Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5]C)=[O:4].[OH-].[Na+].[Cl:9][CH2:10][CH2:11][N:12]([CH2:36][CH2:37][Cl:38])[P:13]([N:29]([CH2:33][CH2:34][Cl:35])[CH2:30][CH2:31][Cl:32])(=[O:28])[O:14][CH2:15][CH2:16]OS(C1C=CC(Br)=CC=1)(=O)=O.C1(C)C=CC=CC=1>CO>[Cl:35][CH2:34][CH2:33][N:29]([P:13]([N:12]([CH2:11][CH2:10][Cl:9])[CH2:36][CH2:37][Cl:38])([O:14][CH2:15][CH2:16][S:1][CH2:2][C:3]([OH:5])=[O:4])=[O:28])[CH2:30][CH2:31][Cl:32]
Reactant: COC(=O)CS
Reactant: O=P(OCCOS(=O)(=O)c1ccc(Br)cc1)(N(CCCl)CCCl)N(CCCl)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(O)CSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl

Procedure:
Methyl 2-mercapto-acetate, 2.6 mL (28.5 mmol), was dissolved in 10 mL dry methanol, and sodium hydroxide, 2.24 mL of 25 M solution (56 mmol), and 10 mL methanol were added, followed by 2-(4-bromobenzene-sulfonyloxy)ethyl tetrakis(2-chloroethyl)phosphorodiamidate, 26 mL of 1 M solution in toluene (26 mmol) with stirring, and a further 20 mL methanol. A white precipitate formed immediately, and a further 30 mL methanol was added to enable easy stirring overnight. The solid was filtered, and an additional 2 mL of the sodium hydroxide solution added to the filtrate and stirred for 2 hours. The basic solution was washed with ethyl acetate, then hydrochloric acid added until the solution became cloudy. This solution was extracted three times with ethyl acetate, and the combined ethyl acetate extracts backwashed with water, dilute hydrochloric acid, water, and brine, and then dried over Na2SO4 and concentrated, to give 7.31 g of 2-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]thio]acetic acid as an oil that solidified on standing. The identity was verified by 1H NMR.
Reaction SMILES: [H-].[Na+].[C:3](#[N:5])[CH3:4].[Br:6][C:7]1[N:12]=[C:11]([C:13]([O:15]CC)=O)[CH:10]=[CH:9][CH:8]=1>C1COCC1>[Br:6][C:7]1[N:12]=[C:11]([C:13](=[O:15])[CH2:4][C:3]#[N:5])[CH:10]=[CH:9][CH:8]=1
Reactant: CC#N
Reactant: CCOC(=O)c1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To a suspension of sodium hydride (0.6 g, 60% in oil, 15.7 mmol) in anhydrous THF (70 mL) was added dropwise anhydrous acetonitrile (1.02 mL, 19.6 mmol). The mixture was stirred for about 30 min at rt and then ethyl 6-bromopyridine-2-carboxylate (3.00 g, 13.0 mmol, Apollo Scientific) was added. Subsequently, the resulting mixture was heated under reflux, for about 2 h. After cooling to rt, the volatiles were removed in vacuo and to the residue was added saturated aqueous ammonium chloride (150 mL) and ethyl acetate (600 mL). The resulting layers were separated, and the aqueous layer was extracted with ethyl acetate (2×125 mL). The combined organic layers were washed with water (2×100 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate/hexanes 1:3) to give crude 3-(6-bromo-2-pyridyl)-3-oxo-propanenitrile (1.71 g, 7.6 mmol, 58%), as a pale yellow solid: 1H-NMR (CDCl3, Bruker 400 MHz) δ 4.38 (2 H, s); 7.74-7.84 (2 H, m); 8.08 (1 H, dd, J=2 Hz, 6.5 Hz).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[C:24]1([C:30]2[C:31]([C:36](O)=[O:37])=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:36]([C:31]3[C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:35][CH:34]=[CH:33][N:32]=3)=[O:37])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: O=C(O)c1ncccc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Product: C[C@@]1(c2cc(NC(=O)c3ncccc3-c3ccccc3)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R3=Me) and 3-phenyl-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: [Cl:1][C:2](=[C:6]([Cl:8])[Cl:7])[C:3](Cl)=[O:4].Cl.[NH2:10][CH2:11][C:12]#[N:13].C(Cl)(Cl)Cl>CCCCCC>[C:11]([CH2:12][NH:13][C:3](=[O:4])[C:2]([Cl:1])=[C:6]([Cl:8])[Cl:7])#[N:10]
Reactant: N#CCN
Reactant: O=C(Cl)C(Cl)=C(Cl)Cl
Agent: Cl
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: N#CCNC(=O)C(Cl)=C(Cl)Cl
Yield: 84.6 %

