Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]([OH:11])=[C:9]([CH3:12])[CH:8]=[C:7]2[C:3]=1[C:4]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[C:5]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:6]12.[CH2:24]([O:26][C:27](=[O:32])[C:28](Br)([CH3:30])[CH3:29])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:32])[C:28]([O:11][C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][C:9]=1[CH3:12])[N:6]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:5]1=[C:4]2[C:18]1[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=1)([CH3:30])[CH3:29])[CH3:25]
Reactant: Cc1cc2c(c(C)c1O)c(-c1ccncc1)c1n2CCCCC1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1c(C)cc2c(c1C)c(-c1ccncc1)c1n2CCCCC1

Procedure:
The above compound was prepared from 7,8,9,10-tetrahydro-1,3-dimethyl-11-(4-pyridyl)-6H-azepino[1,2-a]indole-2-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [O-:1]Cl=O.[Na+].[CH2:5]([O:12][C:13]1[C:14](=[O:33])[CH:15]=[C:16]([CH:31]=[O:32])[N:17]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CC(C)=O.O>[CH2:5]([O:12][C:13]1[C:14](=[O:33])[CH:15]=[C:16]([C:31]([OH:1])=[O:32])[N:17]([C:19]2[CH:20]=[C:21]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:22]=[CH:23][CH:24]=2)[CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1cc(=O)c(OCc2ccccc2)cn1-c1cccc(-c2ccccc2)c1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1cc(=O)c(OCc2ccccc2)cn1-c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
NaClO2 (28.3 g, 315 mmol) was added portion-wise to a mixture of 5-(benzyloxy)-1-(biphenyl-3-yl)-4-oxo-1,4-dihydropyridine-2-carbaldehyde (80 g, 210 mmol) in 800 mL of acetone and 800 mL of water at room temperature. The resulting mixture was stirred at room temperature for 3 h. The solvent was removed to give a residue which was washed with water and MeOH and dried to give 5-(benzyloxy)-1-(biphenyl-3-yl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid. 1H NMR δ (400 MHz, d6-DMSO): 7.79 (s, 1H), 7.77˜7.68 (m, 4H), 7.57 (t, J=8.0 Hz, 1H), 7.48 (t,=7.6 Hz, 2H), 7.42-7.31 (m, 7H), 6.66 (s, 1H), 5.04 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]2[N:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=2[CH:22]=1.[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)#[CH:25].CCOC(C)=O.CO>CN(C=O)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:25]#[C:24][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:4][C:5]2[N:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=2[CH:22]=1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(I)c(Cl)cc21
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(C#Cc3ccccc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 4 mL vial equipped with a stirring bar was charged with copper iodide (2.0 mg, 10 mol %), and Pd(PPh3)2Cl2 (3.5 mg, 5 mol %). A solution of 6-chloro-5-iodo-2-methanesulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (Intermediate 5, 49.0 mg, 0.100 mmol) in DMF (0.5 mL) was added to the vial, followed by a solution of ethynyl-benzene (20.0 mg, 0.200 mmol) in DMF (0.5 mL) and TEA (98 uL, 0.70 mmol). The resulting suspension was stirred at rt for 10 min, during which time it gradually turned brown. The solvent was then removed in vacuo to give brown oily solid, which was suspended in 1:1 EtOAc/MeOH (3 mL) and passed through a Thiol StratoSphere™ SPE cartridge (Polymer Labs). The resulting solution was evaporated to dryness in vacuo to give light yellow oil. LR-MS (API-ES): calculated C22H25ClN2O3SSi 460.1, m/e (M+H)+ not observed, 433.0, 403 (Rt 3.83 min).
Reaction SMILES: [H-].[Na+].ICCO[CH:7]([O:9][CH2:10][CH2:11][I:12])[CH3:8].[C:13]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>O1CCCC1>[CH2:22]([O:21][C:13](=[O:20])[C:14]([CH2:19][CH2:18][O:17][CH2:8][CH2:7][O:9][CH2:10][CH2:11][I:12])([CH2:14][CH2:15][O:16][CH2:8][CH2:7][O:9][CH2:10][CH2:11][I:12])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:23]
Reactant: CC(OCCI)OCCI
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCOCCOCCI)(CCOCCOCCI)C(=O)OCC
Temperature: 25 °C
Yield: 75 %

