Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][C:11]([NH2:13])=[O:12])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[CH2:10][C:11]([NH2:13])=[O:12])=[CH:6][CH:7]=2)=[CH:18][CH:17]=1
Reactant: NC(=O)CC(=O)Nc1ccc(O)cc1
Reactant: Clc1ccc(CBr)cc1
Product: NC(=O)CC(=O)Nc1ccc(OCc2ccc(Cl)cc2)cc1
Yield: 18 %

Procedure:
Prepared in analogy to example 8 from N-(4-hydroxy-phenyl)-malonamide and 4-chloro-benzylbromide. Colorless solid. Yield=18%. MS: m/e=319.1 (M++H).
Reaction SMILES: [CH2:1]([CH:7](C(O)=O)[C:8]([OH:10])=[O:9])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]>C(#N)C>[C:8]([OH:10])(=[O:9])[CH2:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: C#CCCCCC(C(=O)O)C(=O)O
Solvent: CC#N
Product: C#CCCCCCC(=O)O

Procedure:
A mixture of 2-(hex-5-ynyl)malonic acid (2.2 g) and cuprous oxide (60mg) in dry acetonitrile (40 ml) was stirred and refluxed, under nitrogen, for 6 hours. The solvent was removed in vacuo. 5% Aqueous hydrochloric acid was added and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were dried over anhydrous magnesium sulphate and the solvent was removed in vacuo. Oct-7-ynoic acid was obtained as an oil (1.5 g) and was used without further purification.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH3:26])[CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CC(Oc1cc(F)ccc1CO)c1ccccc1
Product: CC(Oc1cc(F)ccc1COc1ccnn1-c1cc(C#N)ccn1)c1ccccc1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-fluoro-2-(1-phenylethoxy)phenyl]methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C24H19FN4O2, 415; Found, 415.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23]([O:30][C:31](=[O:34])[CH2:32]Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:32][C:31]([O:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:34])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(O)c2ccccc2n1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC(=O)OCc2ccccc2)c2ccccc2n1
Reaction time: 16 h

Procedure:
To a solution of 10 g of 4-Hydroxy-quinoline-2-carboxylic acid ethyl ester in 300 ml of DMF, 10 g of potassium carbonate and 15.2 g of Bromo-acetic acid benzyl ester was added and stirred for 16 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate (3×150 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with n-heptane/ethyl acetate (2/8). The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 10.2 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@H:19]([OH:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[C:37]([C:45]3[S:46][CH:47]=[CH:48][CH:49]=3)[CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.O.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>[C:13]([O:12][C:11]([N:10]([CH2:18][C@H:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[C:37]([C:45]3[S:46][CH:47]=[CH:48][CH:49]=3)[CH:36]=2)=[CH:3][CH:4]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Br)cc1)C[C@H](O)c1ccccc1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1-c1cccs1
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: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)cc1-c1cccs1
Temperature: 80 °C
Reaction time: 4 h
Yield: 51.4 %

Procedure:
To a solution of tert-butyl [2-(4-bromophenyl)ethyl]-[(2R)-2-hydroxy-2-phenylethyl]carbamate (280 mg) in 1,2-dimethoxyethane (4 ml) was added methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-thienyl)benzoate (275 mg), tetrakis(triphenylphosphine)palladium (62 mg) and aqueous solution of sodium carbonate (2M, 0.7 ml), and the mixture was stirred at 80° C. for 4 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give methyl 4′-[2-[(tert-butoxycarbonyl) [(2R)-2-hydroxy-2-phenylethyl]amino]-ethyl]-3-(2-thienyl)-4-biphenylcarboxylate (191 mg).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([OH:12])([CH2:10][CH3:11])[CH2:8][CH3:9])=[N:4][N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=3)[O:23][C:22](=[O:32])[CH:21]=2)=[CH:16][CH:15]=1.[C:33](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1C=CC=CC=1.C1COCC1>[CH2:8]([C:7]([C:5]1[S:6][C:2]([NH:1][CH2:33][CH2:30][C:26]2[CH:25]=[C:24]3[C:29]([C:20]([C:17]4[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=4)=[CH:21][C:22](=[O:32])[O:23]3)=[CH:28][CH:27]=2)=[N:3][N:4]=1)([OH:12])[CH2:10][CH3:11])[CH3:9]
Reactant: CCC(O)(CC)c1nnc(N)s1
Reactant: O=Cc1ccc2c(-c3ccc(F)cc3)cc(=O)oc2c1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCC(O)(CC)c1nnc(NCCc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)s1
Reaction time: 8 h

