Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][C@H:14]([N:18]2[C:24](=[O:25])[CH2:23][CH2:22][NH:21][C@H:20]([CH3:26])[CH2:19]2)[CH2:15][O:16][CH3:17])[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[Cl:27][C:28]1[CH:29]=[C:30]([N:34]=[C:35]=[O:36])[CH:31]=[CH:32][CH:33]=1>>[Cl:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]([N:21]2[CH2:22][CH2:23][C:24](=[O:25])[N:18]([C@H:14]([CH2:15][O:16][CH3:17])[CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:7][CH2:6]4)[C@H:4]([OH:3])[CH2:11]3)[CH2:19][C@H:20]2[CH3:26])=[O:36])[CH:31]=[CH:32][CH:33]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: COC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1C[C@@H](C)NCCC1=O
Agent: Cl
Product: COC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1C[C@@H](C)N(C(=O)Nc2cccc(Cl)c2)CCC1=O
Yield: 58 %

Procedure:
In analogy to the procedure described for intermediate 58F, (R)-4-[(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-methoxymethyl-propyl]-2-methyl-[1,4]diazepan-5-one dihydrochloride and 3-chlorophenyl isocyanate gave the title compound in 58% yield as yellow oil. MS: 493.4 (MH+, 1Cl).
Reaction SMILES: [Br:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][C@:7]23[CH2:14][C@@H:13]([NH:15][C:16](=[O:30])[C:17]4[CH:22]=[CH:21][C:20]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:18]=4)[CH2:12][N:11]2[C:10](=[O:31])[N:9]([C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)[C:8]3=[O:40])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][C@:7]23[CH2:14][C@@H:13]([NH:15][C:16](=[O:30])[C:17]4[CH:18]=[CH:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][CH:22]=4)[CH2:12][N:11]2[C:10](=[O:31])[N:9]([C:32]2[CH:33]=[C:34]([Cl:39])[CH:35]=[C:36]([Cl:38])[CH:37]=2)[C:8]3=[O:40])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)N[C@H]2CN3C(=O)N(c4cc(Cl)cc(Cl)c4)C(=O)[C@@]3(Cc3ccc(Br)cc3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(C(=O)N[C@H]2CN3C(=O)N(c4cc(Cl)cc(Cl)c4)C(=O)[C@@]3(Cc3ccc(Br)cc3)C2)cc1
Reaction time: 3 h
Yield: 90.1 %

Procedure:
To a solution of Example 80 (0.161 g) in CH2Cl2 (4 mL) was added TFA (1 mL). After 3 hours at room temperature, the reaction mixture was diluted with CH2Cl2, washed with water and brine, dried (Na2SO4), filtered, concentrated and purified by chromatography (silica gel: 80:20 CH2Cl2:MeOH, Chromatotron) to afford the titled compound (0.133 g). MS (m/z) 614 [M-H]−.
Reaction SMILES: [C:1]1(=[C:6]2[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[C:1]1(=[C:6]2[CH2:10][CH2:9][CH2:8][CH:7]2[OH:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCCC1=C1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCCC1=C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.1 %

Procedure:
A 2 liter round bottom flask, fitted with a mechanical stirrer, a reflux condenser and a thermometer, was charged with 412.4 g (2.75 mol) of 2-Cyclopentylidene-cyclopentanone and 500 ml methanol. The mixture was stirred until homogeneous at room temperature and then 40 g of sodium borohydride was added in small portions over a period of 1.5 hour. The reaction mixture was thereafter stirred for another 4 hours. During addition as well as thereafter the temperature was kept below 40° C. by cooling with a cold water bath if necessary. The reaction mixture was further stirred overnight. Thereafter it was quenched by dropwise addition, with stirring, of 250 ml of water. The aqueous and organic layers were separated and the aqueous layer extracted twice with 200 ml diethyl ether. The combined organic layers were washed with 200 ml water and dried over magnesium sulphate. After filtration the solvent was removed using a rotary evaporator and 444 g of crude product were obtained. This was fractioned under reduced pressure (0.4 kPa) through a 0.5 meter Sulzer-packed column. Fractions were collected at 90°-100° C. and odour assessed. The total of fractions with an acceptable odour was 182.9 g. The product could be further purified by recristallization from methanol.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17]([O:19]C)=[O:18])=[CH:5][CH:4]=1.[OH-].[Na+]>CO.O>[F:21][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17]([OH:19])=[O:18])=[CH:7][CH:8]=1
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1
Yield: 14.6 %

