Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:3][CH:2]=1.[OH-].[Na+]>CCO>[C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1
Reactant: CCOC(=O)COc1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(OCC(=O)O)cc1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-(p-tolyloxy)acetate (200 mg, 1 mmol) in EtOH (10 ml) was added 10% NaOH solution (10 ml) at 26° C. The mixture was stirred for 30 min, concentrated then water (20 mL) added to it before washing with ethyl acetate (2×20 mL). The aqueous layer was acidified with 2N HCL until pH 3 and extracted with EA (2×20 ml). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound which was used in next step without further purification.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH2:18][CH2:19][CH3:20])[C:7]2[O:12][C:11]([C:13](N)=[O:14])=[CH:10][C:9](=[O:16])[C:8]=2[CH:17]=1)[CH2:2][CH3:3].Br.[OH2:22]>C(O)(=O)C>[CH2:1]([C:4]1[CH:5]=[C:6]([CH2:18][CH2:19][CH3:20])[C:7]2[O:12][C:11]([C:13]([OH:22])=[O:14])=[CH:10][C:9](=[O:16])[C:8]=2[CH:17]=1)[CH2:2][CH3:3]
Reactant: O
Reactant: CCCc1cc(CCC)c2oc(C(N)=O)cc(=O)c2c1
Agent: Br
Solvent: CC(=O)O
Product: CCCc1cc(CCC)c2oc(C(=O)O)cc(=O)c2c1

Procedure:
A mixture of 1.0 parts of 6,8-dipropyl-4-oxo-4H-1-benzopyran-2-carboxamide, 20 parts of glacial acetic acid, and 20 parts of a solution of hydrogen bromide (45% weight/volume) in glacial acetic acid was heated at reflux for 3 hours, then added to water and extracted with chloroform. Extraction of the organic layer with saturated sodium bicarbonate solution, followed by acidification of the bicarbonate layer, afforded 0.16 parts of 6,8-dipropyl-4-oxo-4H-1-benzopyran-2-carboxylic acid, melting point 183°-184°C (decomposition). The melting point, IR spectrum and thin layer chromatographic properties of this material were identical with those of the compound prepared in Example 8.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH2:15][CH:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])[CH3:3].[BH4-].[Na+].C(O)(=O)C>C(O)C.O>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH2:15][C@H:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[OH:21])[CH:8]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:10]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(CC2CCCC2=O)cc(C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C[C@H]2CCC[C@H]2O)cc(C(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
To a solution of 710 mg (2.48 mmoles) of the title product of Example 5 in 25 ml of ethanol was added dropwise a solution of 188 mg (4.97 mmoles) of sodium borohydride in 3 ml of water. After 30 minutes, acetic acid was added, most of the ethanol was evaporated, the residue was partitioned between diethyl ether and dilute aqueous hydrochloric acid, the aqueous layer was further extracted with ether, and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue using 15% ethyl acetate/hexane as eluent gave the title cis isomer (105 mg) and the title trans isomer (155 mg) as colorless oils. The structures were supported by 1H NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[Cl:31][CH2:32][S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1>[Cl:31][CH2:32][S:33]([NH:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1)(=[O:35])=[O:34]
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: O=S(=O)(Cl)CCl
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)CCl)ccc3N2)c(O)c2cccnc21
Temperature: 120 °C
Yield: 22.2 %

Procedure:
