Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]1[OH:14].Cl.[NH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]1>C(O)(C)C>[OH:29][C@H:26]1[CH2:27][CH2:28][C@H:23]([NH:22][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[C:9]([CH3:11])[N:10]=2)[C@@H:12]2[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]2[OH:14])[CH2:24][CH2:25]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Cc1nc(Cl)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Agent: Cl
Solvent: CC(C)O
Product: Cc1nc(N[C@H]2CC[C@H](O)CC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reaction time: 17 h

Procedure:
A mixture of 6-chloro-2-methyl-9-(β-D-ribofuranosyl)-9H-purine (902 mg), trans-4-aminocyclohexanol hydrochloride (1.14 g) and DEA (1.94 g) in isopropanol (50 ml) was heated at reflux with stirring under nitrogen for 17 h. The resulting cooled reaction mixture was adsorbed onto silica (Merck 9385) and purified by column chromatography on silica (Merck 9385) eluting with System B (10:1 then 8:1) to give the title compound (0.9 g) as a solid.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[N:17][CH:18]=1.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:20]([NH:19][C:16]1[CH:15]=[CH:14][C:13]([CH3:12])=[CH:18][N+:17]=1[O-:9])(=[O:22])[CH3:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Nc1ccc(C)cn1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
m-CPBA (75% in H2O, 89.6 g, 390 mmol) was added portion wise to a stirred solution of N-(5-methylpyridin-2-yl)acetamide (45.0 g, 300 mmol) in DCM (2.7 L) at rt, and the mixture stirred at rt for 4 h. 5% aqueous Na2SO3 (200 mL) was added slowly, the phases were separated and the organic layer washed with saturated NaHCO3, brine (100 mL), dried (MgSO4) and filtered. After concentration in vacuo purification by gradient column chromatography eluting with 2-5% MeOH in DCM yielded the title compound (37.5 g, 243 mmol) as a pale yellow solid.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].O=[C:12]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:13][C:14](OCC)=[O:15]>>[CH2:19]([C:12]1[CH:13]=[C:14]([OH:15])[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CC(=O)Cc1ccccc1
Reactant: N#Cc1ccnc(NN)c1
Product: N#Cc1ccnc(-n2nc(Cc3ccccc3)cc2O)c1
Yield: 53 %

Procedure:
The title compound was prepared in 53% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 3-oxo-4-phenylbutanoate according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H12N4O, 277. Found, 277.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@@:9]12[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C@@H:10]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2.C[S-].[Li+].Cl>CN(C)P(N(C)C)(N(C)C)=O.O>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@@:9]12[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C@@H:10]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2
Reactant: COc1ccccc1[C@]12CCN(C)C[C@H]1c1ccccc1O2
Agent: C[S-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CN1CC[C@]2(c3ccccc3O)Oc3ccccc3[C@@H]2C1
Yield: 79.3 %

Procedure:
A mixture of 1.51 g of cis-1,2,3,4,4a,9b-hexahydro-4a-(2-methoxyphenyl)-2-methyl-benzofuro[3,2-c]pyridine and 1.56 g of lithium thiomethoxide in 13 ml of dry hexamethylphosphoramide was heated at 140° under a drying tube for 4 hours. The cooled reaction mixture was diluted with 150 ml of water and the pH adjusted to 7 by slow addition of 2N HCl with stirring. As the pH reached neutral, product started to precipitate out. The mixture was cooled to 0° and stirred for 30 minutes. The precipitated material was collected, washed with water and then a small amount of ether, and dried to afford 1.14 g (79.5%) of crystalline solid, m.p. s 178, 188°-191°. Recrystallization from ethanol gave 0.90 (62.7%) of colorless crystals, m.p. s 197, 197.5°-199°.
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]1([CH2:12][CH2:13][C:14](=O)[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[C:6]1([CH2:12][CH2:13][C:14]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH2:1])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [Li]CCCC
Reactant: O=C(CCc1ccccc1)CCc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(CCc1ccccc1)CCc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
A suspension of 1.59 g (4.45 mmol) of methyltriphenylphosphonium bromide in 100 ml of tetrahydrofuran was cooled to -78° C., treated with 2.2 ml (4.5 mmol) of n-butyllithium, warmed to 0° C, was recooled to -78° C. The resulting solution was treated via cannula with a solution of 1.59 g (4.45 mmol) of 1,5diphenyl-3-pentanone in 20 ml of tetrahydrofuran. After being allowed to stir at ambient temperature for 2 h, the solution was diluted with hexane, washed sequentially with water and saturated brine, dried over MgSO4, and concentrated in vacuo. The mixture was purified by flash chromatography to give 0.90 g (86%) of the desired compound as a colorless oil. 1H NMR (CDCl3) δ 2.37 (t, J=8 Hz, 4H), 2.76 (t, J=8 Hz, 4H), 4.81 (s, 2H), 7.15-7.3 (m, 10H). Mass spectrum (M+NH4)+ =254.
Reaction SMILES: [OH-].[Na+:2].[O:3]=[C:4]([OH:15])[C@@H:5]([C@H:7]([C@@H:9]([C@@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8])[OH:6]>>[O:3]=[C:4]([O-:15])[C@@H:5]([C@H:7]([C@@H:9]([C@@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8])[OH:6].[Na+:2]
Reactant: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Growth continued until a suitable mass of cells were produced. During fermentation, the pH was readjusted upward with sodium hydroxide as gluconic acid was produced thus forming sodium gluconate.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[C:22]([O:25][C:26]1[CH:27]=[C:28]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])(=[O:24])[CH3:23]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:37]2[CH2:38][CH2:39][N:34]([C:28]3[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:26]([O:25][C:22](=[O:24])[CH3:23])[CH:27]=3)[CH2:35][CH2:36]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: COc1ccc(N2CCNCC2)cc1OC(C)=O
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccc(OC)c(OC(C)=O)c3)CC2)c(OC)nc1C

