Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]1CCC(=O)CC1)(C)([CH3:3])[CH3:2].C(N(S(F)(F)[F:18])CC)C.[F:21][C:22]1[CH:27]=[CH:26][C:25](OC)=[CH:24][CH:23]=1>C(Cl)Cl>[F:21][C:22]1([F:18])[CH2:27][CH2:26][CH:25]([C:1]([CH3:5])([CH3:3])[CH3:2])[CH2:24][CH2:23]1
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: COc1ccc(F)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C1CCC(F)(F)CC1
Yield: 67 %

Procedure:
A reaction of 4-t-butylcyclohexanone (2 mmol) with diethylaminosulfur trifluoride (3.0 mmol) in CH2Cl2 (10 mL) containing Znl2 (0.3 mmol) at room temperature gave a 99% conversion of starting material to products and a 67% yield of 1,1-difluoro-4-t-butylcyclohexane after 6 h. as determined by NMR (4-fluoroanisole as internal standard).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:54][C:55]1[CH:79]=[CH:78][C:77]([N:80]2[CH2:85][CH2:84][CH2:83][CH2:82][CH2:81]2)=[CH:76][C:56]=1[C:57]([NH:59][C:60]1[CH:65]=[N:64][C:63]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([C:72]([F:75])([F:74])[F:73])[CH:67]=2)=[CH:62][N:61]=1)=[O:58]>CN(C)C=O.C(OCC)(=O)C>[N:80]1([C:77]2[CH:78]=[CH:79][C:55]([NH:54][C:14]([C:13]3[CH:12]=[C:11]([CH:19]=[CH:18][CH:17]=3)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:20])=[O:16])=[C:56]([C:57](=[O:58])[NH:59][C:60]3[CH:65]=[N:64][C:63]([C:66]4[CH:71]=[CH:70][CH:69]=[C:68]([C:72]([F:73])([F:74])[F:75])[CH:67]=4)=[CH:62][N:61]=3)[CH:76]=2)[CH2:81][CH2:82][CH2:83][CH2:84][CH2:85]1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2cccc(C(F)(F)F)c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3cccc(C(F)(F)F)c3)cn2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 108.1 %

Procedure:
To 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid (53.7 mg, 0.18 mmol, 0.80 equiv) in N,N-dimethylformamide (2 mL) was added HATU (172.3 mg, 0.45 mmol, 2.00 equiv) and DIEA (117.0 mg, 0.91 mmol, 4.00 equiv) followed by the dropwise addition of a solution of 2-amino-5-(piperidin-1-yl)-N-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)benzamide 6d (100 mg, 0.23 mmol, 1.00 equiv) in N,N-dimethylformamide (1 mL). The resulting solution was stirred for 4 h at 25° C. in an oil bath. The resulting solution was diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 1×20 mL of water and 3×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 140 mg of crude product as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH:42]([NH:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([CH3:44])[CH3:43]>C(Cl)Cl>[CH:42]([N:45]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:8]([C:5]1[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:26])([F:27])[F:28])[CH:19]=2)(=[O:16])=[O:17])[CH2:12][O:13][CH3:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:44])[CH3:43]
Reactant: CC(C)Nc1ccccc1
Reactant: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCN(c1cc(Cl)cnc1C(=O)N(c1ccccc1)C(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid (229 mg, 0.50 mmol) in anhydrous methylene chloride (5 mL) was added oxalyl chloride (1.0 mL) at room temperature. The reaction was heated at reflux for 2 h, then concentrated to dryness. The residue was dissolved in methylene chloride (4 mL) and this solution was added dropwise to a magnetically stirred solution of triethylamine (1.0 mL) and N-isopropylaniline (135 mg, 1.00 mmol) in methylene chloride (2 mL). The reaction mixture was stirred 1 h (the reaction was monitored by LCMS), then quenched with saturated aqueous NH4Cl (50 mL), and the aqueous layer extracted with EtOAc (3×75 mL). The combined extracts were washed with 0.5 M HCl (50 mL), washed with water (50 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by chromatography on silica gel using a gradient of ethyl acetate-hexane (0:100 to 100:0) to afford pure 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid N-isopropyl-N-phenylamide. MS m/z 576.0 (M+H); 544.0 (M+H-MeOH).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:8][CH2:7][C@@H:6]([N:9]2[C:13]3=[C:14]4[S:20][CH:19]=[CH:18][C:15]4=[N:16][CH:17]=[C:12]3[N:11]=[C:10]2[C@H:21]([OH:23])[CH3:22])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>C(Cl)Cl.C1(C)C=CC=CC=1>[OH:23][C@@H:21]([C:10]1[N:9]([C@@H:6]2[CH2:7][O:8][C@@H:3]([CH2:2][NH:1][C:32](=[O:33])[O:34][CH:35]([CH3:37])[CH3:36])[CH2:4][CH2:5]2)[C:13]2=[C:14]3[S:20][CH:19]=[CH:18][C:15]3=[N:16][CH:17]=[C:12]2[N:11]=1)[CH3:22]
Reactant: CC(C)OC(=O)Cl
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)OC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)NC[C@H]1CC[C@H](n2c([C@@H](C)O)nc3cnc4ccsc4c32)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
To a solution of (1R)-1-{1-[(3S,6R)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol (11 mg, 0.032 mmol) and triethylamine (22 μL, 0.16 mmol) in methylene chloride (1 mL) was added 1.0 M isopropyl chloroformate in toluene (39 μL). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (0.9 mg, 7%). LCMS calculated for C20H27N4O4S (M+H)+: m/z=419.2. Found: 419.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl[C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[CH2:9][CH2:10][O:11][C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1
Reactant: Cc1ccc(CCO)cc1F
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: Cc1ccc(CCOc2cc3n(c(=O)n2)CCCN3C)cc1F

