Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH:13]=[O:14])=[N:4][CH:5]=[CH:6][CH:7]=1.[I:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[C:11]([I:15])[CH:10]=[C:9]2[CH:13]=[O:14])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccn1-c1ncccc1Cl
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(I)cn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.1 %

Procedure:
To a solution of 5.0 g of 3-chloro-2-(2-formyl-1H-pyrrol-1-yl)pyridine in 50 ml of N,N-dimethylformamide was added 5.4 g of N-iodosuccinimide. The resulting mixture was stirred at room temperature for 1 day. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.2 g of 1-(3-chloro-2-pyridinyl)-4-iodo-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: O=S(Cl)Cl.[F:5][C:6]1[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]([F:16])[C:7]=1[C:8]([OH:10])=[O:9].[CH3:17]O>>[F:5][C:6]1[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]([F:16])[C:7]=1[C:8]([O:10][CH3:17])=[O:9]
Reactant: O=C(O)c1c(F)cc(O)cc1F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c(F)cc(O)cc1F
Yield: 99 %

Procedure:
SOCl2 (4.16 g, 30.1 mmol) was added to a solution of 2,6-difluoro-4-hydroxybenzoic acid (1.50 g, 8.62 mmol) in MeOH (20 mL) and the resulting mixture was heated at reflux for 24 h. After cooling the solvent was removed in vacuo to give the title compound (1.62 g, 99%) as a white crystalline solid; mp 177.5-180° C.; 1H NMR (270 MHz, DMSO-d6) 3.80 (3H, s, CH3), 6.50-6.60 (2H, m, ArH), 11.16 (1H, s, OH)
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([NH:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1)=[O:22].B(Br)(Br)Br>>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([NH:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1)=[O:22]
Reactant: COc1cccc(-c2ccc3c(C(=O)Nc4nccs4)c(OC)ccc3c2)c1
Agent: BrB(Br)Br
Product: O=C(Nc1nccs1)c1c(O)ccc2cc(-c3cccc(O)c3)ccc12

Procedure:
The compound is prepared by reaction of 2-methoxy-6-(3-methoxyphenyl)-N(thiazol-2-yl)-1-naphthamide (117 mg, 0.30 mmol, 1 eq) with boron tribromide solution (7 eq) according to method G. Purification by column chromatography with dichloromethane/methanol 95/5 as the eluent yielded the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2([C:13]#[N:14])[CH2:12][CH2:11]CC2)=[C:4]([CH:17]=O)[CH:3]=1.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1.N1CCCC1>CO>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2([C:13]#[N:14])[CH2:12][CH2:11]2)=[C:4](/[CH:17]=[C:24]2\[C:25](=[O:29])[NH:26][C:27]3[C:23]\2=[CH:22][CH:21]=[C:20]([Cl:19])[CH:28]=3)[CH:3]=1
Reactant: N#CC1(COc2ccc(Cl)cc2C=O)CCCC1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: N#CC1(COc2ccc(Cl)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)CC1
Yield: 53.4 %

Procedure:
In a manner similar to the method described in Example 1b, 1-(4-chloro-2-formyl-phenoxymethyl)-cyclopentanecarbonitrile (4.7 g, 20 mmol) was reacted with 6-chlorooxindole (2.78 g, 16.67 mmol) and pyrrolidine (1.54 g, 21.67 mmol) in methanol to give the title compound as a yellow solid (3.43 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[SH:10].[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Br)=[CH:16][CH:15]=1>CO>[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][S:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Sc1nc2ccccc2[nH]1
Solvent: CO
Product: COC(=O)c1ccc(CSc2nc3ccccc3[nH]2)cc1
Yield: 60.3 %

Procedure:
1H-Benzoimidazol-2-thiol (1.5 g, 0.01 mol) and 4-bromomethyl benzoic acid methyl ester (2.29 g; 0.01 mol) were heated at reflux in methanol (100 mL) for a period of 24 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution, then with water. The organic phase was evaporated. The residue was dissolved in methanol. The resulting solution was saturated with hydrogen chloride. The solution was then concentrated to the precipitation point. The solid was collected and dried to give (1.8 g, 54% yield) of the title compound as a mono-hydrochloride, white solid, m.p. 229°-231° C. Anal. Calcd. for C16H14N2 O2S.HCl: C, 57.40; H, 4.52; N, 8.37. Found: C, 57.54; H, 4.47; N, 8.36. Mass spectrum (EI; M+) m/z 298. 1H-NMR (DMSO-d6 ; 400 MHz) δ 7.89 (d, 2H0, 7.62-7.65 (m, 4H); 7.39 (m, 2H), 4.89 (s, 2H), and 3.81 (s, 3H).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([N+:17]([O-])=O)=[C:14]([OH:16])[CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[NH2:17][C:13]1[CH:12]=[CH:11][C:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:15][C:14]=1[OH:16]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2ccccc2)cc1O
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)c2ccccc2)cc1O
Yield: 49.9 %