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-acetoxy-4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. 25 yield: 62% Example 54
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:6]([CH3:24])=[N:7][C:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[N:9][C:10]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:59]1[C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:62]=[CH:61][C:60]=1[C:69](O)=[O:70].C(N(CC)C(C)C)(C)C>C1COCC1.O>[CH3:24][C:6]1[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:25])=[C:10]([N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[N:9]=[C:8]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:69]([C:60]3[CH:61]=[CH:62][C:63]4[C:68](=[CH:67][CH:66]=[CH:65][CH:64]=4)[CH:59]=3)=[O:70])=[CH:21][CH:22]=2)[N:7]=1
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: COC(=O)Cc1c(C)nc(Cc2ccc(N)cc2)nc1N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)Cc1c(C)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N1CCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 36.4 %

Procedure:
A solution of methyl[2-(4-aminobenzyl)-4-methyl-6-pyrrolidin-1-ylpyrimidin-5-yl]acetate (0.034 g, 0.10 mmol) in THF (1 mL) at room temperature was treated with PyBOP (0.052 g, 0.10 mmol), 2-naphthoic acid (0.019 g, 0.11 mmol), and N,N-diisopropylethylamine (0.017 mL, 0.10 mmol). After stirring at room temperature for 17 hours, the reaction mixture was poured into water and extracted with EtOAc. The combined organic extracts was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The remaining residue was chromatographed over silica gel eluting with 60% EtOAc in CH2Cl2 to give methyl {4-methyl-2-[4-(2-naphthoylamino)benzyl]-6-pyrrolidin-1-ylpyrimidin-5-yl}acetate (0.018 g, 36% yield) as a yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][N:18]=2)[CH:13]=[CH:12]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[N:11]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=2)[C:19]2=[N:18][CH:17]=[CH:16][CH:15]=[C:14]2[CH:13]=[CH:12]1
Reactant: OCCc1ccc(I)cc1
Reactant: c1cnc2[nH]ccc2c1
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: OCCc1ccc(-n2ccc3cccnc32)cc1
Temperature: 80 °C
Yield: 88.1 %

Procedure:
A mixture of 1.24 g (5 mmol) of 2-(4-iodophenyl)ethanol, 0.62 g (5.25 mmol) of 7-azaindole, 2.33 g (11.0 mmol) of potassium phosphate, 0.082 g (1.0 mmol) of N,N′-dimethylethylenediamine and 0.095 g (0.50 mmol) of cuprous iodide in 4 ml of toluene is heated at 80° C. overnight with thorough stirring under an argon atmosphere. The mixture is cooled to ambient temperature and diluted with 150 ml of ethyl acetate and 50 ml of water. After the phases have settled and been separated, the organic phase is washed with 25 ml of water and 25 ml of saturated aqueous sodium chloride solution. It is dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on silica gel, eluting with a 70/30 then 60/40 and 50/50 mixture of cyclohexane and ethyl acetate, to give 1.05 g of product in the form of an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][CH2:19][CH2:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25]C)=[O:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(#N)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][CH2:19][CH2:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([OH:25])=[O:24])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1CCCc1ccccc1NS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2CCCc2ccccc2C(=O)O)cc1
Temperature: 50 °C
Yield: 100 %

