Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[S:12](Cl)(=[O:15])(=[O:14])[NH2:13].Cl>O1CCCC1.O>[S:12]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][O:11][S:12](=[O:15])(=[O:14])[NH2:13])(=[O:15])(=[O:14])[NH2:13]
Reactant: NS(=O)(=O)Cl
Reactant: OCCCCCCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)OCCCCCCCOS(N)(=O)=O
Yield: 63.1 %

Procedure:
A 57% oil dispersion of sodium hydride (11.8 g, 0.28 mole NaH) was added to 150 ml of tetrahydrofuran. The suspension was stirred and gently heated, and 15.84 g (0.12 mole) of 1,7-heptanediol in 75 ml of tetrahydrofuran was added gradually over a period of 90 minutes. An additional 25 ml of tetrahydrofuran was then added, and the reaction mixture was stirred at reflux for five hours. An additional 150 ml of tetrahydrofuran was added, and to the stirred warm mixture there was added dropwise a solution of 28.9 g (0.25 mole) of sulfamoyl chloride in 150 ml of tetrahydrofuran over a two hour period. The reaction mixture was stirred at reflux for five hours, then cooled and treaated dropwise with 125 ml of water. The mixture was acidified with 2N hydrochloric acid, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue triturated with ethyl acetate to give a yellow solid which was recrystallized from an ethyl acetate--hexane mixture to give 22.0 g of 1,7-heptanediol disulfamate as colorless granules, m.p. 87°-88° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[CH2:1]([N:3]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([NH:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH:11]=[CH:12][CH:13]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCN(CC)CCCCc1cccc(N)c1
Solvent: c1ccncc1
Product: CCCCCCCN(CC)CCCCc1cccc(NS(C)(=O)=O)c1
Reaction time: 1 h

Procedure:
The amine from Step IV (1.7 g, 0.00585 mol) is mixed with 4.6 ml of pyridine under nitrogen, the mixture cooled in an ice bath and treated dropwise, over 5 min, with 0.5 ml (0.74 g, 0.0064 mol) of methanesulfonyl chloride. The mixture is stirred in the cold for 1 hr and at room temperature overnight. The solvent is removed in vacuo as an azetrope with toluene. The residue is taken up in CH2Cl2 (75 ml), washed with 25 ml of 8% NaHCO3 and the aqueous wash extracted with CH2Cl2 (2×75 ml). The organic pool is washed with brine, dried (Na2SO4) and concentrated to give a dark oil. This material is chromatographed over 500 ml of silica gel (eluted with 0.4% NH4OH-8% MeOH--CH2Cl2); 45 ml fractions are collected. The resulting material is further treated with cold, dilute NaOH to pH 12 and extracted with EtOAc (1×40 ml). The organic extract is washed with cold, dilute NaOH (2×5 ml) and the pooled aqueous wash extracted with EtOAc (2×25 ml) (each extract is washed with 5 ml of H2O). The pooled EtOAc extract is dried (Na2SO4) and concentrated in vacuo to give the title compound. The title compound is chromatographed over 50 ml of silica gel (eluted with 0.25% NH4OH-10% MeOH--CH2Cl2) and 20 ml fractions collected. Theory for C20H37N2O2S 369.2576; measured, 369.2576 by high resolution FAB MS. ##STR1##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[CH3:17][O:18][C:19]1[C:20]([NH2:25])=[CH:21][CH:22]=[CH:23][CH:24]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH3:17])[CH:7]=1
Reactant: COc1ccccc1N
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2ccccc2OC)c1
Yield: 79 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.40 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of o-anisidine (0.19 g, 1.54 mmol) in dioxane (1 ml) and NaHCO3 (0.26 g, 3.06 mmol) in water (3 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with petroleum ether-ethyl acetate (2:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.42 g, 79%) as a white solid. 1H NMR (DMSOd-6, HMDSO), δ: 3.43 (3H, s); 3.72 (3H, s); 6.60 (1H, d, J=16.0 Hz); 6.72-7.27 (4H, m); 7.45-8.12 (5H, m); 9.47 (1H, s).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])=[O:14])[CH:12]=1)[C:7](O)=[O:8])=[O:3].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.FC(F)(F)C(O)=O.[NH2:50][C@@H:51]([CH2:65][C:66]1[CH:71]=[C:70](F)[CH:69]=[C:68](F)[CH:67]=1)[C@H:52]([OH:64])[CH2:53][NH:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([O:62][CH3:63])[CH:57]=1>CN(C=O)C>[CH2:65]([C@H:51]([NH:50][C:7]([C:6]1[CH:5]=[C:4]([C:2]([NH2:1])=[O:3])[CH:12]=[C:11]([C:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])=[O:14])[CH:10]=1)=[O:8])[C@H:52]([OH:64])[CH2:53][NH:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([O:62][CH3:63])[CH:57]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(C(=O)O)c1
Reactant: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNCc2cccc(OC)c2)c1
Temperature: 22.5 °C
Reaction time: 72 h