Procedure:
A stirred mixture of 38.8 g (0.2 moles) trichloroacryloyl chloride, 18.5 g. (0.2 moles) aminoacetonitrile hydrochloride and.150 ml chloroform was refluxed for thirty hours, with evolution of gas and dissolution of most of the aminoacetonitrile hydrochloride. The mixture was filtered hot to remove unreacted aminoacetonitrile hydrochloride. The filtrate was stripped to give an oil. The oil was rubbed with hexane and soon solidified to give 36.1 g of the above-identified product as an off-white solid, which liquified at about 56°-59° C. A small portion of product was recrystallized from a benzene-hexane mixture to give a white solid, melting point 58°-60° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:22]=[C:21]([N:23]2[CH:27]=[N:26][N:25]=[N:24]2)[CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]1[CH:11]=[N:10][N:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH:14]([CH3:18])[CH2:13]2)[N:8]=1.CS([C:32]1[N:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N:33]=1)(=O)=O>>[F:2][C:3]1[CH:22]=[C:21]([N:23]2[CH:27]=[N:26][N:25]=[N:24]2)[CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]1[CH:11]=[N:10][N:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:32]3[N:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N:33]=3)[CH:14]([CH3:18])[CH2:13]2)[N:8]=1
Reactant: CS(=O)(=O)c1ncc(C(F)(F)F)cn1
Reactant: CC1CC(n2ncc(COc3ccc(-n4cnnn4)cc3F)n2)CCN1
Agent: Cl
Product: CC1CC(n2ncc(COc3ccc(-n4cnnn4)cc3F)n2)CCN1c1ncc(C(F)(F)F)cn1

Procedure:
The title compound was synthesized from 4-(4-((2-fluoro-4-(1H-tetrazol-1-yl)phenoxy)methyl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidine hydrochloride and 2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine in a manner similar to that described in Example 9. The title compound was isolated as a mixture of four stereoisomers.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11](OC(=O)C)(=O)[CH3:12].C(=O)(O)[O-].[Na+]>>[CH3:11][C:12]1[O:9][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc2ccccc2c(=O)o1

Procedure:
4-iodo-2-methylbenzenamine (24, 233 mg, 1 mmol) on reaction with ethynyl benzene (25a, 102 mg, 1 mmol) by employing Sonagashira coupling conditions using Pd(PPh3)4 (69.3 mg, 0.06 equiv) as catalyst, CuI (22.8 mg, 0.12 equiv) as cocatalyst, butyl amine (261 mg, 3 equiv) as base and ether as solvent and kept the reaction for 6 h. After completion of the reaction as indicated by TLC and the reaction mixture is extracted into ether (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain 2-methyl-4-(phenylethynyl)benzenamine compound (26a) as pure product. Anthranilic acid (27, 137 mg, 1 mmol) on reaction with acetic anhydride at 150° C. and reflux for 30 min, after completion of reaction aqueous sodium bicarbonate solution is added and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo afforded 2-methyl 4H-benzo[d][1,3]oxazin-4-one compound (28) as pure product. To a stirred solution of 2-methyl-4-(phenylethynyl)benzenamine (26a, 207 mg, 1 mmol) with 2-methyl-4H-benzo[α][1,3]oxazin-4-one (28, 161 mg, 1 mmol) in acetic acid and reflux for 8 h. After completion of the reaction as indicated by TLC. The reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4 afforded 2-methyl-3-(2-methyl-4-(phenylethynyl)phenyl)quinazolin-4(3H)-one (29a). Reaction of 2-methyl-3-(2-methyl-4-(phenyl ethynyl)phenyl)quinazolin-4(3H)-one (29a, 350 mg, 1 mmol) with 4-hydroxy benzaldehyde (30b, 122 mg, 1 mmol) was taken in acetic acid Then the resulting mixture was stirred under reflux conditions for 8 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (4b) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O)([CH3:3])[CH3:2].[BH4-].[Na+].C([OH:15])C>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:15])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCCCC1=O
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a cold solution of 1-isopropylpiperidone (purchased at Chemie Brunschwig AG, 100 g, 1.0 eq.) in ethanol (500 mL) was added sodium borohydride (19.3 g, 0.7 eq.) in small portions. The reaction mixture was allowed to warm up to room temperature and was stirred overnight. After concentrating the mixture in vacuo, ice water (1 kg), sodium hydroxide aqueous solution (28% in mass, 0.5 L) and dichloromethane (1 L) were added. The mixture was stirred vigorously for 4 h and the aqueous layer was extracted with dichloromethane. Combined organic layers were washed with brine, dried over sodium sulfate, filtered and purified by fractionated vacuum distillation (20 mbar). One fraction (boiling point 95° C. at 20 mBar) was isolated to yield 61.3 g (60%) of the desired product as colorless oil. MS (m/e): 144.5 (MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]=[C:11]=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:15]=1[C:16]([NH2:18])=[O:17]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([NH:18][C:16](=[O:17])[C:15]2[C:14]([F:13])=[CH:22][CH:21]=[CH:20][C:19]=2[F:23])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: NC(=O)c1c(F)cccc1F
Reactant: O=C=Nc1cc(Cl)c(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(Cl)c(Cl)c1

