Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[N:6]=1)=O.CC(C[AlH]CC(C)C)C>ClCCl.CCCCCC>[CH3:14][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:3][OH:2])=[N:6]1
Reactant: COC(=O)c1nn(C)c2ccccc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: Cn1nc(CO)c2ccccc21
Temperature: 25 °C
Yield: 90.8 %

Procedure:
To a stirring solution of 440 mg (2.31 mmol) of 1-Methyl-1H-indazole-3-carboxylic acid methyl ester (Fludzinski, P. et. al. J. Med. Chem. 1987, 30, 1535) in 10 mL dichloromethane at -78° C. is added dropwise over 5 min a solution of 5.8 mL (5.8 mmol, 2.5 equiv) of a 1.0M solution of DIBAL-H in hexane. The resulting solution is allowed to slowly warm to RT over a 3 h period then quenched by careful addition of 5 mL of H2O. The reaction mixture is poured into 100 mL of EtOAc and extracted with 1N HCl (1×100 mL), dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 340 mg of the title compound as a pale yellow oil: 1H NMR (CDCl3, 300 MHz) δ7.80 (d, 1H), 7.42-7.12 (m, 3H), 5.02 (d, 2H), 4.00 (s, 3H), 2.27 (m, 1H); Rf =0.25 in hexane/EtOAc 1/1.
Reaction SMILES: [OH:1][C:2]1[C:6]([I:7])=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][N:3]=1.[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23]O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][O:1][C:2]1[C:6]([I:7])=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][N:3]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1noc(-c2ccccc2)c1I
Product: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1I
Yield: 73.4 %

Procedure:
3-Hydroxy-4-iodo-5-phenylisoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.12 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.22 g, 73%) as a colorless powder.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:18][C:8]2=[CH:9][C:10]3[C:11](=[O:17])[NH:12][C:13](=[O:16])[C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:2][CH3:3].Cl[CH2:23][C:24]1[N:28]=[CH:27][O:26][N:25]=1.Cl>>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:18][C:8]2=[CH:9][C:10]3[C:11](=[O:17])[N:12]([CH2:23][C:24]4[N:28]=[CH:27][O:26][N:25]=4)[C:13](=[O:16])[C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:20][CH3:21]
Reactant: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)NC3=O
Reactant: ClCc1ncon1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ncon1)C3=O

Procedure:
Using procedure 48, 6-(dipropylamino)-6,7-dihydrocyclopent[f]isoindole-1,3(2H,5H)-dione (93, 0.14 g, 0.5 mmol) was treated with 3-(chloromethyl)-1,2,4-oxadiazole (0.09 g, 0.75 mmol). Purification using silica gel, eluting with 7:1 CH2Cl2 /acetone, afforded a solid that was converted to an HCl salt and recrystallized from CH2Cl2 /Et2O to give 100 as a white solid (m.p. 190-191° C.).
Reaction SMILES: [CH2:1]([Zn]CC)C.C1(C)C=CC=CC=1.ClCI.[CH3:16]/[C:17](=[CH:20]/[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])/[CH2:18][OH:19].S(=O)(=O)(O)O>>[CH3:16][C@:17]1([CH2:18][OH:19])[CH2:1][C@H:20]1[C@H:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:22]
Reactant: CC[Zn]CC
Reactant: C/C(=C/C(C)c1ccccc1)CO
Agent: ClCI
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: C[C@@H](c1ccccc1)[C@@H]1C[C@]1(C)CO
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 69.8 g, 84.8 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to −20° C. Chloroiodomethane (29.9 g, 169.6 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between −15 and −20° C. After completion of the dropwise addition, the mixture was stirred at −10 to −15° C. for 30 minutes, and then cooled to −25° C. (Z)-2-Methyl-4-phenylpent-2-ene-1-ol (7.59 g, 42.4 mmol) was added dropwise over a period of 60 minutes in the range from −20 to −25° C. After completion of the dropwise addition, the stirring was continued at −15 to −25° C. for 60 minutes. Next, a 20% aqueous sulfuric acid solution (31.3 ml) was added. After stirring for 10 minutes, the aqueous layer was separated. The organic layer was washed twice with water (30 ml), and the solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:2). [(1S*,2S*)-1-Methyl-2-((R*)-1-phenylethyl)cyclopropyl]methanol (4.93 g, 25.9 mmol, 61% yield) was obtained as the main isomer, and [(1S*,2S*)-1-methyl-2-((S*)-1-phenylethyl)cyclopropyl]methanol (0.61 g, 3.2 mmol, yield 7.5%) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
Reaction SMILES: [CH3:1][C:2]1[C:22]([CH3:23])=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl.CCOC(C)=O>[CH3:1][C:2]1[C:22]([CH3:23])=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17]([CH3:18])=[O:32])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CSc1nc2ccc(Cn3cnc4cc(C)c(C)cc43)cc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc2ncn(Cc3ccc4nc(S(C)=O)sc4c3)c2cc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a stirred solution of 6-((5,6-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (450 mg, 1.32 mmol) from the previous step in DCM (20 mL) at 0° C. was added a solution of meta-chloroperbenzoic acid (270 mg, 1.32 mmol) in DCM (3 mL). After stirring for 2 h at 0° C., the reaction solution was diluted with EtOAc (100 mL) and washed sequentially with saturated aq Na2S2O3, saturated aq NaHCO3, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 6-((5,6-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (460 mg, 98%) as a colorless solid which was not purified further. 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J=8.4 Hz, 1H), 7.90 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.37 (m, 1H), 7.02 (s, 1H), 5.48 (s, 2H), 3.06 (s, 3H), 2.37 (s, 3H), 2.32 (s, 3H); LCMS (ESI) m/z 356 (M+H)+.
Reaction SMILES: C([C@H:3]([S:7]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=3)=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-:6])=O)C.[NH2:42][CH2:43][CH:44]([OH:47])[CH2:45][OH:46]>>[OH:47][CH:44]([CH2:45][OH:46])[CH2:43][NH:42][C:4](=[O:6])[CH2:3][S:7](=[O:8])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[N:9][C:10](=[O:11])[C:12]1[CH:17]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=3)=[O:28])[CH:21]=2)[CH:15]=[N:14][CH:13]=1
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cc(C)nn3C)c2)c1)c1ccccc1
Reactant: NCC(O)CO
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=S(=O)(CC(=O)NCC(O)CO)c4ccccc4)c3)c2)n(C)n1