Procedure:
A mixture of 3-(5-amino-1,3,4-thiadiazol-2-yl)pentan-3-ol (0.129 g, 0.689 mmol), 4-(4-fluorophenyl)-2-oxo-2H-chromene-7-carbaldehyde (0.200 g, 0.746 mmol) and acetic acid (7.94 μL, 0.138 mmol) in benzene (2.5 mL) was stirred overnight at reflux with a Dean-Stark trap. After cooling, the mixture was diluted in THF (5 mL) and sodium triacetoxyborohydride (0.731 g, 3.45 mmol) was added. The mixture was then stirred at 45° C. for 3 h. The reaction was quenched with a saturated NaHCO3 solution and portioned between EtOAc and water. The organic layer was dried over MgSO4, filtered and concentrated. The crude residue obtained was purified by column chromatography (Hexane-EtOAc-MeOH, 50:50:0 to 0:98:2) to yield the title compound. 1H NMR (400 MHz, acetone-d6): δ 8.7 (m, 2H), 7.5 (s, 1H), 7.45 (s, 1H), 7.4 (m, 3H), 6.35 (s, 1H), 4.75 (s, 2H), 4.5 (bs, 1H), 2.0-1.75 (m, 4H), 0.9 (t, 6H).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:10]([CH3:13])[CH:11]=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7].C(O)(=O)C.O.[NH2:20][NH2:21]>C(O)C>[CH3:9][O:8][C:6](=[O:7])[CH2:5][CH:4]1[CH:10]([CH3:13])[CH:11]=[N:21][NH:20][C:3]1=[O:2]
Reactant: NN
Reactant: COC(=O)CC(C(=O)OC)C(C)C=O
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: COC(=O)CC1C(=O)NN=CC1C
Temperature: 0 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
To this 2-(1-methyl-2-oxo-ethyl)succinic acid dimethyl ester was added ethanol (13 L), which was cooled to 0° C. Acetic acid (1.2 kg, 20 mol) was added with maintaining the temperature. To the reaction mixture was added hydrazine hydrate (1.08 kg, 21.6 mol), which was warmed to room temperature and stirred for 16 h. Ethanol was removed by distillation under reduced pressure, methylene chloride was added to the residue, which was then extracted-dried-concentrated according to a conventional manner to give the title compound (2.80 kg, Yield: 51%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C@@H:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[C:24]([F:31])[CH:23]=1.[CH3:32][PH:33](=[O:35])[CH3:34]>CCCCCC.C(O)(C)C>[Cl:20][C:13]1[C:14]([F:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C@H:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:25]2[CH:26]=[CH:27][C:22]([P:33]([CH3:34])([CH3:32])=[O:35])=[CH:23][C:24]=2[F:31])[CH:3]=1)[CH3:11]
Reactant: C[C@@H](Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: C[PH](C)=O
Reactant: OB(O)c1ccc(Br)cc1F
Solvent: CCCCCC
Solvent: CC(C)O
Product: C[C@@H](Oc1cc(-c2ccc(P(C)(C)=O)cc2F)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared from 5-bromo-3-[(1R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine, 4-bromo-2-fluoro-phenylboronic acid, and dimethylphosphine oxide followed the same procedures as Example 1 Step 1 and Step 3; ESMS: m/z 471 (M+H)+; chiral purity 93.12% (column AD-H 4.6*250 mm 5 um; solvent:hexane/isopropanol).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.Cl.C([O:10][CH:11]([CH3:13])[CH3:12])(C)C.[CH3:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>O1CCCC1>[CH2:16]([C:17]1[CH:3]=[CH:2][CH:1]=[C:19]2[C:18]=1[CH2:13][CH:11]([OH:10])[CH2:12]2)[CH:15]=[CH2:14]
Reactant: CC(C)OC(C)C
Reactant: CCCCCC
Reactant: [Li]CCCC
Agent: Cl
Solvent: C1CCOC1
Product: C=CCc1cccc2c1CC(O)C2
Temperature: -65 °C
Reaction time: 1 h

