Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([CH2:23][CH2:24][P:25]([O:28]CC)([CH3:27])=[O:26])[C:14]([CH:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1.[Si](I)(C)(C)C.N1C(C)=CC=CC=1C>C(#N)C>[CH3:31][C:2]([CH3:1])([CH3:32])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([CH2:23][CH2:24][P:25]([OH:28])([CH3:27])=[O:26])[C:14]([CH:16]2[CH2:17][CH2:18][CH:19]([CH3:22])[CH2:20][CH2:21]2)=[O:15])[CH:6]=1
Reactant: CCOP(C)(=O)CCN(C(=O)C1CCC(C)CC1)c1cc(C#CC(C)(C)C)sc1C(=O)O
Agent: C[Si](C)(C)I
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: CC1CCC(C(=O)N(CCP(C)(=O)O)c2cc(C#CC(C)(C)C)sc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.3 %

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[[2-(ethoxy-methyl-phosphinoyl)-ethyl]-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (108 mg, 0.225 mmol) was dissolved in acetonitrile (3 mL). This solution was cooled in an ice bath and TMSI (160 μL, 1.12 mmol) was added dropwise. The reaction turned yellow and some precipitate was formed. After approximately 1 minute 2,6-lutidine (156 μL, 1.35 mmol) was added, resulting in a clear solution. The ice bath was removed and the reaction was stirred at room temperature for 2 hours. Additional TMSI (50 μL) and 2,6-lutidine (50 μL) were added. After 45 minutes the reaction was determined by LC/MS to be complete. The reaction was cooled in an ice bath and additional 2,6-lutidine (100 μL) was added, followed by MeOH (2 mL). The reaction was warmed to room temperature and concentrated under vacuum. 5-(3,3-Dimethyl-but-1-ynyl)-3-[[2-(hydroxy-methyl-phosphinoyl)-ethyl]-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (37 mg, 36%) was isolated from the residue by reverse phase HPLC. MS (m/z): 453.93 [M+H]+; 31P NMR (161.9 MHz, CD3OD): d 49.909.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>>[CH3:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:31][CH:30]=1
Reactant: Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-methyl-aniline Rf value: 0.4 (silica gel, methylene chloride/methanol=9:1) C24H20N2O3
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:26])=[CH:10][CH2:11][CH2:12][C:13]([CH3:25])=[CH:14][CH2:15][CH2:16][C:17]([CH3:24])=[CH:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:3]([OH:5])=O.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:26])=[CH:10][CH2:11][CH2:12][C:13]([CH3:25])=[CH:14][CH2:15][CH2:16][C:17]([CH3:24])=[CH:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:3]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:5]
Reactant: C1CCNCC1
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N1CCCCC1

Procedure:
Starting materials: 2,6,10,14-tetramethyl-18-oxo-2,6,10,14-nonadecatetraenoic acid and piperidine.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=1.C([BH3-])#N.[Na+]>CO.O>[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:27])[F:28])=[CH:24][CH:23]=1)[CH2:8]2
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Nc1c([N+](=O)[O-])cc(Br)c2c1CNCC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1c([N+](=O)[O-])cc(Br)c2c1CN(Cc1ccc(C(F)(F)F)cc1)CC2
Reaction time: 2.5 h
Yield: 50.9 %

Procedure:
A solution of the product from Example 5 (1 g, 3.24 mmol) and α,α,α-trifluro-p-tolualdehyde (1.22 g, 7 mmol) in 2:1 MeOH/H2O (50 mL) was treated with sodium cyanoborohydride (0.56 g, 9 mmol) portionwise under nitrogen and stirred for 2.5 hours. The precipitate was filtered, washed with hexane and dried to give the title compound (0.71 g, 51% yield) as a yellow solid, mp=119-120° C.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[NH:7][C:8](=[O:20])[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.[CH3:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[Sn](CCCC)(CCCC)CCCC>>[CH3:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[NH:7][C:8](=[O:20])[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cc1cccc2ccccc12)Nc1ccsc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Product: Cn1ccnc1-c1sccc1NC(=O)Cc1cccc2ccccc12

