Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:18]=[C:17]([NH:19][S:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)(=[O:22])=[O:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[OH:28])(C)(C)C>O1CCOCC1.Cl>[OH:28][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]([NH:19][S:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)(=[O:22])=[O:21])=[CH:18][C:9]=1[O:8][CH2:7][C:6]([OH:29])=[O:5]
Reactant: CC(C)(C)OC(=O)COc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)COc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl-2-(1-hydroxy-4-(thiophene-2-sulfonamido)naphthalen-2-yloxy)acetate (9d, 0.025 g, 0.057 mmol) was dissolved in 4 ml of 1:1 ratio of dioxane and concentrated hydrochloric acid and stirred at r.t. for 3 h. The mixture solution changed from clear to white cloudy. The solvent was evaporated under reduced pressure. The solid was washed with DCM and hexane separately to get pure product as a gray solid, 97%, m.p.=155-157° C.
Reaction SMILES: [C:1](=[O:3])=O.Cl.[CH2:5]([O:7][C:8](=[O:14])[C@H:9]([CH:11]([CH3:13])[CH3:12])[NH2:10])[CH3:6].C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>ClCCl.C(OCC)C>[N-:10]=[C:1]=[O:3].[CH2:5]([O:7][C:8](=[O:14])[C@H:9]([CH:11]([CH3:13])[CH3:12])[NH2:10])[CH3:6]
Reactant: O=C=O
Agent: CCOC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: [N-]=C=O

Procedure:
Carbon dioxide was added subsurface to a dichloromethane (40 mL) solution containing valine ethyl ester hydrochloride salt (0.025 mol, 4.54 g), N-cyclohexyl-N',N',N",N"-tetraethylguanidine (0.023 mol, 5.8 g) and triethylamine (0.10 mol, 10.0 g) at -10° C. (ice and salt bath) for 40 min at a pressure of 0 psig. The reaction mixture was transferred rapidly via cannula under carbon dioxide to the precooled solution of phosphorus oxychloride (0.025 mol, 3.9 g) in 40 mL dichloromethane. After stirring for 20 min at -10° C. diethylether (50 mL) was added to the reaction mixture. A white ppt formed and was filtered off. The filtrate was concentrated in vacuo and the residue was extracted with 3×25 mL diethylether. The ether layers were concentrated and the residue was distilled under vacuum collecting product, valine ethyl ester isocyanate, at 37°-40° C. (2.917 g, 68%) of 99% purity as judged by GC. IR (neat) 2253, 1740 cm-1. 1H NMR (CDCl3) δ 4.28-4.20 (m, 2H), 3.88 (d, 1H, J=3.8), 2.24-2.18 (m, 1H), 1.29 (t, 3H, J=7.2), 1.00 (d, 3H, J=6.9), 0.89 (d, 3H, J=6.8) ppm.
Reaction SMILES: [O:1]=[C:2]1[N:7](CC2C=CC(OC)=CC=2)[C:6]2[CH:17]=[CH:18][C:19]([CH2:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][C:5]=2[O:4][CH2:3]1>C(O)C.[Pd]>[O:1]=[C:2]1[NH:7][C:6]2[CH:17]=[CH:18][C:19]([CH2:21][CH:22]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][C:5]=2[O:4][CH2:3]1
Reactant: CCOC(=O)CC(Cc1ccc2c(c1)OCC(=O)N2Cc1ccc(OC)cc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(Cc1ccc2c(c1)OCC(=O)N2)c1ccccc1