Procedure:
5.50 g of product obtained above is agitated in 30 ml of anhydrous tetrahydrofuran, cooled to -65° C. and 15.7 ml of a 1.6M butyllithium solution in hexane is introduced over half an hour, followed by agitation for one and a half hours at -65° C. 2.21 g of dry cuprous chloride is added in one lot and the suspension obtained is left for half an hour at -65° C. The latter is added in small amounts and under inert atmosphere to a solution, cooled to -70° C., of 4.20 ml of bromoallyl in 21 ml of tetrahydrofuran and the mixture is left for one hour at -70° C., -65° C. The reaction mixture is poured into 200 ml of 2N hydrochloric acid containing ice and 100 ml of isopropyl ether, then agitated for one hour at ambient temperature. The insoluble part is filtered off, decanted, the organic phase is washed with water, and the aqueous phases are extracted with isopropyl ether. The reunited organic phases are dried, concentrated to dryness, and the residue is chromatographed on silica, eluting with a hexane-ethyl acetate mixture (8-2). 0.89 g of expected product is obtained, and 1.04 g of expected impure product is obtained, which is chromatographed again in the same conditions, and 0.75 g of expected product is recovered.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]3[C:14]([C:15]([O:17]CC)=O)=[N:13][N:12]([C:20]4[CH:28]=[CH:27][C:23]5[O:24][CH2:25][O:26][C:22]=5[CH:21]=4)[C:11]=3[C:4]=2[CH:3]=1.ClC1[N:38]=CC=CC=1C(Cl)=O.C(O)C(N)(CO)CO>N1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]3[C:14]([C:15]([NH2:38])=[O:17])=[N:13][N:12]([C:20]4[CH:28]=[CH:27][C:23]5[O:24][CH2:25][O:26][C:22]=5[CH:21]=4)[C:11]=3[C:4]=2[CH:3]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CCOC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1COc1ccc(N)cc1-2
Agent: NC(CO)(CO)CO
Solvent: c1ccncc1
Product: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1COc1ccc(N)cc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.5 %

Procedure:
To a solution of title material from Example 28 (0.0791 g, 0.226 mmol) in dry pyridine (3 ml), 2-chloronicotinoyl chloride (0.0487 g, 0.2712 mmol) was added. The reaction was stirred at RT overnight. The reaction was quenched with PS-trisamine (4.61 mmol/g, 0.2021 g, 0.9318 mmol) and stirred overnight. The resins were filtrated, washed with pyridine. The combined filtrate and washes were concentrated to dryness. The resulting residue was recrystallized with hot methanol, to give 8-amino-1-[1,3-benzodioxol-5-yl]-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (0.0922 g, 83.3%), which was characterized by 1H NMR, LC/MS (MH+ 489), and HPLC (96.6% purity).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>C1(C)C=CC=CC=1>[F:16][C:17]([F:25])([F:26])[C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccccc1C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccccc1C(F)(F)F)C(=O)OCC
Reaction time: 1 h
Yield: 84.4 %

Procedure:
Diethyl ethoxymethylenemalonate (compound III, 50.4 mL, 249.3 mmol) and 2-(Trifluoromethyl)aniline (compound II, 31 mL, 249.3 mmol) was taken into toluene (250 mL) and refluxed overnight twice. Toluene was evaporated and the resulting liquid was taken into hexane and allowed to sit in a freezer for 1 hour. A white solid crashed out and was filtered and dried to yield 69.73 g (84.4%) of the title compound as white crystals. MS ESI (m/z) 332 ([M+H]+); MS ESI (m/z) 330 ([M−H]−); Anal Calcd. For C15H16F3NO4: C, 54.38; H, 4.87; N, 4.23. Found: C, 54.49; H, 4.68; N, 4.06.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[C:7]2[S:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:35])=[CH:12][C:13]([CH:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:16])=[CH:14][C:4]=2[O:3]1.C(O)(=O)C.[S:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][CH2:49][C:50](O)=[O:51])[CH2:43][CH2:42]1.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:36][C:2]1([CH3:1])[C:7]2[S:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:35][C:50](=[O:51])[CH2:49][CH2:48][CH2:47][N:44]3[CH2:43][CH2:42][S:41][CH2:46][CH2:45]3)=[CH:12][C:13]([CH:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:16])=[CH:14][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCSCC1
Reactant: CCCCCCCCCCCCCCCCCCC(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCS1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCC(C)c1cc(OC(=O)CCCN2CCSCC2)c2c(c1)OC(C)(C)C1=C2CCS1