To the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added chloromethylsulfonyl chloride (18 mL, 0.2 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 120 minutes. The reaction was cooled to 25° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered, and washed with of 1:1 hexane:ethyl acetate. The crude product was purified by chromatography on reverse phase gradient eluting with 0.1% trifluoroacetic acid in water/methanol (90/10) to 0.1% trifluoroacetic in water/methanol (5/95) to give the title compound (6 mg, 22%). 1H NMR (300 MHz, DMSO-d6) δ 0.99 (d, J=6.62 Hz, 6 H) 1.57 (m, 2 H) 1.69 (m, 1 H) 4.49 (t, J=7.74 Hz, 2 H) 5.18 (s, 2 H) 7.51 (dd, J=7.91, 4.60 Hz, 1 H) 7.62 (dd, J=8.82, 2.57 Hz, 1 H) 7.67 (d, J=2.57 Hz, 1 H) 7.77 (d, J=8.82 Hz, 1 H) 8.56 (dd, J=8.09, 1.84 Hz, 1 H) 8.90 (dd, J=4.41, 1.84 Hz, 1 H) 10.91 (s, 1 H) 14.10 (s, 1 H). MS (ESI−) m/z 538 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=1[C:17]#[N:18])[CH3:2].CC(C)([O-])C.[K+]>O1CCCC1>[NH2:18][C:17]1[C:8]2[C:7](=[CH:12][C:11]([O:13][CH3:14])=[C:10]([O:15][CH3:16])[CH:9]=2)[NH:6][C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:19]
Reactant: CCOC(=O)CNc1cc(OC)c(OC)cc1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2cc(OC)c(OC)cc2c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
Stir under N2 a solution of (2-cyano-4,5-dimethoxy-phenylamino)-acetic acid ethyl ester (0.124 g, 0.47 mmol) in tetrahydrofuran (6 mL) and add, dropwise, 1M potassium tert-butoxide in tetrahydrofuran (0.66 mL, 0.66 mmol). Stir for 1 h at ambient temperature and pour into ice/water. Extract with ethyl acetate, dry the extract over MgSO4, filter and concentrate under vacuum to a solid. Chromatograph on a Sep Pak silica gel cartridge (2 g) eluting with dichloromethane and then 2:1 heptane-ethyl acetate. Combine like fractions and concentrate to provide 61.9 mg (49%) of the title compound as a solid: MS 265(M+H).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:21])[CH:9]=[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=3)[C:5]2=[N:4][CH:3]=1.[CH3:22][N:23](C=O)C>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[C-]#N.[Zn+2]>[Cl:21][C:8]1[CH:9]=[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)[C:5]2[N:6]([C:2]([C:22]#[N:23])=[CH:3][N:4]=2)[N:7]=1
Reactant: CN(C)C=O
Reactant: CCOc1ccc(Nc2cc(Cl)nn3c(Br)cnc23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCOc1ccc(Nc2cc(Cl)nn3c(C#N)cnc23)cc1
Temperature: 200 °C

Procedure:
In a 5 ml microwave vial was added 3-bromo-6-chloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine (0.3 g, 0.8 mmol) from 1b, Pd(PPh3)4 (0.18 g, 0.16 mmol), Zn(CN)2 (0.47 g, 4.0 mmol) and DMF (3 ml). The reaction was heated via microwave for 25 min at 200° C. Upon cooling, the reaction mixture was diluted with ethyl acetate and filtered through a plug of celite. The solvent was removed in vacuo and the resulting material was purified by silica gel chromatography (ethyl acetate/heptane, 25 min gradient: 5-50% ethyl acetate) to give 0.11 g of 6-chloro-8-(4-ethoxyphenylamino)imidazo[1,2-b]pyridazine-3-carbonitrile.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)=[CH:10][C:9]=1Br)[CH:2]=[CH2:3].[Li]CCCC.C[Si](C)(C)[O:32][C@@H:33]1[C@@H:38]([O:39][Si](C)(C)C)[C@H:37]([O:44][Si](C)(C)C)[C@@H:36]([CH2:49][O:50][Si](C)(C)C)[O:35][C:34]1=O.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>C1COCC1.CC#N>[CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[C@H:34]1[C@H:33]([OH:32])[C@@H:38]([OH:39])[C@H:37]([OH:44])[C@@H:36]([CH2:49][OH:50])[O:35]1)[CH:2]=[CH2:3]