Procedure:
The product from Step 1 (1.00 g, 3.34 mmol, 1.00 equiv) was dissolved in MeOH (11 mL). Following addition of 2.5N NaOH (4 mL), the reaction mixture was heated to reflux for 8 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed again with 1N NaOH. The aqueous phases were combined and acidified to pH˜1 with 5N HCl, and extracted twice with ethyl acetate. The combined organic extracts were washed with satd. NaCl, dried over Na2SO4, and filtered. The filtrate was concentrated en vacuo and azeotroped several times with hexanes. The resulting white solid was triturated with Et2O to afford 146 mg (15%) of the acid as an off-white solid. MS (ES+) m/e 266 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1([C:35]([O:37]CC)=[O:36])[CH2:8][CH2:7][N:6]([C:9]2[S:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:17]4[S:21][C:20]([NH:22][C:23](=[O:27])[NH:24][CH2:25][CH3:26])=[N:19][C:18]=4[CH:28]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[OH-].[Na+]>CCO>[CH2:1]([C:3]1([C:35]([OH:37])=[O:36])[CH2:8][CH2:7][N:6]([C:9]2[S:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:17]4[S:21][C:20]([NH:22][C:23](=[O:27])[NH:24][CH2:25][CH3:26])=[N:19][C:18]=4[CH:28]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3nsc(N4CCC(CC)(C(=O)OCC)CC4)n3)cc(-c3ccccn3)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(-c3nsc(N4CCC(CC)(C(=O)O)CC4)n3)cc(-c3ccccn3)c2s1
Temperature: 25 °C
Yield: 37.2 %

Procedure:
Ethyl 4-ethyl-1-(3-{2-[(ethylcarbamoyl)amino]-7-(pyridin-2-yl)-1,3-benzothiazol-5-yl}-1,2,4-thiadiazol-5-yl)piperidine-4-carboxylate (70 mg, 0.09 mmol) was dissolved in EtOH (15 mL) and 2M aqueous NaOH (5 mL) and stirred at 90° C. for 18 h. The reaction was cooled to rt and concentrated to ˜⅕ volume. Water (10 mL) and DCM (10 mL) were added and the aqueous layer separated, the organic layer discarded and the aqueous layer acidified to pH˜2 and extracted with DCM (3×10 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo to give a brown solid, which was purified by flash column chromatography (Biotage, SP4, 12 g, 2-8% MeOH, DCM) to afford Compound 232 as a cream solid (18 mg, 38%).
Reaction SMILES: [C:1]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=[C:7]([CH3:16])[C:6]=1[N:17]([CH3:19])[CH3:18])([CH3:4])([CH3:3])[CH3:2].[B:20](O)([OH:22])[OH:21]>C1(C)C=CC=CC=1>[B:20]([O:11][C:10]1[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:6]([N:17]([CH3:19])[CH3:18])[C:7]([CH3:16])=[CH:8][C:9]=1[C:12]([CH3:13])([CH3:15])[CH3:14])([OH:22])[OH:21]
Reactant: OB(O)O
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1N(C)C
Solvent: Cc1ccccc1
Product: Cc1cc(C(C)(C)C)c(OB(O)O)c(C(C)(C)C)c1N(C)C
Temperature: 115 °C
Reaction time: 4 h
Yield: 254.5 %

Procedure:
A mixture of 2,6-di-tertiary-butyl-dimethylamino- p-cresol (263 gm, one mole), boric acid (20.7 gm, 0.33 mole), and toluene (650 ml.) was heated while stirring vigorously at 115° C. for four hours and water (6.5 ml.) was collected by azeotropic distillation. At the end of the reaction,the unreacted, insoluble material was removed by filtration, and the toluene was removed under reduced pressure, leaving the product as a golden orange solid (258 gm) with a melting point of 73°-79°C.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12][CH2:13][CH2:14][OH:15])=[CH:10][C:9]2[C:8]([CH3:17])([CH3:16])[CH2:7][CH2:6][C:5]([CH3:19])([CH3:18])[C:4]=2[CH:3]=1.N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C)C=O.C(OCC)C>[Br:1][C:2]1[C:11]([CH2:12][CH2:13][CH2:14][O:15][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[CH:10][C:9]2[C:8]([CH3:17])([CH3:16])[CH2:7][CH2:6][C:5]([CH3:19])([CH3:18])[C:4]=2[CH:3]=1
Reactant: CC1(C)CCC(C)(C)c2cc(CCCO)c(Br)cc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc(CCCO[Si](C)(C)C(C)(C)C)c(Br)cc21
Yield: 66.1 %