Procedure:
1,2-Dihydro-7-(2-eicosyl)-9-hydroxy-4-oxo-4H-thieno[2,3-c] [1]benzopyran is reacted with methyl magnesium bromide according to the procedure described hereinabove in Example 8 to give 1,2-dihydro-4,4-dimethyl-7-(2-eicosyl)-9-hydroxy-4H-thieno[2,3-c] [1]benzopyran. The benzopyran is then reacted with γ-thiomorpholinobutyric acid, acetate salt and dicyclohexylcarbodiimide according to the method of Example 10 to yield the desired ester.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:20]=[C:19]2C([C:15](O)=[C:16]([O:23]C(=O)C)[C:17](=O)[N:18]2C)=[CH:13][CH:12]=1)([O-:10])=[O:9].C[O:29]CCl.[CH2:32]1[CH2:36][O:35][CH2:34][CH2:33]1>>[C:16]([CH2:17][NH:18][C:19]1[CH:20]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=[CH:13][C:33]=1[C:34]([O:35][CH2:36][CH3:32])=[O:29])(=[O:23])[CH3:15]
Reactant: C1CCOC1
Reactant: COCCl
Reactant: CC(=O)Oc1c(O)c2ccc([N+](=O)[O-])cc2n(C)c1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1NCC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After addition of 1.87 g of triethylamine (18.5 mmol) to a mixture of 3.2 g of 7-nitro-3-acetoxy-4-hydroxy-1-methyl-2(1H)-quinolinone (11.5 mmol) in 64 ml of THF, 1.89 g of chloromethyl methyl ether (23.0 mmol) was dropped to the mixture, and stirred at room temperature for 1 hour. Filtration of the reaction mixture, the filtrate was concentrated under reduced pressure to give 3.6 g of 7-nitro-3-acetoxy-4-methoxymethoxy-1-methyl-2(1H-quinolinone. In accordance with EXAMPLE 4, the obtained 7-nitro-3-acetoxy-4-methoxymethoxy-1-methyl-2(1H)-quinolinone was used instead of 7-nitro-3-acetoxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 7-nitro-3-hydroxy-4-methoxymethoxy-1-methyl-2(1H)-quinolinone was provided. Then in accordance with EXAMPLE 2, 7-nitro-3-methoxy-4-methoxymethoxy-1-methyl-2(1H)-quinolinone was given by methylation reaction. Finally, to a mixture of the obtained 7-nitro-3-methoxy-4-methoxymethoxy-1-methyl-2(1H)-quinolinone in 40 ml of methanol was added 0.22 g of p-toluenesulfonic acid monohydrate and stirred at room temperature for 1 hour. To the reaction mixture was added water, extracted (yield=54%) residue was crystallized from THF and hexane to yield 1.45 g of the title compound (18). (yield=54%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C@@:11]2([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[C:23]([F:32])[CH:22]=3)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[O:14][CH2:13][CH2:12]2)=[O:9])=[N:6][CH:7]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].CCN(C(C)C)C(C)C>C(Cl)Cl.[OH-].[Na+]>[F:32][C:23]1[CH:22]=[C:21]([C@:11]2([NH:10][C:8](=[O:9])[C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:7][N:6]=3)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[O:14][CH2:13][CH2:12]2)[CH:26]=[CH:25][C:24]=1[O:27][C:28]([F:31])([F:30])[F:29]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(C(=O)N[C@]2(c3ccc(OC(F)(F)F)c(F)c3)CCOc3cccnc32)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C(=O)N[C@]2(c3ccc(OC(F)(F)F)c(F)c3)CCOc3cccnc32)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-5-amino-N-(4-(3-fluoro-4-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)picolinamide (44 mg, 0.098 mmol) in DCM (0.6 mL) were added methanesulfonyl chloride (8.40 μl, 0.128 mmol) and DIEA (0.022 mL, 0.128 mmol). The resulting mixture was stirred at room temperature overnight. A solution of NaOH (10 N, 2 drops) was added, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by prep HPLC (0-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 527.0 (MH+). 1H NMR (400MHz, d4-MeOH) δ: 8.48 (d, J=2.3 Hz, 1H), 8.30 (dd, J=4.5, 1.4 Hz, 1H), 8.05 (d, J=8.6 Hz, 1H), 7.83 (dd, J=8.6, 2.5 Hz, 1H), 7.37-7.62 (m, 4H), 7.25 (d, J=8.6 Hz, 1H), 4.47 (dt, J=11.9, 4.4 Hz, 1H), 4.05-4.26 (m, 1H), 3.12-3.25 (m, 2H), 3.10 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([Cl:11])=[CH:7][N:6]=1)=O.O.[NH2:13][NH2:14]>CO>[Cl:11][C:8]1[N:9]=[CH:10][C:5]([C:3]([NH:13][NH2:14])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1cnc(Cl)cn1

