Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:8]2[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:7]=2[C:6]1=[O:24].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:26].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O.O>[C:2]([CH2:3][CH2:4][N:5]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:8]2[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:7]=2[C:6]1=[O:24])([OH:26])=[O:1]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: O=C1c2cc(I)ccc2OC(Cc2ccccc2)CN1CCCO
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCN1CC(Cc2ccccc2)Oc2ccc(I)cc2C1=O
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a magnetically stirred solution of 2-(3-hydroxypropyl)-4-benzyl-8-iodo2,3,4,5-tetrahydro-1H-5-oxa-2-benzazepin-1-one (0.75 grams, 1.7mmol) in 5 mL dimethylformamide at room temperature was added a solution of pyridinium dichromate (2.58 grams, 6.86mmol) in 5 mL dimethylformamde. The reaction mixture was stirred overnight, diluted with 75 mL water, washed 3×75 mL diethyl ether, made acidic to a pH of 2 with conc. HCl and extracted 3×75 mL diethyl ether. The combined organics were extracted 3×40 mL 1N sodium hydroxide. The combined aqueous layers were acidified to a pH of 2 with canc HCl and extracted 3×50 mL diethyl ether. These ether layers were combined and dried over magnesium sulfate, filtered, and concentrated in vacuo to yield 0.557 grams (73%) of 2-(2-carboxyethyl)-4-benzyl-8-iodo-2,3,4,5-tetrahydro-1H-5-oxa-2-benzazepin-1-one. 1H NMR (CDCl3, dTMS) 8.07 (1H, d, 4JHH =2 Hz, C9-H), 7.69 (1H, dd, 4JHH =2 Hz, 3JHH =8 Hz, C7-H), 7.4-7.2 (5H, m, C6H5), 6.75 (1H, d, 3JHH =8 Hz, C6-H), 4.75 (1H, m, ArOCH), 3.89 (1H, dt, 2JHH =14 Hz, 3JHH =6 Hz, NCHHCH2CO2), 3.69 (1H, dt, 2JHH =14 Hz, 3JHH =6 Hz, NCHHCH2CO2), 3.44 (2H, d, 3JHH =3 Hz, CH2Ph), 3.07 (1H, dd, 2JHH =14 Hz, 3JHH =7 Hz, C3-H), 2.8-2.7 (3H, m, C3-H, CH2CO2), 13C NMR (CDCl3) 176.1 167.6, 164.4, 152.8, 141.7, 139.5, 136.4, 129.4, 129.1, 128.9, 128.8, 127.0, 124.7, 86.7, 84.7, 51.4, 45.0, 38.8, 33.0.
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH2:30][CH2:31][NH:32][CH2:33][CH:34]3[CH2:36][CH2:35]3)[CH:25]=[CH:24]4)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.[BH4-].[Na+]>CO.C(O)(=O)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH2:30][CH2:31][N:32]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH2:33][CH:34]3[CH2:35][CH2:36]3)[CH:25]=[CH:24]4)=[N:17][CH:18]=2)=[CH:11][CH:12]=1
Reactant: Clc1ccc(-c2ccc(C#Cc3ccc4c(ccn4CCNCC4CC4)c3)nc2)cc1
Reactant: O=CC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Clc1ccc(-c2ccc(C#Cc3ccc4c(ccn4CCN(CC4CC4)CC4CC4)c3)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
36 μL (0.47 mmol) cyclopropanecarbaldehyde are added to a solution of 100 mg (0.24 mmol) (2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethyl)-cyclopropylmethyl-amine in 20 mL MeOH at RT and 15 min later 59 mg (0.94 mmol) NaBH4 and one drop of glacial acetic acid are added. The mixture is stirred for 1 h at RT, evaporated down i.vac., the residue is taken up in dilute K2CO3 solution, extracted exhaustively with EtOAc and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is triturated with PE, suction filtered and dried.
Reaction SMILES: [N+:1]([C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[N:5]=1)([O-])=O>CCO.[Pd]>[F:20][C:17]([F:18])([F:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:6]1[N:5]=[C:4]([NH2:1])[C:9]([NH2:10])=[CH:8][CH:7]=1
Reactant: Nc1ccc(-c2ccccc2C(F)(F)F)nc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-c2ccccc2C(F)(F)F)nc1N
Reaction time: 3 h

