Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1.[CH:21]1([C:24]#[CH:25])[CH2:23][CH2:22]1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:21]1([C:24]#[C:25][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH2:23][CH2:22]1
Reactant: C#CC1CC1
Reactant: COC(=O)c1ccc(OC)cc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)cc1C#CC1CC1
Yield: 95.4 %

Procedure:
Coupling of methyl 4-(methyloxy)-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (77) (0.70 g, 2.23 mmol) with cyclopropyl acetylene (0.30 g, 4.46 mmol) using Pd(PPh3)2Cl2 and CuI in DMF at room temperature gave 0.49 g (96%) of the title compound (149) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 0.80-0.95 (m, 4H), 1.45-1.55 (m, 1H), 3.82 (s, 3H), 3.87 (s, 3H), 6.80 (dd, J1=8.9 Hz, J2=2.7 Hz, 1H), 6.96 (d, J=2.8 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H). LCMS (ESI): m/z 231 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([OH:13])=[C:5]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:23][O:24][CH2:25]Cl>ClCCl>[CH2:1]([C:3]1[C:4]([O:13][CH2:23][O:24][CH3:25])=[C:5]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCc1ccc(C)c(C(=O)O)c1O
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1ccc(C)c(C(=O)O)c1OCOC
Reaction time: 8 h
Yield: 111.7 %

Procedure:
A solution of ethyl 2-hydroxy-6-methylbenzoic acid (4.56 g, 25.3 mmol) and diisopropylethylamine (13.2 ml, 76 mmol) in dry dichloromethane (30 ml) was cooled in an ice-bath. Chloromethyl methyl ether (3.83 ml, 50.6 mmol) was added slowly and the mixture was allowed stand at 0° C., warning slowly to room temperature. After 36 h a further portion of chloromethyl methyl ether (1.9 ml) was added and the mixture was left at room temperature overnight. The mixture was then washed with 10% citric acid, water and brine, dried and evaporated to give the title compound (6.34 g, 100%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([S:21][C:22]2[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)=[C:18]([NH2:20])[CH:19]=1>>[CH3:12][C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:20][C:18]3[CH:19]=[C:14]([CH3:13])[CH:15]=[CH:16][C:17]=3[S:21][C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: Cc1cccc(Sc2ccc(C)cc2N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1cccc(Sc2ccc(C)cc2Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (267 mg, 1.56 mmol) was reacted with the product from Example 48b (358 mg, 1.56 mmol) for 48 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (116 mg, 15%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.10 (s, 3H) 2.38 (s, 3H) 2.76 (s, 3H) 6.27 (d, J=7.35 Hz, 1H) 7.00 (m, 3H) 7.40 (m, 3H) 7.78 (d, J=8.82 Hz, 1H) 8.37 (d, J=6.99 Hz, 1H) 8.92 (d, J=8.82 Hz, 1H) 11.08 (br. s., 1H) 14.45 (br. s., 1H); MS (ESI+) m/z 372 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].N1C=CC=CC=1.Cl.[CH2:15]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)[CH2:16][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][CH3:30]>O>[CH2:15]([NH:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH:1][C:2]([CH3:7])([C:3]([OH:5])=[O:4])[CH3:6])=[O:37])=[CH:39][CH:40]=1)[CH2:16][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][CH3:30]
Reactant: CC(C)(N)C(=O)O
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5.24 g. of α-aminoisobutyric acid, 50 ml. of pyridine, and 25 ml. of H2O was stirred while 21.1 g. of 4-(hexadecylamino)benzoyl chloride hydrochloride was added. The mixture was stirred for 18 hours at ambient temperature and filtered. The filtrate was evaporated and the residual yellow glass was dissolved in 1 N NaOH solution. The solution was extracted with diethyl ether and then acidified with 6 N HCl. The precipitate was collected, dried, and recrystallized from acetone, melting point 199°-202° C.
Reaction SMILES: O.[NH2:2]N.C[N:5](C)/[CH:6]=[CH:7]/[C:8]([C:10]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:17][C:16]2[CH2:26][NH:27][CH2:28][C:29](=[O:30])[N:14]3[C:15]=2[C:11]=1[CH:12]=[CH:13]3)=O>C1COCC1>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]2[C:10]([C:8]3[NH:2][N:5]=[CH:6][CH:7]=3)=[C:11]3[C:15]4=[C:16]([CH2:26][NH:27][CH2:28][C:29](=[O:30])[N:14]4[CH:13]=[CH:12]3)[CH:17]=2)=[CH:24][CH:23]=1
Reactant: NN
Reactant: CN(C)/C=C/C(=O)c1c(-c2ccc(F)cc2)cc2c3c1ccn3C(=O)CNC2
Solvent: C1CCOC1
Solvent: O
Product: O=C1CNCc2cc(-c3ccc(F)cc3)c(-c3ccn[nH]3)c3ccn1c23
Reaction time: 42 h
Yield: 22.5 %

