Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]([O:18][C:19](=[O:29])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Br)=[CH:23][N:22]=1)([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:27][C:24]1[CH:23]=[N:22][C:21]([NH:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:29])=[CH:26][CH:25]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Reaction time: 0.25 h
Yield: 43.7 %

Procedure:
To a suspension of NaH (0.49 g, 16.3 mmol, 80%) in THF (15 mL) at 0° C. was added diethyl malonate (2.61 g, 16.3 mmol). The mixture was stirred for 15 min and was then added dropwise to a refluxed mixture of (5-bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (3.90 g, 13.6 mmol) in THF (25 mL), and the resulting solution was refluxed for 15 min. After evaporation of the solvent, the crude product was purified by flash chromatography (methanol/CH2Cl2, 1:100→2.5:100) to give 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-malonic acid diethyl ester (2.18 g, 44%).
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[C:12]1([C:22](O)=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:22]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)=[O:23])[CH2:2]1)[CH2:8]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1cccc2ccccc12
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cccc2ccccc12

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 1-naphthoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.94-2.71 (m, 7 H), 3.46-3.93 (m, 6H), 4.56 (s, 1H), 7.50-7.59 (m, 3H), 7.61-7.68 (m, 1H), 7.90-7.96 (m, 1H), 7.97-8.03 (m, 1H), 8.11-8.18 (m, 1H); MS (APCI/NH3) m/z 307 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([SH:15])[N:10]=2)=[CH:5][CH:4]=1.[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CN(C=O)C>[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][S:15][C:11]2[N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:14]=[CH:13][N:12]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COc1ccc(-c2ccnc(S)n2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CSc2nccc(-c3ccc(OC)cc3)n2)cc1
Temperature: 60 °C

Procedure:
To a solution of 4-(4-methoxy-phenyl)-pyrimidine-2-thiol (225a) (1.00 g, 4.58 mmol) in DMF (30 mL) was added 4-bromomethyl-benzoic acid methyl ester (1.05 g, 4.58 mmol). The mixture was heated at 60° C. for 1 h and evaporated to dryness to form the compound 226a, which was used in the next without purification. LRMS=366.4 (calc.), 367.4 (found).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][CH2:10][C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[Si:19]([O:26][CH2:27][C@@H:28](O)[CH3:29])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Si:19]([O:26][CH2:27][C@H:28]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[O:9][CH2:10][C@@H:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:12]=2)[CH:3]=1)[CH3:29])([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20]
Reactant: Oc1cccc(C2=N[C@H](c3ccccc3)CO2)c1
Reactant: C[C@H](O)CO[Si](C)(C)C(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cccc(C2=N[C@H](c3ccccc3)CO2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
To a mixture of 4,5-dihydro-2-(3-hydroxyphenyl)-4(R)-phenyloxazole (5.0 g, 20.9 mmol), 1-(tert-butyldimethylsilyloxy)propan-2(S)-ol (4.76 g, 25 mmol) and triphenylphosphine (6.58 g, 25 mmol) in dry tetrahydrofuran (30 ml) was added dropwise a solution of diethyl azodicarboxylate (3.9 ml, 25 mmol) in dry tetra-hydrofuran (5 ml). The reaction mixture was stirred ambient temperature for 1 h and then ay 50° C. for 5 hours. Volatiles were removed by evaporation and the resulting residue purified by column chromatography on silica gel eluting with ethyl acetate-hexane (=1:6) to afford 1-(tert-butyldimethylsilyloxy)-2(R)-[3-(4,5-dihydro-4(R)-phenyloxazol-2-yl)phenoxy]propane (8.7 g, quant.) as a colorless oil.
Reaction SMILES: Br[C:2]([CH3:15])([CH3:14])[C:3]([NH:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].CCOC(C)=O.[CH2:22]([OH:27])[C:23]([F:26])([F:25])[F:24]>O1C=CC=C1>[CH3:14][C:2]([O:27][CH2:22][C:23]([F:26])([F:25])[F:24])([CH3:15])[C:3]([NH:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)(Br)C(=O)NOCc1ccccc1
Reactant: OCC(F)(F)F
Solvent: c1ccoc1
Solvent: CCOC(C)=O
Product: CC(C)(OCC(F)(F)F)C(=O)NOCc1ccccc1

