Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH2:10]([O:12][C:13](=[O:24])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:11]>CO>[CH2:10]([O:12][C:13](=[O:24])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=2)=[CH:17][C:16]=1[O:22][CH3:23])[CH3:11]
Reactant: O=Cc1cccc(F)c1
Reactant: CCOC(=O)Nc1ccc(N)cc1OC
Solvent: CO
Product: CCOC(=O)Nc1ccc(NCc2cccc(F)c2)cc1OC
Temperature: 40 °C
Yield: 45 %

Procedure:
A solution of 3-fluorobenzaldehyde in dry methanol (84 μL, 476 mM) was added to a solution of (4-Amino-2-methyloxyphenyl)-carbamic acid ethyl ester (84 μL, 0.476 M in dry methanol). The resulting mixture was heated to 40° C. for 30 minutes. The solvent was evaporated in vacuo, and the remaining material was dissolved in 1,2-dichloroethane (1 mL). Sodium triacetoxyborohydrate (20 mg) was added, and the resulting mixture was kept at room temperature for 2 hours, under 2 periods of sonication for 10 minutes, respectively. The reaction mixture was filtered through silica gel (500 mg), and the column was washed with 1,2-dichloroethane (3 mL). The solvent was evaporated in vacuo yielding the title compound (5.7 mg, 45%).
Reaction SMILES: [CH2:1]([NH2:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]=[C:12]1[O:16][C:14](=[O:15])[CH2:13]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[O:16]=[C:12]([CH3:11])[CH2:13][C:14]([NH:10][CH2:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:15]
Reactant: C=C1CC(=O)O1
Reactant: NCC=Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)NCC=Cc1ccccc1

Procedure:
3.06 g (23.0 mmol) of cinnamylamine, 2.32 ml (30.1 mmol) of ketene dimer and 0.321 ml (2.30 mmol) of triethylamine were heated at 70° C. under stirring in 23 ml of toluene for 3 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. After the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:30]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:26][CH3:30])[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: CI
Reactant: C#CCOc1ccc(CCNC(=O)C(O)c2ccc(Cl)cc2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc(CCNC(=O)C(OC)c2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(4-Chloro-phenyl)-2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide (2.6 g, 7.0 mmol) is dissolved in N,N-dimethylformamide (30 ml). Sodium hydride (0.18 g, 7.5 mmol) is added in portions at +5° C. The mixture is stirred for 30 minutes at room temperature. Subsequently iodomethane (1.1 g, 7.5 mmol) is added dropwise and the resulting mixture is stirred for further 3 hours at room temperature. The reaction mixture is poured on ice/water (200 ml) and extracted with ethyl acetate (2×200 ml). The combined organic layer is washed with brine (200 ml) and dried over magnesium sulfate. After evaporation of the solvent, the residue is purified by chromatography (ethyl acetate/hexane) to yield 2-(4-chloro-phenyl)-2-methoxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide. 1H-NMR (300 MHz, CDCl3): 2.53 (t, 1H, C≡CH), 2.80 (t, 2H, CH2CH2), 3.34 (s, 3H, OCH3), 3.55 (t, 2H, CH2CH2), 3.84 (s, 3H, OCH3), 4.58 (s, 1H, CHOH), 4.79 (m, 2H, OCH2), 6.68-7.34 (m, 8H, CH arom., NH).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH:7]12[CH2:14]C[CH:10]([CH2:11][CH2:12]1)[CH:9]=[C:8]2C(O)=O>C(Cl)Cl.CN(C=O)C>[CH:10]12[CH2:11][CH2:12][CH:7]([CH2:8][CH2:9]1)[CH:14]=[C:1]2[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1=CC2CCC1CC2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1=CC2CCC1CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.9 %

Procedure:
Oxalyl chloride (2.0 M in CH2Cl2, 2.4 mL, 4.8 mmol, 1.2 eq) was added to a solution of compound 11B (600 mg, 3.95 mmol, 1 eq) in CH2Cl2 (8 mL) containing one drop of DMF. The reaction mixture was stirred at rt for 3 h and then concentrated under reduced pressure to give 680 mg of compound 11C which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:30]([C:27]2[CH:26]=[CH:25][C:24]([NH:23][C:20](=[O:22])[CH3:21])=[CH:29][CH:28]=2)(=[O:32])=[O:31])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 4-acetamidobenzene-1-sulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:13]([O:15]C)=[O:14])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.O.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:1][O:2][C:3]1[C:4]([C:13]([OH:15])=[O:14])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COC(=O)c1cc2ccccc2cc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2ccccc2cc1C(=O)O
Reaction time: 3 h
Yield: 91.8 %