Procedure:
To a 1 liter flask was added 500 mg of a 5% dispersion of palladium metal on charcoal. The solid was wetted with 40 mL of ethanol and the flask was charged with a solution of 5-benzenesulfonyl-2-nitro-phenol (17.35 g., 62.1 mmol) in 350 mL ethanol. The flask was purged with hydrogen gas and a pressure of 1 Atm was maintained for 2 hours. The reaction mixture was filtered through celite, the filtrate concentrated in vacu, and the resulting residue was purified by flash (1:1:2 of “magic base” (6:1:0.1 methylene chloride:methanol:ammonia):CH2Cl2:hexanes.) The resulting solid was recrystallized from 300 mL EtOAc to give 7.68 g (31 mmol, 50%) of 2-amino-5-benzenesulfonyl-phenol as crystalline solid. MS: 250 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.CC1C=CC(S([CH2:20][CH2:21][CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)(=O)=O)=CC=1.ClCCl.[OH-].[Na+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>>[O:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]1[O:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)CCCOC2CCCCO2)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=Cc1ccc(OCCCOC2CCCCO2)cc1

Procedure:
In accordance with literature directions 4-hydroxybenzaldehyde is reacted with the bromo compound 2a in the presence of a phase transfer catalyst (dichloromethane/sodium hydroxide solution/tetra-n-butylammonium hydroxide). After chromatographic purification the aldehyde is obtained as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2([CH2:30][CH3:31])[CH2:21][O:20]C(=O)[N:18]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].C(OCC)(=O)C>CO.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH:18][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])([CH2:30][CH3:31])[CH2:21][OH:20])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC1(CCc2ccc(OCc3ccccc3)cc2)COC(=O)N1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(CO)(CCc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 142 %

Procedure:
To a solution of 4-(2-(4-benzyloxyphenyl)ethyl)-3-tert-butoxycarbonyl-4-ethyloxazolidin-2-one (18 g) in methanol (432 ml) was added a solution of lithium hydroxide monohydrate (9.1 g) in water (50 ml) and the mixture was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture and the mixture was washed with water and a saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure to give the subject compound (24 g).
Reaction SMILES: C[O:2][C:3](=[O:23])[C@H:4]([CH2:6][C:7]1[CH:12]=[C:11]([I:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[C:9]([I:22])[CH:8]=1)[NH2:5].CC([O:28][C:29](=[O:75])[C@H:30]([CH2:70][CH2:71][C:72](O)=[O:73])[N:31]([CH2:51][CH2:52][N:53]([CH2:62][C:63]([O:65]C(C)(C)C)=[O:64])[CH2:54][C:55](=[O:61])[O:56]C(C)(C)C)[CH2:32][CH2:33][N:34]([CH2:43][C:44](=[O:50])[O:45]C(C)(C)C)[CH2:35][C:36](=[O:42])[O:37]C(C)(C)C)(C)C.N[C@H](C(O)=O)CCC(O)=O.N[C@H](C(O)=O)CCCCN.C(N(CC(O)=O)CCN(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.C(P(C#N)(CC)=O)C.C(N(C(C)C)C(C)C)C>CN(C=O)C>[C:44]([CH2:43][N:34]([CH2:35][C:36]([OH:42])=[O:37])[CH2:33][CH2:32][N:31]([CH2:51][CH2:52][N:53]([CH2:62][C:63]([OH:65])=[O:64])[CH2:54][C:55]([OH:61])=[O:56])[CH:30]([C:29]([OH:75])=[O:28])[CH2:70][CH2:71][C:72]([NH:5][C@H:4]([C:3]([OH:2])=[O:23])[CH2:6][C:7]1[CH:12]=[C:11]([I:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[C:9]([I:22])[CH:8]=1)=[O:73])([OH:50])=[O:45]
Reactant: CC(C)(C)OC(=O)CN(CCN(CCN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)[C@@H](CCC(=O)O)C(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](N)Cc1cc(I)c(Oc2ccc(O)cc2)c(I)c1
Agent: CCP(=O)(C#N)CC
Agent: NCCCC[C@H](N)C(=O)O
Agent: N[C@@H](CCC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)CN(CCN(CCN(CC(=O)O)CC(=O)O)C(CCC(=O)N[C@@H](Cc1cc(I)c(Oc2ccc(O)cc2)c(I)c1)C(=O)O)C(=O)O)CC(=O)O
Reaction time: 21 h