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Reactant: C=CCOCCOc1cc(Cl)c(Cc2ccc(CC)cc2)cc1Br
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CC#N
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCOCCOc1cc(Cl)c(Cc2ccc(CC)cc2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-(allyloxy)ethoxy)-2-bromo-5-chloro-4-(4-ethylbenzyl)benzene (AV) (1.74 g, 4.25 mmol) in anhydrous THF (10 mL) at −78° C., was added dropwise n-BuLi (2.9 M, 1.76 mL) and stirring was continued at −78° C. for 1 hour. The mixture was transferred to a solution of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)-tetrahydropyran-2-one (2.18 g, 4.68 mmol) in anhydrous THF (10 mL) at −78° C., and stirring was continued at −78° C. for 2 hours until the starting material was consumed. After quenching with methanesulfonic acid (1 g in 10 mL MeOH), the mixture was allowed to warm to room temperature and stirred overnight. H2O (20 mL) was added, and the organic phase was separated. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with saturated NaHCO3, water and brine, and then dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography to provide crude product (0.8 g, Rf=0.1-0.2, EtOAc:PE=2:1). The crude product was dissolved in anhydrous CH3CN (10 mL), Et3SiH (1 mL) was added, the mixture was cooled to −5° C., and BF3.Et2O (0.6 mL) was added dropwise. The reaction was allowed to warm to 20° C. and stirred overnight. After the reaction was complete, it was quenched with saturated aqueous NaHCO3. The solvent was removed under vacuum and the residue was extracted with EtOAc and washed with water and brine. The residue was then dried with anhydrous Na2SO4, filtered and concentrated to give a solid, which was purified by preparative HPLC and freeze-dried to give final product AW as a white powder. 1H-NMR (CDCl3, 300 MHz) δ 7.34 (s, 1H), 7.07 (s, 4H), 7.04 (s, 1H), 5.96 (m, 1H), 5.28˜5.35 (m, 1H), 5.17˜5.22 (m, 1H), 4.54 (d, J=9.0 Hz, 1H), 4.03˜4.15 (m, 4H), 3.97 (d, J=2.1 Hz, 2H), 3.79˜3.87 (m, 2H), 3.62˜3.72 (m, 1H), 3.45˜3.51 (1,2H), 3.35˜3.44 (m, 2H), 3.29˜3.31 (m, 4H), 2.56 (q, J=7.5 Hz, 2H), 1.18 (t, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8]OS(C)(=O)=O)[CH:5]=[C:4]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:3]=1.[CH:24]([C:27]1[C:32](=[O:33])[NH:31][C:30](=[O:34])[NH:29][C:28]=1[O:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]#[N:46])[CH:39]=[C:40]([CH3:42])[CH:41]=1)([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:29]2[C:28]([O:35][C:36]3[CH:37]=[C:38]([CH:43]=[CH:44][C:45]#[N:46])[CH:39]=[C:40]([CH3:42])[CH:41]=3)=[C:27]([CH:24]([CH3:26])[CH3:25])[C:32](=[O:33])[NH:31][C:30]2=[O:34])[CH:5]=[C:4]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:3]=1
Reactant: COc1ccc(CNc2cc(COS(C)(=O)=O)cc(F)n2)cc1
Reactant: Cc1cc(C=CC#N)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C=CC#N)c4)c(C(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a flask containing Methanesulfonic acid 2-fluoro-6-(4-methoxy-benzylamino)-pyridin-4-ylmethyl ester (44) (1 mmol), 3-[3-(5-Isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yloxy)-5-methyl-phenyl]-acrylonitrile (43) (311 mg, 1 mmol), anhydrous powdered potassium carbonate (138 mg, 1 mmol), lithium iodide (134 mg, 1 mmol) was added anhydrous DMF (5 ml) and stirred for overnight at room temperature. The mixture was evaporated in vacuo. The residue was dissolved in methanol-dichloromethane (1:9), filtered through celite pad, and the filtrate was evaporated in vacuo to give a pale yellow foam. The crude product was purified by silica gel column chromatography (eluent, EA:hexane (1:2); The fraction of Rf=0.19 was collected) to afford 255 mg (46%) of a white foam; 1H NMR (300 MHz, CDCl3) δ: 1.10 (6H, d, J=6.9 Hz), 2.32 (3H, s), 2.68 (1H, m), 3.79 (3H, s), 4.31 (2H, d, J=5.5 Hz), 4.73 (2H, s), 5.02 (1H, t, J=5.5 Hz), 5.81 (1H, d, J=16.6 Hz), 5.85 (1H, s), 5.98 (1H, s), 6.64 (2H, s), 6.86-6.89 (2H, m), 6.98 (1H, s), 7.20-7.24 (3H, m), 8.98 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N+:11]([O-])=O.