Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH:10]([OH:14])[CH2:11][CH2:12][CH3:13])(=[O:9])[O:6]CC.Cl>>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH:10]([OH:14])[CH2:11][CH2:12][CH3:13])(=[O:6])[OH:9]
Reactant: CCCC(O)P(=O)(CCCN)OCC
Agent: Cl
Product: CCCC(O)P(=O)(O)CCCN
Yield: 85.8 %

Procedure:
A mixture of 2.0 g ethyl 3-aminopropyl(1-hydroxybutyl)-phosphinate and 20.0 ml 2 M aqueous hydrochloric acid is refluxed for 2 hours and then evaporated to dryness. The residual oil is dissolved in 10 ml of water, and re-evaporated. The residue is dissolved in 20 ml of ethanol and treated with propylene oxide and to give 1.5 g of 3-aminopropyl(1-hydroxybutyl)phosphinic acid, m.p. 188 °.
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[C:12]#[CH:13]>CO>[NH2:8]/[C:1](=[N:9]\[O:10]/[CH:13]=[CH:12]\[C:11]([O:15][CH2:16][CH3:17])=[O:14])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ccccc1
Reactant: C#CC(=O)OCC
Solvent: CO
Product: CCOC(=O)/C=C\O/N=C(\N)c1ccccc1

Procedure:
6.7 g of benzamidoxime and 5 ml ethyl propiolate were dissolved in 5 ml methanol and heated under reflux for 3 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), to give 4.5 g of ethyl (Z)-3-([(Z)-1-amino-1-phenylmethylidene]aminoxy)-2-propenoate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[CH:3]=1.[Br:10][C:11]1[CH:16]=[C:15](F)[CH:14]=[C:13]([Cl:18])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN1C(=O)CCC1.O>[Br:10][C:11]1[CH:16]=[C:15]([CH:14]=[C:13]([Cl:18])[CH:12]=1)[O:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[CH:3]=1
Reactant: Fc1cc(Cl)cc(Br)c1
Reactant: Cc1cc(O)cc(=O)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(Oc2cc(Cl)cc(Br)c2)cc(=O)[nH]1
Temperature: 140 °C

Procedure:
4-Hydroxy-6-methylpyridin-2(1H)-one (3-2; 10.0 g; 80 mmol) and 1-bromo-3-chloro-5-fluorobenzene (16.74 g; 80 mmol) and potassium carbonate (33.1 g; 240 mmol) were suspended in NMP (200 mL) and then heated at 140° C. for 5 days. The reaction mixture was cooled to room temperature, diluted with water (900 mL) and the pH of the solution was adjusted to 5 with concentrated HCl. The solid was filtered off, washed with water and suctioned dry. The crude material was adsorbed onto silica and purified in 2 runs on a silica column eluted with DCM:MeOH to give the title product (9-1) as a yellow solid. Rf=0.6(DCM:MeOH, 95:5). LCMS: M+=315. 1H NMR (DMSO-d6): δ 11.48 (s, 1H), 7.65 (s, 1H), 7.43 (s, 1H), 7.36 (s,1H), 5.86 (s, 1H), 5.36 (s, 1H), 2.16 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:17][C:11]=2[N:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38](Br)[CH2:39][CH3:40])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]([N:13]2[C:12]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)=[CH:17][C:11]=3[N:10]=[C:9]2[CH2:8][C:2]([CH3:1])([CH3:30])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:39][CH3:40])=[CH:34][CH:33]=1
Reactant: CCOC(=O)C(C)(C)Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2[nH]1
Reactant: CCC(Br)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1C(CC)c1ccc(Br)cc1
Temperature: 100 °C

