Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH3:35])[CH:9]([CH3:23])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=1)[NH:16][CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36]1(=[O:43])[O:42][C:40](=[O:41])[CH2:39][CH2:38][CH2:37]1.P([O-])([O-])([O-])=O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH3:35])[CH:9]([CH3:23])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20](=[O:21])[NH2:22])[CH:19]=1)[N:16]([C:36](=[O:43])[CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])[CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc2c(c(C(N)=O)c1)NCC2
Reactant: O=C1CCCC(=O)O1
Agent: CN(C)c1ccncc1
Agent: O=P([O-])([O-])[O-]
Solvent: c1ccncc1
Product: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc2c(c(C(N)=O)c1)N(C(=O)CCCC(=O)O)CC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 85.9 %

Procedure:
To a solution of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carboxamide (145 mg) in pyridine (0.5 ml) were added 4-dimethylaminopyridine (4 mg) and glutaric anhydride (51 mg), and the mixture was stirred at room temperature for 72 hours. The pH of the reaction mixture was adjusted to pH 7 with phosphate buffer solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of chloroform and methanol (9/1) as eluent to give 154 mg of 5-[5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]-7-carbamoylindolin- 1-yl]-5-oxopentanoic acid as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[N:18]3)=[CH:4][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Cl[CH2:24][C:25](=O)[CH3:26].C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[C:3]([O:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[N:18]3)=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:24]=[C:25]([CH3:26])[N:11]=2)=[N:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: NC(=S)Nc1cc(Oc2cccc3ncccc23)c(Br)cn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1csc(Nc2cc(Oc3cccc4ncccc34)c(Br)cn2)n1
Yield: 77.2 %

Procedure:
A mixture of 1-(5-bromo-4-(quinolin-5-yloxy)pyridin-2-yl)thiourea (2.00 g, 5.330 mmol), 1-chloropropan-2-one (0.6366 ml, 7.995 mmol), triethylamine (1.486 ml, 10.66 mmol), and ethanol (25 ml) was heated at reflux for two days. The organic solvents were concentrated, and hexanes:ethyl acetate (9:1) were added and the reaction was filtered. The residue was washed with water and ethyl acetate, and dried over high vacuum overnight to give the desired compound (1.70 g, 76.40% yield) as very light yellow solid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10]([O:17][C:18]([NH:20][C:21](=[N:24][C:25](=O)[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)SC)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C(O)=O.[CH2:41]([NH:43][NH2:44])[CH3:42].CCOCC>CN(C=O)C>[CH2:10]([O:17][C:18](=[O:19])[NH:20][C:21]1[N:24]=[C:25]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[N:43]([CH2:41][CH3:42])[N:44]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCNN
Reactant: COc1ccc(C(=O)N=C(NC(=O)OCc2ccccc2)SC)cc1
Agent: O=C(O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCn1nc(NC(=O)OCc2ccccc2)nc1-c1ccc(OC)cc1
Temperature: 50 °C
Yield: 92.4 %

Procedure:
N,N-diisoproylethylamine (9.9 g, 76.8 mmol) is added to a solution of 1-benzyloxycarbonyl-3-(4-methoxy-benzoyl)-2-methyl-isothiourea (11.0 g, 30.7 mmol) and ethyl hydrazine oxalate (11.6 g, 76.8 mmol) in DMF (110.0 mL) and the reaction mixture is heated at 50° C. for 12 h. Ice and ether are added to the reaction mixture and the two phases are separated. The organic phase is dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 10 g of [1-ethyl-5-(4-methoxy-phenyl)-1H-1,2,4-triazol-3-yl]-carbamic acid benzyl ester that is used in the next step without further purification. m/z 353 [M+H].
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15].C(N(C(C)C)C(C)C)C.[NH4+].[Cl-]>CS(C)=O>[OH:16][CH:13]([CH2:14][OH:15])[CH2:12][NH:11][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: NCC(O)CO
Reactant: N#Cc1ccc(F)cc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1ccc(F)cc1NCC(O)CO
Yield: 41.4 %