Procedure:
This molecule was synthesized from N-(2-iodothiophen-3-yl)-2-(naphthalen-1-yl)acetamide and 1-methyl-2-(tributylstannyl)-1H-imidazole according to protocol E. The residue was directly purified by HPLC to yield N-(2-(1-methyl-1H-imidazol-2-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide. Method [7] Retention time 3.41 min by HPLC (MH+ 348). 1H NMR (300 MHz, CDCl3) δ 10.27 (s, 1H), 7.87 (m, 3H), 7.51 (m, 6H), 6.91 (d, J=1.5 hz, 1H), 6.82 (d, J=1.5 Hz, 1H), 4.15 (s, 3H), 3.68 (s, 2H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[N:12]=[CH:11][C:10]([C:14]3[CH:22]=[N:21][CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=[O:17])=[CH:9][C:8]=2[CH2:7][CH2:6][CH2:5]1)(=[O:3])[NH2:2].[CH3:23][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[CH3:23][O:17][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][N:21]=[CH:22][C:14]=1[C:10]1[CH:11]=[N:12][C:13]2[N:4]([C:1](=[O:3])[NH2:2])[CH2:5][CH2:6][CH2:7][C:8]=2[CH:9]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: NC(=O)N1CCCc2cc(-c3cnccc3C(=O)O)cnc21
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccncc1-c1cnc2c(c1)CCCN2C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.1 %

Procedure:
To a solution of 3-(8-carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-isonicotinic acid (80 mg, 0.27 mmol) in 8.0 mL of toluene/MeOH 1:1 mixture is added 2.0 M trimethylsilyl-diazomethane (0.20 mL, 0.40 mmol) under N2 atmosphere. The reaction solution is stirred at room temperature for 16 hrs. The solvent is removed and the residue is purified by preparative HPLC to give 33 mg of the titled product.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[S:18][C:17]([CH2:19][CH2:20][CH3:21])=[N:16][C:10]=3[C:11]([NH2:15])=[N:12][C:13]=2[CH:14]=1)(=O)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.BrC(C)[CH2:35][N:36]1[CH:40]=[CH:39][CH:38]=[CH:37]1>ClCCl>[CH2:19]([C:17]1[S:18][C:9]2[C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:1][CH2:2][CH2:35][N:36]4[CH:40]=[CH:39][CH:38]=[CH:37]4)=[CH:14][C:13]=3[N:12]=[C:11]([NH2:15])[C:10]=2[N:16]=1)[CH2:20][CH3:21]
Reactant: CCCc1nc2c(N)nc3cc(OC(C)=O)ccc3c2s1
Reactant: CC(Br)Cn1cccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCc1nc2c(N)nc3cc(OCCCn4cccc4)ccc3c2s1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 45.8 %

Procedure:
A mixture of 4-amino-2-propylthiazolo[4,5-c]quinolin-7-ol acetate (318 mg, 1.0 mmol), cesium carbonate (1.3 g, 4.0 mmol), and DMF (20 mL) was stirred at 75° C. for 10 minutes. 1-(2-Bromopropyl)pyrrole (206 mg, 1.1 mmol) was added dropwise over a period of 10 minutes. After 3 hours an additional equivalent of cesium carbonate was added in a single portion followed by the dropwise addition of an equivalent of 1-(2-bromopropyl)pyrrole. After 1 additional hour the heat source was removed; the reaction mixture was diluted with water (250 mL), stirred for 1 hour, and then filtered. The isolated solid was rinsed with water and then dried to provide a brown powder. This material was dissolved in dichloromethane and then purified by HPFC eluting with a gradient of 0-20% CMA in chloroform over 1500 mL. The resulting solid was recrystallized from acetonitrile to provide 168 mg of 2-propyl-7-[3-(pyrrol-1-yl)propoxy]thiazolo[4,5-c]quinolin-4-amine as an off-white solid, mp 152.0-154.0° C. MS (ESI) m/z 367 (M+H)+; Anal. calcd for C20H22N4OS: C, 65.55; H, 6.05; N, 15.29. Found C, 65.52; H, 5.80; N, 15.37.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:39])/[C:13](=[N:27]\[O:28][C:29]([CH3:38])([CH3:37])[C:30]([O:32]C(C)(C)C)=[O:31])/[C:14]3[N:15]=[C:16]([NH:19]C(OC(C)(C)C)=O)[S:17][CH:18]=3)[C:9](=[O:40])[N:8]2[S:41]([OH:44])(=[O:43])=[O:42])[CH:5]=[N:4][CH:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:39])/[C:13](=[N:27]\[O:28][C:29]([CH3:38])([CH3:37])[C:30]([OH:32])=[O:31])/[C:14]3[N:15]=[C:16]([NH2:19])[S:17][CH:18]=3)[C:9](=[O:40])[N:8]2[S:41]([OH:44])(=[O:42])=[O:43])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cncn2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cncn1)c1csc(N)n1)C(=O)O
Yield: 38.8 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidine-1-sulfonic acid (50.1 mg, 0.076 mmol), DCM (760 μL) and TFA (351 μl, 4.56 mmol). The crude residue purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (14.8 mg, 34%) as a white powder. LCMS: Rt=0.31 min, m/z=503.1 (M+1) Method 2m_acidic; 1H NMR (500 MHz, DMSO-d6) δ 9.39 (d, J=8.83 Hz, 1H), 8.52 (s, 1H), 8.02 (s, 1H), 6.74 (s, 1H), 5.28 (dd, J=8.8, 5.4 Hz, 1H), 4.74-4.64 (m, 1H), 4.58 (d, J=6.9 Hz, 1H), 4.32 (d, J=5.7 Hz, 1H), 1.37 (s, 3H) 1.41 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:14][O:13]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]([OH:13])[CH2:14][NH:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)Oc1ccc([C@H]2CO2)cc1
Product: CS(=O)(=O)Oc1ccc([C@H](O)CNCc2ccccc2)cc1
Temperature: 80 °C
Yield: 68.6 %