Procedure:
Hydrazine monohydrate (5.14 mmol, 0.26 mL) was added to a solution of 7-[(E)-3-Dimethylamino-allanoyl]-6-(4-fluoro-phenyl)-3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-one (Example 159) (0.257 mmol, 0.097 g) in 10 mL THF at rt. The reaction mixture was stirred for 42 h. The reaction mixture was evaporated to dryness. The residue was taken up in 2N HCl and extracted with EtOAc several times. The combined organic layers was dried over anhydrous MgSO4 and concentrated to give a yellow oil which was purified by flash silica gel chromatography eluting with a gradient of 0-3% MeOH in CHCl3 to give 0.020 g (23%) of a yellow solid: mp=173-175° C.; 1H NMR (DMSO-d6) δ 3.45-3.52 (m, 2H), 4.03-4.08 (m, 2H), 5.64 (br s, 1H), 7.23 (t, 1H, J=6.0 Hz), 7.32 (t, 2H, J=9.0 Hz), 7.38-7.55 (m, 3), 7.88 (d, 1H, J=6.0 Hz), 8.36-8.43 (m, 2H), 12.67 (br s, 1H); HRMS calcd. for C20H15N4OF (M+) 346.1221, found (M+) 346.1225; Anal. for (C20H15N4OF.1.0MeOH) C, H, N.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][O:6][N:7]=[C:8]([C:24](=O)[CH2:25]Br)[C:9]([NH:11][CH:12]1[C:22](=[O:23])[N:14]2[C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH2:17][S:18][C@H:13]12)=[O:10]>C(O)C>[NH2:1][C:2]1[S:3][CH:25]=[C:24]([C:8](=[N:7][O:6][CH3:5])[C:9]([NH:11][CH:12]2[C:22](=[O:23])[N:14]3[C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH2:17][S:18][C@H:13]23)=[O:10])[N:4]=1
Reactant: NC(N)=S
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Solvent: CCO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
Thiourea (8.4 mg.) was added to a solution of 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 42 mg.) in ethanol (6 ml.) and stirred at room temperature for an hour and at 50° C. for 30 minutes. After removing ethanol from the reaction mixture in vacuo, water (5 ml.) was added to the residue and adjusted to pH 4.0 with 6N-hydrochloric acid. The precipitates were collected by filtration and dried to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 8 mg.). The filtrate was subjected to column chromatography on nonionic, adsorption resin "Diaion HP-20" (trademark: manufactured by Mitsubishi Chemical Industries Ltd., 5 ml.), washed with chilled water (5 ml.) and eluted with 20% aqueous isopropyl alcohol. The eluate was adjusted to pH 6.5 with 1N aqueous sodium hydroxide under ice-cooling, and concentrated in vacuo. The residue was lyophilized to give sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 15 mg.).
Reaction SMILES: [I:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[BH4-].[Na+]>CO>[OH:13][CH2:12][C:11]1[C:2]([I:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1cc2ccccc2nc1I
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc2ccccc2nc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a stirred solution of 2-iodo-3-quinolinecarboxaldehyde (595 mg, 2.10 mmol) in 40 mL of CH3OH at 0° C. was added NaBH4 (86 mg, 2.31 mmol), and the mixture was stirred at 0° C. for 30 min. After concentrating the mixture to approximately one-half of its original volume, water (30 mL) was added and the mixture was allowed to stand at 5° C. overnight. The solids were filtered and the crude product (570 mg, 95%) was recrystallized from methanol to give 3-hydroxymethyl-2-iodoquinoline (505 mg, 84%) as colorless needles: mp 189°-190° C. 1H NMR (300 MHz, CDCl3) δ 8.19 (s, 1H), 7.99 (d, 1H, J=9 Hz), 7.87 (d, 1H, J=9 Hz), 7.68 (m, 1H), 7.58 (t, 1H, J=9 Hz), 5.45 (t, 1H, J=6 Hz), 4.66 (d, 2H, J=6 Hz); IR (nujol) 3350, 1580, 1320, 1125, 1060, 995, 755, 720, cm-1.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].[OH-].[Na+].Br[CH2:16][CH2:17][CH:18]=[CH2:19]>CO.O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:19][CH2:18][CH:17]=[CH2:16])[C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12]
Reactant: C=CCCBr
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Temperature: 70 °C
Reaction time: 27 h