Procedure:
A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 mL) in MeOH (100 mL) at room temp. was treated with a 1 N NaOH solution (33.4 mL, 33.4 mmol). The mixture was heated at the reflux temp. for 3 h, cooled to room temp., and made acidic with a 10% citric acid solution. The resulting solution was extracted with EtOAc (2×100 mL). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO4) and concentrated under reduced pressure. The residue was triturated with hexane then washed several times with. hexane to give 3-methoxy-2-naphthoic acid as a white solid (5.40 g, 92%): 1H-NMR (DMSO-d6) δ3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H), 7.83 (d, J=8.09 Hz, 1H), 7.91 (d, J=8.09 Hz, 1H), 8.19 (s, 1H), 12.83 (br s, 1H). Step 3. 2-(N-(Carbobenzyloxy)amino-3-methoxynaphthalene
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.Cl.[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([CH2:25]Cl)[CH:24]=1>>[Cl:18][C:19]1[CH:24]=[C:23]([CH2:25][N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=3)[C:12]#[N:13])[N:6]=[C:2]2[CH3:1])[CH:22]=[N:21][CH:20]=1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Reactant: ClCc1cncc(Cl)c1
Agent: Cl
Product: Cc1nc(C#Cc2cccc(C#N)c2)cn1Cc1cncc(Cl)c1

Procedure:
The title compound, MS: m/e=333.1 (M+H+), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 3-chloro-5-chloromethyl-pyridine hydrochloride.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:21]([NH2:23])=[N:20][CH:19]=[N:18][C:17]=3[N:16]([C@@H:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([C:32](=[CH:36][CH:37]1[CH2:39][CH2:38]1)[C:33](O)=[O:34])#[N:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:23][C:21]1[C:22]2[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)=[CH:15][N:16]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:33]([C:32](=[CH:36][CH:37]4[CH2:39][CH2:38]4)[C:30]#[N:31])=[O:34])[CH2:25]3)[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2[C@@H]1CCCNC1
Reactant: N#CC(=CC1CC1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.7 %

Procedure:
To a mixture of (R)-5-(4-phenoxyphenyl)-7-(piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.26 mmol, 1.0 eq), 2-cyano-3-cyclopropylacrylic acid (45 mg, 0.32 mmol, 1.2 eq) and DIPEA (102 mg, 0.78 mmol, 3 eq) in 10 mL DCM was added HATU (150 mg, 0.40 mmol, 1.5 eq) and the reaction mixture was stirred for 4 h at RT under N2. The reaction mixture was purified by Pre-TLC to give the title compound (60 mg, 54% in yield). LCMS: m/z (505.0) (M+H)+ 1HNMR (400 MHz, CDCl3): δ 0.826˜0.837 (m, 2H), 1.147˜1.183 (m, 6H), 1.744˜2.210 (m, 5H), 4.661˜4.699 (m, 1H), 5.212˜5.226 (m, 2H), 6.499˜6.524 (m, 1H), 6.921˜7.367 (m, 10H) and 8.223 (S, 1H).
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([O:32][CH3:33])=[N:15][N:16]2[C:20]([C:21]3[C:26]([O:27][CH3:28])=[CH:25][C:24]([OH:29])=[CH:23][C:22]=3[O:30][CH3:31])=[CH:19][S:18][C:17]=12)([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].I[CH2:42][CH2:43][F:44]>O>[C:6]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([O:32][CH3:33])=[N:15][N:16]2[C:20]([C:21]3[C:22]([O:30][CH3:31])=[CH:23][C:24]([O:29][CH2:42][CH2:43][F:44])=[CH:25][C:26]=3[O:27][CH3:28])=[CH:19][S:18][C:17]=12)([CH3:9])([CH3:8])[CH3:7]
Reactant: FCCI
Reactant: COc1cc(O)cc(OC)c1-c1csc2c(NC(=O)OC(C)(C)C)c(OC)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCCF)cc(OC)c1-c1csc2c(NC(=O)OC(C)(C)C)c(OC)nn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a DMF (2.28 ml) solution of tert-butyl[3-(4-hydroxy-2,6-dimethoxyphenyl)-6-methoxypyrazolo[5,1-b][1,3]thiazol-7-yl]carbamate (115 mg, 0.273 mmol) were added potassium carbonate (49.0 mg, 0.355 mmol) and 1-iodo-2-fluoroethane (61.7 mg, 0.355 mmol), and the mixture was stirred at room temperature for 20 hours and 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product of the title compound (128 mg, 0.273 mmol)
Reaction SMILES: [CH:1]([C@@H:4]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([OH:18])[CH:9]=1)[CH2:5][OH:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH:1]([C@@H:4]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:16])([CH3:15])[CH3:17])=[C:10]([O:18][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:9]=1)[CH2:5][OH:6])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H](CO)Cc1ccc(C(C)(C)C)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)[C@H](CO)Cc1ccc(C(C)(C)C)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At room temperature with stirring, to a solution of 5.65 g of 2(R)-isopropyl-3-(3-hydroxy-4-tert-butyl-phenyl)-propanol in 100 ml of dimethylformamide there are added 11 g of caesium carbonate and, dropwise, a solution of 3.2 ml of benzyl bromide in 20 ml of dimethylformamide. The reaction mixture is stirred at room temperature for a further 16 hours and then concentrated by evaporation, and the residue is partitioned between diethyl ether and water. The organic phases are concentrated by evaporation and the residue is purified by FC (90 g of silica gel, dichloromethane/hexane=9:1), yielding the title compound: Rf (dichloromethane/hexane=9:1)=0.44.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[OH:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].N1C=CC=CC=1>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OB(O)c1cccc(Br)c1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=C1c2ccccc2C(=O)N1Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.6 %