Procedure:
To a solution of 2-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-3-ylamine (130 mg, 0.460 mmol, as prepared in the previous step) in EtOH (10 mL), 10% Pd/C (60 mg) was added. The resulting mixture was hydrogenated at 50 psi for 3 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to obtain the title compound, which was directly used in the next step without further purification. 1H-NMR (400 MHz, CDCl3) δ: 7.62 (d, J=7.8 Hz, 1H), 7.41-7.49 (m, 1H), 7.29-7.41 (m, 2H), 6.81 (d, J=7.8 Hz, 1H), 6.64 (d, J=7.8 Hz, 1H), 4.31 (br. s., 2H), 3.34 (br. s., 2H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.C(Cl)Cl.CO>[N:28]1[CH:33]=[C:32]([C:2]2[N:10]=[CH:9][C:8]3[NH:7][C:6]4[N:11]=[CH:12][C:13]([C:15]5[CH:16]=[CH:17][C:18]([CH2:21][N:22]6[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]6)=[CH:19][CH:20]=5)=[CH:14][C:5]=4[C:4]=3[CH:3]=2)[CH:31]=[N:30][CH:29]=1
Reactant: OB(O)c1cncnc1
Reactant: Clc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC#N
Product: c1ncc(-c2cc3c(cn2)[nH]c2ncc(-c4ccc(CN5CCCCC5)cc4)cc23)cn1
Temperature: 130 °C
Yield: 29.7 %

Procedure:
A mixture of 6-chloro-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (40 mg, 0.08 mmol), pyrimidin-5-yl boronic acid (20 mg, 0.16 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.2 mg, 0.004 mmol) in saturated aqueous sodium carbonate solution (0.15 mL) and acetonitrile (1.50 mL) was heated under microwave irradiation at 130° C. for 30 minutes. The cooled reaction mixture was diluted with DCM (20 mL) and methanol (2 mL) and washed with water (15 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by preparative HPLC [0-30% MeCN in water (0.1% formic acid) over 30 min, 35 mL/min] to afford the title compound as a yellow/orange solid (10 mg, 23%). 1H NMR (DMSO-D6, 400 MHz): 12.44 (s, 1H), 9.52 (s, 2H), 9.21 (s, 1H), 9.08 (d, J=1.7 Hz, 2H), 9.02 (d, J=2.2 Hz, 1H), 8.96 (d, J=2.2 Hz, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 3.50 (s, 2H), 2.37 (s, 4H), 1.53 (m, 4H), 1.41 (m, 2H). LCMS (Method D): RT=6.84 min, M+H+=421.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][O:5][C:4]2[N:9]=[CH:10][C:11]([C:13]([OH:15])=O)=[CH:12][C:3]1=2.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[C:19]([Cl:25])[CH:18]=1>[Zn].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:13]([C:11]2[CH:10]=[N:9][C:4]3[O:5][CH2:6][C:7](=[O:8])[N:2]([CH3:1])[C:3]=3[CH:12]=2)=[O:15])=[C:19]([Cl:25])[CH:18]=1
Reactant: CN1C(=O)COc2ncc(C(=O)O)cc21
Reactant: Clc1cc(Br)ccc1CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Zn]
Product: CN1C(=O)COc2ncc(C(=O)Cc3ccc(Br)cc3Cl)cc21

Procedure:
In analogy to Example 49, step 1, 1-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylic acid was converted to the acid chloride and subsequently reacted with 4-bromo-1-bromomethyl-2-chloro-benzene in the presence of zinc and tetrakis(triphenylphosphine)palladium(0) to give the title compound as a light yellow solid. MS (m/e, ISP neg. ion)=392.9 [M−H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:36][CH3:37])=[C:19]([CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]([O:33]CC)=[O:32])[CH2:27][CH2:26]4)[CH:20]=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:36][CH3:37])=[C:19]([CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][CH:28]([C:31]([OH:33])=[O:32])[CH2:29][CH2:30]4)[CH:20]=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)C1CCN(CCc2cccc(-c3cnc(-c4ccc(OC(C)C)c(Cl)c4)s3)c2CC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCc1c(CCN2CCC(C(=O)O)CC2)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.8 %