Procedure:
To a solution of ethyl 4-[3-oxo-4-[p-methoxybenzyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-3-phenylbutanoate in ethanol is added 10% Pd/C and the compound hydrogenated in a Parr apparatus. Evaporation of the solvent yields the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[C:4]1[CH:5]=[CH:6][C:7]([F:19])=[C:8]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[OH:11])[CH:9]=1.C(N(CC)CC)C.O>ClCCl.CS(C)=O>[CH3:21][O:20][CH:3]([O:2][CH3:1])[C:4]1[CH:5]=[CH:6][C:7]([F:19])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:11])[CH:9]=1
Reactant: COC(OC)c1ccc(F)c(C(O)c2cccc(F)c2)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(OC)c1ccc(F)c(C(=O)c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
In a mixture of 80 ml of dichloromethane and 80 ml of dimethylsulfoxide were dissolved 24.3 g of [5-(dimethoxymethyl)-2-fluorophenyl](3-fluorophenyl)methanol and 27.6 ml of triethylamine, and a suspension of 26.3 g of sulfur trioxide-pyridine complex in 30 ml dimethyl sulfoxide was added, followed by stirring at room temperature for 1 hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:15), to give 18.7 g of the title compound as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]([C:35]1[CH:40]=[CH:39][C:38]([O:41][S:42]([C:45]([F:48])([F:47])[F:46])(=[O:44])=[O:43])=[C:37]([CH3:49])[CH:36]=1)([C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:30]COC)([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])=[C:15]([CH3:34])[CH:14]=1)[CH2:11][CH3:12])[CH3:9]>ClCCl>[CH2:8]([C:10]([C:35]1[CH:40]=[CH:39][C:38]([O:41][S:42]([C:45]([F:46])([F:47])[F:48])(=[O:44])=[O:43])=[C:37]([CH3:49])[CH:36]=1)([C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([OH:30])([C:26]([F:27])([F:28])[F:29])[C:22]([F:23])([F:24])[F:25])=[C:15]([CH3:34])[CH:14]=1)[CH2:11][CH3:12])[CH3:9]
Reactant: CCC(CC)(c1ccc(/C=C/C(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of trifluoromethanesulfonic acid 4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl ester (Example 26-(3); 2.41 g, 3.79 mmol) in dichloromethane (20 mL) at room temperature, and the mixture was stirred for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 70:30) to give the target product as a colorless oil (2.24 g, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[C:24]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)=[N:23][CH:22]=[C:21](Cl)[N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>CN1CCN(C)C1=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[C:24]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)=[N:23][CH:22]=[C:21]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)[N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2nc(Cl)cnc2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCN(C)C1=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2nc(N3CCOCC3)cnc2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Temperature: 100 °C
Reaction time: 72 h

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(6-chloropyrazin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (300 mg) is dissolved in 1,3-dimethylimidazolidinone (2 ml), then thereto are added diisopropylethylamine (0.13 ml) and morpholine (0.6 ml), and the mixture is heated to 100° C. and stirred for 3 days. After adding distilled water, the mixture is extracted with ether. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (NH-silica gel; hexane: ethyl acetate=9:1→7:3) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[6-(morpholin-4-yl)pyrazin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (223.2 mg). MS (m/z): 669 [M+H]+
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:28][C@H:8]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([OH:29])[CH2:6]1)=[N+:2]=[N-:3].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl.O>[CH3:37][S:38]([O:29][C@@H:7]1[CH2:6][C@@H:5]([CH2:4][N:1]=[N+:2]=[N-:3])[O:28][C@@H:8]1[CH2:9][O:10][Si:11]([C:24]([CH3:25])([CH3:26])[CH3:27])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:40])=[O:39]
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@H](CN=[N+]=[N-])C[C@H]1O)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OC[C@H]1O[C@H](CN=[N+]=[N-])C[C@H]1OS(C)(=O)=O)(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a 0° C. solution, under argon, of 3.78 g of product from Example 276 in 20 ml of dry methylene chloride is added, dropwise, 1.02 g of triethylamine and 1.16 g methanesulfonylchloride. The reaction mixture is stirred for 3 hours, diluted with water, extracted with diethyl ether, concentrated in vacuo, and purified by chromatography (silica gel: 0-50% ethyl acetate/hexane) to give 4.30 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Br[CH2:31][C:32]1[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:34][CH:33]=1.C(CN)O>>[C:39]([O:38][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:19]2[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)/[S:21][C:20]2=[O:22])=[CH:44][CH:43]=1)([CH3:42])([CH3:41])[CH3:40]
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Solvent: NCCO
Product: CC(C)(C)OC(=O)c1ccc(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)cc1