[H][H]>[Ni].CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH2:11]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(Cl)c(N)c1

Procedure:
A mixture of 1-chloro-2,4-dinitrobenzene (40.0 g, 0.197 mole), methanol (100 g), and 3.0 g of modified Raney nickel catalyst consisting of about 83.1% Ni, 9.3% Co, 7.1% Al and 0.5% Mo was charged into an autoclave. The autoclave was sealed, pressurized with hydrogen to 700 psig, and the hydrogenation carried out at about 30° C. Hydrogen uptake was observed by monitoring the pressure change. After the hydrogen uptake ceased (approximately 6.0 hrs.), the reaction mixture was heated for a short time longer and then the autoclave was vented. A sample of the reaction mixture was taken and analyzed by liquid chromatography after being separated from the solid catalyst. The desired product 1-chloro-2,4-diaminobenzene was formed in high yield and good purity. Liquid chromatography indicated an area % of 92.4% (excluding the methanol solvent) for the product. Very little dechlorination had occurred.
Reaction SMILES: [C:1]1([C:7]2([OH:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][CH2:21][OH:22].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[OH:22][CH2:21][CH2:20][CH2:19][NH:18][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([OH:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: NCCCO
Reactant: O=C1Nc2ccccc2C1(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: OCCCNC1=Nc2ccccc2C1(O)c1ccccc1

Procedure:
3-Phenyl-3-hydroxy-3H-indol-2-one (4.5 g.) was heated under reflux with 3-aminopropanol (6.0 g.) in xylene (100 ml.) and toluene-p-sulphonic acid (150 mg) in an apparatus fitted with a water separator. After 24 hours the reaction mixture was cooled. The product crystallised and was filtered off and recrystallised from methanol to give the title compound, 3.81 g., m.p. 215°-217°C. (Found C, 72.4; H, 6.7; N. 9.9, C17H18N2O2 requires C, 72.3; H, 6.4; N, 9.9%).
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=O)(C)(C)C.Br[C:20]1[C:21]([C:26]#[N:27])=[N:22][CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO.ClCCl.O>[F:15][C:14]1[C:9]2[C:10](=[C:20]3[C:21](=[C:26]([NH2:27])[N:8]=2)[N:22]=[CH:23][CH:24]=[CH:25]3)[CH:11]=[CH:12][CH:13]=1
Reactant: N#Cc1ncccc1Br
Reactant: CC(C)(C)OC(=O)Nc1c(F)cccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Nc1nc2c(F)cccc2c2cccnc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 2-(tert-butoxycarbonylamino)-3-fluorophenylboronic acid (from step 2) (1.0 eq.) and 3-bromopicolino-nitrile (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. After workup, the crude product was suspended in hot toluene, centrifuged (2500 rpm, 5 min), and the supernatant was removed. The suspension, centrifugation, and removal of supernatant steps were repeated with hot ethyl acetate, ether, and hexane to give a pure solid. 1H NMR (acetone d-6): δ 9.04 (d, 1H), 8.96 (d, 1H), 8.27 (d, 1H), 7.86-7.90 (dd, 1H), 7.28-7.34 (m, 2H), 6.9 (br, 2H). LRMS [M+H]=214.1