Procedure:
A solution of 3,4,5-trichloro-phenyl isocyanate (22.3 g), 2,6-difluoro-benzamide (15.7 g) in toluene (200 ml) was heated for eight hours at 90°-95° C. The title compound slowly crystallized out of the initially clear solution and was isolated by suction filtration after cooling of the reaction mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2F)CC1
Reactant: CN(C)CCCl
Product: CN(C)CCn1cc(C(=O)N2CCC(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) (2-chloro-ethyl)-dimethyl-amine gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[C:6]([F:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[CH:17][C:10]=12.Cl[C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:24]=[C:23]([NH2:33])[N:22]=1>>[F:18][C:6]1[CH:5]=[C:4]([NH:19][C:21]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[N:24]=[C:23]([NH2:33])[N:22]=2)[CH:3]=[C:2]([F:1])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[CH:17][C:10]=12
Reactant: Nc1cc(F)c(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: Nc1nc(Cl)cc(-c2ccncc2)n1
Product: Nc1nc(Nc2cc(F)c(Oc3ccnc4[nH]ccc34)c(F)c2)cc(-c2ccncc2)n1

Procedure:
Analogously to example 25, the title compound is synthesized from 100 mg (0.36 mmol) of [3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amine (from example XXXIV) and 87 mg (0.36 mmol) of 4-chloro-6-(4-pyridinyl)-2-pyrimidineamine (from example XXIX). Purification by preparative HPLC gives the product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([CH2:20][OH:21])[C:3]=1[OH:22]>C(Cl)Cl.CO.O=[Mn]=O>[F:1][C:2]1[C:3]([OH:22])=[C:4]([CH:20]=[O:21])[C:5]2[CH:6]=[CH:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(CO)c(O)c(F)cc21
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CO
Product: O=Cc1c(O)c(F)cc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
A solution of 6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol (200 mg, 687 μmol; Intermediate 95) in MeOH (2.14 mL) was treated with 2M NaOH (860 μL) and formaldehyde (2 mL of a 37 wt. % solution in H2O, 26.8 mmol) and heated in an Emrys optimizer (MW) at 120° C. for 5 min. The solvent was removed in vacuo, the residue taken up with H2O and 1M HCl (pH 1), extracted with EtOAc (3×), washed with sat. NaHCO3, brine, dried (Na2SO4) and the solvent removed in vacuo to yield a brownish syrup (265 mg), which was directly used in the oxidation step. A solution of crude 6-fluoro-4-(hydroxymethyl)-1-(phenylsulfonyl)-1H-indol-5-ol (858 μmol) in CH2Cl2/MeOH (4.5+0.1 mL) was treated with MnO2 (1.12 g, 12.9 mmol) and stirred at rt for 30 min. The reaction mixture was filtrated over a plug of SiO2 and it was washed with CH2Cl2 (40 mL) to give the title compound as yellow solid (72 mg). This material was directly used in the next steps.
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[CH:5]1[CH2:24][C:8]2=[CH:9][C:10]3[C:11](=[O:23])[N:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:13](=O)[C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:2][CH3:3].Cl>CC(O)=O.[Zn]>[CH2:25]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:24][C:8]2=[CH:9][C:10]3[C:11](=[O:23])[N:12]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:13][C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:26][CH3:27]
Reactant: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(c1ccccc1)C3=O
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(c1ccccc1)C3

Procedure:
Using procedure 47, 6-(dipropylamino)-6,7-dihydro-2-phenylcyclopent[f]isoindole-1,3(2H,5H)-dione (121, 0.09 g, 0.23 mmol) was reduced with Zinc dust (0.15 g, 2.3 mmol) in glacial HOAc (5 mL). Purification on silica gel, eluting with 3:1 hexane/acetone gave an oil that was converted to an HCl salt and recrystallized from EtOAc/MeOH to give 127 as a white solid (m.p. 248-249° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[OH:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:21])([F:22])[F:23])[CH:13]=1
Reactant: N#Cc1ccc(O)cc1C(F)(F)F
Reactant: O=Cc1ccc(F)c(F)c1
Product: N#Cc1ccc(Oc2ccc(C=O)cc2F)cc1C(F)(F)F