Procedure:
A suspension of ethyl 2,2-dimethyl-3-(5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)propanoate) (300 mg, 0.74 mmol), 1-bromo-4-(1-bromopropyl)benzene (413 mg, 1.49 mmol) and cesium carbonate (727 mg, 2.23 mmol) in DMF (3.7 mL) was heated to 100° C. for 3 days. The mixture was cooled and partitioned between water and EtOAc. The organic layer was dried and concentrated to a residue. Purification using FCC afforded the title compound. MS (ESI): mass calcd. for C33H34BrN3O3, 599.18; m/z found, 600.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=8.5, 1H), 8.05 (d, J=8.5, 1H), 7.83 (d, J=8.2, 1H), 7.74 (ddd, J=8.4, 6.9, 1.4, 1H), 7.62-7.53 (m, 3H), 7.28-7.25 (m, 2H), 6.97-6.92 (m, 3H), 6.62 (d, J=2.3, 1H), 5.38 (dd, J=10.0, 5.9, 1H), 5.34-5.22 (m, 2H), 4.05 (qd, J=7.1, 0.8, 2H), 3.08 (q, J=15.6, 2H), 2.42-2.23 (m, 2H), 1.37 (s, 3H), 1.35 (s, 3H), 1.15 (t, J=7.1, 3H), 0.72 (t, J=7.3, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[CH2:15](O)[CH:16]=[CH2:17]>>[OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:17][CH:16]=[CH2:15])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C(O)c1ccc(CO)c([N+](=O)[O-])c1
Reactant: C=CCO
Product: C=CCOC(=O)c1ccc(CO)c([N+](=O)[O-])c1

Procedure:
In a 100 mL round bottom flask was placed 4-hydroxymethyl-3-nitrobenzoic acid (1.97 g, 10 mmol). Allyl alcohol (20 mL) was added, followed by p-toluensesulfonic acid (0.190 g, 1 mmol). The mixture was heated to reflux for 24 hr., at which time all the volatiles were removed in vacuo. The residue was taken up in EtOAc and washed with sat'd KHCO3. The organic layer was dried over MgSO4 and concentrated to afford the title compound as a cream colored solid; 2.4 g (100%).
Reaction SMILES: [NH2:1][C:2]1[C:17]([C:18](=[O:20])[CH3:19])=[CH:16][C:5]2[O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][C:4]=2[CH:3]=1.C[O-].[Na+].[CH:24](OCC)=O>COCCOC.O>[NH:1]1[C:2]2[CH:3]=[C:4]3[O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][C:5]3=[CH:16][C:17]=2[C:18](=[O:20])[CH:19]=[CH:24]1
Reactant: CC(=O)c1cc2c(cc1N)OCCOCCOCCO2
Reactant: CCOC=O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=c1cc[nH]c2cc3c(cc12)OCCOCCOCCO3
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a solution of 1-(3-Amino-6,7,9,10,12,13-hexahydro-5,8,11,14-tetraoxa-benzocyclododecen-2-yl)-ethanone (108 mmol, 29.3 g) in DME (700 ml) was added sodium methoxide (432 mmol, 23.35 g). The mixture was stirred for 30 minutes. Ethyl formate (540 mmol, 44 ml) was added and the mixture was stirred overnight. (Additional sodium methoxide may be needed if reaction is not complete as monitored by LC/MS.) After the reaction was completion, the mixture was diluted with water (40 ml) and acidified to neutral with 1M HC 1. The precipitate was filtered and washed with water, dried in vacuo to afford 22 g (72%) of 7,8,10,11,13,14-Hexahydro-1H-6,9,12,15-tetraoxa-1-aza-cyclododeca[b]naphthalen-4-one. 1HNMR (400 MHz, DMSO) δ 8.58 (s, 1H), 7.52 (s, 1H), 7.22 (s, 1H), 7.12 (m, 1H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H). LC/MS Calcd for (M+H)+292.3. found 292.5.
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:6]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:28]
Reactant: CCCCNS(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CCOC(=O)CBr
Product: CCCCN(CC(=O)OCC)S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared with N-butyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide and ethyl bromoacetate according to the procedure of Intermediate 2 as a yellow oil; 1H NMR (CDCl3) δ 0.88 (t, J=7.29 Hz, 3H), 1.23 (t, J=7.11 Hz, 3H), 1.19-1,35 (m, 2H), 1.48-1.56 (m, 2H), 2.58 (t, J=6.18 Hz, 4H), 3.20 (t, J=7.47 Hz, 2H), 3.47 (t, J=6.09 Hz, 4H), 4.03 (s, 2H), 4.13 (q, J=7.14 Hz, 2H), 6.89-6.95 (m, 2H), 7.72-7.78 (m, 2H); MS (ES) m/z 397.2 MH+); HRMS for C19H28N2O5S: 397.1791.
Reaction SMILES: N(OCCC(C)C)=O.[CH3:9][N:10]1[C:14](N)=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:12]=[N:11]1.[CH3:21][S:22]SC>C(Cl)(Cl)Cl>[CH3:9][N:10]1[C:14]([S:22][CH3:21])=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:12]=[N:11]1
Reactant: CSSC
Reactant: CCOC(=O)c1cnn(C)c1N
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnn(C)c1SC
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 96.9 %