Procedure:
1.71 g (0.036 mol) of sodium hydride was added to 40 ml of tetrahydrofuran dried over metallic sodium, and to this solution was added dropwise a mixed solution of 17.6 g (0.048 mol) of bis(2-iodoethoxy)ethane and 1.92 g (0.012 mol) of diethyl malonate, the mixture being refluxed under heating for hours. Tetrahydrofuran was distilled off and the residue was cooled to room temperature, added with 1N hydrochloric acid until the litmus paper came to indicate acidity and then extracted three times with 50 ml of ether. After drying the extract over anhydrous sodium sulfate, ether was distilled off and the oily residue was passed through a silica gel-packed column and eluted with petroleum ether-ether (2:1) to obtain 2.90 g of 2,2-bis(8-iodo-3,6-dioxaoctyl)malonic acid diethyl ester, (ICH2CH2OCH2CH2OCH2CH2)2 -C(CO2Et)2 (yield: 38%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[N+:13]([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[NH2:13][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:5]=1[NH:4][CH2:3][CH2:2][OH:1])[C:9]#[N:10]
Reactant: N#Cc1ccc(NCCO)c([N+](=O)[O-])c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(NCCO)c(N)c1
Yield: 78.2 %

Procedure:
A solution of 4-(2-hydroxyethylamino)-3-nitrobenzonitrile (3.11 g) and tin chloride dihydrate (16.94 g) in ethanol (50 ml) was stirred at 70° C. for 1 hour. After completion of the reaction, the solvent was evaporated and to the obtained residue were added tetrahydrofuran and 15% aqueous sodium hydroxide solution. The mixture was stirred and insoluble material and the aqueous layer were removed. The obtained organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained solid was washed with chloroform, filtrated and dried under reduced pressure to give the title compound (2.08 g).
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]([O:6][CH:7]([Cl:12])[C:8]([Cl:11])([Cl:10])[Cl:9])=[O:5]>ClCCl>[CH3:1][NH:2][C:4](=[O:5])[O:6][CH:7]([Cl:12])[C:8]([Cl:11])([Cl:10])[Cl:9]
Reactant: O=C(Cl)OC(Cl)C(Cl)(Cl)Cl
Reactant: CN
Solvent: ClCCl
Product: CNC(=O)OC(Cl)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
34.7 ml (0.4 mmol) of methylamine (in 40% strength aqueous solution) are added dropwise to a solution maintained at 0° C. of 49.4 g (0.2 mole) of 1,2,2,2-tetrachloroethyl chloroformate in dichloromethane (150 ml). The mixture is then stirred for 2 hours at room temperature. The organic phase is washed with 2×100 ml of water and dried over magnesium sulphate.
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.[CH3:36][O:37][NH2:38]>CN(C=O)C>[Br:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([NH:38][O:37][CH3:36])=[O:15]
Reactant: O=C(O)c1cnn(-c2ccccc2)c1Br
Reactant: CON
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CONC(=O)c1cnn(-c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.7 %

Procedure:
A solution of 2.6 g of 5-bromo-1-phenyl-1H-pyrazole-4-carboxylic acid and 2.4 g of carbonyldiimidazole in 60 ml DMF was stirred at room temperature for 30 minutes. Two grams of triethylamine and 1.7 g of methoxyamine hydrochloride were added to the solution. The mixture was stirred at room temperature for 24 hours and another equivalent of triethylamine and methoxyamine hydrochloride were added. The mixture was heated on the steam bath for two hours and poured into ice water. The precipitated solid was collected by filtration and recrystallized from ethanol to afford 1.0 g of 5-bromo-1-phenyl-N-methoxy-1H-pyrazole-4-carboxamide. Yield 34%. mp=194°-197° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])=[O:14].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CO.Cl[Pd]Cl.O>[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)c1ccnc(-c2ccc(S(C)(=O)=O)cc2)c1
Temperature: 100 °C
Yield: 66.7 %