Procedure:
A mixture of 4-((S)-oxiranyl)phenyl methanesulfonate (69 g, 322 mmol) and benzylamine (104 g, 971 mmol) was heated at 80° C. for 3 hours. An excess benzylamine was evaporated under reduced pressure and the residue was washed with diisopropyl ether to afford 4-((1S)-2-benzylamino-1-hydroxyethyl)phenyl methanesulfonate (71.0 g, 69%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](F)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.CC(C)([O-])C.[Na+].O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Fc1cc(Cl)cc2cccnc12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)cc3cccnc23)CC1
Temperature: 140 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
6-Chloro-8-fluoroquinoline (for example, as prepared for Intermediate 5) (2.18 g, 12 mmol) was dissolved in NMP (20 ml) and treated with 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (commercially available, for example, from Acros and/or Aldrich) (4.85 g, 24 mmol) and sodium tert-butoxide (2.38 g, 25 mmol). Further NMP was added (5 ml) and the resulting mixture was stirred at 140° C. for 1 h, and then allowed to cool overnight. The reaction mixture was treated with water and extracted with toluene. The organic extract was washed with water (×3), dried (MgSO4), and concentrated in vacuo. The residue was purified by silica chromatography (2×70 g), eluting with 0-100% EtOAc-cyclohexane over 30 min. The relevant fractions were concentrated in vacuo to give the title compound as a yellow gum (2.73 g, 63%): LCMS RT=3.37 min, ES+ve m/z 363/365 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CS(O[CH:14]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1)[CH3:15])(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:14]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH2:20][CH2:21]2)[CH3:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CC(OS(C)(=O)=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Br)nc1)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-bromo-3-pyridinol (0.31 g, 1.78 mmol), (±)-phenylmethyl 4-{1-[(methylsulfonyl)oxy]ethyl}-1-piperidinecarboxylate (0.73 g, 2.14 mmol) and K2CO3 (0.50 g, 3.57 mmol) in DMF (12 mL) was stirred at ambient temperature for 30 min, then heated at 70° C. overnight, then heated at 100° C. for 27 h. The mixture was cooled to ambient temperature and poured into water, and extracted with EtOAc (60 mL×2). The combined organic extract was washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to give crude (±)-phenylmethyl 4-{1-[(6-bromo-3-pyridinyl)oxy]ethyl}-1-piperidinecarboxylate as a brown oil, which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]([CH3:10])[C:8](=[O:11])[N:7]([CH3:12])[C:6](=[O:13])[C:5]=1[CH:14]=O)[CH3:2].Cl.[CH3:17][O:18][NH2:19]>>[CH3:17][O:18][N:19]=[CH:14][C:5]1[C:6](=[O:13])[N:7]([CH3:12])[C:8](=[O:11])[N:9]([CH3:10])[C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1c(C=O)c(=O)n(C)c(=O)n1C
Reactant: CON
Agent: Cl
Product: CCOc1c(C=NOC)c(=O)n(C)c(=O)n1C

Procedure:
The process described in Method A was followed. 6-Ethoxy-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (Example 16, Step 1) (0.168 g, 0.79 mmol) and methoxyamine hydrochloride (0.087 g, 1.04 mmol) were used to obtain the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(=O)N1CCC(CCC(=O)c2ccc(F)cc2)CC1
Product: CC(=O)N1CCC(CCC(=O)c2ccc(N3CCCC3)cc2)CC1