Procedure:
To a mixture of 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoic acid (IX, PREPARATION 6, 0.18 g, 0.616 mmol) in dry DMF (16 mL) is added EDC (0.182 9, 0.9 mmol), HOBT (0.127 g, 0.9 mmol), triethylamine (0.062 g, 0.616 mol), and (2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]-4-phenyl-2-butanol (VIII, EXAMPLE 175, 0.185 g, 0.616 mmol). The mixture is stirred at 20-25 degrees C. for 3 days. The mixture is partitioned between water and ethyl acetate. The phases are separated and the organic phase is washed three times with water. The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated. Column chromatography (silica gel, 75 mL; methanol/methylene chloride, 10/90) gives the title compound, IR (diffuse reflectance) 3306, 3301, 3270, 2962, 1676, 1667, 1663, 1645, 1638, 1627, 1615, 1550, 1537, 1450 and 1439 cm−1; NMR (CDCl3) δ 0.645, 0.968, 1.20, 1.43, 1.67, 2.8, 2.97, 3.38, 3.47, 3.73, 3.87, 4.31, 6.78, 6.91, 7.23, 7.72, 7.87, 8.22 and 8.43.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]1[O:14][CH2:13]1>>[C:1]1([C:7]2[S:8][C:9]([CH2:12][CH2:13][OH:14])=[CH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CO1
Reactant: c1ccc(-c2cccs2)cc1
Product: OCCc1ccc(-c2ccccc2)s1

Procedure:
2-Phenylthiophene(16.0g;0.1 mole) was reacted in a similar manner to Example 40 but using ethylene oxide (10ml; 0.2 mole) instead of paraformaldehyde. The title compound was obtained as a pale yellow crystalline solid, m.p. 74° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=O)[N:6]2[N:5]=[CH:4][N:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH2:37][CH2:38][CH:39]1[O:44][CH2:43][CH2:42][N:41]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:40]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]([NH:37][CH2:38][CH:39]3[O:44][CH2:43][CH2:42][N:41]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:40]3)=[O:13])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(CN)C1
Reactant: Nc1ncnn2c(C(=O)O)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOC(CNC(=O)c2ccc3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
4-aminopyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid (215 mg, 1.21 mmol) was combined with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (347 mg, 1.81 mmol) and 1-hydroxybenzotriazole monohydrate (245 mg, 1.81 mmol) in DMF (5 mL). The mixture was stirred at rt for 30 min. before adding tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (274 mg, 1.27 mmol). After 1 hr, the reaction was poured into satd. NaHCO3 solution and stirred for 1 h. The product was collected by vacuum filtration to give a tan solid (400 mg, 88%). MS [M+H]+=377.0; LCMS RT=2.71 min.
Reaction SMILES: [CH:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[CH2:2].I[CH2:15]Cl.C([Zn]CC)C>ClC(Cl)C>[CH:1]1([O:3][C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:15][CH2:2]1
Reactant: ClCI
Reactant: C=COc1cccc(C(=O)OC)c1
Agent: CC[Zn]CC
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc(OC2CC2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-(vinyloxy)benzoate (0.83 g, 3.99 mmol) in dichloroethane (20 mL) was added iodochloromethane (1.09 mL, 14.9 mmol). The solution was cooled to 0° C. and diethyl zinc (1.0 M in hexanes, 7.48 mL, 7.48 mmol) was added. The cooling bath was removed and the reaction was stirred at rt for 30 min. The reaction mixture was quenched with 1N HCl, extracted with methylene chloride (three times), dried with MgSO4 and concentrate under vacuum to afford the desired product.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=1)([F:7])[F:6])=[N+]=[N-]>CO.[Pd]>[F:7][C:5]([F:6])([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=1)[CH2:4][NH2:1]
Reactant: Cc1cccc(C(F)(F)CN=[N+]=[N-])n1
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(C(F)(F)CN)n1
Yield: 99.3 %