Procedure:
A mixture of 2,4-Difluoro-benzonitrile (1.39 g, 10 mmol), 3-amino-propane-1,2-diol (0.911 g, 10 mmol), and ethyl-diisopropyl-amine (1.74 mL) in DMSO (10 mL) was microwaved at 200° C. for 7 min. Then the reaction mixture was poured into a saturated NH4Cl aq. solution (100 mL), extracted with EtOAc (3×100 mL), dried over Na2SO4, filtered, concentrated. The crude mixture was purified by flash silica gel chromatography (EtOAc-Hexane 1:1) to give 2-(2,3-Dihydroxy-propylamino)-4-fluoro-benzonitrile (0.87 g, 41.4% yield). LCMS (m/z): M+H=211.
Reaction SMILES: [Si]([O:8][C@H:9]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[N:23]=[C:22]([C@@H:24]([N:26]4[CH:31]=[CH:30][CH:29]=[N:28][C:27]4=[O:32])[CH3:25])[NH:21][C:20]=3[CH:33]=2)[N:11]1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C.C(#N)C.O>FC(F)(F)C(O)=O>[OH:8][C@H:9]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@@H:10]1[NH:11][C@H:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[N:23]=[C:22]([C@@H:24]([N:26]4[CH:31]=[CH:30][CH:29]=[N:28][C:27]4=[O:32])[CH3:25])[NH:21][C:20]=3[CH:33]=2)[CH2:13][CH2:14]1
Reactant: C[C@@H](c1nc2ccc(C[C@@H]3CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c4ccccc4)N3C(=O)OC(C)(C)C)cc2[nH]1)n1cccnc1=O
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](c1nc2ccc(C[C@@H]3CC[C@H]([C@H](O)c4ccccc4)N3)cc2[nH]1)n1cccnc1=O

Procedure:
A solution of 0.017 g (0.026 mmol) of tert-butyl(2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-5-({2-[(1S)-1-(2-oxopyrimidin-1(2H)-yl)ethyl]-1H-benzimidazo-6-yl}methyl)pyrrolidine-1-carboxylate from Step B above in 2 mL of a 3:3:1 trifluoroacetic acid:acetonitrile:water mixture was stirred at 70° C. for 3 h. All volatiles were removed in vacuo and the crude light brown residue was purified by reverse-phase HPLC (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient) to afford the title compound as a white solid. 1H-NMR (500 MHz, CD3OD) δ 8.85-8.62 (m, 1H), 8.57-8.31 (m, 1H), 7.91-7.65 (m, 2H), 7.64-7.24 (m, 9H), 6.86-6.59 (m, 1H), 6.19-5.87 (m, 1H), 4.85-4.67 (m, 2H), 4.04-3.68 (m, 4H), 3.28-3.10 (m, 2H), 2.30-1.62 (m, 4H). LC/MS: m/z (ES) 430.2 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([Sn](CCCC)(CCCC)CCCC)=[N:21][CH:22]=1>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.C1(C)C=CC=CC=1>[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([C:2]2[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])=[N:21][CH:22]=1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C

