Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[NH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][OH:18].C([O-])([O-])=O.[K+].[K+].CN1CCCC1=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][OH:18])=[C:3]([CH3:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: NCCNCCO
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])ccc1NCCNCCO
Temperature: 60 °C
Yield: 77.8 %

Procedure:
2 g of 4-fluoro-3-methyl nitrobenzene, 1.61 g of 2-(2-aminoethylamino)ethanol and 2.14 g of K2CO3 were added to a solution of 20 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 7 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 2.4 g of 2-[2-(4-nitro-2-methylphenylamino)ethylamino]ethanol (5) were obtained.
Reaction SMILES: [CH:1]([C:3]1[C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>C(O)C>[OH:2][CH2:1][C:3]1[C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC(c1ccccc1)N1c2ccccc2Oc2c(C=O)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(c1ccccc1)N1c2ccccc2Oc2c(CO)cccc21
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3.9 g (12.3 mmoles) of 4-formyl-N-(α-phenylethyl)phenoxazine, 250 ml of ethanol and 0.594 g (18.5 mmoles) of sodium borohydride was heated at 40° C. under stirring during 15 minutes. The solvent was then removed under reduced pressure and the residue diluted with water and extracted with ethyl acetate (2×100 ml). The combined extracts were dried and the solvent removed under reduced pressure. The oily residue (3.5 g) was percolated through a short column of silica gel using ether as the solvent, to yield 4-hydroxymethyl-N-(α-phenylethyl)phenoxazine, as an oil
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[OH-:12].[K+]>COCCOC.O>[Br:1][C:2]1[N:6]2[NH:7][C:8](=[O:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: [OH-]
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: O=c1ccc2ncc(Br)n2[nH]1

Procedure:
To a solution of 3-bromo-6-chloro-imidazo[1,2-b]pyridazine [13526-66-4] (425.7 mg, 1.8 mmol) in 1,2-dimethoxyethane (9 mL) was added a solution of potassium hydroxide [1310-58-3] (185.4 mg, 2.8 mmol) in water (9.0 mL) and the stirred resultant solution heated to reflux under N2 for 3d, cooled and partitioned between ethyl acetate and water. The water phase was evaporated to dryness, taken up in methanol, filtered, and evaporated to yield 3-bromo-imidazo[1,2-b]pyridazin-6-one as 340 mg of yellow solid. LRMS (ESI) m/z 214.0/216.0 [(M+H)]+, calc'd for C6H4BrN3O3: 214.02.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9](OS(C(F)(F)F)(=O)=O)=[CH:8][N:7]=1)(=[O:3])[CH3:2].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Na].[CH3:75][C:76]([SH:79])([CH3:78])[CH3:77]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:9]([S:79][C:76]([CH3:78])([CH3:77])[CH3:75])=[CH:8][N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)S
Reactant: CC(=O)OCc1cc(OCc2ccccc2)c(OS(=O)(=O)C(F)(F)F)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: Cc1ccccc1
Product: CC(=O)OCc1cc(OCc2ccccc2)c(SC(C)(C)C)cn1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of (4-[(phenylmethyl)oxy]-5-{[(trifluoromethyl)sulfonyl]oxy}-2-pyridinyl)methyl acetate (12.15 g, 30 mmol) in toluene (500 ml) was added (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.87 g, 3 mmol). The reaction mixture was purged with argon. Palladium acetate (663 mg, 3 mmol) was added and the mixture was stirred for 10 minutes. 2-Methyl-2-propanethiol sodium salt (4.69, 41.8 mmol) was added and the reaction mixture was flushed again with argon then heated to 80° C. for 7 hours then cooled. The solvent was evaporated. The residue was partitioned between a 1:1 mixture of water and EtOAc. The organic layer was separated and washed with brine, dried over magnesium sulphate and filtered through Kieselguhr. The residue was chromatographed eluting with s 4:1 mixture of hexane:EtOAc affording the product (8.3 g, 80%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[CH2:19][O:20][CH3:21])=[O:13])[CH:11]=1)[C:5]([O:7]C)=[O:6].C([Sn](CCCC)(CCCC)[C:27]1[O:28][CH:29]=[CH:30][N:31]=1)CCC.C(OCC)(=O)C>O1CCOCC1.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>[CH3:21][O:20][CH2:19][C@H:15]1[CH2:16][CH2:17][CH2:18][N:14]1[C:12]([C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([C:27]2[O:28][CH:29]=[CH:30][N:31]=2)[CH:11]=1)[C:5]([OH:7])=[O:6])=[O:13]
Reactant: COC[C@H]1CCCN1C(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC[C@H]1CCCN1C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Temperature: 95 °C
Yield: 75.7 %