Procedure:
A solution of 2-(2-Azido-1,1-difluoro-ethyl)-6-methyl-pyridine (700 mg, 3.54 mmol), as prepared in the preceding step, in MeOH (10 mL) was treated with 10% Pd/C (150 mg) under 39 Psi H2 atmosphere overnight. The reaction mixture was filtered through a pad of celite and the filtrate was evaporated to afford the product as a brown oil (605 mg, 99%). 1H NMR (CDCl3) δ 7.69 (t, J=7.74 Hz, 1H), 7.46 (d, J=7.70 Hz, 1H), 7.22 (d, J=7.81 Hz, 1H), 3.42 (t, J=14.40 Hz, 2H), 2.58 (s, 3H); LC/MS (m/z) [M+1] 173.2 (calculated for C8H11F2N2, 173.1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([I:12])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.CI.[C:16](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC>[Cl:1][C:2]1[C:3]([F:13])=[C:4]([I:12])[C:5]([O:11][CH3:16])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cc(Cl)c(F)c(I)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOCC
Product: COc1c(C(C)=O)cc(Cl)c(F)c1I
Temperature: 60 °C
Yield: 74.2 %

Procedure:
1-(5-Chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone (13 g, 41 mmol) was dissolved in DMF (41.3 mL). Methyl iodide (3.9 mL, 62 mmol) was added followed by potassium carbonate (11 g, 83 mmol). The reaction was heated at 60° C. for 1 hour. The mixture was cooled to room temperature, diluted with ether, washed with water, dried over MgSO4, concentrated. The residue was purified on silica gel (eluting with 0 to 10% EtOAc in hexanes) to give the desired product (10 g, 70%). LCMS calculated for C9H8ClFIO2 (M+H)+: m/z=328.9. found: 328.9.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:43]1([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:15])([F:16])[F:17])[CH:8]=2)[C:3]=1[C:18]([N:46]1[CH2:45][CH2:44][N:43]([C:49]2[CH:50]=[CH:51][C:52]([OH:55])=[CH:53][CH:54]=2)[CH2:48][CH2:47]1)=[O:20]
Reactant: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)O
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)N1CCN(c2ccc(O)cc2)CC1
Yield: 72.8 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-amino-3-(3-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 4-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (601 mg, 1.34 mmol, 72%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:60][CH2:61][C:62]1[CH:63]=[CH:64][C:65]2[C:69]([CH3:71])([CH3:70])[O:68][B:67]([OH:72])[C:66]=2[CH:73]=1>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:26])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:60][CH2:61][C:62]4[CH:63]=[CH:64][C:65]5[C:69]([CH3:71])([CH3:70])[O:68][B:67]([OH:72])[C:66]=5[CH:73]=4)=[O:20])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: CC1(C)OB(O)c2cc(CN)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccc2c(c1)B(O)OC2(C)C
Reaction time: 0.17 h
Yield: 21.4 %