Procedure:
Methyl 2-[3-{2-[(4-methylphenyl)sulfonylamino]phenyl}propyl]benzoate (0.84 mM) obtained in Example 6 and 4.5 ml of aqueous 1M NaOH (4.5 mM) are added to 3 ml of acetonitrile in a 50 ml reactor. The reaction medium is then heated at 50° C. for 2 hours with stirring. The resulting mixture is cooled to room temperature, 2.5 ml of 3M HCl are then added and the mixture is stirred for 20 hours. The solid that precipitates is then filtered off and washed with water. 0.33 g of a pink solid is obtained (100% yield).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[N:13]=[CH:12][N:11]=[C:10]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[O:25][N:24]=[C:23]([CH:26]([CH3:28])[CH3:27])[N:22]=3)[CH2:17][CH2:16]2)[C:9]=1[CH3:29].[CH3:30][C:31]1([CH3:44])[O:36][CH2:35][CH:34]([C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)[CH2:33][O:32]1>CN(C=O)C>[CH3:30][C:31]1([CH3:44])[O:32][CH2:33][CH:34]([C:37]2[CH:42]=[CH:41][C:40]([O:43][C:8]3[N:13]=[CH:12][N:11]=[C:10]([O:14][CH:15]4[CH2:20][CH2:19][N:18]([C:21]5[O:25][N:24]=[C:23]([CH:26]([CH3:28])[CH3:27])[N:22]=5)[CH2:17][CH2:16]4)[C:9]=3[CH3:29])=[CH:39][CH:38]=2)[CH2:35][O:36]1
Reactant: CC1(C)OCC(c2ccc(O)cc2)CO1
Reactant: Cc1c(Cl)ncnc1OC1CCN(c2nc(C(C)C)no2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1c(Oc2ccc(C3COC(C)(C)OC3)cc2)ncnc1OC1CCN(c2nc(C(C)C)no2)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 44.9 %

Procedure:
Cesium carbonate (755 mg, 0.002317 moles) was added to a solution of 5-(4-(6-chloro-5-methylpyrimidin-4-yloxy)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole (1.2 gm, 0.003365 moles) and 4-(2,2-dimethyl-1,3-dioxan-5-yl)phenol (700 mg, 0.003365 moles) in dry DMF (10 ml) and the reaction mixture was stirred at 80° C. for 3 hours. Then reaction mixture was poured into ice cold water and extracted with ethyl acetate. The organic extract was successively washed with water & brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product so obtained was purified by column chromatography (silica gel) using 15% ethyl acetate in hexane as eluent to obtain 770 mg product as white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]([CH3:20])([CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9]#[N:10].O.[OH-].[Na+]>C1COCC1>[CH2:13]([O:12][CH2:11][C:8]([CH3:20])([NH2:7])[CH2:9][NH2:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(N)(C#N)COCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(N)(CN)COCc1ccccc1
Reaction time: 2 h

Procedure:
Under argon and at −78° C., 20.9 ml (20.9 mmol) of lithium aluminium hydride (1 N solution in diethyl ether) were added to 6.8 g (32.17 mmol, purity about 90%) of 2-amino-3-(benzyloxy)-2-methylpropionitrile Example 262A in 329 ml of dry THF. The reaction solution was at −78° C. for 1 h, at −20° C. for 2 h and at 0° C. for 2 h. 3.22 ml of water, 3.22 ml of 2 N aqueous sodium hydroxide solution and 6.44 ml of water were then added carefully. The precipitate was filtered off and washed with THF and methanol, and the filtrate was concentrated. This gave 8 g of the crude product. 7 g of this crude product were purified by silica gel chromatography (mobile phase: dichloromethane/2 N ammonia in methanol=from 20/1 to 10/1). This gave 1.52 g of the target compound (about 28% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1(N=C=NC2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+].[CH3:36][N:37]1[C:41]([OH:42])=[CH:40][CH:39]=[N:38]1.Cl>C(Cl)(Cl)Cl.C(O)(C)(C)C>[Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([C:40]1[CH:39]=[N:38][N:37]([CH3:36])[C:41]=1[OH:42])=[O:6]
Reactant: Cn1nccc1O
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CC(C)(C)O
Product: Cn1ncc(C(=O)c2ccc(S(C)(=O)=O)cc2Cl)c1O
Temperature: 25 °C
Yield: 53 %