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 4-hydroxy-2-(trifluoromethyl)-benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:10]([O:12][C:13](=[O:23])[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][C:18](=O)[CH2:17]1)[CH3:11].N1CCC[C@H]1C(O)=O>C(O)C>[CH2:10]([O:12][C:13](=[O:23])[CH2:14][CH2:15][CH:16]1[CH2:17][C:18]2=[N:1][C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=[C:19]2[CH2:20][CH2:21]1)[CH3:11]
Reactant: Nc1ncccc1C=O
Reactant: CCOC(=O)CCC1CCCC(=O)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)CCC1CCc2cc3cccnc3nc2C1
Temperature: 25 °C

Procedure:
A solution of 2-amino-pyridine-3-carbaldehyde (1-3) (0.244 g, 2.0 mmol) and 3-(3-oxo-cyclohexyl)-propionic acid ethyl ester (14-1) (0.245 g, 2.00 mmol; for prep., see J. R. Wiseman et. al., J. Am. Chem. Soc., 1970, 92, 956-962) in ethanol (10 mL) was treated with L-proline (0.230 g, 2.00 mmol) and heated at reflux for 12 h. The solution was cooled to ambient temperature and concentrated. The residue was purified by flash chromatography (10% acetone in CH2Cl2) to give 14-2.
Reaction SMILES: C([CH:5]([N:9](C(OC(C)(C)C)=O)[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]3[CH:22]=[C:23](/[CH:25]=[CH:26]/[C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)[N:24]=[C:20]3[C:19]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[N:18][CH:17]=2)=[CH:12][N:11]=1)[C:6]([O-:8])=[O:7])(C)(C)C.C(Cl)Cl.[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]>>[F:56][C:55]([F:58])([F:57])[C:53]([OH:59])=[O:54].[O:40]1[CH2:39][CH2:38][N:37]([C:19]2[C:20]3[N:21]([CH:22]=[C:23](/[CH:25]=[CH:26]/[C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)[N:24]=3)[C:16]([C:13]3[CH:14]=[CH:15][C:10]([NH:9][CH2:5][C:6]([OH:8])=[O:7])=[N:11][CH:12]=3)=[CH:17][N:18]=2)[CH2:42][CH2:41]1
Reactant: CC(C)(C)OC(=O)N(c1ccc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cn1)C(C(=O)[O-])C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNc1ccc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cn1
Yield: 25 %

Procedure:
A solution of compound 13b (200 mg, 0.300 mmol) in DCM/TFA (4:1 v/v, 10 mL) was stirred at rt for 30 min. Solvent was evaporated, and water (5 mL) was added. The resulting solids were collected by filtration and washed with Et2O to obtain the title compound as a yellow solid (40.2 mg, 25% yield). 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 8.44 (d, J=8.7 Hz, 1H), 8.29-8.23 (m, 1H), 8.18 (s, 1H), 8.03-7.91 (m, 4H), 7.85-7.73 (m, 2H), 7.71 (s, 1H), 7.65-7.52 (m, 2H), 7.51-7.40 (m, 1H), 7.38 (s, 1H), 6.85 (d, J=8.4 Hz, 1H), 4.40-4.20 (m, 4H), 4.18-4.01 (m, 2H), 3.93-3.77 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H25N7O3: 508.2 (M+H). Found 508.3.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:24])[C:4]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@H:19]2[CH2:23][CH2:22][CH2:21][NH:20]2)=[O:18])=[CH:12][CH:11]=1)=[N:5][S:6]([CH3:9])(=[O:8])=[O:7].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>C(Cl)Cl>[CH3:2][N:3]([CH3:24])[C:4]([C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]([C@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:33]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)=[O:34])=[O:18])=[CH:14][CH:15]=1)=[N:5][S:6]([CH3:9])(=[O:8])=[O:7]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CN(C)C(=NS(C)(=O)=O)c1ccc(NC(=O)[C@H]2CCCN2)cc1
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=NS(C)(=O)=O)c1ccc(NC(=O)[C@H]2CCCN2C(=O)Nc2ccc(Cl)cc2)cc1
Reaction time: 8 h