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E11 starting from of 2-(3-fluoro-4-methylphenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH3:15])=[N:12][CH:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:16][OH:17].C(Cl)Cl>>[CH3:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH3:15])=[N:12][C:11]=2[CH2:16][OH:17])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(Sc2cnc(C)[nH]2)c1
Reactant: CO
Solvent: ClCCl
Product: Cc1cc(C)cc(Sc2[nH]c(C)nc2CO)c1
Yield: 21 %

Procedure:
Heated was a solution of 7.0 g (3.2 mmol)of 5-(3,5-dimethylphenylthio)-2-methyl-1H-imidazole (5b)in 37% aqueous formaline (20 ml)at 120° C. for 15 hours in a sealed tube. The reaction mixture was dissolved in methanol/methylene chloride, and the aqueous layer was separated off. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (methanol:ethyl acetate=2:98), and the crude product was washed with isopropyl ether to obtain 1.7 g of [5-(3,5-dimethylphenylthio)-2-methyl-1H-imidazol-4-yl]methanol (41d)(yield 21%). mp 199-201° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]([CH3:14])([CH3:13])[C:8]([O:10]CC)=[O:9])[CH:6]=1.BrC(C)(C)C(O)=O>>[NH:4]1[CH:3]=[CH:2][CH:6]=[N:5]1.[CH3:14][C:7]([N:5]1[CH:6]=[CH:2][CH:3]=[N:4]1)([CH3:13])[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C(C)(C)n1cc(Br)cn1
Agent: CC(C)(Br)C(=O)O
Product: CC(C)(C(=O)O)n1cccn1
Product: c1cn[nH]c1