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[NH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18](=O)[CH3:19].C(=O)([O-])[O-]>C(Cl)Cl>[Cl:17][C:15]1[CH:16]=[C:11]2[C:12]([C:18]([CH3:19])=[CH:2][C:1]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[N:10]2)=[CH:13][CH:14]=1
Reactant: CC(=O)c1ccccc1
Reactant: CC(=O)c1ccc(Cl)cc1N
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cc1cc(-c2ccccc2)nc2cc(Cl)ccc12
Temperature: 100 °C
Reaction time: 60 h

Procedure:
Acetophenone (0.66 mL, 5.69 mmol) was added to 1-(2-amino-4-chlorophenyl)ethanone (0.868 g, 5.69 mmol) and [Hbim]BF4 (1.50 g, 7.08 mmol) under Ar. The reaction mixture was heated at 100° C. for 57 h then cooled to rt and partitioned between EtOAc and H2O. The aq layer was extracted with EtOAc. The combined organics were dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography on SiO2 (70 g, EtOAc in hexanes 0:100->1:40->1:30) afforded a lightly colored oil. The material was dissolved in DCM (100 mL) and stirred with PS-Ts-NHNH2 (2.07 g, 2.87 mmol/g, 5.94 mmol) for 2.5 d at rt and then with MP-carbonate (˜0.25 g, 2.74 mmol/g, 0.68 mmol) for 4 h. The resins were removed by filtration through Celite. The residue and Celite were rinsed with DCM multiple times. The filtrate was concentrated under reduced pressure to provide the title compound as a light yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.18-8.12 (m, 3H), 7.92 (d, J=8.4 Hz, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.54-7.46 (m, 4H), 2.75 (s, 3H); MS (ES+): m/z 254.24 (35) [MH+]; HPLC: tR=3.82 min (OpenLynx, nonpolar—5 min).
Reaction SMILES: Cl[CH:2](Cl)[C:3]([OH:5])=[O:4].[H-].[Na+].[Cl:9][C:10]1[CH:11]=[CH:12][C:13](C(C)(C)C)([OH:24])[CH:14]([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[OH:17])[CH:15]=1.O>O1CCOCC1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[O:24][CH:2]([C:3]([OH:5])=[O:4])[O:17][C:16]([C:14]([CH3:16])([CH3:15])[CH3:13])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]=2[CH:15]=1
Reactant: O=C(O)C(Cl)Cl
Reactant: CC(C)(C)C1(O)C=CC(Cl)=CC1C(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)C1(c2ccccc2)OC(C(=O)O)Oc2ccc(Cl)cc21
Temperature: 80 °C

Procedure:
A solution of 5.82 ml of dichloroacetic acid in 100 ml of dioxane was added dropwise with stirring to a mixture of 12.8 g of sodium hydride in a 50% oil suspension, 100 ml of anhydrous dioxane and 600 mg of dibenzo-18-couronne-6 kept at room temperature and a solution of 14.1 g of 5-chloro-2-tert.-butyl-2-hydroxy-α-phenyl-benzene-methanol in 100 ml of dioxane was added dropwise at room temperature. The mixture was heated at 80° C. for 6 hours and was then cooled to room temperature which was kept on an ice bath. 400 ml of water were added and the aqueous phase was extracted with 600 ml of ether. The ether extract was extracted 3 times with 100 ml of 0.1 N sodium hydroxide solution and the aqueous phase was acidified with 2 N hydrochloric acid and was extracted 3 times with 150 ml of ether. The organic extracts were washed 3 times with 100 ml of water and were extracted with a saturated sodium bicarbonate solution and then 3 times with 100 ml of water. The combined aqueous phases were washed 3 times with ether and was acidified with 2 N hydrochloric acid. The aqueous phase was extracted 4 times with 150 ml of ether and the ether phases were washed 3 times with water, dried over magnesium sulfate, treated with activated carbon and evaporated to dryness to obtain 9.1 g of raw 6-chloro-4-tert.-butyl-4-phenyl-[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of two racemates diastereoisomers).