Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[C:18]1[CH:23]=[C:22]([O:24][C:25]2[CH:34]=[C:33]3[C:28]([CH:29]=[CH:30][CH:31]=[N:32]3)=[CH:27][CH:26]=2)[N:21]=[CH:20][N:19]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:32]1[C:33]2[C:28](=[CH:27][CH:26]=[C:25]([O:24][C:22]3[N:21]=[CH:20][N:19]=[C:18]([C:9]4[CH:10]=[CH:11][C:12]([C:14]([F:16])([F:15])[F:17])=[CH:13][C:8]=4[NH2:7])[CH:23]=3)[CH:34]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a round-bottom flask was added {2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester, (Example 162), (3.2 g, 6.6 mmol) and CH2Cl2 (100 mL). The mixture was cooled to 0° C. and trifluoroacetic acid (25 mL) was added. After stirring for 5 min at 0° C., the mixture was allowed to warm to room temperature and stirred for 1.5 h. The reaction mixture was concentrated in vacuum and diluted with CH2Cl2 (200 mL) and satd NaHCO3 (200 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (100 mL). The combined extracts were washed with aq NaHCO3 (20% satd NaHCO3/H2O), H2O, brine and then dried over Na2SO4, filtered and concentrated onto silica gel. Purification by silica gel chromatography (gradient, 40 to 75% EtOAc/hexanes) afforded the title compound as a yellow solid. Mp: 193-194° C. MS (ESI, pos. ion) m/z: 383.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[O:11][CH:12]([CH2:15][CH2:16][OH:17])[C:13]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>C1COCC1>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[O:11][CH:12]([CH2:15][CH2:16][OH:17])[C:13]=1[O:14][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=C1OC(CCO)C(O)=C1OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OC(CCO)C(OCc2ccccc2)=C1OCc1ccccc1
Yield: 58.8 %

Procedure:
A mixture of 1.25 g (5 mmol) of 3-benzyloxy-4-hydroxy-5-(2-hydroxyethyl)-2(5H)-furanone, 15 mL of THF, 871 μL (5.0 mmol) of diisopropylethylamine and 631 μL (5.2 mmol) of benzyl bromide were combined under argon. The reaction mixture was warmed to reflux for 5 hours, and upon cooling, a suspension formed which was poured into 50 mL of 5% aqueous HCl solution and extracted with 100 mL of ether. The ether fraction was separated and sequentially washed with 30 mL of 5% aqueous HCl, 30 mL of H2O, 30 mL of saturated NAHCO3 solution, 30 mL of H2O, 30 mL of brine, dried (MgSO4) and concentrated to a colorless oil. Purification over silica gel using EtOAc/hexanes (2/3) provided 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone as a faint pink colored oil (1.0 g, 60% yield).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([CH:15]2[CH2:17][CH2:16]2)[N:12]=[C:11]([Cl:18])[C:10]=1[N+:19]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CC(O)=O.[Fe]>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([CH:15]2[CH2:16][CH2:17]2)[N:12]=[C:11]([Cl:18])[C:10]=1[NH2:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(NCc2ccccc2)cc(C2CC2)nc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(NCc2ccccc2)cc(C2CC2)nc1Cl
Temperature: 25 °C
Yield: 98.2 %