Procedure:
4-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}benzoic acid tert-butyl ester was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and tert-butyl 4-bromomethyl-benzoate (in place of tert-butyl bromoacetate) following General Procedure I, and converted to the corresponding ethanolamine salt following General Procedure T.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1)=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:18][C:15]1[CH:14]=[C:13]([C:6]2[C:7](=[O:12])[NH:8][C:9]3[C:4]([C:5]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:3][C:2]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:11][CH:10]=3)[O:17][N:16]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(-c2c(-c3ccccc3)c3cc(Br)ccc3[nH]c2=O)on1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(-c2c(-c3ccccc3)c3cc(-c4ccccc4)ccc3[nH]c2=O)on1
Temperature: 80 °C

Procedure:
A flask was charged with 6-bromo-3-(3-methyl-isoxazol-5-yl)-4-phenyl-1H-quinolin-2-one (25 mg, 0.066 mmol)(Example 39), phenyl boronic acid (12 mg, 0.098 mmol), Pd(PPh3)4 (7 mg, 10 mol %), 2 M Na2CO3 (0.25 mL), EtOH (0.25 mL), and toluene (0.5 mL) and heated for 2 hrs at 80° C. The reaction was diluted with EtAc (10 mL) and washed with brine (2×10 mL). The organic layer was concentrated and the title product (12 mg, 50%) eluted from a 5 g SPE with 50% EtAc/hex. 1H NMR (400 MHz, CDCl3) δ 11.42 (s, 1H), 7.82 (dd, 1H), 7.20 (m, 12H), 6.52 (s, 1H), 2.24 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C25H18N2O2 378.1, found 379.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[C:27](Cl)(=[O:30])[CH2:28][CH3:29].C(N(CC)CC)C>>[CH3:26][C:24]1[CH:23]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:25]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)N2CCNCC2)c1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCN(S(=O)(=O)c2cc(C#N)ccc2Oc2cc(C)cc(C)c2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of compound 24 (0.102 g, 0.27 mmol) in CH2Cl, (2 mL) was added propionyl chloride (0.035 g, 0.38 mmol) and triethylamine (0.039 g, 0.38 mmol). The reaction mixture was stirred at room temperature for 20 hrs, whereupon the starting material was consumed (TLC, 1% MeOH in CH2Cl2). The reaction mixture was concentrated in vacuo, redissolved in a minimal amount of CH2Cl2, and chromatographed over normal phase silica (MeOH/CH2Cl2). The fractions containing the desired product were combined and concentrated in vacuo to yield a white powder, which was then triturated with CH2Cl2/diisopropyl ether and vacuum filtered to yield the desired product as a powder. The powder was redissolved in CH2Cl2 and chromatographed for a second time over normal phase silica (MeOH/CH2Cl2). The fractions containing the desired product were combined and concentrated in vacuo to yield a white powder. The powder was triturated with diisopropyl ether and vacuum filtered to yield compound 57 (0.061 g, 52.1% yield, 96.6% HPLC purity). 1H NMR (500 MHz, CDCl3): 8.27 (d, J=2 Hz, 1H), 7.67 (dd, J1=9 Hz, J2=2 Hz, 1H), 6.94 (s, 1H), 6.90 (d, J=9 Hz, 1H), 6.68 (s, 2H), 3.71 (m, 2H), 3.54 (m, 2H), 3.35 (m, 4H), 2.34 (s, 6H), 2.32 (m, 2H), 1.13 (t, J=7 Hz, 3H); MS (ESI, EI+): m/z=428 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[C:24]=1[C:25](Cl)=[O:26]>C1COCC1>[F:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[C:24]=1[C:25](=[O:26])[CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:11]
Reactant: COc1ccc(C(C)=O)cc1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CC(=O)c2c(F)cc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.1 %