Procedure:
To a solution of 10.2 g (31.55 mmol) of 2-bromo-3-(3-hydroxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene in 80 mL of dimethlformamide was added 9.46 g (138.8 mmol) of imidazole and 10.46 g (69.4 mmol) of tert-butyldimethylsilyl chloride. After 4 hours the reaction mixture was diluted with diethyl ether and washed with 1 N aqueous ammonium chloride and brine. The organic fraction was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient elution: 1-2% ethyl acetate/hexane) to afford 9.17 g (66%) of 2-bromo-3-(3-t-butyldimethylsiloxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene.
Reaction SMILES: [OH-].[Na+].CO.[C:5]([NH:13][C:14]1[CH:23]=[C:22]([CH2:24][S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1>[C:5]([NH:13][C:14]1[CH:23]=[C:22]([CH2:24][S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(CSc2ccccc2)cc1NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cc(CSc2ccccc2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.50 mL of 2.0 mol/L aqueous sodium hydroxide was added dropwise to a mixed solution of 3 mL of methanol and 3 mL of tetrahydrofuran containing 0.29 g of methyl 2-(benzamido)-4-((phenylthio)methyl)benzoate while ice-cooled and stirred at room temperature for 5 hours. 0.25 mL of 2.0 mol/L aqueous sodium hydroxide was added dropwise and stirred at the same temperature for 14 hours. The solvent was evaporated under reduced pressure and water was added and pH was adjusted to pH 4.0 with 1.0 mol/L hydrochloric acid. A solid substance was separated by filtration to obtain 0.28 g of 2-(benzamido)-4-((phenylthio)methyl)benzoic acid as white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C@@H]1N2C=NC=C2C(=O)C1)C#N.[O:19]=[C:20]1[CH2:25][CH2:24][C@H:23]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[N:22]2[CH:34]=[N:35][CH:36]=[C:21]12>>[F:1][C:2]1[CH:3]=[CH:4][C:7]([C:20]2([OH:19])[CH2:25][CH2:24][C@H:23]([C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)[N:22]3[CH:34]=[N:35][CH:36]=[C:21]23)=[CH:8][CH:9]=1
Reactant: N#Cc1ccc([C@H]2CC(=O)c3cncn32)c(F)c1
Reactant: N#Cc1ccc([C@H]2CCC(=O)c3cncn32)cc1
Product: N#Cc1ccc([C@H]2CCC(O)(c3ccc(F)cc3)c3cncn32)cc1

Procedure:
Following compounds are prepared using similar procedure as example 1-1 through example 1-7 using either 3-fluoro-4-((R)-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile or (R)-4-(8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile with appropriate reagents and conditions: Note when possible, separation of diastereomers were individually achieved with preparation plates, flash chromatography, prep-LCMS, HPLC, and or using HPLC CHIRALPAK® HPLC columns (such as AD, OJ, OD, etc.) which are purchased from Daicel.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O-:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12]OC(OC)OC>CO>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: O=C([O-])Cc1cccc(O)c1
Reactant: COC(OC)OC
Solvent: CO
Product: COC(=O)Cc1cccc(O)c1