Procedure:
Benzyl-(2-chloro-6-cyclopropyl-3-nitro-pyridin-4-yl)-amine (245 mg, 0.8 mmol) was dissolved in AcOH:H2O (9.0:0.9 mL). Iron powder (270 mg, 4.8 mmol) was added and the mixture was vigorously stirred at room temperature under a nitrogen atmosphere over the weekend, during which an off-white precipitate had precipitated out. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL), the mixture filtered through celite, and the filter cake washed with EtOAc (20 mL). The phases were separated and the organic layer was washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4 and concentrated in vacuo. The residue was dried in vacuo at 40° C. overnight to give the title compound (215 mg) as an off-white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][OH:10].CCN(CC)CC.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>C(Cl)Cl>[C:22]([O:21][C:19](=[O:18])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][OH:10])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1ccc(N)c(CO)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)OC(C)(C)C)c(CO)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (2-amino-5-methyl-phenyl)-methanol (18.08 mmol, 2.48 g) in 50 mL CH2Cl2 was added Et3N (20 mmol, 2.8 mL) was added BOC2O and the reaction was allowed to stir overnight at r.t. for two days. The reaction mixture was washed with dilute HCl solution. The organic layer was separated, dried over Na2SO4, filtered and the solvent was removed in vacuo. (2-Hydroxymethyl-4-methyl-phenyl)-carbamic acid tert-butyl ester was obtained as a golden yellow thick oil (4.2 g) which was used in the next step without purification. MS (electrospray): mass calculated for C13H19NO3, 237.14; m/z found 238, [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:25])[N:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)CCC.CCOC(C)=O>C1(C)C=CC=CC=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>[Cl:25][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[C:11]([CH:12]([N:14]1[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]1=[O:24])[CH3:13])[C:2]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)=[N:3]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CC(c1cc2c(Cl)cccc2nc1Cl)N1C(=O)c2ccccc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(c1cc2c(Cl)cccc2nc1-c1ccccn1)N1C(=O)c2ccccc2C1=O
Temperature: 110 °C
Reaction time: 0.01 h

Procedure:
Transferred 2-(1-(2,5-dichloroquinolin-3-yl)ethyl)isoindoline-1,3-dione (197 mg, 531 μmol) from 100 mL flask to 10 mL flask by dissolving/slurrying in toluene and concentrating. Added Pd(Ph3P)4 (61 mg, 53 μmol) and 2-tri-n-butylstannylpyridine (955 μl, 2653 μmol). Bubbled argon through mixture for 30 sec. Equipped with condensor and nitrogen inlet. Heated at 110° C. for ˜16 h. The reaction mixture was concentrated and chromatographed on 12 g silica gel column with 0-60% EtOAc. The desired fractions were combined and concentrated to yield an oil. NMR indicates residual EtOAc. LC. 1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.98 (d, J=7.04 Hz, 3 H) 6.38 (q, J=7.04 Hz, 1 H) 7.24-7.37 (m, 1 H) 7.62-7.76 (m, 8 H) 8.01 (dd, J=8.61, 1.96 Hz, 1 H) 8.56-8.66 (m, 1 H) 9.02 (s, 1 H).−MS (+esi, M+H+=414.1)
Reaction SMILES: Cl.[C:2]([N:9]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]1)([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]>CS(C)=O.C(N(CC)CC)C>[C:5]([O:4][C:2]([N:9]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10]1)=[O:3])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.6 %

Procedure:
In a 1 l three-necked flask, 10 g of N-Boc-3-hydroxypyrrolidine are dissolved in 350 ml of dimethyl sulphoxide in the presence of 52.3 ml of triethylamine. 28 g of pyridine-sulphur trioxide complex dissolved in 350 ml of dimethyl sulphoxide are added dropwise to the above solution. The reaction mixture is stirred for 4 hours at ambient temperature. The reaction medium is acidified to pH 4.5-5 with a 1M solution of hydrochloric acid and the reaction mixture is then extracted with ethyl acetate. The organic phases are combined and then dried over anhydrous sodium sulphate. The residue is filtered through silica gel (1/1 heptane/ethyl acetate). 5.7 g of 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester are obtained. Yield: 58%.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:7][CH2:6][CH2:5][N:4]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:3]1.O[N:31]=[C:32]([NH2:36])[CH:33]([CH3:35])[CH3:34]>>[CH3:29][C:2]1([CH3:1])[O:7][CH2:6][CH2:5][N:4]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=3)[CH2:13][CH:12]([C:26]3[O:27][N:36]=[C:32]([CH:33]([CH3:35])[CH3:34])[N:31]=3)[CH2:11]2)=[O:9])[CH2:3]1
Reactant: CC1(C)CN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CCO1
Reactant: CC(C)C(N)=NO
Product: CC(C)c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOC(C)(C)C3)C2)n1