Procedure:
In a 100 mL 3-neck round-bottomed flask fitted with condenser and magnetic stirrer were placed dry THF (20 mL) and p-methoxy acetophenone (0.386 g, 2.57 mmol) under nitrogen. To this solution, LHMDS (2.69 mL as a 1M solution in THF, 2.57 mmol) was added drop wise at 25° C. After completion of addition, the mixture was stirred for 30 min at rt, then 2,4,6-trifluoro-benzoyl chloride (0.5 g, 2.57 mmol) in THF (5 mL) was added slowly at rt via syringe. The reaction mixture was stirred overnight at rt. The reaction was quenched with saturated NH4Cl solution (10 mL). The organic layer was separated and aqueous layer was extracted with EtOAc. The combined organic layer was dries over Na2SO4, concentrated to give crude product, which was purified by column chromatography using 20% EtOAc in hexane, to give 215 mg of 1-(2,4,6-trifluoro-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (27%). 1-(2,4,6-trifluoro-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (100 mg) in DMSO (2 mL) was heated at 100-110° C. for 1 h. Then the reaction mixture was cooled to rt and diluted with water. The product was filtered and dried to give 62 mg of 5,7-difluoro-2-(4-methoxy-phenyl)-chromen-4-one (68%). MS (ES) m/z: 289.07 (M+1); 19F-NMR (DMSO-d6): δ −101.9, −109.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2ccc(F)cc2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2ccc(F)cc2)cnc1N
Yield: 93.9 %

Procedure:
A solution of 2.59 g of 2-amino-5-(4-fluorophenyl)-3-nitro-pyridine (compound G1) in 36 ml ethanol is treated with 12.9 g of SnCl2.2H2O at 90° C. for 24 h under a nitrogen atmosphere. Thereafter, the solution is concentrated to dryness. The residue is dissolved in 600 ml H2O and adjusted to pH 8 using a 1.0 M solution of aqueous sodium hydroxide. Subsequently, the aqueous layer is extracted six times each with 50 ml of ethyl acetate. The combined organic phases are extracted once with 100 ml of brine, dried using magnesium sulfate, filtered with suction, and evaporated to dryness to yield 2.12 g of the pure title compound of m.p. 261° C. MS: 204.3 (MH+). TLC: Rf=0.50 (dichloromethane/methanol 5:1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[CH2:17][C:18]1[NH:23][C:22](=[O:24])[C:21]([CH:25]([NH:28][C:29](=[O:43])[CH:30]([CH:40]([OH:42])[CH3:41])[CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:26][CH3:27])=[N:20][N:19]=1)[CH3:12].C(N(C(C)C)C(C)C)C>>[C:40]([CH:30]([CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:29]([NH:28][CH:25]([C:21]1[C:22](=[O:24])[NH:23][C:18]([CH2:17][C:16]2[CH:44]=[CH:45][C:46]([O:47][CH3:48])=[C:14]([O:13][CH2:11][CH3:12])[CH:15]=2)=[N:19][N:20]=1)[CH2:26][CH3:27])=[O:43])(=[O:42])[CH3:41]
Reactant: CCOc1cc(Cc2nnc(C(CC)NC(=O)C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)ccc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(Cc2nnc(C(CC)NC(=O)C(CCCc3ccccc3)C(C)=O)c(=O)[nH]2)ccc1OC