Procedure:
Produced as a by-product 56% from the reaction of 2-bromo-2-methyl-N-(phenylmethoxy)propanamide with TEA in furan and trifluoroethanol. Rf=0.26 (3:1, hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 8.88 (s, 1H), 7.56-7.31 (m, 5H), 4.94 (s, 2H), 3.68 (q, J=8.3 Hz, 2H), 1.43 (s, 6H); 13C NMR (125 MHz, CDCl3) 13C NMR (101 MHz, cdcl3) δ 170.8, 134.9, 129.4, 129.0, 128.7, 123.7 (q, J=278 Hz), 80.4, 78.3, 61.6 (q, J=35 Hz), and 23.6; FT-IR 3218 (br), 3036; 2942, 2886, 1663 (st), 1430, 1455, 1485, 1386, 1369, 1307, 1285, 1217, 1181, 1145, 1029, 1010 cm-1; HR-ESIMS calculated for C13H17F3NO3 (M+H)+ 292.1155, observed 292.1160.
Reaction SMILES: Cl(O)(=O)(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]([CH2:12]N2CCCC2)[NH:10][CH:11]=1.[OH-].[Na+].S(OC)(OC)(=O)=O.[C-:27]#[N:28].[Na+]>CS(C)=O>[Cl:6][C:7]1[CH:8]=[C:9]([CH2:12][C:27]#[N:28])[NH:10][CH:11]=1
Reactant: [C-]#N
Reactant: Clc1c[nH]c(CN2CCCC2)c1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: CS(C)=O
Solvent: COS(=O)(=O)OC
Product: N#CCc1cc(Cl)c[nH]1
Temperature: 25 °C

Procedure:
An aqueous solution of 114.0 g. of the product of Example VI is converted into the free base form by addition of 10% aqueous sodium hydroxide solution. The solid that is thus precipitated is filtered, washed with water and dried to give 67.1 g. (0.364 mole) of free base. The free base is dissolved in 350 ml. of dry dimethyl sulfoxide and stirred in an ice bath while 45.9 g. (0.364 mole) of dimethyl sulfate is added dropwise. The whole is then stirred for a half hour and warmed to room temperature, whereupon 20.0 g. (0.41 mole) of freshly ground and dried sodium cyanide is added all at once. After the resulting solution has been stirred for 2 hours at ambient temperature, it is poured onto ice and this aqueous solution is extracted four times with 250 ml. of diethyl ether. The combined ether extracts are washed successively with brine, 3N hydrochloric acid solution, aqueous sodium bicarbonate solution, and brine, and are dried over sodium sulfate. Evaporation of the ether yields 4-chloropyrrole-2 -acetonitrile as a brown oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6](=[O:7])[CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[O:3]1.C(O)(=O)C.[Br:21]Br>C(Cl)(Cl)(Cl)Cl>[Br:21][C:5]1[C:6](=[O:7])[C:2]([CH3:16])([CH3:1])[O:3][C:4]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=1
Reactant: BrBr
Reactant: CSc1ccc(C2=CC(=O)C(C)(C)O2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CSc1ccc(C2=C(Br)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2,2-dimethyl-5-{4-(methylthio)phenyl}-3(2H)-furanone (45 mg) in 20 ml carbon tetrachloride, were added acetic acid (0.5 ml) and bromine (0.1 ml). The reaction solution was stirred at room temperature for one hour. Then the reaction was quenched by adding 20 ml of saturated aqueous sodium thiosulfate solution to the reaction solution. After removing the carbon tetrachloride in vacuo, the resulting aqueous layer was extracted with dichloromethane (50 ml×3) and the organic layer was then washed with water (50 ml×1). The organic layer was concentrated in vacuo and the resulting residue was chromatographed (hexane/ethylacetate=2:1) to yield 69 mg of 4-bromo-2,2-dimethyl-5-{4-(methylthio)phenyl}-3(2H)-furanone as a solid. NMR: δ1.52 (s, 6H), 2.55 (s, 3H), 7.33 (d, J=9.3 Hz, 2H), 8.15 (d, J=9.0 Hz, 2H); IR (cm−1): 1704, 1594, 1574, 1486, 1348, 1184, 1069.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N+:13]([O-])=O)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.O.NN>[Ni].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH2:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1cc([N+](=O)[O-])c2ncccc2c1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc(N)c2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.5 %

