Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20].[F:21][C:22]1[CH:39]=[CH:38][C:25]([CH2:26][NH:27][S:28]([C:31]2[C:32](Br)=[N:33][CH:34]=[CH:35][CH:36]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>ClCCl.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>[F:21][C:22]1[CH:39]=[CH:38][C:25]([CH2:26][NH:27][S:28]([C:31]2[CH:32]=[N:33][CH:34]=[C:35]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:2]([CH3:1])[C:3](=[O:20])[CH2:4]4)[CH:36]=2)(=[O:29])=[O:30])=[CH:24][CH:23]=1
Reactant: CN1C(=O)Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: O=S(=O)(NCc1ccc(F)cc1)c1cccnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1C(=O)Cc2cc(-c3cncc(S(=O)(=O)NCc4ccc(F)cc4)c3)ccc21
Temperature: 100 °C

Procedure:
To 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one, prepared as described in Example 3a (124 mg, 0.45 mmol) was added bromo-pyridine-3-sulfonic acid 4-fluoro-benzylamide (140 mg, 0.41 mmol), tripotassium phosphate (260 mg, 1.25 mmol) and DMF (2.5 mL). The reaction mixture was degassed and placed under an argon atmosphere, at which time tetrakis(triphenylphosphine)palladium(0), (23 mg, 0.02 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 100° C. for 60 minutes. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (heptane-ethyl acetate, 20 to 100%) to furnish 5-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyridine-3-sulfonic acid 4-fluoro-benzylamide; HRMS: (ESI) m/z 412.1136 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.17 (s, 3H), 3.65 (s, 2H), 4.12 (s, 2H), 7.03 (t, J=8.8 Hz, 2H), 7.14 (d, J=8.1 Hz, 1H), 7.25 (dd, J=8.6, 5.6 Hz, 2H), 7.65 (s, 1H), 7.67 (d, J=8.1 Hz, 1H), 8.20 (t, J=2.3 Hz, 1H), 8.44 (t, J=6.3 Hz, 1H), 8.80 (d, J=2.0 Hz, 1H), 9.04 (d, J=2.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12](O)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([Cl:28])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2O)cc1
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2Cl)cc1
Temperature: 25 °C
Yield: 29 %

Procedure:
A solution of 2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 332, in POCl3 was heated to reflux for 3 hours while stirring under nitrogen. The mixture was cooled to room temperature and poured into ice with constant swirling. The resulting white solid was extracted with ethyl acetate. The combined organics were washed with H2O, dried over MgSO4, and concentrated to a solid. The crude product was purified using flash chromatography (SiO2, eluting with 1:1 ethyl acetate/hexanes) to provide the desired product (yield: 0.151 g, 29%). mp 203–204° C. 1H NMR (300 MHz, DMSO d6) δ 3.29–3.36 (3H, obstructed by H2O), 7.60 (m, 3H), 7.76 (m, 1H), 7.92 (m, 2H), 8.14 (m, 2H), 8.25 (s, 1H). MS (DCI/NH3) m/z 395 (M+H)+, 412 (M+NH4)+. Anal. calc. for C17H12Cl2N2O3S: C, 51.66; H, 3.06; N, 7.09. Found: C, 51.67; H, 3.03; N, 6.93.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:21])[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[C:12]([C:13]=1O)=[CH:11][CH:10]=[CH:9][N:8]=2)(=O)[CH3:2].Cl.Cl.[CH2:24]([NH:31][NH2:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(O)(=O)C>[CH2:24]([N:31]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[N:8][C:7]=3[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:5](=[O:21])[C:4]=2[C:1]([CH3:2])=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1nn(Cc2ccccc2)c2c1c(=O)n(-c1ccccc1)c1ncccc21
Temperature: 25 °C
Yield: 61.5 %