Procedure:
O-(4-Hydroxyphenyl)-3,5-diiodo-L-tyrosine methyl ester, prepared according to Example 4 Step A, was reacted with N,N-bis[2-[bis[2-(1,1-dimethylethoxy)-2-oxoethyl]amino]ethyl]-L-glutamic acid 1-(1,1-dimethyl-ethyl) ester (prepared according to: Anelli P. L., Fedeli F., Gazzotti O., Lattuada L., Lux G. and Rebasti F., “L-Glutamic Acid and L-Lysine as Useful Building Blocks for the Preparation of Bifuctional DTPA-like Ligand”, Bioconjugate Chem. (1999), 10, 137-140), diethylphosphoryl cyanide (DEPC) and ethyldiisopropylamine (DIEA), in DMF, under nitrogen atmosphere at 0° C. After purification by flash chromatography, the pentaester was deprotected at first with TFA in CH2Cl2 at room temperature for 47 h, then with 2 M LiOH for 21 h. The solution was acidified to pH 3.3 with aq. HCl and loaded onto an Amberlite® XAD 1600 resin column. Eluting with a H2O/CH3CN gradient afforded the ligand.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][CH:26]=3)[O:20][C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:10][CH:9]=1)([CH3:6])[CH3:5].[OH-].[Na+]>C(O)C>[C:28]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:27]=[CH:26][C:25]([C:19]2[O:20][C:21]([CH2:22][CH2:23][CH3:24])=[C:17]([CH2:16][CH2:15][O:14][C:11]3[CH:12]=[CH:13][C:8]([O:7][C:4]([CH3:5])([CH3:6])[C:3]([OH:37])=[O:2])=[CH:9][CH:10]=3)[N:18]=2)=[CH:30][CH:29]=1
Reactant: CCCc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A sample of 2-{4-[2-(2-biphenyl-4-yl-5-propyl-oxazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionic acid methyl ester (484 mg, 0.97 mmol) was dissolved in ethanol (5 mL) followed by addition of 5.0 N NaOH (2 mL). The mixture was warmed with magnetic stirring at 50° C. for two hours. The reaction mixture was then allowed to cool to room temperature then partitioned between 50 mL of methylene chloride and 15 mL of 1.0 N HCl. The organic phase was separated, dried over sodium chloride and concentrated in vacuo to yield 384 mg (82%)of a glassy solid. HPLC RT1=6.37 min; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=8.3 Hz, 2H), 7.63-7.58 (m, 4H), 7.43-7.33 (m, 3H), 6.86 (d, J=9.3 Hz, 2H), 6.73 (d, J=9.3 Hz, 2H), 4.13 (t, J=6.3 Hz, 2H), 2.97 (t, J=6.3 Hz, 2H), 2.66 (t, J=7.3 Hz, 2H), 1.73-1.68 (m, 2H), 1.49 (s, 6H), 0.98 (t, J=7.3 Hz, 3H); MS (EI) 486.33 (M+H)+, 484.37 (M−H)−.
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.I[CH:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.[C:22]([Si:26]([O:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1I)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN(C)C=O.[Zn].C1(/C=C/C(=O)/C=C/C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Si:26]([O:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[CH:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)cc1I
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(c2cc(Cl)ccc2O[Si](C)(C)C(C)(C)C)C1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Zinc powder (700 mg, 10.7 mmol) was suspended in N,N-dimethylformamide (20 ml) under nitrogen. 1,2-dibromoethane (120 ul) was added and suspension heated to 60° C. for 10 minutes before cooling to room temperature. Chlorotrimethylsilane (180 ul) was added and the mixture heated to 60° C. for 10 minutes then cooled to room temperature. tert-Butyl 3-iodoazetidine-1-carboxylate (3.0 g, 10.6 mmol) was added with a slight-exotherm observed. The mixture was stirred at room temperature for 1 hour before the addition of tert-butyl(4-chloro-2-iodophenoxy)dimethylsilane (Preparation 239, 2.2 g, 5.97 mmol) followed immediately by tri-2-furylphosphine (250 mg, 1.08 mmol) and (1E, 4E)-1,5-diphenylpenta-1,4-dien-3-one-palladium (2:1) (300 mg, 0.52 mmol). The mixture was stirred at room temperature for 30 minutes then heated at 70° C. for 5 hours before concentration in vacuo. The residue was partitioned between ethyl acetate (100 ml) and aqueous sodium carbonate solution (50 ml). The organic extract was dried over sodium sulphate, filtered and evaporated in vacuo to afford the title compound as a brown oil, 3.2 g,
Reaction SMILES: [N:1]([C@@H:4]([C@@H:40]([C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([Cl:55])[CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:5]([NH:7][C:8]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:9]=1[CH2:10][CH2:11][C@H:12]1[O:17][CH2:16][C@@H:15]([CH2:18][O:19][C:20](=[O:27])[NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])[N:14]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:13]1)=[O:6])=[N+]=[N-].CP(C)C>CCOC(C)=O.O>[NH2:1][C@@H:4]([C@@H:40]([C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([Cl:55])[CH:48]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:5]([NH:7][C:8]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:9]=1[CH2:10][CH2:11][C@H:12]1[O:17][CH2:16][C@@H:15]([CH2:18][O:19][C:20](=[O:27])[NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])[N:14]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:13]1)=[O:6]
