Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C:8]([NH:17][S@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])([CH:14]([F:16])[F:15])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:7]=1>C(O)C.CCCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C@:8]([NH:17][S@:18]([C:20]([CH3:22])([CH3:21])[CH3:23])=[O:19])([CH:14]([F:16])[F:15])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:7]=1
Reactant: COC(=O)CC(N[S@@](=O)C(C)(C)C)(c1cc(Br)ccc1F)C(F)F
Solvent: CCO
Solvent: CCCCCCC
Product: COC(=O)C[C@](N[S@@](=O)C(C)(C)C)(c1cc(Br)ccc1F)C(F)F
Yield: 40.8 %

Procedure:
Chiral separation of methyl 3-(5-bromo-2-fluorophenyl)-3-((S)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate (3.8 g, 8.83 mmol) (intermediate A3.14) by preparative chiral HPLC on Reprosil Chiral NR column with a mixture of 5% ethanol/n-heptane as the eluent yielded the (S)-methyl 3-(5-bromo-2-fluorophenyl)-3-((S)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate (1.55 g, 40.8% yield) (intermediate A3.15) as a colorless oil and the (R)-methyl 3-(5-bromo-2-fluorophenyl)-3-((S)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate (1.65 g, 43.4% yield)) (intermediate A3.15) as a colorless oil.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.[Li]CCCC.[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCOCC>[Br:7][C:5]1[CH:6]=[C:2]([CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[OH:20])[S:3][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: Brc1csc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC(c1ccccc1)c1cc(Br)cs1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2,4 dibromothiophene (3 g, 12.4 mmol) was dissolved in Et2O (50 mL) and cooled to −78° C. BuLi (1.6 M in hexanes)(8.1 mL, 13 mmol, 1.05 eg) was added dropwise over 20 min. then the yellow solution was stirred at −78° C. for 1 hour. Benzaldehyde (1.45 g, 13.64 mmol, 1.1 eg) dissolved in Et2O (15 mL) was added dropwise at a rate to maintain internal temperature <−70° C., then reaction mixture was allowed to warm slowly to 0° C. Quenched with Sat NH4Cl (50 mL) and phases partitioned. Organic fraction was washed with brine, dried, concentrated. Residue was chromatographed with 10% EtOAc/hexane to yield the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]=O)[CH:4]=[N:3]1.[C:10]([S:14]([NH2:16])=[O:15])([CH3:13])([CH3:12])[CH3:11]>C1COCC1.[Cl-].[Na+].O>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5](/[CH:8]=[N:16]/[S:14]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:15])[CH:4]=[N:3]1
Reactant: Cc1c(C=O)cnn1C
Reactant: CC(C)(C)S(N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(/C=N/S(=O)C(C)(C)C)cnn1C
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of 1,5-dimethyl-1H-pyrazole-4-carbaldehyde (Zhumal Obshchei Khimii 1980, 50, 2370-5, 2.0 g, 16.1 mmol), tert-butylsulfinamide (2.05 g, 16.9 mmol), and Ti(OEt)4 (6.76 ml, 32.2 mmol) in THF (32 ml) was heated under reflux for 18 h under nitrogen. After being cooled to rt, the mixture was poured into brine (32 ml) with stirring. The resulting suspension was filtered through a plug of Celite, and the filter cake was washed with EtOAc. The filtrate was transferred to a separation funnel, and organic layer was washed with brine. Then the aqueous layer was washed with EtOAc and the combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography (CH2Cl2:MeOH=50:1-30:1) to give the desired product as a white solid (3.55 g, 97% yield). 1H NMR (300 MHz, CDCl3) δ 1.23 (9H, s), 2.52 (3H, s), 3.83 (3H, s), 7.81 (1H, s), 8.49 (1H, s). MS (ESI) m/z 228 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][NH:8]1.ClC1C=C(Cl)C=C(Cl)C=1[O:47][S:48](=O)(=[O:50])[NH2:49].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:9][N:8]1[S:48]([NH2:49])(=[O:50])=[O:47]
Reactant: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1F
Reactant: NS(=O)(=O)Oc1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NS(=O)(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1COCc1cc(F)c(F)cc1F
Yield: 43.8 %