Procedure:
Compound 102 obtained in Example 2, 3.0 g (10.7 millimoles), was suspended in 20 ml of glacial- acetic acid, and 3.1 g (16.1 millimoles) of benzylhydrazine dihydrochloride and 9.0 ml (64.2 millimoles) of triethylamine were added to the suspension. The mixture was heated under reflux for 10 hours. The reaction solution was cooled to room temperature, and the precipitate was collected by filtration and recrystallized from DMF-water to give 2.4 g (61.5%) of Compound 5.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:28])=[C:7]([N:9]2[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[C:11]([Br:26])[C:10]2=[O:27])[CH:8]=1.C(N(CC)CC)C.[C:36]([O:39][CH2:40][C:41](Cl)=[O:42])(=[O:38])[CH3:37].[Cl-].[NH4+]>O1CCCC1>[C:36]([O:39][CH2:40][C:41]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([F:28])=[C:7]([N:9]2[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[C:11]([Br:26])[C:10]2=[O:27])[CH:8]=1)=[O:42])(=[O:38])[CH3:37]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(N)ccc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)Nc1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the compound of Example 722 (0.5 g, 1.05 mmol) in tetrahydrofuran (20 mL) was treated with triethyl amine (0.3 mL, 2.1 mmol) and acetoxy acetylchloride (0.12 mL, 1.15 mmol). After stirring at room temperature for 2 h, the reaction was complete. The reaction mixture was poured into saturated aqueous ammonium chloride. The solids were filtered off and were washed with water and diethyl ether. Title product was isolated as a white solid (0.32 g, 58%). 1H NMR (400 MHz, CD3OD) δ 7.65 (m, 3H), 7.32 (t, J=8.4 Hz, 1H), 7.04 (t, J=8.4 Hz, 2H), 6.64 (s, 1H), 5.35 (s, 2H), 4.68 (s, 2H), 2.15 (s, 3H), 2.10 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −111.56 (1F), −115.99 (1F), −129.48 (1F) ppm. LC/MS, tr=5.35 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 540 (M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[C:12]([C:14](OCC)=[O:15])[CH:11]=[C:10]([CH3:19])[N:9]=1.C(O)(=O)C>C1COCC1>[Cl:7][C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:10]([CH3:19])[N:9]=1
Reactant: CCOC(=O)c1cc(C)nc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(CO)cc(Cl)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.7 %

Procedure:
Lithium aluminium hydride (350 mg, 9.26 mmol) was added in portions to a solution of ethyl 2-chloro-6-methyl-4-pyridinecarboxylate (1.85 g, 9.26 mmol) in THF (40 ml) cooled at 0° C. The mixture was stirred for 15 minutes at 0° C. and acetic acid (2 ml) was added. The mixture was partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH7.5 with 5 % aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (35/65) to give 2-chloro-4-hydroxymethyl-6-methylpyridine (1.28 g, 88%).
Reaction SMILES: C(OC([NH:11][C:12]1[CH:13]=[C:14]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:15]=[CH:16][C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=O)C1C=CC=CC=1.[OH:29][C:30]1[CH:31]=[C:32]([NH:46][C:47](OC2C=CC=CC=2)=[O:48])[C:33](=[CH:44][CH:45]=1)[C:34](OCC1C=CC=CC=1)=[O:35]>>[OH:29][C:30]1[CH:31]=[C:32]2[C:33]([C:34](=[O:35])[N:28]([S:25]([C:14]3[CH:13]=[C:12]([NH2:11])[C:17](=[CH:16][CH:15]=3)[C:18]([OH:20])=[O:19])(=[O:26])=[O:27])[C:47](=[O:48])[NH:46]2)=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1NC(=O)OCc1ccccc1
Reactant: O=C(Nc1cc(O)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Product: Nc1cc(S(=O)(=O)n2c(=O)[nH]c3cc(O)ccc3c2=O)ccc1C(=O)O
Yield: 4 %

Procedure:
620 mg (1.53 mmol) of 3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide and 550 mg (1.51 mmol) of benzyl 4-hydroxy-2-N-phenoxycarbonylanthranilate were treated in the same way as in Example 17 to obtain 25 mg (yield 4%: 4 steps) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 6.48 (1H, s), 6.61 (1H, d), 7.14 (1H, d), 7.51 (1H, s), 7.70 (1H, d), 7.90 (1H, d), 10.80 (1H, s), 11.39 (1H, s).
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[Br:10][C:11]1[C:12]([OH:20])=[C:13]([CH:16]=[C:17]([Br:19])[CH:18]=1)[CH:14]=O>C(O)(=O)C>[Br:10][C:11]1[C:12]([OH:20])=[C:13]([CH:16]=[C:17]([Br:19])[CH:18]=1)[CH:14]=[C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][C:8]1=[O:9]
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: O=Cc1cc(Br)cc(Br)c1O
Solvent: CC(=O)O
Product: O=C1NC(=O)C(=Cc2cc(Br)cc(Br)c2O)C(=O)N1
Reaction time: 36 h
Yield: 84.6 %