Procedure:
To a solution of 3-hydroxyphenylacetate (2.0 g) in methanol (10 ml), 250 mg of tosic acid monohydrate and 2.9 ml of trimethoxymethane were added, and the reaction solution was heated to reflux for 5 hours. The reaction solution was cooled, and then the solvent was distilled off under reduced pressure. The residual residue was diluted with diethyl ether, washed with a saturated aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:100-50:50)) to afford the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][N:20]=[N+:21]=[N-:22])=[CH:15][CH:14]=[C:13]([F:23])[CH:12]=2)[C:5]([O:7][CH3:8])=[O:6].[CH3:25][O-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:24])[C:4]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][N:20]=[N+:21]=[N-:22])=[CH:15][CH:14]=[C:13]([F:23])[CH:12]=2)([CH3:25])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C[O-]
Reactant: COC(=O)C(C(=O)OC)c1[nH]c2cc(F)ccc2c1CCN=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)(C(=O)OC)c1[nH]c2cc(F)ccc2c1CCN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[3-(2-azidoethyl)-6-fluoro-1H-indol-2-yl]-propanedioic acid dimethyl ester (37 mmol) in dry MeOH (0.25 L) at 0° C. under argon was added a solution of 25% NaOMe in MeOH (8.56 mL, 37.4 mmol). The mixture was stirred for 30 min at 0° C. Mel (3.56 mL, 56.6 mmol) was added. The mixture was refluxed for 42 h, cooled, and concentrated. The residue was partitioned between H2O and Et2O. The Et2O extracts were washed with H2O, dried, and concentrated to an oil. This oil was purified by silica chromatography to give the title compound: TLC Rf=0.50 (CH2Cl2); MS (ESI+) m/z 371.1; 1H NMR (CDCl3, 300 MHz) δ 9.63 (1H), 7.44 (1H), 7.05 (1H), 6.97 (1H), 3.82 (6H), 3.44 (2H), 2.94 (2H), 1.93 (3H).
Reaction SMILES: N1C=CC=CC=1C.[NH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH2:14]([O:16][C:17]([C:19]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][C:24](Cl)=[C:25]([F:30])[CH:26]=2)[N:21]([CH2:32][CH3:33])[CH:20]=1)=[O:18])[CH3:15]>>[CH2:14]([O:16][C:17]([C:19]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][C:24]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[C:25]([F:30])[CH:26]=2)[N:21]([CH2:32][CH3:33])[CH:20]=1)=[O:18])[CH3:15]
Reactant: CCOC(=O)c1cn(CC)c2cc(Cl)c(F)cc2c1=O
Reactant: C1CNCCN1
Solvent: Cc1ccccn1
Product: CCOC(=O)c1cn(CC)c2cc(N3CCNCC3)c(F)cc2c1=O
Reaction time: 5 h
Yield: 79 %

Procedure:
A mixture of 18 ml of picoline, 10.3 g of anhydrous piperazine, and 8.9 g of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester was refluxed with stirring for 5 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was treated by the same manner described in Example 1 to give 8.2 g (79% yield) of 1-ethyl-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester. mp: 178°-180° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O>C(Cl)(Cl)Cl>[C:12]1([C:10]2[N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]3[CH:9]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1ccccc1
Solvent: ClC(Cl)Cl
Product: c1ccc(-c2cn3ccccc3n2)cc1

Procedure:
0.1 m. Quantities of 2-aminopyridine and α-bromoacetophenone are heated in 150 ml. of chloroform at reflux for 2 hours. The chloroform is evaporated and the oily residue taken up in 10% HCl, warmed, charcoal added and filtered. The filtrate is neutralized with NH4OH and the solid product isolated and recrystallized from ethanol. The yield of product is 12.7 g., melts at 135°-137° C. and has the structure: ##STR13##
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.F[C:20]1C=C(C)C=C(F)C=1B1OC(C)(C)C(C)(C)O1>>[F:1][C:2]1[CH:7]=[C:6]([CH3:20])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Reactant: Cc1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: Cc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with 2-(2,6-difluoro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 125) gave the title compound.
Reaction SMILES: [C:1]([N:4]([C:12]1[C:16]2[CH:17]=[C:18]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[O:28][C:29]3[CH:34]=[C:33]([F:35])[C:32]([S:36](=[O:55])(=[O:54])[N:37](CC4C=CC(OC)=CC=4OC)[C:38]4[S:42][N:41]=[CH:40][N:39]=4)=[CH:31][C:30]=3[F:56])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)C(=O)OC(C)(C)C)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[S:42]1[C:38]([NH:37][S:36]([C:32]2[C:33]([F:35])=[CH:34][C:29]([O:28][C:22]3[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=3[C:18]3[CH:19]=[CH:20][C:15]4[O:14][N:13]=[C:12]([NH:4][C:1](=[O:3])[CH3:2])[C:16]=4[CH:17]=3)=[C:30]([F:56])[CH:31]=2)(=[O:54])=[O:55])=[N:39][CH:40]=[N:41]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4onc(N(C(C)=O)C(=O)OC(C)(C)C)c4c3)cc2F)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1noc2ccc(-c3cc(Cl)ccc3Oc3cc(F)c(S(=O)(=O)Nc4ncns4)cc3F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
A solution of tert-butyl acetyl(5-(5-chloro-2-(4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2,5-difluorophenoxy)phenyl)benzo[d]isoxazol-3-yl)carbamate (0.21 g, 0.25 mmol) in dichloromethane (20 mL) at 0° C., under nitrogen, was treated with trifluoroacetic acid (75 μL, 0.8 mmol) and stirred for 1 h. The reaction mixture was allowed to warm to ambient temperature, stirred for 3 h and concentrated in vacuo. The residue was purified by reverse phase HPLC to afford N-(5-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2,5-difluorophenoxy)-5-chlorophenyl)benzo[d]isoxazol-3-yl)acetamide as a colorless solid in 35% yield (0.05 g): 1H NMR (300 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.47 (s, 1H), 8.11 (s, 1H), 7.76-7.63 (m, 3H), 7.59, (d, J=2.3 Hz, 1H), 7.49 (dd, J=9.1, 2.7 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H), 7.13 (dd, J=10.3, 6.5 Hz, 1H), 2.12 (s, 3H), (Note: sulfonamide N—H not observed); MS (ES+) m/z 599.6 (M+23), 601.6 (M+23).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][NH2:6])=[O:4].[C:7]1([CH:13]=[C:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[CH3:1][O:2][C:3]([NH:5][N:6]=[C:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:14]1=[CH:13][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4]
Reactant: O=C1CCCCCC1=Cc1ccccc1
Reactant: COC(=O)NN
Solvent: CCO
Product: COC(=O)NN=C1CCCCCC1=Cc1ccccc1
Yield: 91 %