Procedure:
A solution of 567 mg (1.09 mmol) (2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine, 302 mg (1.09 mmol) sulfamic acid 2,4,6-trichloro-phenyl ester [Hedayatullah, M. & Hugueny, J. Phosphorus, Sulfur Silicon Relat. Elem. (1991), 61(1-2), 19-25.] and 0.15 ml triethylamine in 2 ml CH2Cl2 was heated for 1 h at reflux, evaporated and purified by flash column chromatography on silica gel with hexane/EtOAc (9:1 to 1:1) to give 286 mg (44%) (2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine-1-sulfonic acid amide. [Hedayatullah, M. & Hugueny, J. Phosphorus Sulfur (1985), 25(1), 33-8.] MS: 621 (M+Na+).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23](OCC)=[O:24])[N:22]=2)[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23]([NH:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=3)=[O:24])[N:22]=2)[CH:19]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (4-(trifluoromethyl)phenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](O)=[O:45])=[CH:40][CH:39]=2)[S:32]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:45])=[CH:47][CH:48]=2)[S:32]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3ccccc3)cc2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3ccccc3)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 89.2 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-phenylphenoxy)phenyl]-N-methylcarbamate (1.60 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (1.26 g), diethyl cyanophosphonate (0.73 g), triethylamine (0.45 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (2.39 g).
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=1[C:9]([C:11]1[C:20]([Cl:21])=[C:19]2[C:14]([C:15]([CH3:25])([CH3:24])[CH2:16][CH2:17][S:18]2(=[O:23])=[O:22])=[CH:13][CH:12]=1)=[O:10].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1.C(N(CC)CC)C.O>O1CCCC1>[Cl:21][C:20]1[C:11]([C:9]([C:3]2[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]=2[S:33][C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=2)=[O:10])=[CH:12][CH:13]=[C:14]2[C:19]=1[S:18](=[O:22])(=[O:23])[CH2:17][CH2:16][C:15]2([CH3:25])[CH3:24]
Reactant: CC1(C)CCS(=O)(=O)c2c1ccc(C(=O)C1=C(Cl)CCCC1=O)c2Cl
Reactant: Sc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCS(=O)(=O)c2c1ccc(C(=O)C1=C(Sc3ccc(Cl)cc3)CCCC1=O)c2Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.8 g (2 mmol) of 1-chloro-2-(8-chloro-4,4-dimethyl-1,1-dioxothiochroman-7-yl)carbonylcyclohex-1-en-3-one was dissolved in 10 ml of tetrahydrofuran and 0.29 g (2 mmol) of 4-chlorothiophenol and 0.22 g (2.2 mmol) of triethylamine were added dropwise. The mixture was stirred at 25° C. for 2 hours, stirred into water, extracted with ethyl acetate and the organic phases were extracted with 1N hydrochloric acid and dried, and the solvent was removed. This gave 0.9 g of beige crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].Br[CH2:11][CH2:12][CH2:13][C:14]1C=C[CH:22]=[C:16]2[C:17]([NH:19][C:20](=[O:21])[C:15]=12)=O.[Na].O.[CH2:27]([OH:29])[CH3:28]>>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:22][CH2:16][CH2:17][N:19]1[C:27](=[O:29])[C:28]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:20]1=[O:21]
Reactant: CCO
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Reactant: OCc1cccc(O)c1
Agent: [Na]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccc(CO)c1
Yield: 54 %

Procedure:
28.03 g (0.226 mol) of 3-Hydroxybenzyl alcohol are reacted with 60.47 g (0.226 mol) of bromopropylphthalimide and 5.2 g of sodium (0.226 mol) in 400 ml of ethanol at the reflux temperature (5 h). After the ethanol has been drawn off, water is added and the product is extracted with ethyl acetate. Concentration of the organic phase by evaporation yields 60.8 g of a light brown oil from which 38 g (54%) of N-[3-[3-(hydroxymethyl)phenoxy]propyl]phthalimide crystallize as a colourless solid melting at 78° to 80° C. 13.8 ml of hydrazine hydrate (80%) are added to 35.3 g (113 mmol) of N-[3-[3-(hydroxymethyl)phenoxy]propyl]phthalimide in 300 ml of ethanol and the reaction mixture is boiled under reflux for 5 hours. The ethanol is to a large extent removed by evaporation under vacuum, and 100 ml of H2O and 40 ml of conc. HCl (pH 1) are added to the residue. The solid is removed by suction filtration and the filtrate is extracted with ethyl acetate, made alkaline with NaOH (pH 12), saturated with NaCl and extracted with 80:20 CH2Cl2 /CH3OH. After concentration by evaporation and distillation of the oil left behind in a bulb tube (140° to 160° C., 5/10-2 mm Hg), 13.7 g (67% of theoretical) of a light colored solid melting at 68.5 to 69° C. are obtained.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[NH2:6][C:7]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].O>N1C=CC=CC=1>[S:1]([NH:6][C:7]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH3:4])(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2Cl)c1N
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Cc1cccc(Oc2ccccc2Cl)c1NS(C)(=O)=O
Yield: 24.2 %