Procedure:
Analogously to Example 40A, 12.9 mg (0.10 mmol) of oxalyl chloride, 9.91 mg (0.13 mmol) of dimethyl sulphoxide, 43.0 mg (0.08 mmol) of N-{1-[3-(3-ethoxy-4-methoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}2-(1-hydroxyethyl)-5-phenylpentanamide and 32.8 mg (0.25 mmol) of N-ethyldiisopropylamine are reacted to give 2-acetyl-N-{1-[3-(3-ethoxy-4-methoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}-5-phenylpentanamide.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.Cl.[CH2:11]([C@H:13]([NH2:19])[CH2:14][O:15][N+:16]([O-:18])=[O:17])[CH3:12].C(OP(C#N)(=O)OCC)C.C(OC(C)C)(C)C>O1CCCC1.CC(C)=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:11]([C@H:13]([NH:19][C:7]([C@@H:5]1[CH2:4][S:3][C:2](=[O:1])[NH:6]1)=[O:9])[CH2:14][O:15][N+:16]([O-:18])=[O:17])[CH3:12]
Reactant: CC[C@H](N)CO[N+](=O)[O-]
Reactant: O=C1N[C@H](C(=O)O)CS1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC[C@@H](CO[N+](=O)[O-])NC(=O)[C@@H]1CSC(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
In 10 ml of dry tetrahydrofuran were suspended 0.50 g of (4R)-2-oxothiazolidine-4-carboxylic acid and 0.70 g of (1S)-1-ethyl-2-nitroxyethylamine hydrochloride, 1.40 ml of triethylamine and 0.62 ml of diethylcyanophosphoric acid were added thereto, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography employing cyclohexane-ethyl acetate (1:2) as an eluent to obtain a pale yellow oil. Isopropyl ether was added to the oil to obtain a pale yellow powder. The powder was dissolved in 10 ml of acetone and further 5 ml of ethyl acetate was added thereto. The acetone was distilled off under reduced pressure and the mixture was left to stand at room temperature to obtain 0.24 g of the desired compound as colorless columnar crystals.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11](C(OCCC(C)(C)C)=O)[C:10]([C:24]([O-:26])=[O:25])=[CH:9]2.Cl.[CH2:28]1COC[CH2:29]1>O1CCOCC1>[CH3:1][S:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:24]([O:26][CH2:28][CH3:29])=[O:25])=[CH:9]2
Reactant: C1CCOC1
Reactant: CSCCOc1ccc2c(c1)cc(C(=O)[O-])n2C(=O)OCCC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2cc(OCCSC)ccc2[nH]1
Reaction time: 5 h
Yield: 61 %

Procedure:
A solution of 1-(1,1-dimethylethyl)2-ethyl 5-{[2-(methylthio)ethyl]oxy}-1H-indole-1,2-dicarboxylate (0.500 g, 1.31 mmol) in THF was treated with 4 M HCl in dioxane and stirred for 5 hours. The solvent was evaporated to an oil and the residue was dissolved in DCM and TFA was added and stirred until no starting material remained as evident by TLC. The mixture was evaporated to a solid and purification was accomplished by silica gel column chromatography (0-50% EtOAc/hexanes) to afford the title compound (0.228 g, 61%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.21-9.37 (m, 1H), 7.32 (d, 1H), 7.12-7.16 (m, 1H), 7.09 (d, 1H), 7.00 (dd, 1H), 4.42 (q, 2H), 4.19 (t, 2H), 2.91 (t, 2H), 2.22 (s, 3H), 1.42 (t, 3H). LCMS: m/z=279.9 (M+1).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=2)[N:3]=1.[C:20](B1OC(C)(C)C(C)(C)O1)([CH3:22])=[CH2:21]>>[C:20]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=2)[N:3]=1)([CH3:22])=[CH2:21]
Reactant: Cc1cc(Nc2cc3cc(O)ccc3c(Br)n2)n[nH]1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Product: C=C(C)c1nc(Nc2cc(C)[nH]n2)cc2cc(O)ccc12

Procedure:
Similar procedure as described in example 131 was used, starting from 1-Bromo-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol and isopropenylboronic acid pinacol ester to give 1-Isopropenyl-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol. LC-MS m/e 281(MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[OH:17].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:10])=[O:9])=[CH:4][C:3]=2[OH:17])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(=O)(=O)c3ccccc3)cc2O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 112.8 %

Procedure:
To a solution of 2-amino-5-benzenesulfonyl-phenol (1.00 g., 4.016 mmol) in 20 mL dichlormethane was added 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.880 g, 4.418 mmol) followed by sodium triacetoxyborohydride (1.78 g, 8.43 mmol) and the resulting suspension was stirred at room temperature under nitrogen for 24 hours. The reaction mixture was washed twice with 50 mL water, once with 50 mL brine, then dried over sodium sulfate and concentrated in vacuo. The resulting crude solid was purified by flash chromatography (20-30% ethyl acetate in hexanes) to give 1.823 g (4.53 mmol, 94%) of 4-(4-benzenesulfonyl-2-hydroxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a foam. MS: 333 (M−CO2tBu+H)+, 377 (M−tBu+H)+.