Procedure:
Add isopentyl nitrite (0.5 mL, 3.75 mmol) to a stirred 5° C. solution of ethyl 1-methyl-5-amino-1H-pyrazole-4-carboxylate (1.69 g, 10.0 mmol) and dimethyl disulfide (1.79 mL, 20.0 mmol) in CHCl3 under nitrogen in a 3-necked flask equipped with a thermometer and a condenser. Allow the reaction to warm to 20° C. in a H2O bath, and treat with additional isopentyl nitrite (1.5 mL, 11.3 mmol) dropwise. After 15 min, remove the reaction from the 20° C. H2O bath (exotherm raises temperature to 50° C. over approximately 1 min). Stir at ambient temperature under N2 overnight. Wash with H2O, and separate the layers. Extract the aqueous layer with CHCl3, combine the organic layers, dry over MgSO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (gradient of 0 to 35% EtOAc in hexanes) to afford the title compound (1.94 g, 97%). ES/MS m/z 201.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.Cl[CH:8]=[CH:9][C:10](=O)[CH2:11][CH3:12]>C(O)(=O)C>[CH2:11]([C:10]1[N:3]2[N:4]=[CH:5][N:6]=[C:2]2[N:1]=[CH:8][CH:9]=1)[CH3:12]
Reactant: Nc1nc[nH]n1
Reactant: CCC(=O)C=CCl
Solvent: CC(=O)O
Product: CCc1ccnc2ncnn12

Procedure:
A mixture of 3-amino-1,2,4-triazole (11.74 g) and 1-chloro-1-penten-3-one (16.5 g) in acetic acid (225 ml) was heated under reflux for 45 minutes. The reaction mixture was cooled, poured onto ice and extracted with dichloromethane. The organic layer was dried and the solvent was evaporated under reduced pressure to give 7-ethyl-1,2,4-triazolo[1,5-a]pyrimidine. Yield 11.72 g.
Reaction SMILES: [CH3:1][N:2]([CH2:26][CH2:27][CH3:28])[CH2:3][CH2:4][C:5]#[C:6][CH:7]1[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9][CH2:8]1>CCO.O=[Pt]=O.O>[CH3:1][N:2]([CH2:26][CH2:27][CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9][CH2:8]1
Reactant: CCCN(C)CCC#CC1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: O
Product: CCCN(C)CCCCC1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Yield: 93.7 %

Procedure:
A suspension of 83 mg (0.198 mmol) of Methyl-propyl-{4-[1-(4-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-but-3-ynyl}-amine in 4 ml EtOH and 8 mg of PtO2.H2O was hydrogenated (1 atm) for 7 h. The reaction was filtered and evaporated. Flash column chromatography on silica gel (CH2Cl2/MeOH 19:1 to 9:1) gave 78 mg (93%) of Methyl-propyl-{4-[1-(4-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-butyl}-amine, mp: 73.0-74.8° C., MS: 421 (MH+).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15]2[NH:19][N:20]=[CH:21][C:14]=12>C(Cl)(Cl)Cl>[Br:12][C:13]1[CH:18]=[N+:17]([O-:9])[CH:16]=[C:15]2[NH:19][N:20]=[CH:21][C:14]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1cncc2[nH]ncc12
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc(Br)c2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.5 %