Procedure:
0.01 mol (1.28 g) of barbituric acid (5a) were dissolved in 25 ml of glacial acetic acid while heating. Then 0.011 mol (3.08 g) of 3,5-dibromo-2-hydroxybenzaldehyde (6a) were added to the obtained solution while stirring and the resulting reaction mixture was left at room temperature during 36 hours. The produced crystal product was filtered, washed with cold acetic acid, then washed with ether and air-dried. Thereby 3.3 g of product 1a were obtained in the form of yellow needle crystals with melting temperature of 255-260° C. (with decomposition). Output amounted to 77% of the theoretical value.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[CH:4][C:3](=[O:7])[CH2:2]1.[C:8](=[O:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:9].O.O.O.O.O.[N+]([O-])([O-])=O.[Bi+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(Cl)Cl>[O:7]=[C:3]1[CH2:2][O:1][CH2:6][CH:5]([NH:9][C:8](=[O:18])[O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4]1
Reactant: NC(=O)OCc1ccccc1
Reactant: O=C1C=CCOC1
Agent: O=[N+]([O-])[O-]
Agent: [Bi+3]
Solvent: ClCCl
Solvent: O
Product: O=C1COCC(NC(=O)OCc2ccccc2)C1
Yield: 73.5 %

Procedure:
2H-pyran-3(6H)-one (2.33 g, 23.75 mmol), benzyl carbamate (4.31 g, 28.5 mmol), and DCM (2.375 mL) were added to a small vial and stirred vigorously. To the thick syrup was added bismuth(III) nitrate pentahydrate (1.728 g, 3.56 mmol). The vial was capped and the reaction was stirred vigorously overnight. The reaction was diluted with DCM and filtered through a pad of celite. The filtrate was condensed and purified on a 100G SNAP Biotage column (10-100% ethyl acetate in hexane) to give benzyl 5-oxotetrahydro-2H-pyran-3-ylcarbamate (4.35 g, 17.45 mmol, 73.5% yield) as a pale yellow oil; 1H NMR (400 MHz, CDCl3) δ ppm 7.28-7.41 (m, 5H), 5.20-5.28 (m, 1H), 5.05-5.15 (m, 2H), 4.24-4.35 (m, 1H), 4.01-4.06 (m, 1H), 3.89-3.95 (m, 1H), 3.80-3.87 (m, 1H), 2.73 (d, J=5.47 Hz, 1H), 2.64-2.71 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22]Cl>>[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][N:8]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[C:6]=1[CH3:7])[S:9]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:11]
Reactant: Cc1noc(NS(=O)(=O)c2cccs2)c1C
Reactant: COCCOCCl
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1cccs1
Yield: 34 %

Procedure:
N-(methyoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 32B using N-(3,4-dimethyl-5-isoxazolyl)thiophene-2-sulfonamide and methoxyethoxymethyl chloride resulting in 34% yield. HPLC analysis of the crude oil obtained after workup showed that the oil was approximately 96% pure and so was used in the next step without further purification.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[CH2:6]1[O:14][C:13]2[CH:12]=[CH:11][C:10]([C:15](=[O:17])[CH3:16])=[CH:9][C:8]=2[O:7]1>O>[CH2:6]1[O:14][C:13]2[CH:12]=[CH:11][C:10]([C:15](=[O:17])[CH2:16][CH:2]([OH:3])[C:1]([OH:5])=[O:4])=[CH:9][C:8]=2[O:7]1
Reactant: O=CC(=O)O
Reactant: CC(=O)c1ccc2c(c1)OCO2
Solvent: O
Product: O=C(CC(O)C(=O)O)c1ccc2c(c1)OCO2
Reaction time: 3 h

Procedure:
29.6 g (0.2 M) of glyoxylic acid, 50% in water, are heated under reduced pressure until about 80% of the water present has been eliminated; then, after cooling, 65.5 g (0.4 M) of 3', 4'-methylenedioxyacetophenone are introduced into the reaction medium. Heating is performed for 3 hours at 95° C. under reduced pressure, the residual water present being simultaneously distilled off. After the medium has been cooled, there are introduced 200 cm3 of chloroform and 400 cm3 of water containing 12 g of sodium carbonate.
Reaction SMILES: [F-:1].[K+].C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1.[N+]([C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][N:36]=[C:35]2[O:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:47][CH:46]=1)([O-])=O.O>C1COCC1>[F:1][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][N:36]=[C:35]2[O:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:47][CH:46]=1
Reactant: [F-]
Reactant: CC(C)(C)c1ccc(CCOc2ncnc3ccc([N+](=O)[O-])cc23)cc1
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CCOc2ncnc3ccc(F)cc23)cc1