Procedure:
To a solution of (R)-methyl 3-bromo-5-(2-(methoxymethyl)pyrrolidine-1-carbonyl)benzoate (Step H (1), 350 mg, 1.0 mmol) in dioxane (5 mL) were added Pd(PPh3)4 (173.5 mg, 0.15 mmol) and 2-(tributylstannyl)oxazole (1.8 g, 5.0 mmol) above made and the reaction mixture was stirred at 95° C. with sealed cap for 16 h. Ethyl acetate (200 mL) was added and the mixture was washed with H2O and concentrated under vacuum. The crude mixture was purified by silica gel Flash Chromatography (0% to 30% to 50% to 70% EtOAc/Hexane step gradient) to give 250 mg of the title compound: 1H NMR (CDCl3, 500 MHz) δ ppm 1.75-2.11 (4H, m), 3.08 (1H, brd s), 3.38 (3H, s), 3.50 (1H, m), 3.63 (2H, s), 3.83 (3H, s), 4.43 (1H, s), 7.24 (1H, s), 7.73 (1H, s), 8.22 (1H, s), 8.35 (1H, s), 8.71 (1H, s). MS (ESI) (M+H)+ 345.26.
Reaction SMILES: [CH3:1]N1CCCC1=O.[CH2:8]([O:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15](Cl)=[N:14][C:13]=1[NH2:19])[CH3:9].C[Sn](C)(C)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.O>[CH2:8]([O:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([CH3:1])=[N:14][C:13]=1[NH2:19])[CH3:9]
Reactant: CCOC(=O)c1ccc(Cl)nc1N
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)(C)C
Solvent: O
Product: CCOC(=O)c1ccc(C)nc1N
Temperature: 130 °C
Reaction time: 0.67 h
Yield: 48 %

Procedure:
To a N-methylpyrrolidinone (20 mL) solution of 2-amino-6-chloro-nicotinic acid ethyl ester (2.00 g, 7.78 mmol) described in Manufacturing Example 170-1-1 were added tetramethyltin (1.62 mL, 11.7 mmol) and tetrakis(triphenylphosphine)palladium(0) (899 mg, 0.778 mmol), which was stirred under nitrogen atmosphere for 5 hours and 40 minutes at 130° C. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under a reduced pressure. The residue thus obtained was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:1), and then further purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (670 mg, 48%).
Reaction SMILES: CS(C)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:19]([C:21]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]3[N:46]=[N:47][N:48]([C:50]([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[N:49]=3)=[CH:35][CH:34]=2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:69][CH2:70][CH2:71][OH:72])[N:27]=2)[N:22]=1)[CH3:20].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C(N(CC)CC)C>[CH2:19]([C:21]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]3[N:46]=[N:47][N:48]([C:50]([C:63]4[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=4)([C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[N:49]=3)=[CH:37][CH:38]=2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:69][CH2:70][CH:71]=[O:72])[N:27]=2)[N:22]=1)[CH3:20]
Reactant: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2nc(OCCO)ccc2n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2nc(OCC=O)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
DMSO (2.0 ml) and phosphorus pentoxide (4.0 g) were added to a solution of 2-ethyl-6-(2-hydroxyethoxy)-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,5-naphthyridine (1.0 g) in dichloromethane (20 ml) at 0° C. The mixture was stirred at ambient temperature for 1 hour and then cooled again to 0° C. Triethylamine (0.69 ml) was added and stirring was continued for 30 minutes. 1M citric acid solution (20 ml) was added and the organic phase was separated and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:1 v/v), to give 2-ethyl-6-(formylmethoxy)-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,5-naphthyridine (B) (0.46 g), m.p. 168°-169° C. (after trituration with ether; NMR (d6 -DMSO): 1.25(t, 3H), 2.9(q, 2H), 5.0(s, 2H), 5.35(s, 2H), 6.8-6.95(m, 6H), 7.1-7.85(m, 19H), 8.25(d, 1H), 9.7(s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:22])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>O1CCCC1.[Ni].C(O)C>[NH2:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:22])[C:13]=1[NH:12][CH:9]1[CH2:8][CH2:7][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]1
Reactant: CCOC(=O)N1CCC(Nc2c(C)cccc2[N+](=O)[O-])CC1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(Nc2c(C)cccc2N)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
1-Ethoxycarbonyl-4-[(2-methyl-6-nitrophenyl)amino]piperidine (38 mg) was dissolved in tetrahydrofuran (0.4 ml), added with a suspension of Raney nickel in ethanol (0.2 ml) and stirred at 40° C. for 2 hours under hydrogen gas atmosphere. After insoluble matters were removed, the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane:ethyl acetate=2:1) to obtain (28.6 mg) of the title compound. Yield: 83%.
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl>>[CH3:13][C:12]1[C:11]2[C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:15][CH:16]=[CH:17][C:10]=2[O:9][C:8]=1[C:6]([OH:7])=[O:5]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(N3CCOCC3)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)O)oc2cccc(N3CCOCC3)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.8 %

