Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH2:25]O)=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].C([N:33](CC)CC)C.CS(Cl)(=O)=O.O.N>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH2:25][NH2:33])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: CCN(CC)CC
Reactant: OCc1ccc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: CC#N
Solvent: O
Product: NCc1ccc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
{6-[3-(3,4,5-Trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-(trifluoromethyl)pyridin-3-yl}methanol (Reference document: WO2010/043315) (1.8 g) and triethylamine (0.5 g) were dissolved in acetonitrile (30 mL), and an acetonitrile (10 mL) solution of methanesulfonyl chloride (0.5 g) was added dropwise thereto under ice cooling. Upon the completion of the dropwise addition, the reaction solution was stirred at room temperature for 1 hour, and then the resulting solution was added dropwise to a mixture solution containing 28% ammonia water (50 mL) and acetonitrile (200 mL), which had been prepared separately, under ice cooling. After stirring at room temperature for 12 hours, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was distilled off and the purification was carried out by silica gel chromatography to obtain the title compound (1.25 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:31]=[C:30]([C:32]([N:34]2[CH2:43][C:42]3[CH:41]=[N:40][N:39]([CH3:44])[C:38]=3[NH:37][C:36]3[CH:45]=[CH:46][CH:47]=[CH:48][C:35]2=3)=[O:33])[CH:29]=[CH:28][C:27]=1[CH2:49][CH2:50][CH2:51][CH2:52][C:53]([OH:55])=O.Cl.Cl.[CH3:58][C:59]([CH3:69])([CH3:68])[CH2:60][CH2:61][N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:58][C:59]([CH3:69])([CH3:68])[CH2:60][CH2:61][N:62]1[CH2:63][CH2:64][N:65]([C:53](=[O:55])[CH2:52][CH2:51][CH2:50][CH2:49][C:27]2[CH:28]=[CH:29][C:30]([C:32]([N:34]3[CH2:43][C:42]4[CH:41]=[N:40][N:39]([CH3:44])[C:38]=4[NH:37][C:36]4[CH:45]=[CH:46][CH:47]=[CH:48][C:35]3=4)=[O:33])=[CH:31][C:26]=2[CH3:25])[CH2:66][CH2:67]1
Reactant: CC(C)(C)CCN1CCNCC1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCCCC(=O)N1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
HBTU (104 mg, 0.27 mmol) was added to a solution of 5-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-pentanoic acid from E83.2 (105 mg, 0.25 mmol) and 1-(3,3-dimethyl-butyl)-piperazine dihydrochloride from Example E4 (69 mg, 0.28 mmol) in DMF (10 ml) and DIEA (0.2 ml, 1.15 mmol). The mixture was stirred for 24 h at room temperature then concentrated in vacuo. The residue was dissolved in di-chloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 4% methanol:96% dichloromethane to 8% methanol:92% di-chloromethane) to give a white solid identified as the title compound (88 mg, 62%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:15]([C:16]2[CH:20]=[CH:19][O:18][C:17]=2[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[CH:14][CH:13]=[C:12]([NH:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C(Cl)Cl.N1C=CC=CC=1>[C:1]([NH:5][C:6]1[C:15]([C:16]2[CH:20]=[CH:19][O:18][C:17]=2[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[CH:14][CH:13]=[C:12]([NH:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc(-c2ccoc2CO[Si](C)(C)C(C)(C)C)c1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc(-c2ccoc2CO[Si](C)(C)C(C)(C)C)c1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (0.09 mL) was added to a stirred solution of methyl 2-amino-3-[2-(tert-butyldimethylsilanyloxymethyl)furan-3-yl]-6-(2,2-dimethylpropionylamino)-benzoate (Intermediate 35, 0.47 g) in DCM (5 mL) and pyridine (0.16 mL) and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with DCM and washed with water and brine, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 20-50% to give methyl 2-acetylamino-3-[2-(tert-butyldimethylsilanyloxymethyl)-furan-3-yl]-6-(2,2-dimethylpropionylamino)benzoate (0.442 g) as a colourless foam.
Reaction SMILES: ClC(Cl)C(O)=[O:4].[CH3:7][C:8]1[C@@H:13]2[C:14]([CH3:16])([CH3:15])[C@@H:11]([CH2:12]2)[CH2:10][CH:9]=1>O>[CH3:7][C:8]1[CH2:13][CH2:12][C@@H:11]([C:14]([OH:4])([CH3:16])[CH3:15])[CH2:10][CH:9]=1
Reactant: O=C(O)C(Cl)Cl
Reactant: CC1=CC[C@@H]2C[C@H]1C2(C)C
Solvent: O
Product: CC1=CC[C@H](C(C)(C)O)CC1
Reaction time: 8 h
Yield: 61.7 %