Procedure:
41.5 g of 3-methyl-xanthine are added with stirring at 70° C. to a solution of 10.2 g of NaOH in 400 ml of methanol/water (1:1). After mixing with 35.1 g of 4-bromobut-1-ene the mixture is stirred under a nitrogen atmosphere for 27 hours at 70° C. The reaction mixture is then cooled to 20° C. and the precipitate formed is filtered off. By re-precipitation from alkaline solution (pH 13.5) and acidification with dilute sulphuric acid to pH 10, 29.6 g (89.7% of theory relative to reacted 3-methyl-xanthine) of the title compound of melting point 245° to 246° C. are obtained after drying.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1.[H][H]>CC(O)=O.[Pt](=O)=O>[ClH:1].[CH3:2][CH:3]1[CH2:4][CH2:5][NH:6][CH2:7][CH:8]1[C:9]([OH:11])=[O:10]
Reactant: Cc1ccncc1C(=O)O
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(=O)O
Product: CC1CCNCC1C(=O)O
Yield: 112.9 %

Procedure:
4-Methylnicotinic acid hydrochloride (5.00 g, 36.5 mmol, ASDI) and platinum (IV)oxide (0.35 g, 1.54 mmol) were shaken in AcOH (100 mL) under about 60 psi hydrogen for about 72 h at room temperature. The reaction mixture was filtered through Celite® and concentrated under reduced pressure to give 4-methylpiperidine-3-carboxylic acid hydrochloride (7.4 g, contained residual AcOH) that was carried forward without additional purification. To a portion of the acid (1.0 g, 4.92 mmol) in 1,4-dioxane (10 mL) was added HCl (4 N in 1,4-dioxane, 4.0 mL, 16 mmol). The mixture was stirred for about 10 min before adding Et2O (10 mL). The precipitate was collected by vacuum filtration was washed with Et2O (5 mL) to give a solid (0.27 g). To the filtrate was added HCl (4 N in 1,4-dioxane, 4.0 mL, 16 mmol) and the mixture was concentrated under reduced pressure to constant weight, while adding DCM (20 mL) to the resulting residue to give a thick yellow oil (0.56 g). The two portions were combined to give 4-methylpiperidine-3-carboxylic acid hydrochloride (0.83 g, 93%). To the acid (0.83 g, 4.6 mmol) was added N-(benzyloxycarbonyloxy)succinimide (1.27 g, 5.08 mmol), Na2CO3 (1.71 g, 16.2 mmol), and water:1,4-dioxane (1:1, 20 mL). The mixture was stirred at room temperature for about 16 h and the organic solvent was removed under reduced pressure. The aqueous phase was neutralized by the addition of 1N HCl. The solution was extracted with EtOAc (2×25 mL) and the combined organic extracts were washed with brine and dried over anhydrous MgSO4. The solution was filtered and concentrated under reduced pressure to give 1-(benzyloxycarbonyl)-4-methylpiperidine-3-carboxylic acid (1.28 g, 100%): LC/MS (Table 2, Method a) Rt=1.97 min; MS m/z: 278 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].Cl.[CH3:13][NH:14][O:15][CH3:16].C(Cl)(=O)C(Cl)=O>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1F
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cccc(Cl)c1F
Yield: 88.2 %