Procedure:
250 mg (0.410 mmol, 68% pure) of 1-[(2,2-dimethylmorpholin-4-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 208A) and 46.1 mg (0.451 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 1. Yield: 118 mg (59% of theory).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].C(O)(=O)C.[CH3:22][NH2:23]>O>[CH3:22][NH:23][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: CN
Reactant: O=C(O)CCC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: O
Product: CNc1ccc(C(=O)CCC(=O)O)cc1[N+](=O)[O-]

Procedure:
A solution of 20.0 g (0.0776 mol) of 4-(4-chloro-3-nitrophenyl)-4-oxobutanoic acid in 200 ml of 40% aqueous methylamine solution was stirred for 3 hours in a sealed vessel. Then the mixture was diluted with the same volume of water and acidified with acetic acid. The product precipitated was suction filtered, thoroughly washed with water and dried at 50° C. in a circulating air dryer. 18.5 g (95% of theoretical) of the desired compound were obtained in the form of yellow crystals.
Reaction SMILES: O=C1O[N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][CH:16]([C:18]([N:20]4[CH2:25][CH2:24][CH:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]4)=[O:19])[O:15][C:14]3=[O:33])=[CH:9][CH:8]=2)[NH:3]1.C(OCC)(=O)C>CO.[Ni]>[C:4]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:17][CH:16]([C:18]([N:20]3[CH2:21][CH2:22][CH:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:24][CH2:25]3)=[O:19])[O:15][C:14]2=[O:33])=[CH:11][CH:12]=1)(=[NH:3])[NH2:5]
Reactant: CC(C)(C)OC(=O)C1CCN(C(=O)C2CN(c3ccc(-c4noc(=O)[nH]4)cc3)C(=O)O2)CC1
Agent: [Ni]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1CCN(C(=O)C2CN(c3ccc(C(=N)N)cc3)C(=O)O2)CC1

Procedure:
1.37 g of tert-butyl 1-{3-[4-(5-oxo-1,2,4-oxadiazolin-3-yl)phenyl]-2-oxo-5-oxazolidinylcarbonyl}piperidine-4-carboxylate are dissolved in 50 ml of methanol and hydrogenated over Raney nickel. The reaction mixture is, subsequently filtered and the filtrate is concentrated in vacuo. The product obtained is treated with 20 ml of ethyl acetate, with heating, and the product, after cooling, is filtered off with suction. Tert-butyl 1-[3-(4-amidinophenyl)-2-oxo-5-oxazolidinylcarbonyl}piperid-4-yl-carboxylate is obtained, m.p. 160°.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11].[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][O:19][CH2:20][CH:21]2[CH2:26][CH2:25][CH:24]=[CH:23][O:22]2)=[CH:16][CH:15]=1>C(OCC)C.O=P(Cl)(Cl)Cl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][O:19][CH2:20][C@@H:21]2[O:22][C@@H:23]([O:12][CH:3]([C:4]3[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=3[Cl:11])[CH2:2][Br:1])[CH2:24][CH2:25][CH2:26]2)=[CH:27][CH:28]=1
Reactant: OC(CBr)c1ccc(Cl)cc1Cl
Reactant: Clc1ccc(COCC2CCC=CO2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: Clc1ccc(COC[C@H]2CCC[C@H](OC(CBr)c3ccc(Cl)cc3Cl)O2)cc1
Yield: 69.2 %