Procedure:
In a manner similar to that described in Example 534, (S)-Ethyl[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate and 3-amino-1,2-propanediol were reacted to give the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][N:4]=1.[Br:13]N1C(=O)CCC1=O.[Cl-].[NH4+]>CN(C=O)C>[CH3:1][NH:2][C:3]1[C:8]([Br:13])=[CH:7][C:6]([C:9]([F:12])([F:10])[F:11])=[CH:5][N:4]=1
Reactant: CNc1ccc(C(F)(F)F)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CNc1ncc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a mixture of N-methyl-(5-trifluoromethyl-pyridin-2-yl)-amine (3.48 g) and DMF (20 ml), N-bromosuccinimide (4.27 g) was added, and stirred at room temperature for 1 hour. Into the reaction mixture, saturated aqueous ammonium chloride solution was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 4.8 g of N-methyl-(3-bromo-5-trifluoromethyl-pyridin-2-yl)-amine.
Reaction SMILES: C(=[N:14][N:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH3:16])(C1C=CC=CC=1)C1C=CC=CC=1.Cl.[OH-].[Na+]>O1CCCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([N:15]([CH3:16])[NH2:14])=[CH:18][CH:19]=1
Reactant: CN(N=C(c1ccccc1)c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(N)c1ccc(Cl)cc1