Procedure:
Raney Nickel (60 mg, 20% wt) was added portionwise to a solution of 6-methoxy-8-nitroquinoline (300 mg, 1.40 mmol) in MeOH (10 ml), under argon. Hydrazine hydrate (270 μl, 5.6 mmol) was added and the reaction stirred at room temperature for 1 h. The mixture was filtered through celite and washed with MeOH. The filtrate was concentrated in vacuo, re-dissolved in DCM and washed with water. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the title compound (250 mg, 100%) which was used in the next step without purification.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[C:7]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=1[C:9](O)=[O:10].B.C1COCC1.O>O1CCCC1>[S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[C:7]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=1[CH2:9][OH:10]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1C1SCCCS1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(C2SCCCS2)c(CO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cooled, stirred solution of the Compound 3b (5.00 g, 17.5 mmol) in tetrahydrofuran (100 mL) was added dropwise over 30 minutes 1.0M BH3.THF (20 mL). The solution was allowed to warm to room temperature and was stirred overnight. Additional 1.0M BH3.THF (5 mL) was added, and the solution was stirred another 4 hours. Water was added to hydrolyze the reaction, and the solution then was evaporated to dryness. The residue was dissolved in diethyl ether, and this solution was washed with a saturated solution of sodium carbonate, brine, and was dried over anhydrous magnesium sulfate. Evaporation of the solvent and recrystallization of the product from acetonitrile afforded the Compound 3c; m.p. 130°-131° C.; IR 3600 cm-1 (OH); 1H NMR (CDCl3 +D2O) δ1.8-2.2 (m, 2H, --CH2CH2CH2 --), 2.8-3.2 (m, 4H, --CH2CH2CH2 --), 4.61 (s, 2H, CH2O), 5.48 (s, 1H, SCHS), 7.7-8.3 (m, 3H, ArH).
Reaction SMILES: Cl.[C:2](Cl)(=O)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.I.[CH:12]1([NH:15][C:16](=[N:19][NH2:20])[NH:17][CH3:18])[CH2:14][CH2:13]1.O>N1C=CC=CC=1>[CH:12]1([NH:15][C:16]2[N:17]([CH3:18])[C:2]([C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)=[N:20][N:19]=2)[CH2:14][CH2:13]1
Reactant: CNC(=NN)NC1CC1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: I
Solvent: c1ccncc1
Solvent: O
Product: Cn1c(NC2CC2)nnc1-c1ccncc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isonicotinoyl chloride hydrochloride (630 mg, 3.5 mmol) was added to N-cyclopropyl-N′-methylcarbonohydrazonic diamide hydroiodide (900 mg 3.5 mmol) in pyridine (10 ml) and the mixture was stirred at r.t. for 2 h. The mixture was the heated to 160° C. under microwave irradiation for 10 min. Water (50 ml) was added and the mixture was extracted with DCM. The pooled organic phases were dried and concentrated and the desired product was obtained by prep. HPLC. LCMS (M++1) 216
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[C:15](N)(=O)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH3:15])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: NC(=O)c1ccccc1
Reactant: COc1cc(C(=O)O)cc(Cl)c1OC
Product: COc1cc(C(C)=O)cc(Cl)c1OC