Procedure:
102 mg of α-bromomethyl-2,4-dichlorobenzyl alcohol and the 82 mg of 2-(4-chlorobenzyloxymethyl)-3,4-dihydro-2H-pyran prepared above were then dissolved in 2 ml of diethyl ether, and one drop of phosphorus oxytrichloride was then added. The mixture was then allowed to react at room temperature for 4 days, after which it was treated and the product purified essentially as described in Example 34(a), to give 121 mg of trans-6-(4-chlorobenzyloxymethyl)-2-[2-bromo-1-(2,4-dichlorophenyl)ethoxy]tetrahydropyran.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:9]([OH:12])[CH2:10][OH:11].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Si:1]([O:11][CH2:10][CH2:9][OH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyldimethylsilylchloride (100 g, 0.66M) in dry dichloromethane (70 ml) was added, drop-wise, to a stirred mixture of distilled ethylene glycol (205.6 g, 3.31M), dry dichloromethane (200 ml), triethylamine (120 ml, 0.86M) and 4-dimethylaminopyridine (8 g, 0.066M) at 0° C. under a nitrogen atmosphere. After the addition the mixture was allowed to warm to ambient temperature and was stirred for a further 3 hours. The mixture was then filtered and the filtrate washed with dilute sodium bicarbonate solution, brine, dried over magnesium sulphate, filtered and then evaporated in vacuo to give a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=3)([OH:17])[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-:28].[K+]>C(O)(C)(C)C.[Cl-].[Na+].O>[CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([NH2:25])=[O:28])=[N:22][CH:23]=3)([OH:17])[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: [OH-]
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(C#N)nc2)CCN(C)C1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(C(N)=O)nc2)CCN(C)C1
Temperature: 80 °C

Procedure:
A mixture of 5-(1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-hydroxypropan-2-yl)picolinonitrile (300 mg, 0.833 mmol), crushed KOH (140 mg, 2.499 mmol) in 12 mL tert-butanol was heated at 80° C. for 2 h. The reaction was monitored by TLC. The reaction mixture was allowed to cool at RT, diluted with brine (30 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with water (3×100 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by Preparative HPLC followed by chiral HPLC to obtain 5-(1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-hydroxypropan-2-yl)pyridine-2-carboxamide. 1H NMR (CDCl3, freebase) δ (ppm): 8.49 (s, 1H), 8.04 (d, 1H), 7.86 (d, 1H), 7.66 (s, 1H), 7.01 (s, 1H), 6.85 (s, 1H), 6.78 bs (NH), 5.48 s (OH),4.16 (dd, 2H), 3.44 (q, 2H), 2.9 (m, 2H), 2.7 (m, 2H), 2.45 (s, 3H), 2.35 (s, 3H), 2.35 (s, 3H), 1.6 (s, 3H). Separation by chiral HPLC provided enantiomers II-136a-b.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([N:14]([CH2:28][CH2:29][CH3:30])[C:15]([C:17]1[CH:18]=[C:19]([CH:24]=[C:25](I)[CH:26]=1)[C:20]([O:22][CH3:23])=[O:21])=[O:16])[CH2:12][CH3:13]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:28]([N:14]([CH2:11][CH2:12][CH3:13])[C:15]([C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH:26]=1)[C:20]([O:22][CH3:23])=[O:21])=[O:16])[CH2:29][CH3:30]
Reactant: c1cocn1
Reactant: CCCN(CCC)C(=O)c1cc(I)cc(C(=O)OC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-[(Dipropylamino)carbonyl]-5-iodobenzoic acid (12 g, 32 mmol) is dissolved in 20% methanol/benzene (480 mL), and 2M trimethylsilyldiazomethane in hexane (19 mL, 38 mmol) is added slowly. Upon completion of the addition, the solution is concentrated under reduced pressure to give methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate for use without further purification in the following reaction. To a −70° C. stirred solution of oxazole (120 mg, 1.7 mmol) in tetrahydrofuran (4 mL) is added n-butyllithium (1.6 M in hexanes, 1.2 mL, 1.9 mmol). After 30 min, zinc chloride (1 M in diethyl ether, 5.2 mL, 5.2 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is added a solution of methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate (643 mg, 1.6 mmol) in anhydrous tetrahydrofuran (3 mL) followed by palladium(0)tetrakis(triphenylphosphine) (80 mg, 0.07 mmol). The reaction mixture is heated at reflux for 3 h. The reaction mixture is cooled, diluted with ethyl acetate, filtered, washed with saturated sodium bicarbonate, water, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 60% ethyl acetate/hexane) provides the title compound in pure form. 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.27 (s, 1H), 8.14 (s, 1H), 7.80 (s, 1H) 7.32 (s, 1H), 3.52 (t, 2H), 3.22 (t, 2H), 1.75 (m, 2H), 1.30 (m, 2H), 0.97 (t, 3H), 0.79 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:15]1([CH2:18]Br)[CH2:17][CH2:16]1>CN(C)C=O.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:18][CH:15]2[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: BrCC1CC1
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Brc1ccc(SCC2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.4 %