Procedure:
To a mixture of 3-bromophenylboronic acid (246 mg, 1.23 mmol), 2-hydroxyisoindoline-1,3-dione (100 mg, 0.61 mmol), cupric acetate (223 mg, 1.23 mmol) and activated 4 Å molecular sieves (155 mg) in 1,2-dichloroethane (3 mL) under a nitrogen atmosphere was added pyridine (0.11 mL, 1.35 mmol). The reaction was stirred at ambient temperature for 24 h, concentrated in vacuo and purified by flash column chromatography (82:18 hexanes/ethyl acetate) to provide 2-(3-bromophenoxy)isoindoline-1,3-dione (102 mg, 52%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 7.93 (dd, J=5.4, 3.0 Hz, 2H), 7.83 (dd, J=5.6, 3.0 Hz, 2H), 7.33 (t, J=2.1 Hz, 1H), 7.29 (dt, J=7.8, 2.0 Hz, 1H), 7.22 (t, J=8.1, 1H), 7.16-7.10 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[N:5]=[C:4]([CH3:17])[C:3]=1[C:18](=O)[CH3:19].[CH3:21][O:22][C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:26]=1)=[O:24]>CN(C=O)C>[OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[N:5]=[C:4]([CH3:17])[C:3]=1[C:18](=[N:32][NH:31][C:29]([C:28]1[CH:33]=[CH:34][C:25]([C:23]([O:22][CH3:21])=[O:24])=[CH:26][CH:27]=1)=[O:30])[CH3:19]
Reactant: CC(=O)c1c(C)nn(-c2ccc(C(F)(F)F)cn2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2c(C)nn(-c3ccc(C(F)(F)F)cn3)c2O)cc1
Yield: 71.5 %