Procedure:
Methyl 2-chloroisonicotinate (5 g, 29.14 mmol), 4-(methylsulfonyl)phenylboronic acid (7.58 g, 37.88 mmol), potassium carbonate (2.416 g, 17.48 mmol) and PdCl2 (dppf) (0.633 g, 0.87 mmol) were dissolved in methanol (30 mL) and divided up in two microwave vials. Each vial was heated to 100° C. in a single node microwave reactor for 35 min. DCM (250 mL) and water (250 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (250 mL). The combined organic phases were washed with brine (500 mL), dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on two Biotage® KP-SIL 340 g columns. A gradient of 20-70% EtOAc in heptane over 10 CV and then 70% EtOAc in heptane over 5 CV was used as mobile phase. The product was collected using the wavelength 253 nm. The product fractions were collected and evaporated in vacuo yielding methyl 2-(4-(methylsulfonyl)phenyl)-isonicotinate (5.66 g, 66.7%) as a white solid. 1H NMR (600 MHz, CDCl3) δ 3.09 (s, 3H), 3.98 (s, 3H), 7.85 (dd, 1H), 8.05 (d, 2H), 8.25 (d, 2H), 8.34 (s, 1H), 8.86 (t, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH:19]1([S:22](Cl)(=[O:24])=[O:23])[CH2:21][CH2:20]1.Cl>N1C=CC=CC=1>[F:18][C:12]1[CH:13]=[C:14]([I:17])[CH:15]=[CH:16][C:11]=1[NH:10][C:3]1[C:2]([NH:1][S:22]([CH:19]2[CH2:21][CH2:20]2)(=[O:24])=[O:23])=[CH:7][N:6]([CH3:8])[C:5](=[O:9])[CH:4]=1
Reactant: Cn1cc(N)c(Nc2ccc(I)cc2F)cc1=O
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: c1ccncc1
Product: Cn1cc(NS(=O)(=O)C2CC2)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To a solution of 5-amino-4-(2-fluoro-4-iodophenylamino)-1-methylpyridin-2(1H)-one (62.3 mg, 0.174 mmol) in dry pyridine (3 mL) at 0° C. (ice-salt bath), was added cyclopropanesulfonyl chloride (29 mg, 0.206 mmol). The resultant reaction mixture was allowed to warm to room temperature and stirred for 16 hours. Aqueous HCl (1N) (5 mL) was added and the mixture stirred for 15 minutes, resulting in the formation of a precipitate which was isolated by filtration, dried under vacuum, to afford the desired compound as a tan solid. (64 mg, 79% yield)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:12])[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:15][C:13]([CH3:16])([CH3:14])[C@@H:11]([N:7]1[CH2:6][CH2:5][C@:4]([CH2:3][CH2:2][NH:1][S:32]([CH3:31])(=[O:34])=[O:33])([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8]1=[O:10])[CH3:12]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](N1CC[C@](CCN)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](N1CC[C@](CCNS(C)(=O)=O)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Temperature: 25 °C
Yield: 67.1 %