Procedure:
Scheme 7 shows the synthesis of ethyl 2-(4-bromo-1H-pyrazol-1-yl)-2-methylpropanoate IV starting from 2-bromo-2-methylpropanoic acid 15. Alkylation of pyrazole with 15 gave 2-methyl-2-(1H-pyrazol-1-yl)propanoic acid 16 (Example 12). Esterification of 16 with sulfuric acid in ethanol gave ethyl 2-methyl-2-(1H-pyrazol-1-yl)propanoate 17 (Example 13). Regiospecific bromination of 17 with N-bromosuccinimide (NBS) gave IV (Example 14). Alternatively, 16 was treated in situ with a brominating reagent such as 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) to give 2-(4-bromo-1H-pyrazol-1-yl)-2-methylpropanoic acid which was esterified to give IV, where R is ethyl. Other esters can also be prepared, such as methyl, iso-propyl, or any alkyl, benzyl or aryl ester.
Reaction SMILES: [N:1]#[C:2][NH2:3].[C:4](OCC)(=[S:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Na].Cl[CH2:17][C:18]#[N:19]>C(O)C>[C:5]1([C:4]2[S:11][C:17]([C:18]#[N:19])=[C:2]([NH2:3])[N:1]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: N#CCCl
Reactant: CCOC(=S)c1ccccc1
Reactant: N#CN
Agent: [Na]
Solvent: CCO
Product: N#Cc1sc(-c2ccccc2)nc1N
Temperature: 78 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
21 parts of cyanamide and 83 parts of ethyl thiobenzoate are successively introduced into a solution of 12.5 parts of sodium in 260 parts of ethanol, and the mixture is refluxed for one hour at 78° C. It is then left to stand for 12 hours, 40 parts of chloroacetonitrile are added, and the reaction mixture is refluxed for one hour at 78° C. The product is precipitated by means of 300 parts of water, and filtered off. 78 parts of 2-phenyl-4-amino-5-cyano-thiazole (78% of theory) of melting point 178°-179° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH3:20])[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:21]=[C:22]([Cl:26])[C:23]([Cl:25])=[CH:24][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(CC(O)=O)=O>C(O)C.CO.O>[Br:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH3:20])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:21]=[C:22]([Cl:26])[C:23]([Cl:25])=[CH:24][C:4]=2[N:3]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Agent: CC(=O)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: C[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 47.5 %

Procedure:
2-Bromo-5,6-dichloro-1-(2,3-di-O-acetyl-5deoxy-beta-D-ribofuranosyl)-1H-benzimidazole (7.70 g, 16.52 mmol) was dissolved in ethanol (100 mL) and methanol (100 mL). A solution of sodium carbonate (1.75 g, 16.52 mmol) in water (30 mL) was added to the diacetate solution. The resulting mixture was stirred at rt for 17 h. The reaction mixture was concentrated, dissolved in ethyl acetate (125 mL) and extracted with water (3×50 mL). The ethyl acetate layer was dried with magnesium sulfate (anhyd), filtered, and evaporated. The crude residue was purified on a silica gel column with 1:30 methanol:CH—2Cl2. The resulting product was further purified on a silica gel column with 1:2 ethyl acetate: hexanes, followed by 1:1 ethyl acetate:hexanes to give the title compound (3.00 g, 7.85 mmol, 48%); MS (El): m/z (rel. intensity) 405 (0.05, M++Na); 1H NMR (DMSO-d6) δ8.00 (s, 1H, Ar—H), 7.87 (s, 1H, Ar—H), 5.87 (d, 1H, OH, J=6.7 Hz), 5.53 (d, 1H, OH, J=6.2 Hz), 5.29 (d, 1H, CH, J=5.1 Hz), 4.52 (m, 1H, CH), 4.01 (m, 1H, CH), 3.91 (m, 1H, CH), 1.42 (d, 3H, CH3, J=6.5 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[C:21]([O:30][CH3:31])=[CH:22][C:23]([CH3:29])=[C:24](B(O)O)[CH:25]=1>>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:24]2[CH:25]=[C:20]([F:19])[C:21]([O:30][CH3:31])=[CH:22][C:23]=2[CH3:29])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C)c(B(O)O)cc1F
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Product: COc1cc(C)c(-c2ccnc(OCc3ccccc3)c2[N+](=O)[O-])cc1F
Yield: 83 %