Procedure:
Using 3.2 g of 1-acetyl-4-[2-(4 -fluorobenzoyl)ethyl]piperidine and 6 ml of pyrrolidine, the procedure of Example 53 was repeated to give 2.7 g of a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16](=O)[CH3:17])=[CH:11][C:10]=1[CH3:19])([CH3:7])[CH3:6])[CH3:2].[F:21][C:22]([F:41])([F:40])[O:23][C:24]1[CH:25]=[C:26]([C:30]#[C:31][CH2:32]CCOS(C)(=O)=O)[CH:27]=[CH:28][CH:29]=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][CH2:17][CH2:32][C:31]#[C:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:22]([F:21])([F:40])[F:41])[CH:25]=2)=[CH:11][C:10]=1[CH3:19])[CH3:6])[CH3:2]
Reactant: CS(=O)(=O)OCCCC#Cc1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(SC(C)=O)cc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(SCCCC#Cc2cccc(OC(F)(F)F)c2)cc1C

Procedure:
In analogy to the procedure described in example 1D], 2-(4-acetylsulfanyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 1C]) was reacted with methanesulfonic acid 5-(3-trifluoromethoxy-phenyl)-pent-4-ynyl ester (example 3D]) to give 2-methyl-2-{2-methyl-4-[5-(3-trifluoromethoxy-phenyl)-pent-4-ynylsulfanyl]-phenoxy}-propionic acid ethyl ester as light brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[F:26])=[C:10]([C:13]1[N:17]([CH3:18])[N:16]=[N:15][N:14]=1)[CH:11]=O.C1(P(=[CH:46][CH:47]=[O:48])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[F:26])=[C:10]([C:13]1[N:17]([CH3:18])[N:16]=[N:15][N:14]=1)[CH:11]=[CH:46][CH:47]=[O:48]
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C(=C(C=O)c2nnnn2C)c2ccc(C)cc2F)c(F)c1
Solvent: c1ccccc1
Product: Cc1ccc(C(=C(C=CC=O)c2nnnn2C)c2ccc(C)cc2F)c(F)c1
Yield: 89.9 %

Procedure:
A solution of 3,3-bis(2-fluoro-4-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal (1.35 g, 3.8 mmoles) and triphenylphosphoranylidene acetaldehyde (1.16 g, 3.8 mmoles) in benzene was heated at reflux for 3 hours. The solvent was removed and the residue purified by column chromatography on silica gel eluting with 1% (v/v) methanol in methylene chloride. The fractions containing material having Rf =0.9 [methanol-methylene chloride; 1:20 (v/v)] were combined and concentrated to give 1.3 g of the title compound; m.p.=88°-108° C.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=[O:2].S(=O)(=O)([OH:20])N.Cl([O-])=O.[Na+]>CC(C)=O.O.O>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([O:7][C:6]2[CH:16]=[CH:17][C:3]([C:1]([OH:20])=[O:2])=[CH:4][CH:5]=2)=[N:9][CH:10]=1)#[N:13]
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc(C(=O)O)cc2)nc1
Temperature: 0 °C
Yield: 86.9 %

Procedure:
6-(4-formyl-phenoxy)-nicotinonitrile (310 mg, 1.38 mmol) was dissolved in acetone-water mixture (3.5:3) (6.5 mL) and cooled to 0° C. Sulphamic acid (403 mg, 4.15 mmol) and sodium chlorite (499 mg, 5.52 mmol) dissolved in minimum amount of water were added and the resulting mixture was stirred at room temperature for half an hour. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulphate and concentrated to afford 288 mg 4-(5-cyano-pyridin-2-yloxy)-benzoic acid, (85.2% yield). LCMS Purity: 83.2%,
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:14]=1[CH:15]=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:15][C:14]3[CH:17]=[C:18]([C:21]([F:22])([F:24])[F:23])[CH:19]=[CH:20][C:13]=3[Cl:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Cl
Reactant: O=C1Cc2ccc(Cl)cc2N1
Product: O=C1Nc2cc(Cl)ccc2C1=Cc1cc(C(F)(F)F)ccc1Cl