Procedure:
A solution of mesyl chloride (0.95 g) in pyridine (3 ml) was added to a solution of ethyl 2-[2-amino-3-(2-chlorophenoxy)phenyl]acetate (2.3 g) in pyridine (10 ml), and the mixture was stirred for an hour. The reaction mixture was poured into water (100 ml) and extracted with diethyl ether (80 ml×2). The extract was washed with 5% hydrochloric acid (50 ml×2) and saline, dried over magnesium sulfate and then evaporated in vacuo. The oily residue (2.5 g) was crystallized by treating with ethanol and the resultant solid substance was recrystallized from ethanol to give ethyl 2-[2-mesylamino-3-(2-chlorophenoxy)phenyl]acetate (0.7 g). mp 145°-149° C.
Reaction SMILES: [C:1]1(=[O:12])[C@H:10]2[C@@H:5]([C:6](=[O:11])[CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.[O:13]([CH3:15])[Na].[CH:16](OCC)=[O:17].N1C=CC=CC=1>O.CC(O)=O>[OH:17][CH:16]=[C:7]1[CH2:8][CH2:9][C@H:10]2[C@@H:5]([CH2:4][CH2:3][C:2](=[CH:15][OH:13])[C:1]2=[O:12])[C:6]1=[O:11]
Reactant: O=C1CCC[C@H]2C(=O)CCC[C@H]12
Reactant: CCOC=O
Reactant: CO[Na]
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccncc1
Product: O=C1C(=CO)CC[C@H]2C(=O)C(=CO)CC[C@H]12
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A mixture of 1.66 g (10 mmole) of trans-decalin-1,5-dione, 2.16 g (40 mmole) of NaOCH3, 9.2 ml (130 mmole) of ethyl formate, and 70 ml of dry pyridine was stirred under nitrogen at room temperature for 21 hr. After the mixture was adjusted to a pH between 5 and 6 with the aid of 51 ml of AcOH and 471 ml of water, it was extracted with benzene several times. The benzene layers were thoroughly washed with water and then were extracted with 2% KOH solution. The basic extracts were washed with ether and then after reacidification with AcOH they were thoroughly extracted again with benzene. The benzene extracts were dried (Na2SO4) and then were reduced to dryness to give 2 g (90%) of crude product. Recrystallization from ethanol afforded trans-2,6-Bis(hydroxymethylene)decalin-1,5-dione as a fine yellow powder, mp 155°-157°; ir (nujol) 1640 and 1570 cm-1 ; nmr (CDCl3)δ2.3 (broad multiplet, 10), 9.00 (s,2), and 14.50 (s,2); mass spectrum m/e 222(M+.).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].[Cl:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([C:38]([C:41]([CH3:45])([CH3:44])[C:42]#[N:43])=[N:39][N:40]=2)[N:37]=1>O1CCCC1>[ClH:31].[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([C:41]([CH3:45])([CH3:44])[C:42]#[N:43])=[N:39][N:40]=4)[N:37]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C#N)c1nnc2ccc(Cl)nn12
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1nnc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Product: Cl
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 47.1 %

Procedure:
6.55 g of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 100 ml of tetrahydrofuran; 2.12 g of sodium tert-butoxide was added, followed by stirring at an external temperature of 60° C. for 40 minutes. After cooling, 4.86 g of 2-[6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-2-methylpropionitrile was added, followed by refluxing under heating for 5 hours. After cooling, saline was added; the reaction mixture was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; in 7.90 g of the residue was dissolved in 5 ml of pyridine; 5 ml of acetic anhydride was added, followed by stirring at room temperature for 15 hours. After saline was added, the reaction mixture was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and extracted with ethyl acetate-methanol-triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; the residue (6.26 g) was dissolved in ethanol; 1.52 ml of a 4 N solution of hydrogen chloride in ethyl acetate was added, followed by concentration under reduced pressure. The residue was crystallized from methanol-ethanol (1:5), washed with ethanol-ethyl acetate (1:5), and dried, to yield 5.19 g of the title compound.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.CO.C1COCC1.CO.[CH3:37][N:38]([CH3:48])[CH2:39][C:40]1[N:41]=[C:42]([N+:45]([O-])=O)[NH:43][CH:44]=1>[Ni].C(Cl)Cl.CO>[CH3:37][N:38]([CH2:39][C:40]1[N:41]=[C:42]([NH:45][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=3[F:22])=[CH:14][CH:15]=2)=[O:5])[NH:43][CH:44]=1)[CH3:48]
Reactant: CN(C)Cc1c[nH]c([N+](=O)[O-])n1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3nc(CN(C)C)c[nH]3)c3nccnc23)c1F