Reactant: COc1ccc([C@@H](c2ccccc2)[C@H](N=[N+]=[N-])C(=O)Nc2cccc(F)c2CC[C@@H]2CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO2)cc1Cl
Agent: CP(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H](c2ccccc2)[C@H](N)C(=O)Nc2cccc(F)c2CC[C@@H]2CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product from step 2 (160 mg, 0.20 mmol) in EtOAc (8 mL) and water (2 mL), was added trimethylphosphine (1.0 mL, 1M solution in THF, 1.0 mmol). The reaction mixture was stirred at ambient temperature for 2 h, then diluted with water (20 mL) and extracted with EtOAc (25 mL×3). The combined organic extracts were washed with brine (25 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as colorless oil. (M+H)+=767.
Reaction SMILES: Cl.Cl.C(OC[N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[C@H:16]1[C@H:25]2[CH2:26][CH2:27][N:28]([C:29]([C@H:31]3[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]3[NH2:37])=[O:30])[C@H:24]2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:17]1)(=O)C(C)(C)C.[C:38]([C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1)#[N:39].N>C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].CO>[C:38]([C:40]1[CH:48]=[CH:47][C:43]([C:44]([NH:37][C@@H:32]2[CH2:33][CH2:34][CH2:35][CH2:36][C@@H:31]2[C:29]([N:28]2[C@@H:24]3[C@@H:25]([C@H:16]([C:12]4[NH:13][CH:14]=[CH:15][N:11]=4)[NH:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=43)[CH2:26][CH2:27]2)=[O:30])=[O:45])=[CH:42][CH:41]=1)#[N:39]
Reactant: CC(C)(C)C(=O)OCn1ccnc1[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1N
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1ccc(C(=O)N[C@@H]2CCCC[C@@H]2C(=O)N2CC[C@@H]3[C@H](c4ncc[nH]4)Nc4ccccc4[C@@H]32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
[2-((3aR,4R,9bR)-1-{[(1S,2R)-2-aminocyclohexyl]carbonyl}-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-4-yl)-1H-imidazol-1-yl]methyl pivalate dihydrochloride (7.16 g, 13.0 mmol) was dissolved in ethyl acetate (170 ml) and 10% aqueous sodium carbonate solution (140 ml), and 4-cyanobenzoyl chloride (2.59 g, 15.6 mmol) was added under ice-cooling. The reaction mixture was stirred at room temperature for 2 hrs., and the separated aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (1:0-10:1, v/v) to give an amorphous form. This was dissolved in methanol (200 ml), 28% aqueous ammonia (100 ml) was added dropwise, and the mixture was stirred for 5 hrs. The solvent was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (1:0-5:1, v/v) to give the title compound (6.06 g, 94%) as an amorphous form.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:33])=[C:4]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=1[S:42](Cl)(=[O:44])=[O:43]>N1C=CC=CC=1>[Cl:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:22][CH2:21]3)=[N:9][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:42]([C:36]3[C:37]([F:41])=[CH:38][CH:39]=[CH:40][C:35]=3[F:34])(=[O:44])=[O:43])[C:3]=2[F:33])[CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(N)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reaction time: 3 h
Yield: 79.5 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-(3-amino-2-fluorophenyl)-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate (300 mg, 0.612 mmol) in pyridine (3 mL) was added 2,6-difluorobenzenesulfonyl chloride (130 mg, 0.612 mmol), and the reaction mixture was stirred for 3 h. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (3×). The extracts were dried, filtered and concentrated. The residue was purified using column chromatography (40 to 100% EtOAc/hexane) to give 324 mg of the title compound. MS (ESI): 610.1 [M+1−56]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[N:10]1>CCOC(C)=O.CCO.O=[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]1
Reactant: COc1cccc(OCCn2cc([N+](=O)[O-])cn2)c1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cccc(OCCn2cc(N)cn2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(2-(3-methoxyphenoxy)ethyl)-4-nitro-1H-pyrazole (533 mg, 1.90 mmol), in EtOAc (2 mL, degassed) and EtOH (6 mL, degassed), PtO2 (42 mg, 0.19 mmol) was added and the reaction mixture was stirred at rt under a H2-atmosphere for 3 h. The mixture was diluted with EtOH, filtered over celite and the filter cake was rinsed with EtOH. The filtrate was concentrated to obtain the title compound as a pale brown oil. LC-MS conditions A: tR=0.53 min, [M+H]+=234.41.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:10]2[S:14][C:13]3[CH:15]=[C:16]([O:19]C)[CH:17]=[CH:18][C:12]=3[C:11]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8]C.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:10]2[S:14][C:13]3[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:12]=3[C:11]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OC)c(C)c3)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: Cc1cc(-c2sc3cc(O)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)ccc1O
Yield: 63.8 %