Procedure:
A mixture of dimethyl 5-bromoisophthalate (1.0 g, 3.66 mmol), 5-methyl-2-(tributylstannyl)pyridine (1.5 mL, 4.5 mmol), tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.17 mmol), and toluene (10 mL) under nitrogen was subjected to microwave irradiation at 120° C. for 2 hour. The mixture was cooled to room temperature and the precipitate was collected via filtration and rinsed with hexane to afford a white solid which was the desired product. The filtrate was purified via flash chromatography to afford another crop of the desired product (0.8 g in total). LC-MS: 286.3 [M+1]+; 1H NMR (400 MHz, CDCl3): 8.84 (d, J=1.6 Hz, 2H), 8.71 (t, J=1.6 Hz, 1H), 8.56 (t, J=0.8 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.61 (dd, J=2.0, 8.1 Hz, 1H), 3.98 (s, 6H), 2.41 (s, 3H).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)[CH3:2].[Li+].C[C:10]1([CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:17].C(Br)C#C.[Cl-].[NH4+]>C1COCC1>[CH2:18]([CH:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:17])[C:1]#[CH:2]
Reactant: CC1(C)CCCCCC1=O
Reactant: CC(C)[N-]C(C)C
Agent: C#CCBr
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C#CCC1CCCCCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A solution of lithium diisopropylamide (LDA) in THF (50 ml) was added to a solution of 2,2-dimethylcycloheptanone (13) (10.55 g, 75.37 mmol) in THF (30 ml) at a temperature of 0° C. The mixture was stirred at room temperature for one hour. To this was added dropwise propargylbromide (6.85 ml, 90.44 mmol) at 0° C. The mixture was stirred at room temperature for one hour, and then heated at 50° C. for 3 hours. The mixture was treated with an aqueous ammonium chloride solution, and then purified by distillation (100° C., 2 mmHg) to obtain propargyl-cycloheptanone (14) (7.34 g, 55%).
Reaction SMILES: [CH2:1]([NH:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([N:22]1[CH:26]([C:27]([O:29]CC)=[O:28])[CH2:25][S:24][CH2:23]1)=[O:21])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].S1CC(C(O)=O)NC1>C(=O)(O)[O-].[Na+].CC(C)=O>[CH2:1]([NH:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([N:22]1[CH:26]([C:27]([OH:29])=[O:28])[CH2:25][S:24][CH2:23]1)=[O:21])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCC=CCCCNc1cccc(C(=O)N2CSCC2C(=O)OCC)c1
Agent: O=C(O)C1CSCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCCCCCC=CCCCNc1cccc(C(=O)N2CSCC2C(=O)O)c1

Procedure:
By means of the alkaline hydrolysis method of Example 2 the ethyl ester of Example 548 is converted to the subject carboxylic acid. This acid is also prepared using the procedure of Example 548 except that the acylation of the thiazolidine-4-carboxylic acid is carried out in aqueous acetone sodium bicarbonate solution.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11](S(C3C=CC(C)=CC=3)(=O)=O)[CH:10]=2)O1.[CH2:29]([NH:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39](Cl)[N:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+].CC([O-])(C)C.[Na+]>CS(C)=O.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>[CH2:29]([NH:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[N:38]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cccnc32)cc1
Reactant: Clc1nccc(NCc2ccccc2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: c1ccc(CNc2ccnc(-c3c[nH]c4ncccc34)n2)cc1
Temperature: 160 °C
Yield: 11 %

Procedure:
A solution of 4 (0.36 g, 0.09 mmol), 10 (0.028 g, 0.108 mmol), 2.0M Na2CO3 (0.108 ml, 0.271 mmol) and catalytic PdCl2(PPh3)2 in 1 ml of DMSO was heated in the microwave at 160° C. for 5 minutes resulting in conversion to tosyl protected product by LC/MS(M+1)=456. NaOtBu (0.026 g, 0.271 mmol) was added to the reaction and it was heated in the microwave for 5 minutes at 160° C. resulting in complete conversion to product 11. The reaction was filtered and purified by preparative HPLC giving 0.0032 g of 11 as a white solid in 11% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([O:13]CC3C=CC(OC)=CC=3)[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.CO.C(Cl)Cl>C(#N)C.O>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[NH:9][C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1
Reactant: COc1ccc(COc2ccc3ncc(OC)nc3n2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: COc1cnc2ccc(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
3-(Methyloxy)-6-({[4-(methyloxy)phenyl]methyl}oxy)pyrido[2,3-b]pyrazine (0.6 g, 2 mmol) was dissolved in acetonitrile (100 mL) and then ammonium cerium (IV) nitrate (1.09 g, 2 mmol) dissolved in water (50 mL) was added. The reaction was stirred at rt for 0.5 h and then 20% MeOH/DCM and water were added. The layers were separated and the aqueous was extracted with 20% MeOH/DCM twice more. The combined organic phases were dried, filtered and evaporated and the crude was purified by trituration with diethyl ether to afford the title compound (0.3 g, 85%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1.O>CN(C)C=O>[C:3]1([S:8][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: Sc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(Sc2ccccc2Sc2ccc(Cl)cn2)nc1