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2, dimethyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine (Step 22.1) instead of 2-nitroimidazole in Step 14.3. The title compound: ESI-MS: 469.1 [M+H]+; tR=3.15 min (System 1); TLC: Rf=0.22 (DCM/MeOH/NH3aq, 91.5:7.5:1).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][C@H:16]([CH2:21][N:22]([CH2:30][C@H:31]([O:38][Si](C(C)(C)C)(C)C)[C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)C(=O)OC(C)(C)C)[CH2:15][CH2:14]3)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].CCN(CC)CC.[CH3:53][C:54]1[CH:59]=[CH:58][C:57]([N:60]=[C:61]=[O:62])=[CH:56][CH:55]=1.[Cl:63]C(Cl)C>>[ClH:63].[OH:38][C@H:31]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[CH2:30][NH:22][CH2:21][C@H:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([NH:1][C:61]([NH:60][C:57]4[CH:58]=[CH:59][C:54]([CH3:53])=[CH:55][CH:56]=4)=[O:62])(=[O:4])=[O:3])[CH:6]=3)[CH:12]=2)[O:17]1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CC(Cl)Cl
Reactant: CC(C)(C)OC(=O)N(C[C@@H]1CCc2cc(-c3cccc(S(N)(=O)=O)c3)ccc2O1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)NS(=O)(=O)c2cccc(-c3ccc4c(c3)CC[C@H](CNC[C@H](O)c3cccnc3)O4)c2)cc1
Product: Cl
Reaction time: 2.5 h
Yield: 50 %

Procedure:
To a stirred solution of Example 281 (45 mg) in dichloroethane (10 mL), were added Et3N (0.014 mL) and 4-methylphenyl isocyanate (0.013 mL). Stirring was continued at room temperature over a 2-3 hour period. The solvent was removed under reduced pressure. Crude product was purified by combiflash column chromatography to give the free base of the desired product (27 mg, 50% yield). This material was treated with HCl (4 M) in dioxane and stirred at room temperature overnight. The solvent was removed under reduced pressure to provide the crude product, which was purified by preparative HPLC to provide the title compound. MS [M+H]+573.21, Rf=0.68 (CH2Cl2:MeOH=50:50); H1 NMR (MeOH-d4, δ ppm): 2.25 (s, 3H), 2.85-3.08 (m, 2H), 3.38-3.67 (m, 6H), 4.50 4.54 (m, 1H), 5.45-5.47 (m, 1H), 7.04-7.07 (m, 4H), 7.24 (d, 2H, J=6.3 Hz), 7.40 (dd, 1H, J=6.3 Hz), 7.42-7.45 (m, 2H), 7.63 (t, 1H, J=6.0 Hz), 7.87 (d, 1H, J=6.0 Hz), 7.93 (d, 1H, J=6.0 Hz), 8.10-8.20 (m, 1H), 8.22 (s, 1H), 8.78-8.79 (m, 1H).
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Cl[CH2:14][C:15]1[C:16]([CH3:21])=[N:17][O:18][C:19]=1[CH3:20].[CH3:22][C:23]1[N:24]=[C:25]([N:38]2[C:42](=[O:43])[NH:41][N:40]=[CH:39]2)[S:26][C:27]=1[C:28]([NH:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:29]>>[CH3:21][C:16]1[C:15]([CH2:14][N:41]2[C:42](=[O:43])[N:38]([C:25]3[S:26][C:27]([C:28]([NH:30][CH2:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)=[O:29])=[C:23]([CH3:22])[N:24]=3)[CH:39]=[N:40]2)=[C:19]([CH3:20])[O:18][N:17]=1
Reactant: Cc1nc(-n2cn[nH]c2=O)sc1C(=O)NCc1cccnc1
Reactant: Cc1noc(C)c1CCl
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: Cc1nc(-n2cnn(Cc3c(C)noc3C)c2=O)sc1C(=O)NCc1cccnc1
Yield: 45 %