Procedure:
To a solution of (R)-6-(2-aminoethyl)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (144 mg, 0.45 mmol) and triethylamine (136 mg, 1.35 mmol) in CH2Cl2 (5 mL) was added methanesulfonyl chloride (153 mg, 1.35 mmol) at 0° C., and the reaction mixture was stirred at rt until the reaction was over. The reaction was quenched with H2O. The mixture was extracted with EtOAc, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give crude product, which was purified by preparative TLC to afford N-(2-((S)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)methanesulfonamide (121 mg, 67%). LC-MS Method 1 tR=1.192, min, m/z=401.1; 1H NMR (CDCl3): 0.65 (s, 9H), 1.01-1.07 (d, 3H), 1.96-2.06 (m, 1H), 2.12-2.18 (m, 2H), 2.21-2.28 (m, 1H), 2.57-2.66 (m, 1H), 2.78 (s, 3H), 2.85-2.97 (m, 1H), 3.01-3.12 (m, 2H), 4.31-4.39 (m, 1H), 4.64-4.72 (m, 1H), 6.98-7.07 (m, 2H), 7.19-7.24 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.[CH:22](OC1C=CC([N+]([O-])=O)=CC=1)=[O:23]>C1COCC1>[CH:22]([NH:1][CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)=[O:23]
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)NC(CN)c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CNC=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Of the compound from Example 22A, 75 mg (0.25 mmol) were introduced in 1.5 ml of THF and admixed at 0° C. in small portions with 43.25 mg (0.26 mmol) of 4-nitrophenyl formate. The mixture was stirred at 0° C. for 2 h and then at RT overnight. The solvent was removed on a rotary evaporator and the residue was taken up in DMSO and purified by preparative HPLC (method 10). This gave 66 mg (81% of theory) of the title compound.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([Cl:12])[C:6]([CH:9]([CH3:11])[NH2:10])=[N:7][CH:8]=1.C(N(CC)CC)C.[Cl:20][C:21]1[N:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:22]=1[C:23](Cl)=[O:24]>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([Cl:12])[C:6]([CH:9]([NH:10][C:23]([C:22]2[C:21]([Cl:20])=[N:29][CH:28]=[CH:27][C:26]=2[Cl:30])=[O:24])[CH3:11])=[N:7][CH:8]=1
Reactant: O=C(Cl)c1c(Cl)ccnc1Cl
Reactant: CC(N)c1ncc(Br)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)c1c(Cl)ccnc1Cl)c1ncc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of Step C (0.80 g), 1.21 mL of triethyl amine and 0.62 g of 2,4-dichloronicotinoyl chloride were combined in that order at <20° C. in 25 mL of methylene chloride, and the mixture was stirred at room temperature overnight. The reaction mixture was reduced in vacuo to produce the title compound, a compound of the invention, as a solid. NMR (CDCl3; 300 MHz): δ1.59 (d, 3H, J is 6.6 Hz), 5.75 (m, 1H), 7.3 (bs, 1H), 7.34 (d, 1H, J is 5.2 Hz), 7.91 (d, 1H, J is 1.9 Hz), 8.33 (d, 1H, J is 5.4 Hz), 8.49 (d, 1H, J is 1.9 Hz).
Reaction SMILES: [F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=O)=[C:20]([N+:28]([O-])=O)[CH:19]=2)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]>C(O)C.OS(O)(=O)=O.[Zn]>[F:1][C:2]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[C:20]3[C:21]([CH2:24][C:25](=[O:27])[NH:28]3)=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:9])[CH3:10])(=[O:6])=[O:7]
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccc(CC(=O)O)c([N+](=O)[O-])c2)cc1
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: CCO
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccc3c(c2)NC(=O)C3)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a stirred solution of {4′-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)ethyl]-3-nitro-biphenyl-4-yl}-acetic acid (0.311 g, 0.71 mmol, prepared in example 48) dissolved in Ethanol (4.0 mL)/50% H2SO4 (3.0 mL) at ambient temperature then heated to 90° C. is added Zn (0.186 g, 2.84 mmol) in divided portions over 30 minutes. Heating and stirring is continued for 2 h after addition of the Zn. The mixture is allowed to cool to ambient temperature. It is then extracted (EtOAc) and the EtOAc is extracted with 5% NaHCO3, washed with brine, dried (MgSO4), filtered and the filtrate concentrated in vacuo. Chromatography of the residue (silica gel, EtOAc/hexane) provides the title compound.
Reaction SMILES: [CH:1]([C:11]1[CH:12]=[C:13]([N+:17]([O-])=O)[CH:14]=[CH:15][CH:16]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>[Pd].C(O)(=O)C>[CH2:1]([C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC=Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCc1cccc(N)c1
Reaction time: 12 h
Yield: 18.8 %

Procedure:
A mixture of 3-(1-decenyl)nitrobenzene (43.9 g), acetic acid (200 ml) and palladium black (2.0 g) was hydrogenated at room temperature and at atmospheric pressure for 12 hours. The catalyst was changed and the reaction was continued for 12 hours under the same conditions. The catalyst was filtered off and the residue was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane/chloroform=10:1→1:2) to give 7.36 g of 3-decylaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.Br.[CH3:27][NH:28][CH2:29][CH:30]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[OH:31].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:28]([CH2:29][CH:30]([OH:31])[C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)[CH3:27])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: CNCC(O)c1cccnc1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c(CN(C)CC(O)c2cccnc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 30 h
Yield: 68.1 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 2-(methylamino)-1-pyridin-3-ylethanol hydrobromide (Arch. Pharm. 1961, 294 453-68)(89 mg, 0.38 mmol) and diisopropylethylamine (134 μL, 0.76 mmol) in dry DMF (5.0 mL) was stirred for 30 hours at room temperature. The solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (87 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].[Cl:16][C:17]1[CH:26]=[CH:25][C:20]([CH2:21][N:22]=[C:23]=[O:24])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:3]=1[CH2:4][N:5]([CH2:6][CH3:7])[C:23]([NH:22][CH2:21][C:20]1[CH:25]=[CH:26][C:17]([Cl:16])=[CH:18][CH:19]=1)=[O:24]
Reactant: CCNCc1cc(C(F)(F)F)ccc1Br
Reactant: O=C=NCc1ccc(Cl)cc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(=O)NCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 95, Step 1, using the following starting materials: (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine and 4-chlorobenzyl isocyanate.
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.[ClH:15].[Cl:16][CH2:17][CH2:18][NH2:19]>CN(C)C=O>[ClH:16].[ClH:15].[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:17][CH2:18][NH2:19])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: NCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NCCOc1ccc(-n2ccnc2)cc1
Temperature: 70 °C