Procedure:
mCPBA (270 mg) was added to a CHCl3 (5 ml) suspension containing 4-bromo-1H-pyrazolo[3,4-c]pyridine (197 mg), followed by stirring at room temperature for 10 minutes. IPE (10 ml) was added to the reaction solution and a solid precipitate was collected by filtration. A white solid of 4-bromo-1H-pyrazolo[3,4-c]pyridine 6-oxide (148 mg) was thus obtained.
Reaction SMILES: Cl[C:2]([C:4]1[S:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=1)=[O:3].[C:13]([CH:15]1[CH2:17][CH2:16]1)#[CH:14]>C(N(CC)CC)C.CO.[Cu]I>[CH:15]1([C:13]#[C:14][C:2]([C:4]2[S:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=2)=[O:3])[CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc(C(=O)Cl)s1
Reactant: C#CC1CC1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(C(=O)C#CC2CC2)s1
Reaction time: 8 h

Procedure:
Methyl 5-(chlorocarbonyl)thiophene-2-carboxylate (500 mg, 2.443 mmol) was dissolved in triethylamine (5 mL) and the suspension was degassed with nitrogen. Copper(I) iodide (40 mg, 0.210 mmol) and bistriphenylphosphine palladium (II) chloride (40 mg, 0.057 mmol) were added followed by ethynylcyclopropane (162 mg, 2.443 mmol). The mixture was stirred overnight, diluted with methanol and concentrated to dryness. The crude material was partitioned between dichloromethane and water. The organic extracts were dried with sodium sulfate, filtered, concentrated and purified by normal phase chromatography to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:38][C@H:39]([CH2:68][C:69]1[CH:78]=[CH:77][C:76]2[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=2)[CH:70]=1)[C:40]([NH:42][C@@H:43]([C:55]1[N:59]([CH2:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[N:58]=[N:57][N:56]=1)[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1)=[O:41]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:38][C@@H:39]([C:40](=[O:41])[NH:42][C@@H:43]([C:55]2[N:59]([CH2:60][CH2:61][C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)[N:58]=[N:57][N:56]=2)[CH2:44][C:45]2[CH:54]=[CH:53][C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[CH:46]=2)[CH2:68][C:69]2[CH:78]=[CH:77][C:76]3[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=3)[CH:70]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: N[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc2ccccc2c1)c1nnnn1CCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N[C@H](Cc2ccc3ccccc3c2)C(=O)N[C@H](Cc2ccc3ccccc3c2)c2nnnn2CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.4 %