Procedure:
Following the procedure as described in Example 19, making variation as required to replace 4-(trifluoromethyl)benzyl bromide with 4-(chloromethyl)-3,5-dimethylisoxazole to react with 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 45% yield: mp 233-234° C. (ethyl acetate/hexane): 1H NMR (300 MHz, CDCl3) δ 8.74 (br s, 1H), 8.60 (br s, 1H), 8.22 (s, 1H), 7.87-7.80 (m, 1H), 7.52-7.31 (m, 1H), 6.51 (t, J=5.8 Hz, 1H), 4.74 (s, 2H), 4.64 (d, J=5.8 Hz, 2H), 2.64 (s, 3H), 2.48 (s, 3H), 2.32 (s, 3H); MS (ES+) m/z 426.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.P(Cl)(Cl)([Cl:30])=O>O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:30])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Temperature: 100 °C

Procedure:
A 2-liter round bottom flask was charged with 7-(benzyloxy)-3-nitroquinolin-4-ol (100.0 g, 0.3 mol) and N,N-dimethylformamide (DMF) (650 mL). Phosphorous oxychloride (62.1 g, 37.7 mL, 1.2 equivalents (eq)) was slowly added dropwise. The resulting mixture was heated at 100° C. for 10 minutes, and then allowed to cool to 39° C. The reaction mixture was poured over ice (3 L). A brown precipitate formed. The mixture was diluted with water (1 L) and stirred to break up the precipitate. The precipitate was collected by vacuum filtration. The filter cake was washed with water (2 L) and air-dried on vacuum filter for 1 hour. The solid was dissolved in dichloromethane and placed in a separatory funnel. The water was removed, and the dichloromethane solution was dried over magnesium sulfate. The solution was then filtered through filter agent to provide a solution of 7-(benzyloxy)-4-chloro-3-nitroquinoline in dichloromethane (approximately 1700 mL).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12](C(O)=O)[CH2:13][O:14][C:15]([C@@H:17]1[CH2:21][C@@H:20]([CH3:22])[CH2:19][N:18]1[C:23](=[O:49])[C@@H:24]([NH:26][C:27]([C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[C:35]([C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42](OC(C)(C)C)=[O:43])=[O:36])=[O:28])[CH3:25])=[O:16])=[O:10])C1C=CC=CC=1.F[C:54]1[C:59](O)=[C:58](F)[C:57](F)=[C:56](F)[C:55]=1F.C(Cl)CCl>ClCCl>[CH3:22][C@H:20]1[CH2:19][N:18]2[C@H:17]([C:15](=[O:16])[O:14][CH2:13][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:42](=[O:43])[N:38]3[C@H:37]([C:35](=[O:36])[N:30]4[C@H:29]([C:27](=[O:28])[NH:26][C@@H:24]([CH3:25])[C:23]2=[O:49])[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:41][CH2:40][CH2:39]3)[CH2:21]1
Reactant: C[C@@H]1C[C@@H](C(=O)OC[C@H](NC(=O)OCc2ccccc2)C(=O)O)N(C(=O)[C@H](C)NC(=O)[C@@H]2CCCCN2C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)C1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@@H]1C[C@H]2C(=O)OC[C@H](NC(=O)OCc3ccccc3)C(=O)N3CCC[C@H]3C(=O)N3CCCC[C@H]3C(=O)N[C@@H](C)C(=O)N2C1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
3.95 g (5.41 mm ol) of the acid from example 25A and 3.98 g (21.65 mmol) of pentafluorophenol are dissolved in dichloromethane (13 ml) and cooled to −20° C. under argon. 1.14 g (5.95 mmol) of EDC are added, and the reaction mixture is stirred overnight with slow warming to RT. The reaction solution is concentrated to dryness and the residue is treated at 0° C. with 4N hydrogen chloride solution in dioxane (80 ml). The mixture is stirred for 3 h and the solvent is subsequently removed in vacuo. The residue is dissolved in dichloromethane (about 900 ml) and slowly added dropwise at RT to a vigorously stirred two-phase mixture of 1N aqueous sodium hydrogencarbonate solution (700 ml) and dichloromethane (1200 ml). The reaction mixture is stirred overnight. The phases are separated, the aqueous phase is extracted three times with dichloromethane and the combined organic phases are dried over sodium sulfate, filtered and concentrated to dryness. The residue (2.7 g of yellow hard foam) is purified by chromatography in 3 portions by means of preparative RP-HPLC using acetonitrile/water (gradient). 1.98 g (60% of th.) of the product are obtained.