Procedure:
4-Bromothiophenol (37.8 g) in N,N-dimethylformamide (200 mL) was treated with potassium carbonate (30.4 g) and cyclopropylmethyl bromide (29.7 g). The suspension was stirred at ambient temperature for 16 hrs then diluted with diethyl ether (500 mL). The organic phase was washed with water (2×500 mL), dried (MgSO4) and concentrated to give the title compound as an oil (46.4 g). 1H NMR (360 MHz, CDCl3): δ 7.38 (2H, d, J=8.0 Hz), 7.21 (2H, d, J=8.0 Hz), 2.83 (2H, d, J=7.0 Hz), 1.08-0.98 (1H, m), 0.58 (2H, q, J=5.1 Hz), 0.24 (2H, q, J=5.1 Hz).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:9]1([B-](F)(F)F)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[K+].Cl[C:21]1[C:26]2[O:27][CH:28]([CH3:32])[C:29](=[O:31])[NH:30][C:25]=2[CH:24]=[C:23]([CH:33]=[O:34])[CH:22]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>C1(C)C=CC=CC=1.O>[CH3:32][CH:28]1[O:27][C:26]2[C:21]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:22][C:23]([CH:33]=[O:34])=[CH:24][C:25]=2[NH:30][C:29]1=[O:31]
Reactant: F[B-](F)(F)c1ccccc1
Reactant: CC1Oc2c(Cl)cc(C=O)cc2NC1=O
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1Oc2c(cc(C=O)cc2-c2ccccc2)NC1=O
Temperature: 115 °C
Reaction time: 42 h
Yield: 19.4 %

Procedure:
To a solution of potassium phosphate, tribasic (0.564 g, 2.66 mmol), potassium phenyltrifluoroborate (0.245 g, 1.330 mmol), and 8-chloro-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde 15 (0.2 g, 0.886 mmol) in toluene (Ratio: 4.00, 16 mL) and water (Ratio: 1.000, 4.0 mL) was added PdOAc2 (0.015 g, 0.066 mmol) and dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (0.062 g, 0.133 mmol) at 23° C. The reaction was stirred at 115° C. for 42 hr. The reaction mixture was poured into water (2 mL) and extracted with Et2O (3×5 mL). The organic layer was dried over Na2SO4, filtered, and the organic phase stripped to dryness via rotary evaporation. The resulting crude material was purified via medium pressure chromatography using a gradient eluant of CH2Cl2/MeOH. The appropriate fractions were combined and concentrated via rotary evaporation. The impure material was reconstituted in DMSO (1.0 mL) and purified via preparative mass trigger LCMS using a gradient eluant of 45-70% ACN:0.05% TFA (aq). The early fractions were combined and the solvent was removed via rotary evaporation. The purified product was dried in vacuo to provide the title compound as an off-white solid (0.0459 g, 0.172 mmol, 19.37% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (d, J=6.82 Hz, 3H) 4.85-4.92 (m, 1H) 7.38-7.43 (m, 2H) 7.46-7.51 (m, 2H) 7.57-7.62 (m, 2H) 7.64 (d, J=2.02 Hz, 1H) 9.91 (s, 1H) 11.04 (s, 1H). ESI-MS: m/z 268.1 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=2[C:11]([NH:13][O:14][CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)=[O:12])=[CH:3][CH:2]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:20]([C:19]2[CH:18]=[CH:17][C:16]([CH2:15][O:14][NH:13][C:11](=[O:12])[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=3[NH:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[CH:24][CH:23]=2)=[O:21])[CH2:32][CH2:31]1
Reactant: O=C(O)c1ccc(CONC(=O)c2ccccc2NCc2ccncc2)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2ccc(CONC(=O)c3ccccc3NCc3ccncc3)cc2)CC1