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[N:14]=2)[N:11]=1.[CH3:23][N:24]1[C:28]([C:29](Cl)=[O:30])=[CH:27][C:26]([CH3:32])=[N:25]1>CN(C)C(=O)C>[C:16]([NH:15][C:13]1[N:14]=[C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]3[CH:19]=[CH:20][C:21]([CH3:22])=[C:2]([NH:1][C:29]([C:28]4[N:24]([CH3:23])[N:25]=[C:26]([CH3:32])[CH:27]=4)=[O:30])[CH:3]=3)=[N:11][N:10]2[CH:12]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1cn2nc(Oc3ccc(C)c(N)c3)ccc2n1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1cn2nc(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Yield: 77.5 %

Procedure:
In the same manner as in Example 264 and using N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide (840 mg, 2.8 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonylchloride (540 mg, 3.4 mmol) and N,N-dimethylacetamide (35 mL), the title compound (910 mg, 77%) was obtained as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH:4]([C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])[CH3:3].Cl.CNC.S1C=CC(C=O)=C1.N1(C2CCCCC=2)CCCC1.[Cl:39][CH2:40][C:41]1[CH:42]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:44]=[CH:45][CH:46]=1.Cl>>[ClH:39].[CH3:3][N:2]([CH:4]([C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:48])([F:49])[F:50])[CH:42]=1)[OH:11])[CH3:1]
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: CN(C)C(c1ccsc1)C1CCCCC1=O
Agent: C1=C(N2CCCC2)CCCC1
Agent: CNC
Agent: Cl
Product: CN(C)C(c1ccsc1)C1CCCCC1(O)Cc1cccc(C(F)(F)F)c1

Procedure:
In the manner described for Example 6, 2-(dimethylaminothiophen-3-ylmethyl)cyclohexanone was first prepared from dimethylamine hydrochloride, thiophene-3-carbaldehyde and 1-(pyrrolidino)-1-cyclohexene and then, by reaction with 3-chloromethyl benzotrifluoride in a Grignard reaction and subsequent precipitation of the hydrochloride, 2-(dimethylaminothiophen-3-ylmethyl)-1-(3-trifluoromethylbenzyl)cyclohexanol hydrochloride was obtained.
Reaction SMILES: [N:1]1([C:10](=[O:26])/[CH:11]=[CH:12]/[C@@H:13]([NH:18]C(=O)OC(C)(C)C)[CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[N:1]1([C:10](=[O:26])/[CH:11]=[CH:12]/[C@@H:13]([NH2:18])[CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)C[C@@H](/C=C/C(=O)N1CCc2ccccc21)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)/C=C/C(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
To a solution of 1,1-dimethylethyl [(1S,2E)-4-(2,3-dihydro-1H-indol-1-yl)-1-(2-methylpropyl)-4-oxo-2-buten-1-yl]carbamate (3.21 g, 8.95 mmol) in CH2Cl2 (10.0 mL) was added TFA (10 mL, 130 mmol). The reaction mixture was stirred for 17.5 h at RT and then concentrated under reduced pressure and dried under high vacuum to afford the title compound. LC-MS m/z 259 (M+H)+, 0.76 min (ret time).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:14][S:15]([CH2:18][CH2:19]COS(C)(=O)=O)(=[O:17])=[O:16].[ClH:26].Cl.COCC(NC(=O)CN1CCNCC1)C>>[ClH:26].[ClH:26].[CH3:14][S:15]([CH2:18][CH2:19][CH2:6][N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)CCCOS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: COCC(C)NC(=O)CN1CCNCC1
Agent: Cl
Product: CS(=O)(=O)CCCN1CCNCC1

Procedure:
1-(3-Methanesulfonyl-propyl)-piperazine dihydrochloride was prepared from 1-tert-butyloxycarbonyl-piperazine and methanesulfonic acid 3-methanesulfonyl-propyl ester (prepared according to Baerlocher, F. J. et al. Aust. J. Chem. 1999, 52, 167-172) in an analogous manner as described for the preparation of N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide dihydrochloride (example 40).