Procedure:
To a solution of ethyl 1-{2-[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-4-piperidinecarboxylate (D89) (120 mg) in isopropanol (40 mL) and water (10 mL) stirred under nitrogen at room temperature was added a solution of NaOH (17.7 mg) in water in one charge. The reaction mixture was stirred at room temperature overnight. Isopropanol was removed in vacuo. The residue was dissolved in water and acidified with 1N HCl to pH=5. The solvent was removed in vacuo, the residue was dissolved in THF, and filtered. The filtrate was purified by Mass Directed AutoPrep to give 1-{2-[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-4-piperidinecarboxylic acid (E40) (18 mg) as a TFA salt (white solid). δH (DMSO-d6, 400 MHz): 1.11 (3H, t), 1.34 (6H, d), 1.76 (2H, m), 2.11 (2H, m), 2.71 (2H, m), 3.07 (4H, m), 3.27 (2H, m), 3.53 (1H, m), 3.67 (2H, m), 4.80 (1H, m), 7.33 (4H, m), 7.82 (1H, s), 7.87 (1H, dd), 7.99 (1H, d), 9.29 (1H, br s), 12.59 (1H, br s). δF (DMSO-d6, 376 MHz): −73.5. MS (ES): C28H33ClN2O3S requires 512. found 513.1 (M+H+).
Reaction SMILES: C(#N)C.[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH:12][CH:13]=[O:14])=[CH:7][CH:6]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27].[Cl-].[Na+]>CN(C)C(=O)C.N1C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:4][C:5]2[CH:6]=[CH:7][C:8]([NH:11][NH:12][CH:13]=[O:14])=[CH:9][CH:10]=2)(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27]
Reactant: Nc1ccc(NNC=O)cc1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CC#N
Solvent: c1ccncc1
Product: O=CNNc1ccc(NS(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Temperature: -5 °C
Yield: 77.8 %

Procedure:
In a mixture of 90 ml of N,N-dimethylacetamide, 76 ml of acetonitrile, and 19 ml of pyridine were dissolved 35.4 g of 2-(4-aminophenyl)-1-formylhydrazine in a nitrogen gas atmosphere and after cooling the solution to -5° C., 59.9 g of 4-chloro-3-nitrobenzenesulfonyl chloride were gradually added to the solution while cooling and with stirring so that the liquid temperature was not over -5° C. After further stirring the mixture for 1.5 hours at a temperature below -5° C., the temperature was raised to room temperature and the reaction mixture was poured into 1 liter of a saturated aqueous sodium chloride solution. Crystals thus formed were collected by filtration and washed with water to provide 67.5 g of the desired compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[F:13])(=O)[CH:2]=[CH2:3].[CH2:14]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH:23]=[CH:24][N:25]2CCCCC2)[CH2:19][CH2:18]1)[CH2:15][CH3:16].Cl.NO.Cl>O.C(O)C>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]2[CH:2]=[CH:3][C:23]([C@H:20]3[CH2:21][CH2:22][C@H:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19]3)=[CH:24][N:25]=2)=[C:6]([F:13])[CH:7]=1
Reactant: CCC[C@H]1CC[C@H](C=CN2CCCCC2)CC1
Reactant: C=CC(=O)c1ccc(OC)cc1F
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: CCC[C@H]1CC[C@H](c2ccc(-c3ccc(OC)cc3F)nc2)CC1
Reaction time: 2 h

Procedure:
0.03 mol of 1-acrylyl-2-fluoro-4-methoxybenzene was mixed at 0° C. with 0.03 mol of 1-[2-(trans-4-propylcyclohexyl)vinyl]piperidine and held at room temperature for 2 hours. The mixture was then treated with 90 ml of ethanol, 10 ml of water, 0.14 mol of hydroxylamine hydrochloride and 1 ml of concentrated hydrochloric acid and heated to reflux for 8 hours. Subsequently, about 2/3 of the solvent were removed by distillation. The concentrated mixture was diluted with 150 ml of water and adjusted to pH 8 with aqueous sodium carbonate solution. The organic layer was extracted with benzene. The extract was washed neutral with water, dried over sodium sulfate, filtered and concentrated. Chromatographic purification of the resulting residue on silica gel with benzene/hexane (vol. 1:1) gave 2-(4-methoxy-2-fluorophenyl)-5-(trans-4-propylcyclohexyl)pyridine in 20% yield; m.p. (C-N) 56.3° C., cl.p. (N-I) 180.6° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[H-].[Na+].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.C(OC(=O)C)C>[C:20]1([S:26]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]2[C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Fc1cccc(F)c1-c1nc2ccccc2[nH]1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c(-c2c(F)cccc2F)nc2ccccc21
Reaction time: 0.08 h
Yield: 83 %