Procedure:
N-tert-butyloxycarbonylpiperidine-4-carboxylic acid (68 mg; 0.296 mmol) was dissolved in methylene chloride (7 ml). HOBT (40 mg; 0.296 mmol) and EDAC (62 mg; 0.326 mmol) were added and the mixture was stirred 15 min at RT. (2R)-2-Amino-3-(2-naphthyl)-N-((1R)-2-(2-naphthyl)-1-(1-phenethyl-1H-tetrazol-5-yl)ethyl)propionamide (152 mg; 0.296 mmol) was added and stirring was continued overnight. Methylene chloride (25 ml) was added. The organic phase was washed with aqueous sodium hydrogencarbonate (25 ml), aqueous sodium hydrogensulfate (10%; 25 ml) and water (25 ml). The organic phase was dried (Magnesium sulfate) and the solvent removed in vacuo to afford 170 mg of 4-((1R)-2-(2-Naphthyl)-1-((1R)-2-(2-naphthyl)-1-(1-phenethyl-1H-tetrazol-5-yl) ethylcarbamoyl)ethylcarbamoyl)piperidine-1-carboxylic acid tert-butylester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][N:6]([C:30]1[S:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[C:28]([F:29])=[CH:27][C:13]2[N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3I)[CH3:19])[C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].[O:41]=[C:42]1[CH2:45][N:44]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:43]1>C1COCC1.CS(C)=O>[CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][N:6]([C:30]1[S:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[C:28]([F:29])=[CH:27][C:13]2[N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:42]3([OH:41])[CH2:43][N:44]([C:46]([O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[O:47])[CH2:45]3)[CH3:19])[C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n([C@H](C)c4ccccc4I)c3cc2F)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n([C@H](C)c4ccccc4C4(O)CN(C(=O)OC(C)(C)C)C4)c3cc2F)c(OC)c1
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
In an oven-dried 25 mL RB flask, added (R)—N-(2,4-dimethoxybenzyl)-5-fluoro-3-(1-(2-iodophenyl)ethyl)-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (32-1, 400 mg, 0.574 mmol) to THF (2154 μl) and cooled to −40° C. Was a suspension. Added isopropylmagnesium chloride-lithium chloride complex (1325 μl, 1.723 mmol) dropwise, stirred at −40° C. for 20 min—became a dark orange solution. Following this duration, added tert-butyl 3-oxoazetidine-1-carboxylate (32-2, 295 mg, 1.723 mmol) in THF (718 μl) dropwise via syringe. Solution turned yellow in color. After 60 min at −40° C., partitioned between 10 mL saturated NH4Cl+15 mL EtOAc, separated layers. Back-extracted aqueous with 2×10 mL EtOAc. Dried combined organics over Na2SO4, filtered, concentrated to give a yellow oil. Dissolved in 2 mL DMSO, purified by reverse-phase HPLC (C18 column, 10-90% (0.1% TFA/CH3CN:0.1% TFA/H2O) to give 32-3 as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[O:7])=[CH:4][CH:3]=1.Br[CH2:20][C:21]([OH:23])=[O:22].[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:16][C:10]1[C:11]([Cl:15])=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:20][C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)=[O:7]
Reactant: O=C(O)CBr
Reactant: O=C(Nc1cccc(Cl)c1Cl)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)COc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Yield: 73.5 %

Procedure:
2.82 g of 4-hydroxy-N-(2,3-dichlorophenyl)-benzamide and 1.67 g of bromoacetic acid were dissolved in 10 ml of dioxane. To this solution, a mixture of 0.97 g of sodium hydroxide and 2 ml of water was dropwise added over a period of 10 minutes at a temperature of 20° C. under stirring. After the dropwise addition, the reaction solution was stirred at a temperature of 80° C. for 2 hours. After completion of the reaction, the reaction solution was poured into 50 ml of water, and acidified with hydrochloric acid. Then, the crude product obtained by collecting precipitates by filtration, was recrystallized from toluene/methanol to obtain 2.5 g of desired 4-(2,3-dichlorophenyl-carbamoyl)-phenoxyacetic acid. Yield: 70.6% Melting point: 198°-199.5° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C:11](=[O:13])[O:10][CH2:9][C:8]=2[CH:14]=1.Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>CN(C)C=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:11](=[O:13])[O:10][CH2:9][C:8]=2[CH:14]=1
Reactant: O=C1Nc2ccc(Br)cc2CO1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)OCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a solution of sodium hydride (55 wt % in mineral oil, 1.36 g, 31.2 mmol) in N,N-dimethylformamide (37 ml) was added 6-bromo-1,4-dihydro-2H-3,1-benzoxazin-2-one (5.93 g, 26.0 mmol) in N,N-dimethylformamide (37 ml) at 0° C. The mixture was stirred at room temperature for one hour, then 2-(chloromethoxy)ethyltrimethylsilane (4.77 g, 28.6 mmol) was added at 0° C. The mixture was stirred at room temperature overnight. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with water (four times), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=90/10 to 60/40) to afford 6-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydro-2H-3,1-benzoxazin-2-one as a pale yellow solid (7.96 g, 22.2 mmol, 85%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:21]=[CH:20][C:7]([C:8]([N:10]2[CH2:19][CH2:18][CH2:17][CH:12]([C:13](OC)=O)[CH2:11]2)=O)=[CH:6][CH:5]=1.[OH-:22].[Na+]>CO.O>[CH3:2][O:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][N:10]2[CH2:19][CH2:18][CH2:17][C:12](=[CH2:13])[C:11]2=[O:22])=[CH:6][CH:5]=1
Reactant: COC(=O)C1CCCN(C(=O)c2ccc(OC)cc2)C1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=C1CCCN(Cc2ccc(OC)cc2)C1=O
Yield: 74.7 %