Procedure:
9.0 g (0.1 mole) of N-methoxycarbonyl hydrazine are dissolved in 250 ml of anhydrous ethanol, under stirring, and 20.0 g (0.1 mole) of 2-phenylmethylenecycloheptan-1-one are added to the solution. The reaction mixture is kept at the boiling point under stirring, thereafter clarified with activated carbon, filtered and the filtrate is crystallized. 24.78 g of the named compound are obtained. Yield: 91%.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH2:25][NH2:26])=[CH:16]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C=O)C>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH2:25][NH:26][C:12]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:5][CH:4]=2)=[O:14])=[CH:16]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=C(O)c1ccc2cccnc2c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccccc12)c1ccc2cccnc2c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 8-hydroxyquinoline-7-carboxylic acid (0.23 g, 1.25 mmol), 2-(1H-Indol-3-yl)ethylamine (0.20 g, 1.25 mmol), 1-hydroxybenzotriazole (0.18 g, 1.37 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.26 g, 1.37 mmol), and triethylamine (0.7 mL, 4.99 mmol) in DMF (12 mL) was stirred at room temp overnight. The reaction mixture was concentrated under vacuum. The residue was dissolved in DMSO and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provide the title compound as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21]([C:23](=[O:30])[CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[CH3:22])=[CH:19][CH:18]=[C:17]([Cl:31])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.[OH-].[Na+].Cl>CO.C(Cl)(Cl)Cl>[C:26]([CH2:25][CH2:24][C:23]([N:21]([C:20]1[C:2]([Cl:1])=[C:3]([C:17]([Cl:31])=[CH:18][CH:19]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2)[CH3:22])=[O:30])([OH:28])=[O:27]
Reactant: COC(=O)CCC(=O)N(C)c1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CCC(=O)O)c3Cl)c2n1
Yield: 82.4 %

Procedure:
To a solution of 8-[2,6-dichloro-3-[N-(3-methoxycarbonylpropionyl)-N-methylamino]benzyloxy]-2-methylquinoline (303 mg) in methanol (3 ml) was added 1N aqueous solution of sodium hydroxide (1.0 ml) at ambient temperature. The mixture was stirred for 1 hour and neutralized to pH 4 with 1N hydrochloric acid. The reaction mixture was diluted with chloroform and washed with water. The aqueous layer was saturated with sodium chloride and extracted with chloroform. The combined organic layers were dried over magnesium sulfate and evaporated in vacuo to give 8-[3-[N-(3-carboxypropionyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (242 mg) as an off-white powder.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].[Cl:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[C:11]([CH2:16][O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:10]=1.O>CO.C(#N)C>[N:1]1([C:13]2[CH:12]=[C:11]([CH2:16][O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:10]=[C:9]([Cl:8])[N:14]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CO
Product: FC(F)(F)COCc1cc(N2CCC2)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of azetidine (0.224 g, 2.39 mmol) and sodium methoxide (0.326 mL, 1.75 mmol) in MeOH (2 mL) was added to an ice-cold solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)-methyl)pyrimidine (0.208 g, 0.80 mmol) in acetonitrile (2 mL). The mixture was stirred at 0° C. for 15 minutes. Water was added. The mixture was purified by preparative HPLC to give the title compound, 0.091 g (41%).