Procedure:
N′-Benzhydrylidene-N-(4-chlorophenyl)-N-methylhydrazine (1.5 g, 4.68 mmol) is placed in 20 mL of tetrahydrofuran with stirring. 5 mL of 5 N hydrochloric acid are added thereto and the solution is then left stirring at a temperature in the region of 50° C. for 16 hours. The aqueous phase is then neutralized with 5 N sodium hydroxide and is then extracted with ethyl acetate. The oil obtained after extraction is purified by chromatography on silica gel, eluting at the start with an ethyl acetate/heptane mixture (10/90 by volume). N-(4-Chlorophenyl)-N-methylhydrazine is thus obtained in the form of a pale yellow oil, 0.53 g (72%). (Rf=0.48. 20/80 EtOAc/heptane (v/v)).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[O:16][N:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)=[CH:26][C:23]=1[CH:24]=O.C[O-].[Li+].Cl>CN(C)C=O.CO.O>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)=[CH:26][C:23]=1/[CH:24]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[O:16][N:15]=2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:3]
Reactant: COc1cc(OC)c(-c2cccs2)cc1C=O
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2cc(C)on2)cc1
Agent: C[O-]
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(-c2cccs2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)Nc2cc(C)on2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
4-Acetyl-N-(5-methylisoxazole-3-yl)benzenesulfonamide (Ex-1B, 2.50 g, 8.9 mmol) and 2,4-dimethoxy-5-thien-2-ylbenzaldehyde (Ex-1A, 2.20 g, 8.9 mmol) were dissolved in a dimethylformamide-methanol solution (55 mL, 7:3). After complete dissolution, lithium methoxide (1.35 g, 35.6 mmol) was added and the resulting orange slurry was stirred in the dark at room temperature for 1 h. Upon completion, as determined by HPLC, the mixture was diluted with water (80 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (3×40 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethanol (20 mL) and warmed to 60° C. to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 3.78 g (83%) of the title compound as an orange solid, mp 202–203° C. 1H-NMR (300 MHz, DMSO-d6) 8.31 (d, 2H, J=8.1 Hz), 8.27 (s, 1H), 8.08 (d, 1H, J=15.9 Hz), 8.01 (d, 2H, J=8.1 Hz), 7.88 (d, 1H, J=15.9 Hz), 7.66 (d, 1H, J=3.3 Hz), 7.53 (d, 1H, J=5.1 Hz), 7.13 (dd, 1H, J=5.1, 3.3 Hz), 6.84 (s, 1H), 6.18 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 2.31 (s, 3H). Anal. Calcd. for C25H22N2O6S2: C, 58.81; H, 4.34; N, 5.49; S, 12.56; Found: C, 58.68; H, 4.40; N, 5.61; S, 12.62. HRMS (EI) Calcd. for C25H22N2O6S2: 511.0997 (M+); Found: 511.0983.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:6][C:7]([O:9][CH:10](Cl)[CH3:11])=[O:8])[CH2:3][CH2:4][CH3:5].[OH:14][C@@H:15]([C@H:17]1[C:37](=[O:38])[N:19]2[C:20]([C:34]([O-:36])=[O:35])=[C:21]([C:24]3[S:28][C:27]4=[C:29]([S:32][CH3:33])[N:30]=[CH:31][N:26]4[CH:25]=3)[C@H:22]([CH3:23])[C@H:18]12)[CH3:16].[Na+].O>CN(C=O)C.[Ag]I>[OH:14][C@@H:15]([C@H:17]1[C:37](=[O:38])[N:19]2[C:20]([C:34]([O:36][CH:10]([O:9][C:7]([O:6][C:2]([CH3:13])([CH3:1])[CH2:3][CH2:4][CH3:5])=[O:8])[CH3:11])=[O:35])=[C:21]([C:24]3[S:28][C:27]4=[C:29]([S:32][CH3:33])[N:30]=[CH:31][N:26]4[CH:25]=3)[C@H:22]([CH3:23])[C@H:18]12)[CH3:16]
Reactant: CCCC(C)(C)OC(=O)OC(C)Cl
Reactant: CSc1ncn2cc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Agent: [Ag]I
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(C)(C)OC(=O)OC(C)OC(=O)C1=C(c2cn3cnc(SC)c3s2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
A solution of 156.6 mg of 1-(1,1-dimethyl-1-butyloxycarbonyloxy)ethyl chloride in 2.0 ml of DMF was added to a suspension of 176.1 mg of silver iodide in 2.0 ml of DMF. The mixture was stirred in an argon atmosphere at room temperature for one hr. A solution of 200.0 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate in 1.0 ml of DMF was added thereto, followed by stirring for 3 hr. Water (10 ml) was added to the reaction solution to terminate the reaction. The system was extracted three times with 10 ml of ethyl acetate, followed by washing three times with 30 ml of semisaturated brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The residue was purified by chromatography on silica gel (chloroform:methanol=20:1) to give 82.3 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.N[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: NCCN1CCOCC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)cc1NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.2 %