Procedure:
2-chloro-4-methanesulfonyl benzoic acid 3.87 g (0.0165 mol) was added to 40 ml of tert.-butanol, and then were added thereto 3.47 g (0.0168 mol) of N,N'-dicyclohexylcarbodiimide and 1.21 g (0.088 mol) of anhydrous potassium carbonate. The resulting mixture was incorporated with 1.65 g (0.0168 mol) of 1-methyl-5-hydroxypyrazole with stirring at room temperature and heated at 60° C. to effect reaction for 5 hours. After completion of the reaction, solvent was distilled away from the reaction mixture under reduced pressure and the resulting residue was washed with chloroform. Thereafter, the residue was incorporated with 30 ml of water and stirred. Insoluble matter was filtered out. The aqueous solution thus obtained was incorporated with conc. hydrochloric acid to adjust the pH thereof to 1 or lower and then with chloroform to effect extraction. An organic layer was separated, dried over anhydrous sodium sulfate, freed of solvent by distillation under reduced pressure, and dried to give 2.75 g of the final product (yield: 53%), m.p. 272°-275° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]([Cl:18])=[C:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:8](O)=[O:9].N1C=CC=CC=1>C(OCC)C>[Cl:5][C:6]([Cl:18])=[C:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:8]([Cl:3])=[O:9]
Reactant: O=C(O)C(=C(Cl)Cl)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(Cl)C(=C(Cl)Cl)c1ccc(Cl)cc1
Temperature: 22.5 °C
Reaction time: 6 h
Yield: 78.4 %

Procedure:
35.5 g (0.298 mol) of thionyl chloride were added dropwise at 0° C. to the solution of 50 g (0.199 mol) of the acid of Example 4 in 200 ml of diethyl ether and 23.6 g (0.298 mol) of pyridine. The solution was stirred for 6 hours at 20 to 25° C. and then filtered. After the solvent had been distilled off, 42.1 g of the product were obtained, and this was reacted further without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4](=[O:14])[CH2:3]1>C(OCC)(=O)C.CO.[Pt]=O>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:15])([CH3:1])[CH2:3][C:4]2=[O:14])=[CH:9][CH:8]=1
Reactant: CC1(C)CC(=O)c2cc([N+](=O)[O-])ccc21
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)CC(=O)c2cc(N)ccc21
Yield: 194.1 %

Procedure:
3,3-Dimethyl-6-nitro-indan-1-one (22.2 g, 54.1 mmol) and platinum oxide (0.44 g, 1.94 mmol) in 30 mL of ethyl acetate and 60 mL of methanol was hydrogenated on a Parr Shaker for 40 min. The mixture was filtered through a pad of celite. The filtrate was evaporated and the residue was triturated with hexane to give 18.4 g (97% yield) of the title product as yellow solids; 1H-NMR (CDCl3) δ1.38 (s, 6H), 2.56 (s, 2H), 6.98 (d, J=2.3 Hz, 1H), 7.02 (dd, J=2.3, 8.2 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H); MS m/e 176 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C@H:11]([C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[C:20]([F:31])[CH:19]=2)[N:14]=1)[CH3:12])(=O)C.Cl>CO>[F:31][C:20]1[CH:19]=[C:18]([C:15]2[N:14]=[C:13]([C@@H:11]([OH:10])[CH3:12])[O:17][N:16]=2)[CH:30]=[CH:29][C:21]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: CC(=O)O[C@@H](C)c1nc(-c2ccc(C(=O)OC(C)(C)C)c(F)c2)no1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@H](O)c1nc(-c2ccc(C(=O)OC(C)(C)C)c(F)c2)no1
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
Potassium carbonate (12.7 g, 91.6 mmol) was added to a methanol (360 mL) solution of the obtained tert-butyl 4-{5-[(1S)-1-acetoxyethyl]-1,2,4-oxadiazol-3-yl}-2-fluorobenzoate (32.1 g, 91.6 mmol) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. 2 N Hydrochloric acid was added to the reaction mixture at the same temperature until a pH value of 6.0 was obtained, and the solvent was distilled off under reduced pressure. Water was added to the resulting residue, and the mixture was subjected to extraction twice with ethyl acetate. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was solidified by using hexane. Thus, the title compound (26.4 g, yield: 93%) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)=[N:13]2)=[N:6][CH:7]=1.[O:28]1CCC[CH2:30][CH:29]1OCCO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl.C1COCC1>[OH:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)=[N:13]2)=[N:6][CH:7]=1
Reactant: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(O)cn4)c3)n2)cn1
Reactant: OCCOC1CCCCO1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(OCCO)cn4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
252 mg of 2-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one (0.7 mmol) are suspended in abs. THF under a protective-gas atmosphere in a 25 ml three-necked flask, 0.19 ml of 2-(tetrahydropyran-2-yloxy)ethanol (1.4 mmol) and 367 mg of triphenylphosphine (1.4 mmol) are added, and the mixture is stirred at RT for 30 min. 275 μl of diisopropyl azodicarboxylate (1.4 mmol) are subsequently added dropwise, and the reaction mixture is stirred at RT for a further 2 h. For work-up, the reaction mixture is diluted with 20 ml of dichloromethane, washed with 10 ml of water, dried over sodium sulfate, evaporated to dryness and purified by chromatography. (silica gel: MTB ether→DCM→DCM:30% of MeOH). The THP-protected product is stirred at RT for 20 h in 5 ml of 4 N HCl in dioxane. The reaction solution is evaporated to dryness and crystallised from methanol/diethyl ether, giving “A294”; ESI 405; m.p. 182-3° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH3:20])=[O:18])[CH:15]=3)[C:10]([S:26][CH3:27])=[CH:9]2)=[N:6][CH:7]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=1B(O)O>>[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=1[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH3:20])=[O:18])[CH:15]=3)[C:10]([S:26][CH3:27])=[CH:9]2)=[N:6][CH:7]=1
Reactant: Cc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)CN(C)C(=O)c1ccc2c(SC)cn(-c3ncc(Br)cn3)c2c1
Product: COC(=O)CN(C)C(=O)c1ccc2c(SC)cn(-c3ncc(-c4cc(C)ccc4F)cn3)c2c1