Procedure:
0.2 mmol of 1-{5-hydroxy-3-methyl-1-[5-(trifluoromethyl)-2-pyridinyl]-1H-pyrazol-4-yl}ethanone and 0.2 mmol of 4-methoxycarbonylbenzhydrazide were heated in 2 ml of DMF at 100° C. for 9 hours with stirring. After the solvent was removed by evaporation, the resulting crude product was dissolved in chloroform and recrystallized from hexane to obtain 66 mg of the desired product, methyl 4-{([2-(1-{5-hydroxy-3-methyl-1-[5-(trifluoromethyl)-2-pyridinyl]-1H-pyrazol-4-yl}ethylidene)hydrazino]carbonyl}benzoate (yield 72%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.ClC(Cl)(Cl)C(=N)O[C:12]([CH3:15])([CH3:14])[CH3:13].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:12]([O:7][CH:5]1[CH2:6][C:2](=[O:1])[CH:3]=[CH:4]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: O=C1C=CC(O)C1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC1C=CC(=O)C1
Temperature: 6.5 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
A solution of 4-hydroxy-2-cyclopentenone (1.15 g, 11.7 mmol) in methylene chloride is cooled to 3° C. and treated sequentially with tert-butyl trichloroacetimidate (4.2 mL, 23.7 mmol) and boron trifluoride diethyl etherate (0.15 mL). The reaction mixture is stirred at 3-10° C. for 2 hours and then allowed to warm to room temperature and stirred for 22 hours. The reaction mixture is then treated with sodium bicarbonate (250 mg) and filtered. The filtrate is concentrated under vacuum and the residue is purified by chromatography (silica gel, 39 g, 20% ethyl acetate/hexane, 600 mL) to provide the title compound (355 mg, 40%) as a yellow oil; 1H NMR (CDCl3)δ7.44 (dd, 1H, J=18 Hz), 6.2 (d, 1H, J=5.4 Hz), 4.8 (m, 1H), 2.68 (dd, 1H, J=5.8, 18 Hz), 2.25 (d, 1H, J=18 Hz), 1.27 (s, 9H); IR (neat) νmax 2976, 2936, 1721, 1368, 1352, 1188, 1103, 1161 cm-1 ; MS (CI) m/e (% relative intensity) 155 (M+H+, 22), 99 (100).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[C:4]([C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=1)[CH:5]=NO.Cl.C=[O:18].O>O1CCCC1>[Br:1][C:2]1[C:3]([CH3:15])=[C:4]([C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=1)[CH:5]=[O:18]
Reactant: Cc1c(Br)ccc(S(C)(=O)=O)c1C=NO
Reactant: C=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Br)ccc(S(C)(=O)=O)c1C=O
Temperature: 25 °C

Procedure:
7.1 g of 3-bromo-2-methyl-6-methylsulfonylbenzaldoxime (23 mmol) are stirred at 65° C. in a mixture of 17 g of 5% strength hydrochloric acid, 2 g of 37% strength formaldehyde solution, 15 ml of water and 30 ml of tetrahydrofuran for 32 hours. During this time, a further 3.5 g of 37% strength formaldehyde solution are added in portions of 0.5 g. The mixture is then cooled to room temperature and the product is filtered off with suction.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[CH:7][S:8][CH:9]=1)[CH2:3][NH2:4].[C:10]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=O)[CH3:24])=[CH:18][CH:17]=1)([O:12][CH3:13])=[O:11]>>[C:10]([CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH:23]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[CH:7][S:8][CH:9]=2)[CH3:24])=[CH:20][CH:21]=1)([O:12][CH3:13])=[O:11]
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1cscn1
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2cscn2)cc1