Procedure:
To a cold solution of 11.3 g (0.235 mol) 50% sodium hydride in 50 mL dimethylformamide add 15 g (0.094 mol) 4-(1H-imidazol-1-yl)phenol portionwise. Maintain the temperature below 0° C. during the addition. After the addition, add dropwise a solution of 10.89 g (0.094 mol) 2-chloroethylamine hydrochloride in 50 mL dimethylformamide. After addition, warm the reaction mixture to 70° C., and heat for 24 hours. After this time, cool the reaction mixture and quench with water. Filter the solids and wash the mother liquors with 2X250 mL ether, 3X250 mL methylene chloride. Dry the methylene chloride layers over Na2SO4 and evaporate the solvents. Dissolve the resultant oil in methanolic HCl and evaporate the solvent to obtain the title compound.
Reaction SMILES: Cl.C([O:4][C:5](=[O:23])[CH2:6][CH:7]([NH2:22])[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]([OH:21])([CH3:20])[CH3:19])[CH:9]=1)C.[OH-].[Na+].OP([O-])(O)=O.[K+].P([O-])([O-])([O-])=O>O.C(OC)(C)(C)C>[NH2:22][C@H:7]([C:8]1[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[C:10]([C:18]([OH:21])([CH3:19])[CH3:20])[CH:9]=1)[CH2:6][C:5]([OH:23])=[O:4]
Reactant: CCOC(=O)CC(N)c1cc(C(C)(C)O)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)(O)c1cc([C@@H](N)CC(=O)O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 63 h

Procedure:
A suspension of racemic ethyl 3-amino-3-(3-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)phenyl)propanoate hydrochloride (Example J) (540.4 mg, 1.52 mmol) in water (2.0 mL) was basified with 2.5 N NaOH solution (pH 12) by drop wise addition to give a dirty pink oily residue. The pH of the aqueous phase was adjusted to pH 8.20 by the addition of 50 mom KH2PO4 solution (40.0 mL). Amano Lipase PS (607.6 mg) was added to the above suspension and the reaction mixture was stirred at room temperature for 63 h to give a pale pink suspension. The reaction mixture was diluted with methyl t-butyl ether (MTBE) (50 mL) and the reaction mixture was stirred at room temperature for 30 min. After 30 min, the organic layer containing the (R)-ester was separated. Evaporation of the aqueous layer in vacuo afforded a cream gummy solid containing the (S)-acid as well as Amano Lipase and Phosphate buffer salt. LC-MS analysis of the crude residue shows the desired (S)-acid's mass: m/z 292 (M+H), m/z 314 (M+Na), and m/z 274 (M+H−H2O); Calcd for C13H16F3NO3: 291.27. The crude product was purified by reverse-phase HPLC with a gradient 10-40% CH3CN in water containing 0.05% TFA to give the desired product, after lyophilization, as a colorless lyophilized solid (324 mg) (TFA salt).
Reaction SMILES: O=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.Cl.[CH3:14][NH:15][CH:16]1[CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH:16]1([N:15]([CH3:14])[CH:2]2[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]2)[CH2:18][CH2:17]1
Reactant: CNC1CC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C1CC1)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
Combined a solution of tert-butyl 3-oxoazetidine-1-carboxylate (175 mg, 1.022 mmol) and N-methylcyclopropanamine hydrochloride (121 mg, 1.124 mmol) in methylene chloride (5 mL) and added sodium triacetoxyborohydride (325 mg, 1.533 mmol) and the solution stirred at 20° C. for 30 min. The solution was concentrated in vacuo to give white solid which was taken up in ethyl acetate (50 mL), washed with saturated sodium bicarbonate (50 mL) and brine, dried with magnesium sulfate and concentrated in vacuo, and then purified on a 40 g silica gel column eluted with 0 to 50% ethyl acetate in hexanes to give the title compound (128 mg, 0.566 mmol, 55.3%) as a clear, colorless oil. MS: 227 (M+H). 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.41-0.47 (m, 2H) 0.48-0.56 (m, 2H) 1.43 (s, 9H) 1.64 (tt, J=6.7, 3.9 Hz, 1H) 2.28 (s, 3H) 3.50 (tt, J=7.5, 5.7 Hz, 1H) 3.84-4.01 (m, 4H).