Procedure:
In 50 ml of stirred dimethylformamide, a mixture of 3.0 grams (0.02 mole) dimercaptobenzene, 7.0 grams potassium carbonate, and 7.0 grams of 2,5-dichloropyridine is heated at 80° for 5 hours. Thereafter pouring into excess H2O, the mixture is extracted with ethyl ether (200 ml) and washed with H2O, saturated NaHCO3, and brine, dried (MgSO4), and evaporated to yield the crude product which can be recrystallized from 1-chlorobutane.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.S(Cl)([Cl:17])(=O)=O.C(OCC)C>C(Cl)Cl>[Cl:17][C:7]1[CH:6]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1]
Reactant: CCOC(=O)Cc1ccc(O)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(O)c(Cl)c1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (25 g, 138 mmol) in 375 ml of DCM, sulfuryl chloride (9.48 mL 118 mmol) was slowly added at 0° C. over a period of 30 min. Diethyl ether (19.6 mL) was slowly added reaction mixture at 0° C. and stirring was continued for 30 min at 0° C. The reaction mixture was slowly warmed to 15° C. for 1 h. After completion of reaction, the mixture was poured onto crushed ice and extracted with DCM (×2). The combined organic layers were washed with 10% NaHCO3 solution followed by water. The organic layer was dried over Na2SO4, filtered and evaporated under vacuum to give compound ethyl 2-(3-chloro-4-hydroxyphenyl)acetate (15 g) as a thick oil.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:18])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11](=O)[C:10](=[C:14](O)[CH3:15])[C:9](=[O:17])[CH2:8]1.O.[NH2:20][NH2:21]>C(O)C>[Cl:1][C:2]1[S:3][C:4]([Cl:18])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11]2[NH:21][N:20]=[C:14]([CH3:15])[C:10]=2[C:9](=[O:17])[CH2:8]1
Reactant: CC(O)=C1C(=O)CC(c2cc(Cl)sc2Cl)CC1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Yield: 87.8 %

Procedure:
A solution of 5-(2,5-dichlorothiophen-3-yl)-2-(1-hydroxyethylidene)cyclohexane-1,3-dione (2.48 g) and hydrazine hydrate (0.508 g) in ethanol (10 ml) was refluxed for 2 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and concentrated under reduced pressure. The residue was washed with diisopropylether to give 6-(2,5-dichlorothiophen-3-yl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (2.15 g) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[C:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC(OC)=CC=3)=[CH:20][CH:19]=2)[C:3]=1[C:4](O)=[O:5].P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1>>[Cl:1][C:2]1[C:3]2[C:4](=[O:5])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:24])[CH:22]=3)[NH:17][C:7]=2[C:8]([N+:14]([O-:16])=[O:15])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1ccc(COc2ccc(Nc3c([N+](=O)[O-])cc([N+](=O)[O-])c(Cl)c3C(=O)O)cc2)cc1
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1c2cc(O)ccc2[nH]c2c([N+](=O)[O-])cc([N+](=O)[O-])c(Cl)c12