Procedure:
5-chloro-pyrazine-2-carboxylic acid methyl ester (10.02 g, 58.25 mmol) and hydrazine monohydrate (12.5 mL, 250 mmol) were dissolved in methanol (400 mL) and the reaction mixture heated to reflux for 48 hours. The reaction mixture was then filtered and the precipitate collected dried in vacuo to yield the title compound, 5.01 g (50%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][NH:4][CH2:3]1.C[O:7][C:8]([C:10]1[C:14]([NH:15][C:16]([C:18]2[C:23]([NH:24][C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)=[CH:22][CH:21]=[C:20]([CH:31]3[CH2:33][CH2:32]3)[N:19]=2)=[O:17])=[CH:13][N:12]([CH3:34])[N:11]=1)=O>>[OH:1][CH:2]1[CH2:5][N:4]([C:8]([C:10]2[C:14]([NH:15][C:16]([C:18]3[C:23]([NH:24][C:25]4[CH:26]=[N:27][CH:28]=[N:29][CH:30]=4)=[CH:22][CH:21]=[C:20]([CH:31]4[CH2:33][CH2:32]4)[N:19]=3)=[O:17])=[CH:13][N:12]([CH3:34])[N:11]=2)=[O:7])[CH2:3]1
Reactant: OC1CNC1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)N2CC(O)C2)n1
Yield: 13 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 3-hydroxy-azetidine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (13%) as sticky yellow solid.
Reaction SMILES: [OH:1][CH:2]([N:15]1[C@H:18]([SH:19])[C@H:17]([NH:20][C:21](=[O:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]1=[O:30])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].Br[CH2:32][C:33]([CH:35]1[CH2:39][CH2:38][CH2:37][O:36]1)=[O:34].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[OH:1][CH:2]([N:15]1[C@H:18]([S:19][CH2:32][C:33]([CH:35]2[CH2:39][CH2:38][CH2:37][O:36]2)=[O:34])[C@H:17]([NH:20][C:21](=[O:29])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:16]1=[O:30])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4]
Reactant: O=C(CBr)C1CCCO1
Reactant: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SCC(=O)C2CCCO2)cc1
Reaction time: 0.17 h

Procedure:
The crude thiol was dissolved in acetone (35 ml) and treated with a solution of (RS)-2-bromoacetyltetrahydrofuran (3.48 g, 18.0 mmol) in acetone (5 ml). After 10 min, potassium carbonate (1.24 g, 8.9 mmol) was added, and the mixture stirred for a further 30 min. The reaction mixture was diluted with ethyl acetate, washed successively with water (×2) and brine, dried and concentrated. The residue was flash chromatographed on silica gel eluting with 50, 70 and is 80% ethyl acetate in hexane yielding the title compound as a colourless foam (5.40 g, 55%); νmax (CH2Cl2) 3409, 1781, 1745, 1684, 1613, 1516 cm-1. [Mass spectrum +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (565)].
Reaction SMILES: [CH:1]1([O:7][CH:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C:9]([NH:11]C2SC=CN=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)N[Si](C)(C)C>ClCCl.CN(C)C=O>[CH:1]1([O:7][CH:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C:9]([NH2:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=C(Nc1nccs1)C(OC1C=CCCC1)c1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)C(OC1C=CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
A solution of rac-(cyclohex-2-enyloxy)-(3,4-dichloro-phenyl)-acetic acid (Example 3; 409 mg, 1.36 mmol) in dichloromethane (10 mL) and N,N-dimethylformamide (one drop) cooled to 0° C. was treated with oxalyl chloride (2.0 M solution in dichloromethane, 0.95 mL, 1.90 mmol). The reaction was stirred at 0° C. for 1 h, then 1,1,1,3,3,3-hexamethyldisilazane (1.0 mL, 4.75 mmol) was added and the resulting cloudy mixture was stirred at 25° C. for 16 h. The reaction was quenched with methanol (10 mL), washed with an aqueous solution of 5% sulfuric acid (2×15 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine (1×10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The reaction product was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) to give rac-2-(cyclohex-2-enyloxy)-2-(3,4-dichloro-phenyl)-acetamide (311 mg, 76% yield) as a white solid: 103.6-108.9° C.; EI-HRMS m/e calcd for C14H15NCl2O2(M+) 299.0479, found 299.0492.