Procedure:
2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et. al. WO 99/01454) (1.0 g, 3.78 mmol) and 5-fluoro-4-methoxy-2-methyl-phenylboronic acid (prepared substantially as described in Speicher, A.; Kolz, J.; Sambanje, R. P. Synthesis, 2002, 17, 2503, which is incorporated herein by reference) (1.2 mg, 5.67 mmol) were treated substantially as described in Part A of Example 19a to give 1.15 g (83%) of 2-benzyloxy-4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridine: MS (EI) m/z 369.3 [(M+H)+, 100].
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2)[CH3:6])=[O:4].C(N(CC)CC)C.[C:35](Cl)(=[O:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>ClCCl>[Cl:27][C:8]1[C:7]([N:5]([C:3](=[O:4])[CH2:2][NH:1][C:35](=[O:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH3:6])=[CH:25][CH:24]=[C:23]([Cl:26])[C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Reactant: CCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Reaction time: 0.5 h

Procedure:
To a mixture of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (100 mg), triethylamine (50 mg) and dichloromethane (2.0 ml) was added heptanoyl chloride (0.05 ml) in an ice-water bath. The mixture was stirred at the same temperature for 30 minutes and washed with water. The organic layer was collected and dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (dichloromethane--methanol) to give 8-[2,6-dichloro-3-[N-(heptanoylglycyl)-N-methylamino]benzyloxy]-2-methylquinoline (130 mg) as a pale yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[C:25]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:26][C:27]([O-])=[O:28].C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH3:22][C:21]([CH3:24])([O:20][C:18]([N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:27](=[O:28])[CH2:26][C:25]([O:31][CH2:32][CH3:33])=[O:30])[CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[O:19])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCCCN(CCCCN)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CC(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(=O)NCCCCN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
After stirring for 0.5 hour, a solution of 1.04 g (3×10-3 mol) of 1,1-dimethylethyl 10-amino-6-[(1,1-dimethylethoxy)carbonyl]-2,6-diazadecanoate in 5 ml of anhydrous chloroform is added dropwise at 0° C. The mixture is stirred for 5 hours at room temperature and 1.06 g (8×10-3 mol) of ethyl malonate and 1.64 g (8×10-3 mol) of 1,3-dicyclohexylcarbodiimide are added. The mixture is stirred for 1 hour and the solvent is evaporated off under reduced pressure. The pasty residue obtained is chromatographed on silica using an ethyl acetate/hexane mixture (1/1 v/v) and then ethyl acetate as the eluent to give 0.95 g (yield: 69%) of the expected product in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([CH:9]=1)[NH2:8].C(O)(C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:34][S:35][C:36]1[O:37][C:38]2[CH:44]=[C:43]([CH:45]=O)[CH:42]=[CH:41][C:39]=2[N:40]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([CH:9]=1)[NH:8][CH2:45][C:43]1[CH:42]=[CH:41][C:39]2[N:40]=[C:36]([S:35][CH3:34])[O:37][C:38]=2[CH:44]=1
Reactant: COc1ccc([N+](=O)[O-])c(N)c1
Reactant: CSc1nc2ccc(C=O)cc2o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])c(NCc2ccc3nc(SC)oc3c2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 102.6 %

Procedure:
To a solution of 5-methoxy-2-nitroaniline (500 mg, 2.99 mmol) and TFA (3.07 mL) in DCM (15 mL) at 5° C. was added NaBH(OAc)3 (1.9 g, 8.97 mmol). To the resulting mixture at 0° C. was added dropwise a solution of 2-(methylthio)benzo[d]oxazole-6-carbaldehyde (630 mg, 3.29 mmol) in DCM (10 mL) and. the mixture was stirred at 0° C. for 2 h. The reaction mixture was diluted with DCM and washed with H2O, aq NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give 5-methoxy-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitro aniline as a light brown solid (1.06 g, 100%). 1H NMR (300 MHz, DMSO-d6) δ 8.90 (t, 1H), 8.04 (d, J=8.7 Hz, 1H), 7.68 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.41 (d, J=7.5 Hz, 1H), 6.28-6.32 (m, 2H), 4.73 (d, J=6 Hz, 2H), 3.72 (s, 3H), 2.74 (s, 3H). LCMS (ESI) m/z 345 (M+H)+.
Reaction SMILES: C(O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:28])C=CC=CC=1.C([N:40]([CH2:43]C)CC)C>C1C=CC=CC=1>[CH2:2]([N:40]=[C:43]=[O:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCN=C=O