Procedure:
A mixture of 5.0 g of 2-chloro-6-[[4-[(4-methoxyphenyl)methoxy]phenyl]amino]-3,5-dinitrobenzoic acid, 10 ml of phosphorus oxychloride, 0.2 ml of N,N-dimethylaniline and 50 ml of 1,2-dichloromthane was heated at reflux for 15 minutes and the reaction mixture was filtered hot. The filter cake was washed with 1,2-dichloroethane to provide the title compound, mp 278°-281° C.
Reaction SMILES: C(O)C.[C:4]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([Br:19])=[CH:13][C:14]=2[N+:16]([O-])=O)[CH2:9][CH2:8]1)(=[O:6])[CH3:5].Cl>[Fe].O>[C:4]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([Br:19])=[CH:13][C:14]=2[NH2:16])[CH2:9][CH2:8]1)(=[O:6])[CH3:5]
Reactant: CC(=O)N1CCc2cc(Br)cc([N+](=O)[O-])c21
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=O)N1CCc2cc(Br)cc(N)c21
Yield: 32.2 %

Procedure:
To a mixed solution of ethanol (400 ml) and water (100 ml), were added N-acetyl-5-bromo-7-nitroindoline (133.1 g), iron powder (10 mesh; 75 g) and concentrated hydrochloric acid (5 ml), and the mixture was subjected to refluxing for 5 hours with vigorous stirring. The reaction mixture was filtered by suction while hot to remove insoluble matter, and then the filtrate thereof was concentrated and cooled on standing to give the intended compound 38.3 g (32.2%) as a brown needle crystal. M.P.: 154°-155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH2:5][C:6]1[C:7]([CH2:15][CH3:16])=[N:8][N:9]([CH2:13][OH:14])[C:10]=1[CH2:11][CH3:12].ClC(Cl)(Cl)[C:23]([N:25]=C=O)=[O:24]>ClCCl>[C:23](=[O:24])([O:14][CH2:13][N:9]1[C:10]([CH2:11][CH3:12])=[C:6]([CH2:5][C:4]2[CH:17]=[C:18]([Cl:20])[CH:19]=[C:2]([Cl:1])[CH:3]=2)[C:7]([CH2:15][CH3:16])=[N:8]1)[NH2:25]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CCc1nn(CO)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Product: CCc1nn(COC(N)=O)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
A solution of the alcohol of Example 41 (280 mg, 0.90 mmol) in dichloromethane (5 ml) was cooled to 0° C., treated with trichloroacetyl isocyanate (128 l, 1.1 mmol) and stirred at 0° C. for 30 minutes. The solution was soaked into a pad of alumina (neutral, activity II, Brockmann), washed with dichloromethane and then extracted with ethyl acetate. The organic extract was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a solvent gradient of cyclohexane:ethyl acetate (2:1, by volume) gradually changing to cyclohexane:ethyl acetate (1:1, by volume) to afford the title compound (238 mg) as a solid, m.p. 153-155° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:20])=[C:4]([S:8]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH2:17][CH2:18]O)[N:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:41].O>CN(C=O)C>[Br:41][CH2:18][CH2:17][C:15]1[N:16]=[C:12]([NH:11][S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:20])(=[O:10])=[O:9])[S:13][CH:14]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCO)cs1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCBr)cs1
Temperature: 0 °C
Yield: 41 %

Procedure:
An ice-cold mixture of EXAMPLE 181A (2.03 g, 6.10 mmol), triphenylphosphine (4.80 g, 18.31 mmol) and carbontetrabromide (6.07 g, 18.31 mmol) in DMF (30 mL) was stirred for 1.5 h, and was then poured into water. The mixture was extracted with DCM, dried (sodium sulfate) and the solvent was evaporated. The crude material was twice purified by flash chromatography on silica gel gradient eluting with 0-4% acetone in DCM giving N-[4-(2-bromoethyl)-1,3-thiazol-2-yl]-3-chloro-2-methylbenzenesulfonamide as a solid (990 mg, 41%). MS (Ionspray, [M+H]+) m/z 394; Anal. Calcd. (found) for C12H12BrClN2O2S2: C, 36.4 (36.6)%; H, 3.1 (3.3)%; N ,7.1 (7.2)%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]1.CN(C)C=O.O1CCOCC1>C(OCC)(=O)C>[Cl:9][C:4]1[N:3]=[C:2]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)[CH:7]=[C:6]([I:8])[CH:5]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O[C@H]1CC[C@H](Nc2cc(I)cc(Cl)n2)CC1
Temperature: 200 °C