Procedure:
To 140 mg 3-methyl-4-morpholin-4-yl-benzofuran-2-carboxylic acid tert-butyl ester was added 4 mL of TFA/dichloromethane (1:1). The solution was stirred at room temperature for 5 h. The solvents were removed under vacuum and the residue was triturated with ether. Filtration gave 107 mg of 3-methyl-4-morpholin-4-yl-benzofuran-2-carboxylic acid as a white solid.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:27])([F:26])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:25])OC2C=CC=CC=2)[CH:11]=1.[NH2:28][C:29]1[CH:30]=[C:31]([CH:42]=[CH:43][CH:44]=1)[CH2:32][NH:33][C:34]1[C:35]([C:39]([NH2:41])=[O:40])=[N:36][NH:37][CH:38]=1>C1COCC1.C(OCC)(=O)C>[F:27][C:9]([F:8])([F:26])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:25])[NH:28][C:29]2[CH:30]=[C:31]([CH:42]=[CH:43][CH:44]=2)[CH2:32][NH:33][C:34]2[C:35]([C:39]([NH2:41])=[O:40])=[N:36][NH:37][CH:38]=2)[CH:11]=1
Reactant: NC(=O)c1n[nH]cc1NCc1cccc(N)c1
Reactant: O=C(Nc1cc(C(F)(F)F)ccn1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: NC(=O)c1n[nH]cc1NCc1cccc(NC(=O)Nc2cc(C(F)(F)F)ccn2)c1
Yield: 27.6 %

Procedure:
88 μl of triethylamine and 0.18 g of phenyl (4-trifluoromethylpyrid-2-yl)carbamate are added at 20° C. to a solution of 0.12 g of 4-(3-aminobenzylamino)-1H-pyrazole-3-carboxamide in 5 ml of anhydrous THF. The reaction medium is heated in a microwave reactor for 20 minutes and, after cooling, is diluted with 25 ml of ethyl acetate. The organic phase is washed with twice 15 ml of distilled water and then separated out by settling of the phases, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue obtained is chromatographed on a column of silica (15 g of Merck cartridge silica with a particle size of 15 to 45 μm, column diameter 2.2 cm, 3.5 ml fractions, flow rate of 7 ml/min, ethyl acetate eluent). Fractions 36 to 60 are combined and evaporated to dryness under reduced pressure. 0.06 g of 4-{3-[3-(4-trifluoromethylpyrid-2-yl)ureido]benzylamino}-1H-pyrazole-3-carboxamide is obtained in the form of a white solid. ([M+H]+): 420). RT: 0.78 min (Method D).
Reaction SMILES: [C:1]1([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[OH:23])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH3:9].[OH-].[K+].C(O)(=O)C1C(=CC=CC=1)[NH2:29].S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl>CO.O>[NH2:29][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([OH:23])=[C:13]([C:11](=[O:12])[NH:10][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[O:7][CH2:8][CH3:9])[CH:22]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: CCOc1ccccc1NC(=O)c1ccc2ccccc2c1O
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOc1ccccc1NC(=O)c1cc(N)c2ccccc2c1O
Reaction time: 0.5 h

Procedure:
11.64 g (0.04 mol) of 2-(N-2-phenetylcarbamoyl)-1-naphthol was dissolved in a mixture composed of 12 g of potassium hydroxide, 25 ml of water and 200 ml of methanol. To the resulted solution, an aqueous solution of diazonium salt prepared with using 5.75 g of anthranilic acid was added to 0° to 5° C. After stirred at 5° to 10° C. for 30 minutes, 100 ml of a 20% aqueous solution of potassium hydroxide was added thereto and 50 g of sodium hydrosulfite was added at 50° to 60° C. After stirring at the same temperature for 10 minutes, it was cooled with ice and neutralized with diluted hydrochloric acid. The formed light yellow precipitate was filtered off.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][NH:6][CH:7]=1.[CH2:14](SSCCC)[CH2:15]C.BrC1C(C2C=NC=CC=2)=NNC=1>C(OCC)(=O)C.C(OCC)C>[CH2:1]([S:2][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][NH:6][CH:7]=1)[CH2:14][CH3:15]
Reactant: CCCSSCCC
Reactant: CSc1c[nH]nc1-c1cccnc1
Agent: Brc1c[nH]nc1-c1cccnc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCSc1c[nH]nc1-c1cccnc1
Yield: 76 %

