62 (s, 3H, CH3); MS (ESI) Calcd for C25H42O4Na (M+Na+): 429.3. Found: 429.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:10]=[C:11]([O:18][C@@H:19]([C@@H:21]3[CH2:25][C:24](=[O:26])[NH:23][CH2:22]3)[CH3:20])[C:12]3[N:13]([N:15]=[CH:16][CH:17]=3)[CH:14]=2)[CH:6]=[CH:5][C:4]=1[N:27]1[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:10]=[C:11]([O:18][C@@H:19]([C@H:21]3[CH2:22][NH:23][C:24](=[O:26])[CH2:25]3)[CH3:20])[C:12]3[N:13]([N:15]=[CH:16][CH:17]=3)[CH:14]=2)[CH:6]=[CH:5][C:4]=1[N:27]1[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]1.[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41]
Reactant: COc1cc(-c2cn3nccc3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cn3nccc3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-butyl 4-(2-methoxy-4-(4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazin-6-yl)phenyl)piperazine-1-carboxylate 5.47 (51 mg, 0.1 mmol) was dissolved in TFA (4 mL, 52.23 mmol) and mixture was stirred at room temperature. After 4 hours, reaction mixture was concentrated and azeotroped with toluene to yield (R)-4-((R)-1-((6-(3-methoxy-4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one 5.48 as a trifluoroacetic acid salt (40 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:14][CH2:13]1)[CH:7]=O)([O-:3])=[O:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:13][CH2:14][CH:15]([CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:16][CH2:17]1)[CH2:7][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)([O-:3])=[O:2]
Reactant: C1COCCN1
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)c([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cc(CN2CCOCC2)ccc1N1CCC(CN2CCCC2)CC1

Procedure:
Prepared from the product of Example 64 and morpholine.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH3:11][NH:12][C:13]([N:15]1[CH2:18][CH:17](OS(C)(=O)=O)[CH2:16]1)=[O:14]>CN(C)C=O.O>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH:17]1[CH2:18][N:15]([C:13]([NH:12][CH3:11])=[O:14])[CH2:16]1
Reactant: CNC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: Oc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)N1CC(Oc2cccc(F)c2)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
A stirred slurry of 0.38 g (0.02 mole) of 60% sodium hydride as a mineral oil suspension in 10 ml of dry dimethylformamide was treated under nitrogen with the dropwise addition of 1.12 g (0.01 mole) of 3-fluorophenol in 20 ml of dimethylformamide. After 1 hr, the mixture was heated at 90° C. for 20 min then 2.1 g (0.01 mole) of N-methyl-3-[(methanesulfonyl)oxy]-1-azetidinecarboxamide was added as a solid. The reaction mixture was then stirred at 90° C. for 8 hr. The reaction mixture was cooled by adding ice water then further diluted to 200 ml with water and extracted with 3×50 ml of methylene chloride. Less than 1 g of oil was obtained upon concentrations of the extracts. Extraction with 4×50 ml of benzene gave only a trace of product. The mass spectrum (CI) showed the expected p+1 at 225 m/e. The product solidified on standing and was recrystallized from methanol/water to yield 650 mg (29.0%) of flake-like silver crystals, m.p. 156°-158° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)=[CH:17][CH:18]=2)[N:13]=1.C(#N)C>O>[CH3:28][C:24]1[CH:23]=[C:22]([C:16]2[N:15]=[C:14]3[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)=[N:13]3)=[CH:18][CH:17]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)c1cccc(Br)c1
Reactant: Cc1cccc(-c2ccc3ccc(N)nc3n2)c1
Solvent: O
Solvent: CC#N
Product: Cc1cccc(-c2ccc3ccc(NC(=O)c4cccc(Br)c4)nc3n2)c1
Temperature: 4 °C
Yield: 23.4 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with 3-bromobenzoic acid (2.8 g), N,N'-carbonyldiimidazole (2.3 g) and 2-amino-7-(3-methylphenyl)-1,8-naphthyridine (2.4 g). The product obtained by precipitation in water (2.3 g) is dissolved in boiling acetonitrile (300 cc). After 4 hours of cooling at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (3×5 cc) and dried at 35° C. under reduced pressure (0.07 kPa). N-[7-(3-Methylphenyl)-1,8-naphthyridin-2-yl]-3-bromobenzamide (1 g), m.p. 100° C., is obtained.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1O)=[CH:15][CH:14]=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)([Br:25])=O.O>CN(C=O)C>[CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[Br:25])=[CH:15][CH:14]=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: Oc1c(Cc2ccccc2)nnc2c(C(F)(F)F)cccc12
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc2c(Br)c(Cc3ccccc3)nnc12
Reaction time: 1 h
Yield: 105.2 %