Procedure:
A suspension of 2,6-dichloro-4-iodopyridine (6 g, 21.9 mmol) and trans 4-aminocyclohexanol (5.05 g, 43.8 mmol) in 15 mL of a 1:4 mixture of N,N-dimethylformamide/1,4-dioxane was heated in a Biotage Initiator microwave at 200° C. for 55 min. Ethyl acetate (150 mL) was added and the mixture washed with water (100 mL) and brine (50 mL). The organics were concentrated and the residue purified by flash chromatography on silica gel eluting with 60% ethyl acetate in hexanes to provide the title compound. Yield: 3.8 g (49%). MS (DCI/NH3) m/z 353 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[F:17])=[N:4][CH:5]=[CH:6][CH:7]=1>ClCCl.C(O)C.[Pt]=O>[F:17][C:9]1[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:8]=1[C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ncccc2F)c1
Agent: O=[Pt]
Solvent: CCO
Solvent: ClCCl
Product: Nc1ccc(F)c(-c2ncccc2F)c1
Reaction time: 4 h

Procedure:
3-Fluoro-2-(2-fluoro-5-nitrophenyl)pyridine (1.0 g) was dissolved in dichloromethane (25 ml) and diluted with ethanol (50 ml). Platinum oxide (0.1 g) was added, and the mixture shaken on a Parr hydrogenation apparatus under an atmosphere of hydrogen at 45 psi for 4 h. The reaction was filtered and the filtrate evaporated, to afford 4-fluoro-3-(3-fluoropyridin-2-yl)phenylamine, which was used without further purification: 19F NMR (400 MHz, CDCl3) δ 128.48 (1F, d, J 36 Hz), 122.66 (1F, d, J 36 Hz).
Reaction SMILES: [Zn](CC)[CH2:2]C.C(O)(C(F)(F)F)=O.C(I)I.[C:16]([O:19][C@H:20]1[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@@H:24]([O:30][C:31](=[O:33])[CH3:32])[C@H:23]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([C:48]([CH2:50][O:51][CH3:52])=[CH2:49])=[CH:44][CH:43]=3)[CH:35]=2)[O:22][C@@H:21]1[CH2:53][O:54][C:55](=[O:57])[CH3:56])(=[O:18])[CH3:17]>C(Cl)Cl>[C:16]([O:19][C@H:20]1[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@@H:24]([O:30][C:31](=[O:33])[CH3:32])[C@H:23]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([CH2:41][C:42]3[CH:43]=[CH:44][C:45]([C:48]4([CH2:50][O:51][CH3:52])[CH2:2][CH2:49]4)=[CH:46][CH:47]=3)[CH:35]=2)[O:22][C@@H:21]1[CH2:53][O:54][C:55](=[O:57])[CH3:56])(=[O:18])[CH3:17]
Reactant: C=C(COC)c1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCC1(c2ccc(Cc3cc([C@@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc3Cl)cc2)CC1
Reaction time: 0.33 h

Procedure:
To a cooled (0° C.) solution of ZnEt2 (0.16 mL, 0.16 mmol) in CH2Cl2 (0.4 mL) was added a solution of TFA (12 μL, 0.16 mmol) in CH2Cl2 (0.2 mL). After stirring for 20 min, a solution of CH2I2 (43 mg, 0.16 mmol) in CH2Cl2 (0.2 mL) was added. After stirring for an additional 20 min, a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(3-methoxyprop-1-en-2-yl)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (intermediate BC) (32 mg, 0.053 mmol) in CH2Cl2 (0.4 mL) was added. The mixture was stirred overnight prior to quenching with a saturated solution of NaHCO3. The mixture was extracted 3× with CH2Cl2, and the organic portion was washed with brine prior to drying over Na2SO4. Concentration of the solution gave crude intermediate BC (25 mg).