Procedure:
To a 25 ml round bottom flask is added potassium fluoride (82.6 mg, 1.42 mmol) and kryptofix 222 (0.53 g, 1.42 mmol). The above mixture is stirred in THF for 20 minutes after which 6-Nitro-4-(2-(4-tert-butylphenyl)ethoxy)quinazoline (0.1 g, 0.284 mmol) is added to it. The solution is refluxed for 30 minutes after which it is cooled and water is added to it. It is then extracted in dichloromethane, washed with water and dried. Purification by flash chromatography (silica gel; ethyl acetate/hexanes) gives the above compound.
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12]Cl.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH2:30][CH2:31][C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CC(CC(C)C)=O>[S:34]1[CH:35]=[CH:36][C:32]([CH2:31][CH2:30][N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([CH:18]3[CH2:19][CH2:20][N:15]([CH2:12][CH2:11][O:10][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]([OH:2])=[O:14])[CH2:16][CH2:17]3)=[CH:22]2)=[CH:33]1
Reactant: COC(=O)c1ccccc1OCCCl
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2CCc1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(CCc3ccsc3)c3ccccc23)CC1
Yield: 99.3 %

Procedure:
A solution of 1.5 g (0.007 mol) of 2-(2-chloro-ethoxy)-benzoic acid methyl ester (prepared in Example 1, part C) in 5 mL of methyl-iso-butylketone was added to a suspension of 2 g (0.065 mol) of 3-piperidin-4-yl-1-(2-thiophen-3-yl-ethyl)-1H-indole and 1.8 g (0.013 mol) of potassium carbonate in 45 mL of methyl-iso-butylketone. The reaction mixture was refluxed for 18 h. The crude mixture was filtered to remove inorganic salts and the solvent was removed under reduced pressure affording 3.3 g of a crude oil. The crude mixture was purified by flash chromatography over silica gel affording 1.5 g (48% of yield) of 2-(2-{4-[1-(2-thiophen-3-yl-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid methyl ester. This ester was dissolved in a mixture of 25 mL of methanol/THF 3:2 and hydrolysed with 2N NaOH at room temperature for 16 hours. The crude mixture was neutralised with 2N HCl aqueous solution and the solvent was removed under reduced pressure. The crude residue was precipitated with dichloromethane and then recrystallised with methanol affording 1.3 g of the expected acid.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[CH:22][CH:21]=3)=[O:19])[CH2:13][CH2:12]2)=[CH:3][CH:2]=1>C(N(CC)CC)C.O>[N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)=[O:19])[CH2:13][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccnc4c3CCCC4)CC2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)COc1ccc(C(=O)CN2CCN(c3ccnc4c3CCCC4)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a similar manner to Example 42, the product of Example 45 (180 mg), and 0.5% v/v triethylamine/water (40 ml) gave, after stirring overnight at room temperature, washing with ether, filtration and lyophilisation, the title compound (121 mg) as an off-white fluffy solid: NMR (CDCl3) δ 1.75(2H,m), 1.90(2H,m), 2.61(2H,m), 2.75(4H,m), 3.08(2H,m), 3.23(4H,m), 3.78(2H,s), 4.66(2H,s), 6.79(1H,d), 6.99(2H,d), 7.98(2H,d), 8.41(1H,d); m/Z 410 (M+H)+ ; calculated for C23H27N3O4. 0.03 Et3N. 1.0 H2O: C, 64.7%; H, 6.89%; N, 9.86%; found: C, 64.4%; H, 6.6%; N, 9.5%.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)([CH3:8])[CH3:7].CN1CCN(C)C1=O.O.C(O[CH:28](OCC)[N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[N:34][N+:35]([O-:37])=[O:36])C>>[CH:6]([C:9]1[CH:15]=[CH:14][C:12]([N:13]=[CH:28][N:29]2[CH2:33][CH2:32][NH:31][C:30]2=[N:34][N+:35]([O-:37])=[O:36])=[CH:11][CH:10]=1)([CH3:8])[CH3:7]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: CC(C)c1ccc(N=CN2CCNC2=N[N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 41.6 %