Procedure:
A solution of 3-benzyl-8-trifluoromethyl-cinnolin-4-ol (1.6 g, 4.4 mmol) and POBr3 (2.5 g, 8.7 mmol) in DMF (30 ml) was heated to 75° C. After 1 hr, the reaction was cooled and poured into water. The aqueous layer was extracted with EtOAc which was dried (MgSO4) and concentrated to give a solid. The solid was triturated with MeOH and filtered to give 3-benzyl-4-bromo-8-trifluoromethyl-cinnoline (1.7 g). MS (ES) m/z 366.7.
Reaction SMILES: C([N:8]([CH2:13][CH2:14][CH3:15])[O:9][CH2:10][CH2:11][CH3:12])(OC(C)(C)C)=O.[ClH:16].O1CCOCC1>>[ClH:16].[CH2:13]([NH:8][O:9][CH2:10][CH2:11][CH3:12])[CH2:14][CH3:15]
Reactant: CCCON(CCC)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCNOCCC
Temperature: 25 °C
Reaction time: 7 h

Procedure:
N-Boc-N-propyl-N-propoxyamine (5.8 g) was dissolved in 4 N HCl/dioxane (10 mL) and stirred at room temperature for 7 hours. The solvent was removed in vacuo and the residue triturated with diethyl ether. The resulting yellow solid (2.1 g) was collected by filtration and washed with diethyl ether.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]([N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[CH:13]=2)[C:8]1=[O:26])[CH3:6])C.[OH-].[Li+]>O.O1CCCC1>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:26])[N:7]([CH:5]([CH3:6])[C:4]([OH:27])=[O:3])[CH2:16][CH2:15]2
Reactant: CCOC(=O)C(C)N1CCc2cc(OCc3cccc(F)c3)ccc2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C(=O)O)N1CCc2cc(OCc3cccc(F)c3)ccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the 2-[6-(3-fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionic acid ethyl ester (0.087 g, 0.234 mmol) (example 2) and lithium hydroxide (0.0062 g, 0.258 mmol) in water and tetrahydrofuran (1:1 v:v, 9 mL) was stirred at room temperature for 2 h. The THF was evaporated and the mixture acidified to pH 3-4 with 0.1N HCl. After extraction with ethyl acetate, drying of the organic layer with MgSO4, filtration and evaporation a white solid was obtained (0.080 g, 99%). MS: m/e=342.1 (M−H+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([CH3:13])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:14].CO.O1CCCC1.[BH4-].[Na+]>CC(C)=O>[CH3:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([CH3:13])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[OH:14]
Reactant: COc1cc(C)c2c(c1C)C(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C)c2c(c1C)C(O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 4,7-dimethyl-6-methoxy-1-indanone (7.0 g) in a mixed solvent of methanol (100 ml) and tetrahydrofuran (50 ml) was added sodium borohydride (1.2 g) at 0° C. and then the mixture was stirred at room temperature for 1 hour. Acetone (10 ml) was added and the solvent was distilled off under reduced pressure. Water (50 ml) and ethyl acetate (50 ml) were added and the organic layer was washed with water and saturated saline. The organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure to obtain 4,7-dimethyl-6-methoxy-1-indanol (7.0 g) (Compound A-14). The physical properties and NMR spectrum data thereof are shown in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[O:40][CH3:41])[C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[NH:15][CH2:14][CH2:13]1.CN(C=O)C.[H-].[Na+].[C:49](OC(=O)C)(=[O:51])[CH3:50]>O.CCOC(C)=O.[Cl-].[Na+].O>[C:49]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[C:18]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[O:40][CH3:41])[C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])[CH:17]=2)[N:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:9])[F:11])=[CH:7][C:2]=2[Cl:1])[CH2:13][CH2:14]1)(=[O:51])[CH3:50]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(c2)NCCN3c2ccc(C(F)(F)F)cc2Cl)c(OC)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(c2)N(C(C)=O)CCN3c2ccc(C(F)(F)F)cc2Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A vial was charged with 1-(2-chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide (INTERMEDIATE V, 0.045 g, 0.072 mmol) and DMF (0.719 mL). Sodium hydride (60% in mineral oil) (4.31 mg, 0.108 mmol) was added to give a dark brown solution. Acetic anhydride (0.014 mL, 0.144 mmol) was added dropwise, and the mixture lightened significantly and thickened up. After stirring for 30 minutes at room temperature, additional acetic anhydride (0.014 mL, 0.144 mmol) was added and the reaction was heated to 50° C. and stirred for one hour. Additional sodium hydride (60% in mineral oil) (4.31 mg, 0.108 mmol) and acetic anhydride (0.014 mL, 0.144 mmol) were added and the reaction was stirred at 70° C. for one hour. The mixture was diluted with water and EtOAc, then with brine to break up an emulsion. The layers were separated, and the aqueous layer was extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, and concentrated. The material was purified via silica gel chromatography (12 g column, gradient elution 0 to 100% EtOAc:Heptane) to afford 4-acetyl-1-(2-chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide as a white solid. m/z (ESI) 667.7 (M+H)+.