Procedure:
Part F: 10.6 mg (0.028 mmol) of the hydrochloride were dissolved in 2 mL of anhydrous CH2Cl2. 2 eq of TEA and 1 eq of p-chlorophenyl isocyanate were added, and the mixture was stirred under N2 atmosphere for 8 h. Volatiles were evaporated. 3 mL of CH2Cl2 were added and the mixture was washed twice with 1 mL of water, dried over MgSO4, and concentrated. The crude product was purified by prep HPLC to give the title compound. 1H NMR (500 MHz, CDCl3) δ 9.76 (s, 1H), 7.45–7.24 (m, 8H), 6.4 (s, 1H), 4.72 (d, J=5 Hz, 1H), 3.6 (m, 1H), 3.45 (m, 1H), 3.25 (s, 3H) 2.93 (s, 3H), 2.84 (s, 3H), 2.65 (m, 1H), 2.3–1.9 (m, 3H), ppm. LC-MS (ESI) 492.15 [M+H]+, tR=4.928 min (Shimadzu Phenomenex S5 ODS 4.6×50 mm Luna flow rate 2.5 ml/mn; detection at 220 nM; Gradient elution 0% to 100% B over 8 min; (A=10% MeOH, 90% H2O, 0.2% H3PO4 & B=90% MeOH, 10% H2O, 0.2% H3PO4). HRMS (ESI) m/z calcd for C22H27N5O4SCl [M+H]+ 492.14724, found 492.1506.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10](Cl)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[F:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=1.N1C=CC=CC=1>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:21][C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:20][N:19]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: Nc1ccc(F)cn1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cc(S(=O)(=O)Nc2ccc(F)cn2)ccc1F

Procedure:
3-Cyano-4-fluorobenzenesulfonyl chloride (5 g, 20 mmol), 5-fluoropyridin-2-amine (3.37 g, 30 mmol) and pyridine (4.87 mL, 60 mmol) in dichloromethane (100 mL) were stirred at room temperature for 2 hours before concentrating in vacuo. The residue was triturated in hydrochloric acid (2 N aqueous solution, 100 mL) for 16 hours. The precipitate was filtered to afford the title compound as a pale pink solid, 6.1 g.
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[N:6]=1.[H-].[Na+].[C:24]1([CH:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:31][CH2:32]I)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C)C=O>O>[C:24]1([CH:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:31][CH2:32][O:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=3[N:6]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ICCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(O)nc1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc2c1CCc1sc(OCCC(c3ccccc3)c3ccccc3)nc1-2
Temperature: 70 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
A mixture of ethyl [(2-hydroxy-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (1.40 g, 4.58 mmol), sodium hydride (60% dispersion in liquid paraffin, 200 mg, 5.00 mmol), 3,3-diphenylpropyl iodide (1.60 g, 5.04 mmol), and N,N-dimethylformamide (30 ml) was stirred at 70° C. for 2 hours. This reaction mixture was poured into water (50 mL) and extracted with 2 portions of ethyl acetate. The pooled organic solution was washed with water, dried over MgSO4, and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=8:1) to provide 810 mg of ethyl [[2-(3,3-diphenylpropyl)oxy-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]acetate. To a solution of this compound (700 mg, 1.40 mmol) in a mixture of tetrahydrofuran (8 mL) and methanol (2 mL) was added 1N-aqueous sodium hydroxide solution (1.4 mL) dropwise and the mixture was stirred at room temperature for 5 minutes. To this reaction mixture was added 1N-hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was recrystallized from ethyl acetate-hexane to provide 500 mg of the title compound. Yield 24%.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[N:23][O:24][CH2:25][CH2:26][Br:27])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=1>O>[CH:1]([NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[N:23][O:24][CH2:25][CH2:26][Br:27])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=1)=[O:3]
Reactant: CCOC(=O)C(=NOCCBr)c1csc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: O=CO
Product: CCOC(=O)C(=NOCCBr)c1csc(NC=O)n1
Temperature: 50 °C
Yield: 61.6 %

Procedure:
A mixture of acetic anhydride (15.9 g.) and formic acid (7.15 g.) was stirred at 50° C. for an hour. After cooling, ethyl 2-(2-aminothiazol-4-yl)-2-(2-bromoethoxyimino)acetate (syn isomer, 25 g.) was added to the solution and stirred at room temperature for an hour. The resultant solution was poured into water and extracted with ethyl acetate twice. The extracts were washed with a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium bicarbonate (three times) and a saturated aqueous solution of sodium chloride in turn, and dried over magnesium sulfate. After concentrating the solution in vacuo, the oily residue was triturated with a mixture of diisopropyl ether and diethyl ether. The precipitates were collected by filtration to give ethyl 2-(2-formamidothiazol-4-yl)-2-(2-bromoethoxyimino)acetate (syn isomer, 16.75 g.), mp. 95° to 98° C.