Procedure:
3-Chloro-4,5-dimethoxybenzoic acid (1 g) was converted to the benzamide derivative analogously to O3.043, and the latter to the title compound analogously to O2.059. 495 mg of the title compound were obtained. LC-MS rt: 1.55 min [M+H]+: 215.1 (met. a)
Reaction SMILES: FC1C=CC(CC(=O)[CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[CH:29][N:17]3[C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:13])=CC=1.CN1CC[O:44][CH2:43]C1.ClC(OCC)=O.CN(C)O>C1COCC1.C(Cl)Cl>[CH3:43][O:44][N:11]([CH3:10])[C:12]([C:14]1[N:15]=[C:16]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][N:17]2[C:18](=[O:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:13]
Reactant: CN1CCOCC1
Reactant: O=C(CNC(=O)c1nc2ccc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1)Cc1ccc(F)cc1
Agent: CCOC(=O)Cl
Agent: CN(C)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CON(C)C(=O)c1nc2ccc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1
Temperature: -12 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
3-Benzyloxy-7-morpholin-4-yl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid (product of example 5, 100 mg, 0.263 mmol) was dissolved in THF (1 mL) and DCM (11 mL) and cooled to −20° C. N-Methylmorpholine (30 μL, 0.265 mmol) was added and the temperature was raised to −12° C. Ethyl chloroformate was added and after 2 minutes, the solution of dimethylhydroxylamine. The reaction was warmed to room temperature and stirred for one hour. After this time, the mixture was quenched by addition of 0.2 M HCl. The layers were separated and the organic layer was washed sequentially with 0.2 M HCl, 0.5 M NaOH (2×) and brine. Then dried and concentrated. The product was isolated as a yellow solid (112 mg, 100% yield) and was used without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16]>CCO.N1C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:14][C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Solvent: CCO
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C=CC(=O)O)cc1
Temperature: 0 °C
Yield: 47.2 %

Procedure:
A solution of aldehyde 4-methylsulfonylbenzaldehyde 4 (1.0 g, 5.9 mmol) and malonic acid (0.63 g, 6.0 mmol) in 10:1 EtOH/pyridine (12.1 mL) was heated at a gentle reflux for 24 h. After cooling to 0° C., the resulting precipitate was collected and rinsed with cold Et2O. The solid was resuspended in EtOH (13 mL) and heated at reflux for an additional 2 h. After cooling to 0° C., the resulting precipitate was collected and dried in vacuo to afford 0.63 g (51%) of 3-(4-methanesulfonyl-phenyl)-acrylic acid 5 as a white solid; 1H NMR (DMSO) δ 3.18 (s, 3H), 6.65 (d, 1H, J=16.1), 7.60 (d, 1H, J=16.1), 7.89 (m, 4H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][NH2:10])=[O:8].[CH2:11]([O:18][CH2:19][C:20](Cl)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][CH2:19][C:20]([NH:10][NH:9][C:7](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: NNC(=O)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COCc1ccccc1)NNC(=O)c1ccccn1

Procedure:
Picolinohydrazide (4.55 g) was dissolved in dichloromethane (40 mL) and 2-(benzyloxy)acetyl chloride (6.06 mL) was added slowly with cooling. Triethylamine (5.98 mL) was added slowly with a strong exotherm. Additional dichloromethane (45 mL) was added to aid stirring. The reaction was allowed to stir overnight. The reaction was partitioned between ethyl acetate and sodium hydrogen carbonate aqueous solution. The organic phase was washed with brine, dried and purified by column chromatography using an eluant of 10% ethyl acetate/dichloromethane to provide the title compound (4.1 g) having the following physical data.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20](I)=[CH:21][N:22]=3)[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:21][N:22]=3)[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3ncc(I)n3n2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3ncc(-c4ccccc4)n3n2)CC1