Procedure:
Prepared according to Method A step A from 3-chloro-2-fluorobenzoic acid (3.0 g, 17.2 mmol), N,O-dimethylhydroxylamine hydrochloride (2.34 g, 24 mmol), oxalyl chloride (1.5 mL, 17.2 mmol) and 5 mL of pyridine to give the title compound (3.3 g) as an oil. Used as is in the next prep
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])(=[O:17])[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][CH3:16]>FC(F)(F)C(O)=O>[C:1]([O:18][CH:19]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:20][C:21]([OH:23])=[O:22])(=[O:17])[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][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To tert-butyl 3-hexadecanoyloxyoctadecanoate (156 g) was added trifluoroacetic acid (200 ml) at 0° C. After the temperature of the mixture was reached to ambient temperature, the resulting solution was allowed to stand at the same temperature for 3 hours. Excess trifluoroacetic acid was distilled off under reduced pressure. The residue was taken up in benzene and the solvent was evaporated off. This operation was repeated twice to remove trifluoroacetic acid completely. The residue was recrystallized from petroleum ether in refrigerator to afford crystals of 3-hexadecanoyloxyoctadecanoic acid (125 g).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH2:27][CH:28]([NH:37][OH:38])[CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:26])=[O:25])[CH2:20][CH2:19]2)[CH:13]=1>O1CCCC1>[Cl:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([N:18]2[CH2:19][CH2:20][N:21]([S:24]([CH2:27][CH:28]([N:37]([OH:38])[CH:5]=[O:7])[CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:26])=[O:25])[CH2:22][CH2:23]2)[CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(CC(CCc1ccccc1)NO)N1CCN(c2cc(Cl)ncn2)CC1
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CN(O)C(CCc1ccccc1)CS(=O)(=O)N1CCN(c2cc(Cl)ncn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (19 ml) was added directly to formic acid (76 ml). The solution was stirred at room temperature for 30 minutes. A solution of 1-(6-chloropyrimidin-4-yl)-4-{[2-(hydroxyamino)-4-phenylbutyl]sulphonyl}piperazine (17.2 g) in tetrahydrofuran (85 ml) was added in portions, to the above solution at 27° C. over 25 minutes. The solution was stirred at room temperature for 1 hour. The solution was evaporated (water-bath temperature 30° C.) and the residual gum was dissolved in ethyl acetate (500 ml). This solution was treated with saturated aqueous sodium hydrogen carbonate solution (200 ml) and the mixture (pH8) was stirred at room temperature for 16 hours. The ethyl acetate layer was separated, washed with saturated brine (100 ml), dried (Na2SO4), and evaporated to dryness. The residual foam was dissolved in ethanol, a solid separated and the miixture was stirred for 2 days. The solid was collected by filtration, slurry washed with diethyl ether (100 ml), and dried to give N-[1-({[4-(6-chloropyrimidin-4-yl)piperazino]sulphonyl}methyl)-3-phenylpropyl]-N-hydroxyformamide as a colourless solid (12.8 g). mp 155-157° C.
Reaction SMILES: [ClH:1].CC(O)C.[NH2:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[C:14]([CH:31]=[O:32])=[N:15][N:16]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[CH:17]=2)=[CH:9][C:8]=1[C:33]1[O:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1>>[ClH:1].[NH2:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[C:14]([CH:31]=[O:32])=[N:15][N:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:17]=2)=[CH:9][C:8]=1[C:33]1[O:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)c(C=O)n2)CC1
Agent: Cl
Solvent: CC(C)O
Product: Nc1ncc(-c2cn(C3CCNCC3)nc2C=O)cc1-c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of hydrogen chloride in 2-propanol (2047 μl, 8.19 mmol) at 25° C. was added to tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-formyl-pyrazol-1-yl]piperidine-1-carboxylate (200 mg). The resulting mixture was stirred at 25° C. for 2 hours. The solid was filtered and washed with isopropanol to afford 4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-1-(4-piperidyl)pyrazole-3-carbaldehyde hydrochloride (170 mg). A solution of triethylamine (0.171 ml) was added to 4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-1-(4-piperidyl)pyrazole-3-carbaldehyde hydrochloride (174 mg) dissolved in CH2Cl2 (10 ml) at 0° C. The resulting solution was stirred at 0° C. for 10 minutes. Acetyl chloride (0.032 ml) was added to the mixture at 0° C., then the mixture was stirred at 25° C. for 40 minutes. The mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 1 to 4% methanol in dichloromethane. The solvent was evaporated to dryness to afford 1-(1-acetyl-4-piperidyl)-4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazole-3-carbaldehyde (148 mg) as a pale beige foam. NMR Spectrum: (CDCl3): 2.02-2.15 (m, 2H), 2.17 (s, 3H), 2.23-2.38 (m, 2H), 2.78-2.88 (m, 1H), 3.25-3.36 (m, 1H), 3.99-4.10 (m, 1H), 4.43-4.55 (m, 1H), 4.76-4.87 (m, 1H), 6.92 (bs, 2H), 7.34-7.41 (m, 2H), 7.59 (dd, 1H), 7.65 (s, 1H), 7.74 (dd, 1H), 8.42 (d, 1H), 8.64 (d, 1H), 10.09 (s, 1H); Mass spectrum: M+H+ 431;
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][O:6][C@@H:5]([CH3:19])[O:4]1.[H-].[Na+].Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]Cl>CN(C)C=O>[CH3:18][O:17][C:15]([CH2:14][CH2:13][CH2:12]/[CH:11]=[CH:10]\[CH2:9][C@H:8]1[CH2:7][O:6][C@@H:5]([CH3:19])[O:4][C@H:3]1[CH2:2][O:1][CH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=1)=[O:16]
Reactant: ClCc1ccccn1
Reactant: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1COCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of (2R,4R,5S)-4-hydroxymethyl-5-[(Z) -6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (272 mg) in N,N-dimethylformamide (10 ml) were added sodium hydride (80 mg, 60% in oil) and 2-picolyl chloride hydrochloride (110 mg) and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified with preparative thin layer chromatography with ethyl acetate as an eluent to give (2R,4R,5S)-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl -4-(2-pyridylmethoxymethyl)-1,3-dioxane (201 mg) as a pale yellow oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:30])[C:10]([CH3:29])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18](C(OC(C)(C)C)=O)[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl>O1CCOCC1>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][N:17]=[CH:16]4)[C:10]([CH3:29])=[C:9]([F:30])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 17.3 %