Procedure:
A solution of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (1.65 g, 3.95 mmol) and Et3N (1.6 g, 15.8 mmol) in MeCN (35 ml) was stirred at rt for 5 min and then HATU (3 g, 7.9 mmol) was added. The mixture was stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (906 mg, 4.74 mmol). And the resulting mixture was stirred at rt overnight. It was then concentrated under vacuum, and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer separated was concentrated under vacuum, and the residue was purified by column chromatography and preparative HPLC to provide the product (500 mg, yield 21%). 1H NMR (300 MHz, DMSO-d6): δ 9.05 (s, 1H), 8.92 (s, 1H), 7.82 (s, 1H), 7.61 (m, 5H), 7.40 (m, 3H), 4.49 (d, 2H), 4.37 (d, 2H), 2.39 (s, 3H), 1.44 (s, 6H) ppm; HPLC purity: 97.4% at 220 nm and 98.1% at 254 nm; MS: m/z=591.3 (M+H, ESI+).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:3]=1[CH3:30].[CH3:31]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCO>[C:26]([O:25][CH:19]([C:4]1[C:3]([CH3:30])=[C:2]([CH3:31])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:28])([CH3:27])[CH3:29]
Reactant: CB1OB(C)OB(C)O1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)c(C)c2ccccc2c1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A suspension of ethyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (25 mg, 51 μmol), trimethylboroxine (21 μL, 0.153 mmol), PdCl2(dppf) (3.7 mg, 5.1 μmol), K2CO3 (70 mg, 0.510 mmol), PhMe (500 μL), EtOH (absolute, 250 μL), and H2O (250 μL) was stirred in a sealed vessel at 100° C. for 3 h. The reaction was cooled to 23° C., diluted with H2O and extracted with EtOAc (3×). Combined organic phases were dried (Na2SO4), filtered, and concentrated, giving crude product. (Yield was not found). 1H NMR (400 MHz, CD3OD) δ 8.08 (d, J=8.2 Hz, 1H), 7.48-7.44 (m, 3H), 7.29-7.26 (m, 4H), 5.15 (s, 1H), 4.20-4.12 (m, 2H), 2.65 (s, 3H), 2.55 (s, 3H), 1.21 (t, J=7 Hz, 3H), 1.00 (s, 9H).
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[C:9]([OH:23])=[N:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][CH:14]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)=[O:7])C>CO.C1COCC1>[OH:23][C:9]1[C:8]([C:6]([OH:7])=[O:5])=[C:17]([CH3:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([F:21])([F:20])[F:22])=[CH:14][CH:15]=2)[N:10]=1
Reactant: CCOC(=O)c1c(O)nc2cc(C(F)(F)F)ccc2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)c(O)nc2cc(C(F)(F)F)ccc12
Temperature: 60 °C
Yield: 88.2 %

Procedure:
2M aq. LiOH sol. (125 ml) was added to a solution of 15.0 g (50.1 mmol) 2-hydroxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester in a MeOH/THF mixture (in each case 175 ml) and the solution was subsequently heated to 60° C. for 16 h. The solution was subsequently concentrated in a vacuum. The residue was taken up with water and adjusted to pH 2 with a 2M hydrochloric acid. Extraction was then performed with EtOAc. The organic phase was washed with brine, dried over MgSO4 and concentrated in a vacuum. 12.0 g (44.2 mmol, 88%) 2-hydroxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid was obtained as a residue. The raw product was further converted without additional purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:10]I)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][CH:23]([C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1)[C:24](=[O:26])[CH3:25])[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H](CI)NC(=O)OC(C)(C)C
Reactant: CC(=O)Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(CC(C(C)=O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
To a solution of methyl N-(tert-butoxycarbonyl)-3-iodo-L-alaninate (215 g, 652 mmol) and 4-chlorophenylacetone (100 g, 593 mmol) in N,N-dimethylformamide (1.5 L) was added cesium carbonate (483 g, 1.48 mol) at room temperature. After 4 h, the mixture was then added to a stirring solution of pH 7 buffer and EtOAc. The aqueous layer was extracted with EtOAc and the combined organics were washed with pH 7 buffer, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (10% ethyl acetate/heptane→>30% ethyl acetate/heptane) to provide the title compound as a mixture of diastereomers. MS: m/z=392.1 (M+Na).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:31])[C@@H:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:20]([CH3:22])[CH3:21])=[CH:11][C:10]=1[O:32][CH3:33])C1C=CC=CC=1>O1CCCC1.[H][H].[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:31])[C@@H:19]([NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH:20]([CH3:22])[CH3:21])=[CH:11][C:10]=1[O:32][CH3:33]
Reactant: COc1cc(CCNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)ccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(CCNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)ccc1O