Procedure:
Prepared by a similar procedure as described for preparation of example 405. Starting materials: 4-{2-[(Pyridin-4-ylmethyl)-amino]-benzoylaminooxymethyl}-benzoic acid (see example 404) and 1-methylpiperazine. The title compound was crystallised from toluene. 13C-NMR (DMSO-d6) δ 168.6, 167.2, 149.5, 148.9, 148.2, 137.3, 135.7, 132.4, 128.7, 128.0, 126.8, 121.9, 114.8, 113.3, 111.4, 76.4, 54.4, 46.8, 45.5, 44.8.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4]Br)[CH3:2].[CH:10]1[C:11]([I:19])=[CH:12][C:13]([I:18])=[C:14]([OH:17])[C:15]=1[I:16].C(=O)([O-])[O-].[K+].[K+].IC1C=C(I)C=C(I)C=1OC(CC)C>CN(C=O)C>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][O:17][C:14]1[C:15]([I:16])=[CH:10][C:11]([I:19])=[CH:12][C:13]=1[I:18])[CH3:2]
Reactant: CCCCC(CC)CBr
Reactant: Oc1c(I)cc(I)cc1I
Agent: CCC(C)Oc1c(I)cc(I)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1c(I)cc(I)cc1I
Reaction time: 20 h
Yield: 73.7 %

Procedure:
2-Ethyl-bromohexane (10.4 g, 53.0 mmol), triiodophenol (25.5 g, 54.0 mmol) and potassium carbonate (7.5 g, 54.3 mmol) were reacted in dry DMF (110 ml) at 77° C. as for 2-(2,4,6-triiodophenoxy)butane. After stirring for 20 hrs, the reaction was cooled, diluted with DMF, filtered through a pad of celite and evaporated in vacuo. The resulting residue was taken up in EtOAc (500 ml), washed with water (200 ml), 1N aqueous sodium hydroxide (200 ml), water (2×200 ml) and brine (200 ml), dried (Na2SO4), filtered and evaporated. Flash column chromatography (silica, hexanes) provided 2-ethyl-1-(2,4,6-triiodophenoxy)-hexane (22.8 g, 73.7%) as a clear viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>>[O:24]=[C:23]1[NH:22][N:21]=[C:20]([CH2:25][CH2:26][CH3:27])/[C:19]/1=[C:11]1/[NH:12][C:13]2[C:18]([C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])=[CH:7][CH:6]=3)=[CH:10]/1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Reactant: CCS(=O)(=O)Cl
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NS(=O)(=O)CC)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and ethanesulfonyl chloride according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.84 (t, J=7.45 Hz, 3H) 1.33 (t, J=7.33 Hz, 3H) 1.56 (dq, J=15.00, 7.46 Hz, 2H) 2.77-2.83 (m, 2H) 3.49-3.51 (m, 2H) 6.72 (d, J=8.59 Hz, 2H) 7.29 (d, J=8.34 Hz, 2H) 7.63 (t, J=7.58 Hz, 1H) 7.80 (t, J=7.71 Hz, 1H) 7.94 (d, J=8.34 Hz, 1H) 8.14 (d, J=8.08 Hz, 1H) 12.92 (s, 1H); ESI-MS: m/z calc'd for C23H24N4O3S2 468.59. found 469.2 (M+H)+.