Procedure:
Prepared analogously to Example 13 by reaction of 2-hydroxy-2-(thiazol-4-yl)ethylamine with 1-(4-carbomethoxymethoxyphenyl)propan-2-one followed by purification of the base on a silica gel column using ethyl acetate/methanol=8:2 as eluant.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)[C:11]2[CH2:16][O:15][C:14](=[O:17])[NH:13][C:12]=2[N:18]=1.[ClH:32]>O1CCOCC1>[ClH:32].[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[C:11]2[CH2:16][O:15][C:14](=[O:17])[NH:13][C:12]=2[N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3O)nc3c2COC(=O)N3)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1Nc2nc(-c3ccccc3O)cc(C3CCCNC3)c2CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of tert-butyl 3-[7-(2-hydroxyphenyl)-2-oxo-1,4-dihydro-2H-pyrido-[2,3-d][1,3]oxazin-5-yl]-1-piperidinecarboxylate (45 mg, 0.11 mmol) in 1,4-dioxane (1.0 mL) was added 4N HCl in 1,4-dioxane (2.0 mL). The mixture was stirred for 1 hr at room temperature. The resulting solid was collected by filtration, washed with 1,4-dioxane, and dried under reduced pressure to give 7-(2-hydroxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one hydrochloride as a white solid. (22.8 mg, yield; 60%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C1(P(=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
In a 2 l three necked flask fitted with mechanical stirrer and dropping funnel under inert atmosphere, 106.2 g (755 mmoles, 1 eq) of 3-chlorobenzaldehyde are dissolved in 1 l of THF and cooled down to 0° C. 341.9 g (980 mmoles, 1.3 eq) of ethyl (triphenylphosphoranylidene)acetate are then added under efficient stirring, the temperature raising to 10° C. The mixture is kept under stirring one hour at 0° C., and then overnight at room temperature. The mixture is concentrated to dryness, the residue suspended in diethyl ether, the triphenylphosphine oxide is filtered off and the filtrate concentrated to dryness. The residue is purified by PrepLC (1 kg SiO2, pet. ether/EtOAc, 75:35) to give 191.8 g of pure 375, 92% yield. 1H NMR (250 MHz, (CD3)2SO): 1.30 (t, 3H), 4.25 (q, 2H), 6.70 (d, 1H), 7.40 (m, 2H), 7.50-7.70 (m, 2H), 7.85 (s(broad), 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@@H:6]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][C:14]([OH:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)[CH2:7]1)=[O:4].CCN(CC)CC.Cl[C:32]1[S:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1>C(O)(C)C>[S:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[NH:1][CH2:2][C:3]([NH:5][C@@H:6]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:12][CH2:13][C:14]([OH:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:15][CH2:16]2)[CH2:7]1)=[O:4]
Reactant: NCC(=O)N[C@@H]1CCN(C2CCC(O)(c3ccccn3)CC2)C1
Reactant: Clc1nc2ccccc2s1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C(CNc1nc2ccccc2s1)N[C@@H]1CCN(C2CCC(O)(c3ccccn3)CC2)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
The mixture of 2-amino-N-[(3R)-1-(4-hydroxy-4-pyridin-2-ylcyclohexyl)pyrrolidin-3-yl]acetamide (0.080 g, 0.25 mmol), Et3N (0.35 mL, 2.5 mmol) and 2-chloro-benzothiazole (0.424 g, 2.5 mmol) in isopropanol was stirred overnight at 90° C. The reaction mixture was concentrated and chromatographed to provide 55 mg of the title compound in 49% yield. MS (EI) calculated: (M+)+=452.2; found: 452.2.
Reaction SMILES: [Br:1][CH2:2][CH:3]1[CH2:7][C:6]2[CH:8]=[C:9]([NH2:12])[CH:10]=[CH:11][C:5]=2[O:4]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].CCN(CC)CC>C(Cl)Cl>[Br:1][CH2:2][CH:3]1[CH2:7][C:6]2[CH:8]=[C:9]([NH:12][S:14]([CH3:13])(=[O:16])=[O:15])[CH:10]=[CH:11][C:5]=2[O:4]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)CC(CBr)O2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)CC(CBr)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
(RS)-2-bromomethyl-2,3-dihydro-benzofuran-5-ylamine (410 mg, 1.80 mmol), methansulfonyl-chloride (206 mg, 1.8 mmol), Et3N (182 mg, 1.80 mmol) were dissolved in CH2Cl2 (50 ml) and stirred overnight at room temperature. Solvent was then evaporated and the residue was chromatographed over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2—MeOH (95:5) to provide (RS)-N-(2-bromomethyl-2,3-dihydro-benzofuran-5-yl)-methansulfonamide (516 mg, 94%) as an oil. MS: m/e=305.9 (M−H+)
Reaction SMILES: [CH:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]2[C:10]([O:12][C:13](=[O:14])[C:3]=2[CH:2]=1)=O.[NH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(O)(=O)C>[O:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][N:15]2[C:10](=[O:12])[C:4]3[C:3](=[CH:2][CH:1]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=3)[C:13]2=[O:14])[CH2:19][CH2:20]1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: NCCN1CCOCC1
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)C(=O)N(CCN1CCOCC1)C2=O
Temperature: 25 °C
Yield: 81.8 %

Procedure:
1,2,4-Benzenetricarboxylic anhydride (356, 0.487 g, 2.53 mmol) and 4-(2-aminoethyl)morpholine (0.33 g, 2.53 mmol) were allowed to stir 2 hours at 130° C. in acetic acid (10 mL). The reaction mixture was then cooled to room temperature and the precipitated solid was collected by filtration, washed with H2O and dried under vacuum, to afford title compound 357 as a white powder (0.63 g, 82% yield). 1H NMR (DMSO) δ (ppm): 8.26 (dd, J=7.6, 1.4 Hz, 1H), 8.15 (dd, J=1.4, 0.6 Hz, 1H), 7.92 (dd, J=7.6, 0.6 Hz, 1H), 3.73 (t, J=6.5 Hz, 2H), 3.50 (t, J=4.5 Hz, 4H), 2.59 (t, J=6.5 Hz, 2H), 2.47 (overlapped with DMSO, 4H). MS: 304.3 (calc), 305.1 (obs).