Procedure:
A solution of methyl N-(p-methoxybenzoyl)nipecotate hydrochloride (30.7 g) and 8.4 g of sodium hydroxide in 900 ml of methanol and 45 ml of water is stirred at room temperature for seventeen hours. The solution is evaporated to dryness in vacuo, the residue diluted with toluene, and this again evaporated in dryness in vacuo. To the residue is added 1 liter of acetic anhydride and 140 ml of triethylamine, and the resulting mixture is heated under reflux for four hours. The reaction mixture is evaporated to dryness in vacuo, the residue taken up in chloroform, washed with water, dried and concentrated in vacuo. The residual oil is chromatographed on silica gel using 1:1 hexane-ethyl acetate as the eluant, and yields 16.9 g of N-(p-methoxybenzyl)-3-methylene-2-piperidone as a chromatographically pure yellow oil. Alternatively, the oil can be distilled to give analytically pure N-(p-methoxybenzyl)-3-methylene-2-piperidone, m.p. 145°-155°/0.05 mm.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10]1>C(Cl)(Cl)(Cl)Cl.Cl(O)(=O)(=O)=O.C([O-])(O)=O.[Na+]>[Br:1][C:10]1[S:9][CH:13]=[CH:12][C:11]=1[CH2:14][C:15]#[N:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CCc1ccsc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClC(Cl)(Cl)Cl
Product: N#CCc1ccsc1Br
Reaction time: 4 h
Yield: 42.6 %

Procedure:
Perchloric acid (0.025 mL, 0.28 mmol) was added to a rapidly stirring suspension of N-bromosuccinimide (5.06 g, 28.4 mmol) and 2-(thiophen-3-yl)acetonitrile (3.50 g, 28.4 mmol) in carbon tetrachloride (15 mL). After 4 h at room temperature, the reaction mixture was treated with solid NaHCO3 (100 mg, 1.2 mmol), then filtered and concentrated. The residue was purified by chromatography, eluting with a gradient of 2-15% EtOAc/hexanes to afford pure 2-(2-bromothiophen-3-yl)acetonitrile as a pale green oil (2.44 g, 12.1 mmol, 43% yield). MS (M+H)+ 202/204.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:31])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:23][C:22]([N:19]1[CH2:18][CH2:17][CH:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[C:14]=2[CH3:15])[CH2:21][CH2:20]1)=[O:31]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3ccccc3Cl)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(C(=O)Nc2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 47.1 %

Procedure:
To a solution of {4-[1-(2-chloro-phenylcarbamoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (10 mg, 0.021 mmol) in THF (2.0 mL) was added a solution of lithium hydroxide monohydrate (10.2 mg, 0.426 mmol) in water (0.5 mL) at room temperature. The resulting solution was stirred for 15 hours at room temperature under nitrogen atmosphere. The solvent was removed and the aqueous layer was neutralized with 1.0N HCl. The resulting white solids were collected by filtration, washed with water and hexanes, and dried in the air to give {4-[1-(2-chloro-phenylcarbamoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (4.5 mg, 46%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.42 (br. s, 1H), 7.9 (dd, J=8.91, 6.65 Hz, 1H), 7.69 (s, 1H), 7.48 (d, J=8.03 Hz, 2H), 7.25-7.42 (m, 3H), 7.09-7.23 (m, 1H), 4.27 (d, J=10.79 Hz, 2H), 3.79 (br. s, 4H), 2.43 (s, 4H), 1.65 (d, J=12.05 Hz, 3H), 1.23 (s, 2H). MS cald. for C25H25ClFN2O3 [(M+H)+] 455, obsd. 455.0.