Procedure:
Suzuki coupling of 304a) (0.5 g, 1.11 mmol) and (2-fluoro-5-methylphenyl)boronic acid (0.34 g, 2.22 mmol) under use of (Ataphos)2PdCl2 (79 mg, 0.11 mmol) as catalyst analogously to the protocol for example 261. White solid. Yield: 0.51 g (96% of theory)
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]2[CH2:15][O:14][CH2:13][CH2:12][C:10]=2[N:11]=1.[F:17][C:18]1[CH:35]=[CH:34][C:21]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1.CC#N.O>C(O)=O>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([CH:24]2[CH2:25][CH2:26][N:27]([CH2:30][C:31]([N:4]([CH2:3][CH2:2][F:1])[CH2:5][C:6]3[NH:7][C:8](=[O:16])[C:9]4[CH2:15][O:14][CH2:13][CH2:12][C:10]=4[N:11]=3)=[O:32])[CH2:28][CH2:29]2)=[O:23])=[CH:34][CH:35]=1
Reactant: O=c1[nH]c(CNCCF)nc2c1COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Solvent: CC#N
Solvent: O=CO
Solvent: O
Product: O=C(c1ccc(F)cc1)C1CCN(CC(=O)N(CCF)Cc2nc3c(c(=O)[nH]2)COCC3)CC1

Procedure:
Following the general procedure of Example 5, the title compound was prepared (0.09 g) from 2-((2-fluoroethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (0.18 g, 0.79 mmol, 1 eq.) and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid (0.19 g, 0.71 mmol, 0.9 eq.). 1H NMR (400 MHz, MeOD) δ ppm 8.04-8.18 (m, 2H), 7.26 (m, 2H), 4.71-4.80 (m, 1H), 4.60-4.67 (m, 1H), 4.59 (s, 2H), 4.48-4.53 (m, 1H), 4.46 (s, 1H), 4.37 (s, 2H), 3.89-3.96 (m, 2H), 3.83-3.90 (m, 1H), 3.77-3.84 (m, 1H), 3.66-3.78 (m, 3H), 3.46-3.61 (m, 1H), 3.16-3.28 (m, 1H), 2.49-2.73 (m, 2H), 1.91-2.25 (m, 4H). HRMS calculated for C24H29F2N4O4 475.2157. found (ESI, [M+H]+) 475.2178. MS (ESI) m/z 475.2 (M+H)+. Retention time: 4.08 min (5-95% CH3CN/H2O over 7.75 min with 0.1% formic acid, Inertsil ODS3 100×3 mm C18 column with flow rate of 1.0 m L/m in).