Procedure:
By the method described in Example 2, the product of Example 6 (640 mg, 1.24 mmol), ethanethiol (0.45 mL, 6.18 mmol), and aluminum chloride (1.16 g, 8.70 mmol) were stirred in anhydrous CH2Cl2 (20 mL). After chromatography (silica gel, 5-10% methznol in CH2Cl2), the remnant crystallized from MeOH/CH2Cl2 to give 386 mg (64%) of the title product as a yellow solid: 1H NMR (DMSO-d6) d 1.34 (m, 2H), 1.44 (m, 4H), 2.37 (m, 4H), 2.60 (t, J=5.7 Hz, 2H), 4.05 (t, J=5.7 Hz, 2H), 6.64 (d, J=8.3 Hz, 1H), 6.82 (dd, J=2.1 Hz, 8.8 Hz, 1H), 6.89 (d, J=8.8 Hz, 2H), 6.96 (dd, J=2.1 Hz, 8.3 Hz, 1H), 7.05 (d, J=1.8 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.30 (d, J=1.8 Hz, 1H), 7.61 (d, J=8.8 Hz, 2H), 9.62 (br s, 1H), 9.75 (br s, 1 H); 13C NMR (DMSO-d6) d 15.7, 23.8, 25.4, 54.2, 57.0, 65.9, 107.0, 114.4, 114.8, 115.1, 123.2, 123.6, 124.3, 126.9, 129.5, 129.7, 130.6, 131.6 , 132.3, 139.1, 140.5, 155.3, 155.9, 162.7, 192.6; MS (FD) m/e 487 (M+); Anal. calc'd. for C29H29NO4S: C, 71.43; H, 6.00; N, 2.87. Found: C, 71.33; H, 6.05; N, 2.92.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH:5]=[C:6](F)[C:7]=1[F:8].BrC1C=CC([F:22])=CC=1F.BrC1C=C(F)C(F)=C(F)C=1>>[F:22][C:5]1[CH:6]=[C:7]([F:8])[CH:2]=[CH:3][C:4]=1[C:10]1[CH:14]=[CH:13][S:12][CH:11]=1
Reactant: Fc1ccc(Br)c(F)c1
Reactant: Fc1cc(-c2ccsc2)cc(F)c1F
Agent: Fc1cc(Br)cc(F)c1F
Product: Fc1ccc(-c2ccsc2)c(F)c1
Temperature: 80 °C
Yield: 97 %

Procedure:
The same procedures set forth above in Example (1)(a) for synthesizing 3(3,4,5-trifluorophenyl)thiophene were followed, with the exception that 1-bromo-2,4-difluorobenzene was substituted for 1-bromo-3,4,5-trifluorobenzene as the 1-bromo-substituted fluorobenzene, and the coupling reaction mixture was heated to reflux in an oil bath for 10 hours with stirring at 80° C. (as opposed to being heated in an oil bath for 0.5 hour with periodically stirring). No further purification by recrystallization was required to obtain a 97 to 98% pure product.