Procedure:
A mixture of 19.5 g of 4-chloro-1,2-dinitrobenzene and 35 g of 4-(2-aminoethyl)morpholine in 180 ml of EtOH is stirred for 20 hours at RT. The precipitate formed is filtered off and washed with iso ether to give 17.1 g of the expected product after crystallization twice in succession from isopropanol.
Reaction SMILES: [Si:1]([O:18][C@H:19]1[C:24](=[CH2:25])[C@H:23](O)[CH2:22]/[C:21](=[CH:27]/[C:28]([O:30][CH3:31])=[O:29])/[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:38])CC)C>ClCCl>[Si:1]([O:18][C@H:19]1[C:24](=[CH2:25])[C@@H:23]([F:38])[CH2:22]/[C:21](=[CH:27]/[C:28]([O:30][CH3:31])=[O:29])/[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: C=C1[C@H](O)C/C(=C/C(=O)OC)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: ClCCl
Product: C=C1[C@@H](F)C/C(=C/C(=O)OC)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound of Example 18A (600 mg, 0.23 mmol) was dissolved in 2.4 mL of dichloromethane, and the resultant solution was cooled to −78° C. (Diethylamino)sulfur trifluoride (DAST, 0.6 mL) was added; the mixture was stirred for 30 minutes, and then quenched by addition of saturated aqueous sodium bicarbonate solution. The mixture was warmed to ambient temperature; the organic phase was dried over Na2SO4. The solvents were removed in vacuo; the residue was purified by chromatography on an Analogix IntelliFlash 280™, eluting with a gradient of 5% to 7% ethyl acetate in hexanes, to give the titled compound, plus some mixed fractions.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1>ClCCl.C(N(CC)CC)C>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[N:10][CH:11]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(Br)cn1
Temperature: 20 °C
Yield: 55.6 %

Procedure:
A solution of trimethylacetyl chloride (17.5 g, 146 mmol) in dichloromethane (25 ml) was added to a solution of 2-amino-5-bromopyridine (25.0 g, 144 mmol) in dichloromethane (100 ml) and triethylamine (24 ml) dropwise with stirring at 20° C. The reaction mixture was then stirred for 40 minutes, filtered, washed with water, dried and concentrated. Recrystallization from hexanes afforded 20.6 g (70%) of the title product as a white flaky solid. mp 63-64° C. 1H NMR (CDCl3): δ=8.82 (br, 1 H); 8.30 (d, 1 H); 8.19 (m, 2 H); 1.36 (s, 3 H). MS (El): m/z=256, 258 (M+, Br isotopes).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:22]1([S:25](Cl)(=[O:27])=[O:26])[CH2:24][CH2:23]1>>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH:21][S:25]([CH:22]5[CH2:24][CH2:23]5)(=[O:27])=[O:26])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2
Reactant: O=S(=O)(Cl)C1CC1
Product: O=S(=O)(Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2)C1CC1
Yield: 9.1 %

Procedure:
Prepared from N2-(3-Cyclopropyl-phenyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 119) (200 mg, 0.72 mmol) and cyclopropanesulfonyl chloride (161 mg, 1.1 mmol) according to the procedure described for Example 27. Obtained the title compound as an off-white foam (25 mg, 9%), MS (ISP) m/e=382.4 [(M−H)−].
Reaction SMILES: [F:1][CH2:2][O:3][NH2:4].[NH2:5][C:6]1[S:10][N:9]=[C:8]([C:11](=O)[C:12]([OH:14])=[O:13])[N:7]=1.[OH-].[Na+]>C(O)C.O>[NH2:5][C:6]1[S:10][N:9]=[C:8](/[C:11](=[N:4]/[O:3][CH2:2][F:1])/[C:12]([OH:14])=[O:13])[N:7]=1
Reactant: Nc1nc(C(=O)C(=O)O)ns1
Reactant: NOCF
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc(/C(=N/OCF)C(=O)O)ns1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a mixture of a solution of fluoromethoxyamine (0.58 g) in ethanol (25 ml) and water (0.45 ml), 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-oxoacetic acid (1 g) was added. After adjusting the pH of the resulting mixture to 4-5 with a 10% aqueous solution of sodium hydroxide, the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, water (20 ml) and sodium chloride (10 g) were added, and the pH of the solution was adjusted to 1 with concentrated hydrochloric acid. The solution was extracted four times with ethyl acetate (30 ml). After washing the extract with saturated saline, anhydrous magnesium sulfate was added to the extract to dry the same. The solvent was distilled off and the residue was crystallized from a 1:3 mixture of acetone and isopropyl ether, thereby obtaining the target product (0.38 g).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].N[C@@H:14]([C@H](C)CC)C(O)=O>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@H:7]([CH3:9])[CH2:8][CH3:14])[C:10]([OH:12])=[O:11])=[O:4]
Reactant: CC[C@@H](C)[C@H](N)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Product: CC[C@@H](C)[C@H](NC(=O)OC)C(=O)O