Procedure:
4-(3-Phenyl-imidazo[1,2-b]pyridazin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester was prepared using the approach described in example 5.6.112 from 4-(3-iodo-imidazo[1,2-b]pyridazin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester (513.4 mg, 1.2 mmol) and phenyl boronic acid [98-80-6] (178.3 mg, 1.5 mmol) to obtain 220.2 mg of white powder, mp. 101-103° C. (dec.). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (s, 9H) 3.52 (br. s., 8H) 7.22 (d, J=9.85 Hz, 1H) 7.31-7.37 (m, 1H) 7.46-7.54 (m, 2H) 7.95 (d, J=10.11 Hz, 1H) 8.00 (s, 1H) 8.11-8.18 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ ppm 28.03, 42.73, 45.56, 79.08, 110.13, 125.75, 126.24, 126.93, 127.14, 128.61, 129.03, 131.07, 137.15, 153.85, 154.63. LRMS (ESI) m/z 411.3 [(M+H)]+, calc'd for C21H25N5O2: 379.47.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:9]=2[N:10]=1.[ClH:16]>O.[Cu]>[Cl:16][C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:9]=2[N:10]=1
Reactant: Cl
Reactant: Nc1nc2cc(F)ccc2s1
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Fc1ccc2sc(Cl)nc2c1
Yield: 49 %

Procedure:
A solution of 242 g (3.5 mol) of sodium nitrite in 440 ml of water is added dropwise with stirring to a mixture, cooled to -10° C., of 147 g (0.87 mol) of 2-amino-5-fluoro-benzothiazole, 1700 ml of conc. hydrochloric acid and 20 g of copper power and the reaction mixture is stirred at 0° C. for 60 minutes and at 50° C. for a further 60 minutes. It is then extracted with chloroform and the solvent is carefully removed by distillation from the organic phase in a water-jet vacuum. 80 g (49% of theory) of 2-chloro-5-fluoro-benzothiazole are obtained as a crystalline residue of melting point 69° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[O:12][CH:13]1[CH:17]([O:18][CH2:19][S:20][CH3:21])[CH2:16][O:15][CH2:14]1.[NH2:22][C:23]1[C:28]([Cl:29])=[CH:27][N:26]=[CH:25][C:24]=1[Cl:30].[H-].[Na+]>C(Cl)(=O)C(Cl)=O.O1CCCC1>[Cl:30][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Cl:29])[C:23]=1[NH:22][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([O:12][CH:13]2[CH:17]([O:18][CH2:19][S:20][CH3:21])[CH2:16][O:15][CH2:14]2)[CH:5]=1
Reactant: COc1ccc(C(=O)O)cc1OC1COCC1OCSC
Reactant: Nc1c(Cl)cncc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1COCC1OCSC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20.4 %

Procedure:
1.0 g (3.2 mmol) of 4-methoxy-3-(4-methylthiomethyloxytetrahydrofuran-3-yloxy)benzoic acid (starting compound A19) are heated to reflux for 90 min in 4 ml of oxalyl chloride. Excess oxalyl chloride is removed in vacuo and coevaporated using 2×20 ml of toluene. A solution of 520 mg (3.2 mmol) of 4-amino-3,5-dichloropyridine in 10 ml of tetrahydrofuran is added dropwise to a suspension of 200 mg (6.9 mmol) of 80% strength sodium hydride in 10 ml of tetrahydrofuran. The mixture is stirred at RT for 90 min, then the acid chloride is added dropwise in a further 10 ml of tetrahydrofuran and the reaction mixture is stirred at RT for 2 h. It is concentrated, the residue is treated with 25 ml of water and the mixture is extracted with 3×25 ml of ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, concentrated and the residue is chromatographed on silica gel. The product-containing fractions are concentrated and the residue is crystallized from acetonitrile. 300 mg of the title compound of m.p. 195-198° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH3:22].CN(C)C=O>O>[CH2:19]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1)[CH2:20][CH2:21][CH3:22]
Reactant: COc1cc(O)ccc1C(=O)O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1ccc(C(=O)O)c(OC)c1