Procedure:
A mixture of 1,1-dimethylethyl 5-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-1H-indazole-1-carboxylate (Intermediate 2, 0.46 g) in a solution of hydrogen chloride in dioxan (4M, 7 ml) was stirred at room temperature. under nitrogen for 4.5 h. The solvent was evaporated and the residue was partitioned between dichloromethane (20 ml) and aqueous sodium hydroxide (2M, 20 ml). The organic layer was separated using a hydrophobic filter tube, the solvent was evaporated and the residue was purified on a Varian Bond-Elut SPE cartridge (silica, 10 g) eluting with chloroform:methanol (100:0 to 98:2) to give the title compound (0.06 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][CH2:20][N:19]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=4)(=[O:25])=[O:24])[C:18]=3[CH:33]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].F[C:35]1C=C(S(Cl)(=O)=O)C=C[CH:40]=1>>[CH2:35]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][CH2:20][N:19]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=4)(=[O:25])=[O:24])[C:18]=3[CH:33]=2)=[O:13])=[CH:10][C:2]=1[F:1])[CH3:40]
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(F)c1)CCO2
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(F)c2)CCO3)cc1F

Procedure:
2-Fluoro-4-{[4-(3-fluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=473.1 (M−H), was prepared as described for example 21, steps 1 to 8. Step 7 was performed using 3-fluoro-benzenesulfonyl chloride and yielded 2-fluoro-4-{[4-(3-fluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH:8]=[CH:9][C:10]([O-:12])=[O:11])=[CH:5][CH:4]=1)[CH3:2].[CH2:13](O)C>[Pd]>[CH2:1]([C:3]1[O:7][C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCO
Reactant: CCc1ccc(C=CC(=O)[O-])o1
Agent: [Pd]
Product: CCc1ccc(CCC(=O)OC)o1

Procedure:
To a suspension of ethanol (200 mL) and 300 mg of 5% palladium on carbon was added 14.8 g (82.1 mmol) of 3-(5-ethyl-2-furanyl)propenoate at room temperature and the mixture was placed on a Paar hydrogenator and hydrogenated with H2. Palladium on carbon was filtered off bypassing the reaction mixture through a filter aid, Super-Cel™ and the residue was washed with ethanol several times. The filtrate was concentrated in vacuo, methylene chloride was added to the residue and the solvent was removed in vacuo to afford 14.9 g methyl 3-(5-ethyl-2-furanyl)propanoate. This ester was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.[CH3:22][O:23][CH2:24][O:25][C:26]1[C:31]([CH3:32])=[CH:30][C:29]([C:33]2[CH:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][CH:34]=2)=[CH:28][C:27]=1[CH3:42].C(N1C=CN=C1)(N1C=CN=C1)=O>>[CH2:18]([CH:12]([CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:1][C:39]([C:36]2[CH:37]=[CH:38][C:33]([C:29]3[CH:30]=[C:31]([CH3:32])[C:26]([O:25][CH2:24][O:23][CH3:22])=[C:27]([CH3:42])[CH:28]=3)=[CH:34][CH:35]=2)=[O:40])=[CH:6][CH:7]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(Cc1ccc(OCCN)cc1)C(=O)OCC
Reactant: COCOc1c(C)cc(-c2ccc(C(=O)O)cc2)cc1C
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3cc(C)c(OCOC)c(C)c3)cc2)cc1)C(=O)OCC
Yield: 1068.4 %

Procedure:
In a similar manner to that described in Example 5, a reaction was carried out using ethyl 3-[4-(2-aminoethoxy)phenyl]-2-butylpropionate (880 mg), which is the product of Reference example 6, 4′-methoxymethoxy-3′,5′-dimethylbiphenyl-4-carboxylic acid (859 mg), which is the product of reference example 17(b), and carbonyldiimidazole (577 mg) and the reaction mixture was treated to afford the desired compound (1 18 g) as colorless crystals.