Procedure:
2-(2,6-difluorophenyl)benzimidazole (Example 12) (0.31 g, 1.34 mmol) dissolved in THF (5 mL) was added to NaH (0.10 g, 190 M%). After 5 min, benzenesulfonyl chloride (0.25 mL, 0.35 g, 2.00 mmol, 150 M%) was added. After stirring for 2 h, the reaction was dissolved in ethylacetate, and washed with NaHCO3 (sat. aq.) and NaCl (sat. aq.). The combined washings were dried (Na2SO4), filtered, and concentrated. The product was purified by flash chromatography eluting with 2% MeOH/CH2Cl2 and then recrystallized from diethylether/hexane (3:1), to yield white powders of 1-benzenesulfonyl-2-(2,6-difluorophenyl)benzimidazole (0.41 g, (1.10 mmol, 83% yield). M.p. 104-106° C. 1H-NMR (300 MHz, CD2Cl2): δ8.09 (m, 1H, PhSO2), 7.77 (m, 1H, PhSO2), 7.69 (m, 2H, PhSO2), 7.66-7.53 (m, 2H, H4,7), 7.51-7.39 (m, 4H, PhSO2, H3,5), 7.07 (m, 2H, H3′,5′).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[C:6]([CH3:14])=[N:5]2.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(=O)C.S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[C:6]([CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N:5]2
Reactant: O=Cc1ccccc1
Reactant: Cc1nc2cc(F)c(F)cc2[nH]c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(F)c(F)cc2nc1C=Cc1ccccc1
Temperature: 85 °C
Yield: 86.2 %

Procedure:
6,7-Difluoro-3-methyl-1H-quinoxalin-2-one (2 g, 10.2 mmol) was dissolved in a mixture of glacial acetic acid (40 ml) and 98% sulfuric acid (4 ml). Benzaldehyde (1.08 g, 10.2 mmol) was added and the resulting mixture was stirred at reflux temperature for 3.5 hours. The mixture was allowed to cool to 85° C. and then poured onto ice (400 ml). The solid was filtered, washed with water and ethyl acetate and dried in vacuo at 30° C. overnight to afford 2.5 g (88%) of 6,7-difluoro-3-styryl-1H-quinoxalin-2-one.
Reaction SMILES: C([C:4]1[C:5]([S:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[N:6][CH:7]=[CH:8][CH:9]=1)(O)=O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>>[S:10]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:13](=[O:15])[CH2:12][CH2:11]1
Reactant: O=C(O)CCSc1ncccc1C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1CCSc2ncccc21
Reaction time: 2 h
Yield: 27 %

Procedure:
A solution of 14 g. (61.6 mmol) 3-(3-Carboxy-2-pyridylthio)propionic Acid [prepared as described in lit.: J. Heterocyclic Chem., 37, 379 (2000)] and 15 g. (185 mmol, 3 eqs) of anhydrous sodium acetate, in 200 mL. of acetic anhydride was refluxed (160° C.) under stirring, N2 atm, dry conditions, for 2 hours. Cooled, diluted with 300 mL of water, basified with 30% ammonium hydroxide solution to pH 8-9, extracted with 3×200 mL chloroform. Combined organics washed with 2×60 mL Sodium bicarbonate (satn.sol), water, dried, evaporated, gave 2.8 g. (27%) of the title compound, reddish solid, m.p. 66-8° C., (M+H)+=166.2.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CCN(C)CCCC(C(N)=O)(c2ccccc2)c2ccccc2)cc1

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.29 g-see preparation 2), 4-methoxyphenethyl bromide (0.22 g), anhydrous potassium carbonate (0.5 g) and acetonitrile (30 ml) was heated under reflux for 3 hours. The mixture was partitioned between dichloromethane (50 ml) and 5% aqueous sodium carbonate (50 ml), the layers separated and the aqueous layer extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.22 g.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[S:25][C:24]([C:26]([NH:28][NH2:29])=[O:27])=[C:23]([CH3:30])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[C:31](N1C=CN=C1)(N1C=CN=C1)=[O:32]>C1COCC1.CCOC(C)=O>[CH2:1]([C:3]([C:21]1[S:25][C:24]([C:26]2[O:27][C:31](=[O:32])[NH:29][N:28]=2)=[C:23]([CH3:30])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:17])([CH3:18])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)NN)s1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(-c2n[nH]c(=O)o2)s1
Yield: 63.2 %

Procedure:
A mixture of 5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid hydrazide (432 mg, 1 mmol), 1,1′-carbonyldiimidazole (405 mg, 2.5 mmol) and triethylame (0.28 ml, 2 mmol) in THF (10 ml) is stirred at reflux overnight. It is diluted with EtOAc, washed with 1N HCl solution. The organic phase is concentrated and chromatographed (Hex to 20% EtOAc/Hex to give the title compound (290 mg, 63%).
Reaction SMILES: CO[C:3](=[O:26])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([CH2:11][O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][C:5]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25].Cl.C[O:29][C:30](=[O:37])[C@H:31]([CH2:33][CH2:34][S:35][CH3:36])[NH2:32].N>>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH2:11][C:7]2[C:8]([I:10])=[CH:9][C:4]([C:3]([NH:32][C@H:31]([C:30]([OH:37])=[O:29])[CH2:33][CH2:34][S:35][CH3:36])=[O:26])=[C:5]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH:6]=2)[CH:14]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: COC(=O)c1cc(I)c(COc2cccnc2)cc1-c1ccccc1C
Agent: Cl
Agent: N
Product: CSCC[C@H](NC(=O)c1cc(I)c(COc2cccnc2)cc1-c1ccccc1C)C(=O)O