Procedure:
In a manner similar to the methods described in Examples 1a and 1b, 6-chloro-1,3-dihydro-indol-2-one (Aldrich) reacted with 2-chloro-5-trifluoromethyl-benzaldehyde (Aldrich) to give 6-chloro-3-[1-(2-chloro-5-trifluoromethyl-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole, which was subsequently reacted with di-tert-butyl-dicarbonate and DMAP and directly used for the next step.
Reaction SMILES: CO.[C:3]([O:7][C:8](=[O:48])[N:9]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][N:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([O:39]CC3C=CC=CC=3)=[CH:31][C:30]2=[O:47])[CH2:23][CH2:22]1)[CH2:10][C:11]1[CH:20]=[CH:19][C:14]2[O:15][CH2:16][CH2:17][O:18][C:13]=2[CH:12]=1)([CH3:6])([CH3:5])[CH3:4]>[Pd].O1CCCC1>[C:3]([O:7][C:8](=[O:48])[N:9]([CH2:10][C:11]1[CH:20]=[CH:19][C:14]2[O:15][CH2:16][CH2:17][O:18][C:13]=2[CH:12]=1)[CH:21]1[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][N:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([OH:39])=[CH:31][C:30]2=[O:47])[CH2:25][CH2:26]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(OCc3ccccc3)c3ccccc32)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(O)c3ccccc32)CC1
Reaction time: 3.5 h

Procedure:
To a mixed solution of 130 mL methanol and 10 mL tetrahydrofuran containing 1.76 g of tert-butyl(1-(2-(4-benzyloxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate, 0.86 g of 5% palladium on carbon was added, and stirred under hydrogen atmosphere for 3.5 hours. The insoluble material was filtered off, and the solvent was removed under reduced pressure to afford 1.48 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-hydroxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.
Reaction SMILES: B(F)(F)[F:2].CCOCC.[CH:10]1(N)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1.N(OC(C)(C)C)=O>C(COC)OC>[F:2][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH2:10][CH2:11][CH2:12][CH2:13]2
Reactant: FB(F)F
Reactant: NC1CCCc2ccccc21
Agent: CC(C)(C)ON=O
Solvent: CCOCC
Solvent: COCCOC
Product: Fc1cccc2c1CCCC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A modified procedure of Mirsadehgi et al. was used (J. Org. Chem. 1989, 54, 3091). Boron trifluoride etherate (30.0 g, 26.8 mL, 0.21 mol) was dissolved and stirred in dimethoxyethane (50 mL) and cooled to 0° C. A solution of tetrahydro-1-naphthylamine (25 g, 0.17 mol) in dimethoxyethane (75 mL) was added dropwise and the solution was allowed to warm slowly to room temperature over the period of 1 hour. The reaction was cooled to 0° C. and a solution of t-butyl nitrite (18.0 g, 20.7 mL, 0.17 mol) in dimethoxyethane (75 mL) was added dropwise. The reaction was stirred for 2 hours at 0° C. upon which a large quantity of material crystallized. The solvent was removed in vacuo and chlorobenzene (200 mL) was charged to the reaction flask. The flask was stirred vigorously and heated to 135° C. (Caution: N2 evolution) for 1 hour until gas evolution ceased. The flask was cooled to room temperature and the solvent removed in vacuo. Kughelrohr distillation of the residue (1 mm Hg) afforded a yellow liquid. Wt: 14.4 g (56%). 1H NMR (300 MHz, CDCl3) δ 7.04 (dd, 1H), 6.83 (m, 2H), 2.75 (m, 4H), 1.80 (m, 4H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](I)[C:5]([NH2:9])=[C:4]([F:10])[CH:3]=1.[C:11]([OH:17])(=[O:16])[CH2:12][CH2:13][C:14]#[CH:15].C(N(CC)CC)C>CN(C=O)C.[Cu]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>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([F:10])[CH:3]=1)[NH:9][C:14]([CH2:13][CH2:12][C:11]([OH:17])=[O:16])=[CH:15]2
Reactant: Nc1c(F)cc(Br)cc1I
Reactant: C#CCCC(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)CCc1cc2cc(Br)cc(F)c2[nH]1
Temperature: 80 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
To a solution of (4-bromo-2-fluoro-6-iodophenyl)amine (D159) (2 g), 4-pentynoic acid (0.62 g) and copper(I) iodide (0.60 g) in DMF (4 mL) stirred under nitrogen at room temperature was added bis(triphenylphosphine)palladium(II) chloride (0.222 g), then triethylamine (2.2 mL) was added in a portion. The reaction mixture was stirred at 80° C. in microwave reactor for 2 hrs. The solid in the mixture was filtered, the filtrate was diluted with EtOAc (30 mL), washed with brine (80 mL) and water (50 mL×2). The organic layer was dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography to afford 3-(5-bromo-7-fluoro-1H-indol-2-yl)propanoic acid (D160) (700 mg) as a yellow solid. MS (ES): C11H9BrFNO2 requires 285; found 286.0 (M+H+). δH (CDCl3, 400 MHz): 2.75 (2H, t), 3.07 (2H, t), 5.45 (1H, s), 7.05 (1H, d), 7.41 (1H, s).