Procedure:
A mixture of 2.96 g of stearic acid, 1.87 ml of diphenylphosphoryl azide and 1.21 ml of triethylamine in 90 ml of benzene was heated under reflux for 16 hours. At the end of this time, the mixture was cooled and washed, in turn, with a saturated aqueous solution of sodium bicarbonate and with water. The mixture was then dried, and the solvent was evaporated off under reduced pressure, to give 2.40 g of crude heptadecyl isocyanate.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1N.[N:9]1C=CC=CC=1.[C:15]1([CH2:21][S:22](Cl)(=[O:24])=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC#N>[NH2:9][C:5]1[CH:6]=[C:1]([NH:8][S:22]([CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:24])=[O:23])[CH:2]=[CH:3][CH:4]=1
Reactant: Nc1ccccc1N
Reactant: c1ccncc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CC#N
Product: Nc1cccc(NS(=O)(=O)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.9 %

Procedure:
To a stirred solution of phenylenediamine (6.93 g, 64.08 mmol) in CH3CN was added pyridine (6.05 g, 76.89 mmol). After stirring at room temperature for 10 minutes it was cooled to ˜10° c. and added phenylmethylsulfonyl chloride (6 g, 32.04 mmol). Reaction was further stirred for 14 hours at ambient temperature. Reaction was quenched with aqueous NaHCO3 (saturated) and stirred for 30 minutes. Solid was filtered, and dried under high vacuum to obtain crude N-(3-aminophenyl)-1-phenylmethanesulfonamide 26 (3.1 g, 19% yield). MS (ES) m/z 263 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:5]([CH:6]=[O:7])[C:4]=1[OH:14].[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1>[Cl-:1].[CH:6]([C:5]1[C:4]([OH:14])=[C:3]([CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=1)[CH2:2][P+:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:7]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cc([N+](=O)[O-])cc(CCl)c1O
Solvent: c1ccccc1
Product: O=Cc1cc([N+](=O)[O-])cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1O
Product: [Cl-]
Yield: 86 %

Procedure:
A 4.53 g (20.9 mmoles) quantity of 3-chloromethyl-5-nitrosalicylaldehyde and 5.48 g (20.9 mmoles) of triphenylphosphine were dissolved in 30 ml of benzene and the solution obtained was refluxed with heating for 8 hours. After the reaction, the precipitate obtained was isolated by filtration, washed thoroughly with acetone and dried, giving 8.63 g (yield: 86%) of 3-formyl-2-hydroxy-5-nitrobenzyltriphenylphosphonium chloride as a yellow powder.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.Cl.[NH2:21][OH:22]>CO.O.C(OCC)(=O)C>[F:1][C:2]([F:19])([F:18])[CH:3]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[N:21][OH:22])=[CH:6][CH:5]=1
Reactant: NO
Reactant: CC(C)C(=O)NC(c1ccc(C=O)cc1)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)C(=O)NC(c1ccc(C=NO)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 118.5 %

Procedure:
In a solution of 0.16 g of N-[2,2,2-trifluoro-1-(4-formylphenyl)ethyl]isobutyramide in 4.0 mL of methanol and 1.0 mL of water, 0.075 g of hydroxylamine hydrochloride was added, and stirred at room temperature for 1.5 hour. After the completion of the reaction, the reaction mixture was diluted with 20 mL of ethyl acetate, washed with water (10 mL×1), and the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous magnesium sulfate in that order, and the solvent was distilled off under reduced pressure to obtain 0.20 g of the aimed product as white crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([OH:31])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].Br[CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([O:31][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:32][CH:33]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCOC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (150 mg, 0.34 mmol) in 10 ml of anhydrous DMF were added methyl 4-bromobutanoate (123 mg, 0.68 mmol) and potassium carbonate (94 mg, 0.68 mmol). The mixture was heated at 60 C. for 2 hours, cooled to room temperature, and poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 2˜3% of methanol in chloroform to give 4-methoxy-4-oxobutyl 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate as off-white solid. Yield: 130 mg, 71%.