Procedure:
(2S,3R)-2-(methoxycarbonylamino)-3-methylpentanoic acid was synthesized similar to N-methoxycarbonyl-L-Valine, using (2S,3R)-2-amino-3-methylpentanoic acid instead of L-Valine.
Reaction SMILES: [CH2:1]([C:3]([OH:34])([CH2:32][CH3:33])/[CH:4]=[CH:5]/[CH:6]=[C:7](\[C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][CH:31]=1)[O:13][CH2:14][C:15]1[CH:16]=[C:17]([C:25](OC)=[O:26])[C:18](=[CH:23][CH:24]=1)[C:19](OC)=[O:20])/[CH2:8][CH3:9])[CH3:2].[BH4-].[Li+]>>[OH:26][CH2:25][C:17]1[CH:16]=[C:15]([CH:24]=[CH:23][C:18]=1[CH2:19][OH:20])[CH2:14][O:13][C:12]1[CH:11]=[C:10](/[C:7](/[CH2:8][CH3:9])=[CH:6]\[CH:5]=[CH:4]\[C:3]([CH2:32][CH3:33])([OH:34])[CH2:1][CH3:2])[CH:31]=[CH:30][CH:29]=1
Reactant: CC/C(=C/C=C/C(O)(CC)CC)c1cccc(OCc2ccc(C(=O)OC)c(C(=O)OC)c2)c1
Agent: [BH4-]
Agent: [Li+]
Product: CC/C(=C/C=C/C(O)(CC)CC)c1cccc(OCc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to Example 53(e), by reacting 72 mg (0.15 mmol) of dimethyl 4-[3-((1Z,3E)-5-ethyl-5-hydroxy-1-ethylhepta-1,3-dienyl)phenoxymethyl]phthalate (prepared in a manner similar to Examples 66(a-b)) with 10 mg (0.46 mmol) of lithium borohydride, a colourless oil is obtained (m=62 mg; Y=100%).
Reaction SMILES: C([O:3][C:4](=[O:45])[CH:5]([C:10]1[CH:11]=[C:12]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])(=[O:24])=[O:23])[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[K+]>CCO>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:37][CH:36]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:33])([F:32])[F:34])(=[O:24])=[O:23])[CH2:17]2)[CH:15]=1)[C:4]([OH:45])=[O:3]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(S(=O)(=O)c3ccccc3C(F)(F)F)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(S(=O)(=O)c3ccccc3C(F)(F)F)C2)c1
Temperature: 78 °C

Procedure:
To a solution of compound 42a, 4-Methyl-2-{4′-trifluoromethyl-5-[1-(2-trifluoromethyl-benzenesulfonyl)-piperidin-3-yl]-biphenyl-3-yl}-pentanoic acid ethyl ester (34.0 mg, 0.052 mmol) in EtOH (2.6 ml) was added 2M KOH (0.26 ml, 0.52 mmol). The reaction was heated to 78° C. for 1.5 hours, cooled to room temperature, and concentrated in vacuo. Purification via Gilson HPLC, gave the product as a white lyophilate. (17.3 mg, 53%) 1HNMR(300 MHz, MeOD) δ ppm0.79-0.87 (m, 6 H) 1.41 (dt,J=13.28, 6.74 Hz, 1 H) 1.53-1.69 (m, 3 H) 1.79 (dd, J=5.84, 2.83 Hz, 1 H) 1.84-1.96 (m, 2 H) 2.71-2.84 (m, 3 H) 3.64 (t, J=7.72 Hz, 1 H) 3.79 (d, J=6.03 Hz, 2 H) 7.18 (s, 1H) 7.38 (d, J=16.58 Hz, 2 H) 7.62-7.76 (m, 6 H) 7.85-7.90 (m, 1 H) 7.99-8.04 (m, 1 H) Calcd for C31H31F6NO4S (M+H) 627.64, Found 628.3.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][C:5]2[CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:9][C:10]=2[N:11]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:1][CH2:2][C:3]1[S:4][C:5]2[CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:9][C:10]=2[N:11]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2nc(CO)sc2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2nc(COS(C)(=O)=O)sc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a dichloromethane solution (15 ml) of tert-butyl 2-(hydroxymethyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (1 eq.) was added triethylamine (2.5 eq.) and methane sulfonylchloride (1.2 eq.) at 0° C. and the resulting reaction mixture was stirred at ambient temperature for 2 h. The reaction was quenched with ice and diluted with dichloromethane. The organic layer was successively washed with water and brine and finally dried over sodium sulfate. Evaporation of the organic layer under reduced pressure gave the crude product which was used directly in the next step without further purification. Yield: 80%.