Procedure:
0.05 g of concentrated sulfuric acid was dropped in a mixture of 5.0 g of 1-diethoxymethyl-2-nitroiminoimidazolidine, 2.48 g of p-isopropylaniline and 2 ml of 1,3-dimethyl-2-imidazolidinone at 110° C., followed by agitation at the same temperature for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried and evaporated. Ether was added to the resultant oily residue and the resultant crystals were separated by filtration and dried to obtain 2.1 g of 1-(4-isopropylphenyliminomethyl)-2-nitroiminoimidazolidine.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][NH:5][CH:6]=1.N12CCCN=C1CCCCC2.[C:23]([CH:25]=[C:26]1[CH2:29][N:28]([C:30]2[C:44]([F:45])=[CH:43][C:33]([C:34]([NH:36][C@@H:37]([CH3:42])[C:38]([F:41])([F:40])[F:39])=[O:35])=[C:32]([F:46])[CH:31]=2)[CH2:27]1)#[N:24]>C(O)(C)C>[Br:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][N:5]([C:26]2([CH2:25][C:23]#[N:24])[CH2:29][N:28]([C:30]3[CH:31]=[C:32]([F:46])[C:33]([C:34]([NH:36][C@@H:37]([CH3:42])[C:38]([F:39])([F:41])[F:40])=[O:35])=[CH:43][C:44]=3[F:45])[CH2:27]2)[CH:6]=1
Reactant: C[C@H](NC(=O)c1cc(F)c(N2CC(=CC#N)C2)cc1F)C(F)(F)F
Reactant: CCOC(=O)c1n[nH]cc1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)O
Product: CCOC(=O)c1nn(C2(CC#N)CN(c3cc(F)c(C(=O)N[C@@H](C)C(F)(F)F)cc3F)C2)cc1Br
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a microwave vial was added isopropyl alcohol (10 mL), ethyl 4-bromo-1H-pyrazole-3-carboxylate (from ChemBridge) (788 mg, 3.60 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (48.9 μL, 0.327 mmol) and 4-[3-(cyanomethylene)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (from Example 4 step 4, 1.13 g, 3.27 mmol). The reaction mixture was stirred at 80° C. for 2 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was purified with flash chromatography (eluting with 0-35% ethyl acetate in hexanes) to give the desired product as white foam. 1H NMR (500 MHz, DMSO) δ 8.61 (s, 1H), 8.47 (d, J=8.7 Hz, 1H), 7.34 (dd, J=12.5 and 6.3 Hz, 1H), 6.62 (dd, J=11.9 and 7.3 Hz, 1H), 4.76 (dt, J=15.5 and 7.8 Hz, 1H), 4.61 (d, J=9.2 Hz, 2H), 4.39 (d, J=8.0 Hz, 2H), 4.32 (q, J=7.1 Hz, 2H), 3.68 (s, 2H), 1.31 (m, 6H) ppm. LCMS calculated for C21H20BrF5N5O3 (M+H)+: m/z=564.1. Found: 563.8.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[CH2:10][CH2:9][CH:8]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1Cl)CC1C2C(=CC=C(O)C=2)CCC1NC(=O)OC(C)(C)C.[OH-].[K+].Cl[C:59]([F:69])([F:68])C(C1C=CC=CC=1)=O>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:59]([F:69])[F:68])[CH:15]=3)[CH2:10][CH2:9][CH:8]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(O)cc2C1Cc1ccc(Cl)cc1
Agent: CC(C)(C)OC(=O)NC1CCc2ccc(O)cc2C1Cc1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCc2ccc(OC(F)F)cc2C1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Tert-butyl [1-(4-chlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (180 mg, 0.464 mmol, prepared analogously to tert-butyl [1-(3,4-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate, cf. Example 34.2 and potassium hydroxide (1.4 g, 25 mmol) were suspended in acetonitrile (4 mL). After stirring the two phase system for 45 min at room temperature the reaction mixture was cooled to −15° C. and a solution of 2-chloro-2,2-difluoro-1-phenylethanone (442 mg, 2.32 mmol) in acetonitrile (1 mL) was added dropwise over 30 min. The reaction mixture was warmed to room temperature and then heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined extracts were dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography (dichloromethane, silica gel). Yield: 30 mg (0.069 mmol, 15%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.CC(C)([O-])C.[K+].Cl.Cl[C:21]1[CH:26]=[CH:25][NH+:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:5]=1
Reactant: Clc1cc[nH+]cc1
Reactant: COC(OC)c1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)c1cccc(Oc2ccncc2)c1
Temperature: 25 °C

Procedure:
A solution of 1 g of 3-hydroxybenzaldehyde dimethyl acetal and 2 g of potassium tert.butoxide in 10 ml of anhydrous dimethylformamide was heated at 60° C. under an atmosphere of dry nitrogen for 1 hour. The mixture was then cooled to room temperature and 900 mg of 4-chloropyridinium hydrochloride were added portionwise over a period of 20 minutes. The mixture was then heated at 160° C. for 18 hours, cooled, 100 ml of water were added and the product was extracted with ethyl acetate. The combined extracts were washed with 1M aqueous sodium hydroxide solution and with brine, and then dried over anhydrous magnesium sulphate. Evaporation to dryness left a brown oil which was purified by column chromatography on silica gel using hexane/ethyl acetate (gradient: 90:10 to 20:80) for the elution to give 3-(4-pyridyloxy)-benzaldehyde dimethyl acetal as a light brown oil.