Procedure:
A mixture of 4.2 g. (0.025 mole) of 4-hydroxy-2-methoxybenzoic acid, 7 g. of potassium carbonate, and 10 g. of n-butyl bromide in 100 ml. of N,N-dimethylformamide was heated at 70° C. for 24 hours. The mixture was cooled, diluted with water and extracted with diethyl ether. The ether extracts were washed with dilute sodium hydroxide solution, then washed with water and dried. The ether was evaporated and the residue heated at reflux for 4 hours in an equivolume mixture of 10 percent sodium hydroxide solution and ethanol. Evaporation followed by acidification provided the desired 4-(n-butoxy)-2-methoxy-benzoic acid (m.p. 94°-96° C. after recrystallizaiton from cyclohexane).
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH:4]=1)#[N:2].C(N1C=CN=C1)([N:25]1C=CN=C1)=O.N.O>O1CCCC1>[C:1]([C:3]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][N:5]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH2:25])=[O:20])=[CH:21][CH:22]=2)[CH:4]=1)#[N:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N#Cc1cn(-c2ccc(C(=O)O)cc2)cc1-c1ccccc1
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cn(-c2ccc(C(N)=O)cc2)cc1-c1ccccc1
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of 4-(3-cyano-4-phenylpyrrole-1-yl)benzoic acid (0.14 g) in tetrahydrofuran (2 5 mL) was added 1,1′-carbonyldiimidazole (0.16 g). After stirring for 30 minutes, to this reaction mixture was added aqueous ammonia (28% solution 0.75 mL), and this mixture was stirred 2 hours. To this reaction mixture was added water (10 mL), the precipitated white solid was collected by filtration, and wash with methanol, dried to give the title compound (0.13 g).
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH:10]=[CH:11][C:7]=2[CH:6]=1.[CH3:14]I>CS(C)=O>[CH3:14][O:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH:10]=[CH:11][C:7]=2[CH:6]=1
Reactant: CI
Reactant: OCc1ccc2occc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COCc1ccc2occc2c1

Procedure:
To a stirred mixture of powdered KOH in dimethylsulfoxide is added 5-hydroxymethylbenzo[b]furan in dimethylsulfoxide. Then methyl iodide is added dropwise at ambient temperature over several minutes to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[NH:12][C:13]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:14]=1[S:20]([CH3:23])(=[O:22])=[O:21].[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[NH:12][C:13]1[CH:18]=[C:17]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:16]=[CH:15][C:14]=1[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)c1ccc(F)cc1NC1CCOc2ccc(Cl)cc21
Reactant: C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(N2CCNCC2)cc1NC1CCOc2ccc(Cl)cc21
Yield: 15.4 %

Procedure:
A solution of 6-chloro-N-(5-fluoro-2-(methylsulfonyl)phenyl)chroman-4-amine (143.0 mg, 0.4 mmol), piperazine (694.0 mg, 8.00 mmol) and N,N-diisopropylethylamine (0.52 mL, 4.00 mmol) in acetonitrile (5 mL) was stirred at reflux for 16 h. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried and concentrated in vacuo. The crude product was purified by silica chromatography (5% methanol in dichloromethane) to yield 26.0 mg (15% yield) of desired product. 1H NMR (400 MHz, CD3OD): δ 7.64 (d, 1H) 7.25 (d, 1H), 7.15 (dd, 1H), 6.81 (d, 1H), 6.45 (d, 1H), 6.35 (dd, 1H), 6.20 (d, 1H), 4.65 (m, 1H), 4.26 (m, 2H), 3.31 (m, 4H), 3.03 (m, 4H), 2.98 (s, 3H), 2.18 (m, 2H).