Procedure:
50.4 g of (S)-2-(tert-butoxycarbonyl-amino)-3-methyl-butyric acid N-[2-(4-benzyloxy-3-methoxy-phenyl)-ethyl]-amide are dissolved in 1000 ml of tetrahydrofuran and hydrogenated with hydrogen for 2 hours over 10 g of 10% palladium on activated carbon under normal pressure and at room temperature. Filtration with suction is carried out over Celite. The filtrate is concentrated by evaporation, yielding (S)-2-(tert-butoxycarbonyl-amino)-3-methyl-butyric acid N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-amide in the form of an oil.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH3:30])[C:18]([C:20]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:29])[CH:21]=1)=[O:19])=[CH:7]2.[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[NH:33][N:32]=[N:31][N:15]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH3:30])[C:18]([C:20]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:29])[CH:21]=1)=[O:19])=[CH:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: CN(Cc1ccc2c(Br)c(OCC#N)ccc2c1)C(=O)c1cn(C)c2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc2c(Br)c(OCc3nnn[nH]3)ccc2c1)C(=O)c1cn(C)c2ccccc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 83.7 %

Procedure:
A mixture of 1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (1.0 g, 2.0 mmol), prepared in the previous step, sodium azide (0.32 g, 6.0 mmol) and ammonium chloride (0.39 g, 6.0 mmol) in 15 mL of DMF was stirred under nitrogen at 100° C. for 6 h. The reaction was partitioned between ethyl acetate and water. The aqueous layer was made basic by the addition of 1 N NaOH. The organic layer was separated and the aqueous layer extracted five times with ethyl acetate. The aqueous layer was then acidified with 1N HCl. After 2 h a white solid had precipitated from solution. The solid was collected by filtration and dried under reduced pressure to give the title compound (0.8460 g, 84%) as an off-white solid, mp 227-228° C.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[S:4][C:3]1=[O:18]>[C].[Pd].O1CCCC1>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH:5]2[S:4][C:3](=[O:18])[N:2]([CH3:1])[C:6]2=[O:7])=[CH:10][CH:11]=1
Reactant: CN1C(=O)SC(=Cc2ccc([N+](=O)[O-])cc2)C1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CN1C(=O)SC(Cc2ccc(N)cc2)C1=O
Yield: 79.4 %

Procedure:
A mixture of 3-methyl-5-(4-nitrobenzylidene)-1,3-thiazolidine-2,4-dione (1.0 g), 5% palladium carbon (1.0 g) and tetrahydrofuran (150 mL) was subjected to catalytic reduction under hydrogen pressure of 5.0 kgf·cm−2. The catalyst was removed by filtration, and the filtrate was concentrated to give 5-(4-aminobenzyl)-3-methyl-1,3-thiazolidine-2,4-dione as colorless crystals (0.71 g, yield 79%). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 91-92° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:29]C1C=C(C2CCC3C(=CC=C(OC4N=CC(N)=CC=4)C=3)O2)C=CC=1>>[F:29][C:3]1[CH:2]=[C:1]([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2cccc(F)c2)O3)nc1
Product: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2cccc(F)c2)O3)nc1

Procedure:
N-{6-[2-(3-Fluorophenyl)chroman-6-yloxy]pyridin-3-yl}methane sulfonamide was prepared as described for N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]methanesulfonamide in Example 46 starting from 300 mg of 6-[2-(3-fluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine (Example 54). The product was purified by passing through silica gel using ethyl acetate-heptane (5:1) as an eluant. 1H NMR (400 MHz, d6-DMSO) δ: 9.67 (s, 1H), 7.99 (dd, 1H, J 2.8, 0.6 Hz), 7.67 (dd, 1H, J 8.8, 2.8 Hz), 7.46 (m, 1H), 7.31-7.27 (m, 2H), 7.17 (m, 1H), 6.98 (dd, 1H, J 8.8, 0.6 Hz), 6.90-6.88 (m, 3H), 5.16 (dd, 1H, J 10.0, 2.2 Hz), 2.99 (s, 3H), 2.96 (m, 1H), 2.72 (m, 1H), 2.20 (m, 1H), 1.99 (m, 1H).