Procedure:
Compound 21E was prepared following the procedure as described for the synthesis of compound 21A using (see scheme 3) 1-propyldisulfanyl-propane as the disulfide and 3-(4-bromo-1H-pyrazol-3-yl)-pyridine (compound 20A). (flash chromatography conditions ethyl acetate/diethyl ether 5/1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([Li])CCC.[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.Cl>O1CCCC1.CCCCCC>[O:14]1[CH2:15][CH:16]=[C:17]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH2:18][CH2:19]1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Oc1ccc(C2=CCOCC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
[lacuna] is added at −40° C. to 12.7 g of 4-bromophenol in 150 ml of tetrahydrofuran. At this same temperature, 100 ml of 1.6 M butyllithium in hexane are added to the reaction mixture, followed by addition of 8.1 g of 4-tetrahydropyranone. The reaction mixture is left stirring for 18 hours at room temperature and then hydrolysed with 1 N hydrochloric acid. The resulting mixture is extracted several times with diethyl ether, the organic phase is dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. The solid obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane/ethyl acetate mixture varying from 90/10 to 80/20 (v/v).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[O:3]1.[Li]C(C)(C)C.CN([CH:29]=[O:30])C>C1COCC1.CCCCC.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:20])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:29]=[O:30])[CH:8]=2)[O:3]1
Reactant: Cc1ccc(C2=CC(C)(C)Oc3ccc(Br)cc32)cc1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C2=CC(C)(C)Oc3ccc(C=O)cc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (−78° C.) solution of 2,2-dimethyl-4(tol-4-yl)-6-bromo-chrom-3-ene (Compound P, 480 mg, 1.45 mmol) in THF (10 mL), was added t-BuLi in pentane (1.7M solution, 1.1 mL) and the mixture was stirred for 30 minutes. DMF (200 mg, 2.9 mmol) was added, the mixture was warmed to ambient temperature and stirred for 3 hours. The reaction was diluted with ethyl acetate (150 mL), washed with brine (10 mL), dried and the solvent was removed by evaporation. Purification by chromatography on silica gel column gave the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[OH:16])=[O:8].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[C:3]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=2)[C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[OH:16])=[O:8])=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(N[C@@H]1CCCC[C@@H]1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Product: O=C(N[C@@H]1CCCC[C@@H]1O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nc1C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1d, using 5-bromo-N-((1R,2S)-2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide and 4-chlorophenylboronic acid as starting materials, MS (ISP) 497.1 (M+H)+; [α]D20=+22.2°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[NH:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28]([CH:30]2[C:35](=O)[CH2:34][CH2:33][O:32][CH2:31]2)=O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:18]=[C:28]([CH2:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)[C:30]3[CH2:31][O:32][CH2:33][CH2:34][C:35]=3[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cccc(CC(=O)C2COCCC2=O)c1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: COc1cccc(Cc2nc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc3c2COCC3)c1
Yield: 6.2 %

Procedure:
1-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (85 mg, 0.35 mmol), 3-(2-(3-methoxyphenyl)acetyl)dihydro-2H-pyran-4(3H)-one (86 mg, 0.35 mmol) and potassium carbonate (47.9 mg, 0.35 mmol) in ethanol (2 mL) were heated to 60° C. over night. DCM and water were added and the organic phase was separated and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC yielding N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-(3-methoxybenzyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine (10.00 mg, 6%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[CH2:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH3:23]>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:27]2[CH2:28][CH2:29][N:24]([CH2:22][CH3:23])[CH2:25][CH2:26]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: CCN1CCNCC1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CC#N
Product: CCN1CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-ethylpiperazine, and acetonitrile was refluxed for 5 hours. After cooling, the resulting crystals were filtered, washed with water and recrystallized from ethanol to give 5-amino-1-cyclopropyl-6,8-difluoro-7-(4-ethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 236°-237° C.
Reaction SMILES: [F-:1].[K+].C1S(=O)(=O)CCC1.[Cl:10][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][C:16]=1Cl>[Cl-].C[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC.[Al+3].[Cl-].[Cl-].[Cl-]>[Cl:10][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][C:16]=1[F:1]
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1
Yield: 84.9 %

Procedure:
A mixture of 87 g (1.5 mol) of potassium fluoride and 250 g of tetramethylene sulphone in a glass reaction vessel was subjected to incipient distillation for the removal of water until 25 g of tetramethylene sulphone had passed over. 192 g of 3,4-dichloro-nitrobenzene, 10 g (0.025 mol) of methyl -trioctyl-ammonium chloride and 1.65 g (0.0125 mol) of AlCl3 were then added and the was 97% (determined by gas chromatography). The reaction mixture was then worked up by distillation. 149 g of 3-chloro-4-fluoro-nitrobenzene having a boiling point of 92°-93° C. at 10 mbar were obtained. This corresponds to a yield of 85% of theory.