Procedure:
The desired compound was prepared by saponification of 4-(3-pyridyloxymethyl)-5-iodo-2-(2-methylphenyl)benzoic acid methyl ester, prepared as in Example 219G, followed by coupling with methionine methyl ester hydrochloride and saponification of the methyl ester as described above. 1H NMR (300 MHz, DMSO-d6) δ 12.68 (1H, bs), 8.45 (1H, d, J=9 Hz), 8.37 (1H, d, J=3 Hz), 8.20 (1H, d, J=4 Hz), 7.93 (1H, s), 7.48 (1H, m), 7.37 (2H, m), 7.30-7.00 (4H, m), 5.20 (2H, s), 4.22 (1H, m), 2.30-2.00 (5H, m), 1.96 (3H, s), 1.80 (2H, m). MS m/e (DCI, NH3) m/e 577 (M+H)+. Anal calcd for C25H25IN2O4S: C, 51.85; H, 4.40; N, 4.84. Found: C, 51.91; H, 4.47; N, 4.69.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([CH2:26][C:27](O)=[O:28])[C:8]([C:10]2([CH3:25])[CH2:13][CH2:12][N:11]2[C:14](=[O:24])[CH2:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)=[O:9])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[F:44][C:45]([F:51])([F:50])[S:46]([NH2:49])(=[O:48])=[O:47]>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([CH2:26][C:27](=[O:28])[NH:49][S:46]([C:45]([F:51])([F:50])[F:44])(=[O:48])=[O:47])[C:8]([C:10]2([CH3:25])[CH2:13][CH2:12][N:11]2[C:14](=[O:24])[CH2:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)N(CC(=O)O)Cc2ccc(Cl)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)N(CC(=O)NS(=O)(=O)C(F)(F)F)Cc2ccc(Cl)cc2)c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of compound 49 ((4-chloro-benzyl)-{1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carbonyl}-amino)-acetic acid (1 eq.) in DMF was added EDC.HCl (1.3 eq.), DMAP (1.3 eq.) and trifluoromethanesulfonamide (1.3 eq.). The reaction was stirred for 15 h at 20° C. The crude was concentrated under reduced pressure then partitioned between water and EtOAc. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by preparative LCMS to afford 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid (4-chloro-benzyl)-(2-oxo-2-trifluoromethanesulfonylamino-ethyl)-amide.
Reaction SMILES: [Li]N(C(C)C)[CH:3](C)C.[Cl:9][C:10]1[N:18]=[C:17]([Cl:19])[C:16]([F:20])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].CI.Cl>CCCCCC.O1CCCC1.C(OCC)C>[Cl:9][C:10]1[N:18]=[C:17]([Cl:19])[C:16]([F:20])=[C:15]([CH3:3])[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: [Li]N(C(C)C)C(C)C
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1c(F)c(Cl)nc(Cl)c1C(=O)O
Temperature: -70 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
To a solution of 0.516 moles of lithiodiisopropyl amine in 390 mL hexane and 200 mL tetrahydrofuran, cooled to -70° C., was added dropwise a solution of 40 g (0.229 moles) 2,6-dichloro-5-fluoronicotinic acid in 600 mL tetrahydrofuran, over a 1-hour period. The reaction mixture was stirred at -70° C. for 1 hour, then warmed to -60° C. for 1.5 hours at which time a light colored precipitate formed. The slurry was briefly warmed to -50° C., then recooled to -70° C., at which point a solution of 84 mL (1.34 moles) methyl iodide in 90 mL tetrahydrofuran was added dropwise. After the addition was complete, the reaction mixture was allowed to slowly warm to -20° C. over approximately 1 hour. The solution was acidified with dilute HCl pH 1-2 diluted with diethyl ether and allowed to warm to room temperature. The aqueous layer was extracted twice with ether. The combined ether washes were washed with H2O, dried with MgSO4, and evaporated in vacuo to yield a crude solid. The crude material was recrystallized from toluene to yield 31.7 g of the title compound.