Procedure:
Followiwng a procedure described in Matsubara, et al., Chem. Abstr., 84:165069b (1976), 64.5 g of dichloroacetic acid was added dropwise over 20 minutes at 5°-6° C. to a magnetically stirred mixture of 68.0 g of (+)-alpha-pinene ([alpha]D +47.1°) and 9.0 g of water. after stirring overnight at 5°-30° C. (ice allowed to melt slowly), the mixture was extracted with 400 ml of methylene chloride. The extract was washed successively with water, aqueous potassium carbonate solution and water, dried and Claisen distilled at 4 mm to give 11.2 g of forecut, b.p. 40°-71° C. and 47.5 g of the desired (+)-alpha-terpineol, b.p. 71°-83° C. Redistillation through a micro Vigreaux column gave 40.5 g of (+)-alpha-terpineol with [alpha]D +79.3° (CHCl3), b.p. 58°-60° C. (1 mm).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11][CH3:12].C([Li:17])CCC>>[Li:17][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11][CH3:12]
Reactant: [Li]CCCC
Reactant: CCc1oc2ccccc2c1Br
Product: [Li]c1c(CC)oc2ccccc12

Procedure:
comprising contacting 3-bromo-2-ethylbenzofuran with n-butyllithium at a temperature less than −75° C. to form 3-lithio-2-ethylbenzofuran, contacting the 3-lithio-2-ethylbenzofuran at a temperature less than −75° C. with an isopropyl boronate cyclic ester corresponding to the formula:
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(OCC)(=O)C>CN(C=O)C>[N:32]1([CH2:31][CH2:30][N:2]2[CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[C:10]([O:12][C:13]4[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=4)[CH:9]=[CH:8][C:7]=3[CH2:1]2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: ClCCN1CCOCC1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCN(CCN2CCOCC2)C3)nc1
Temperature: 90 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 4-(2-chloroethyl)morpholine hydrochloride (0.217 g, 1.16 mmol) in DMF (5.3 mL). Heat at 90° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (150 mL). Wash with 1.0 N NaOH (1×50 mL), brine (1×50 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 10% to 20% (2.0 M NH3 in methanol) in acetone to give the title compound: MS ES+ 397.2 (M+H)+, HRMS calcd for C22H29N4O3 397.2240 (M+H)+, found 397.2223, time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=5.6 min, 99.0% purity.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[C:29]([CH:32]1[NH:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]1)(=[O:31])[NH2:30]>CC#N>[CH:10]([N:8]1[CH2:9][CH:6]([N:37]2[CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])[CH2:33][CH:32]2[C:29](=[O:31])[NH2:30])[CH2:7]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N1CCNC(C(N)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)C(C(N)=O)C1
Yield: 54 %

Procedure:
A mixture of 1-benzhydrylazetidin-3-yl methanesulfonate (2.69 g, 8.5 mmol), K2CO3 (1.76 g, 12.8 mmol), tert-butyl 3-carbamoylpiperazine-1-carboxylate (1.95 g, 8.5 mmol) in CH3CN (40 mL) was stirred at reflux for 16 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product. (2.08 g, 54% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH:15]1([CH:20]=[CH:21][C:22]#[N:23])[CH2:19][CH2:18][CH2:17][CH2:16]1.N12CCCN=C1CCCCC2>C(#N)C>[CH:15]1([CH:20]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:21][C:22]#[N:23])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#CC=CC1CCCC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OB(c2cnn(C(CC#N)C3CCCC3)c2)OC1(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.00 g, 0.0103 mol) in acetonitrile (30 mL) was added 3-cyclopentylacrylonitrile (1.25 g, 0.0103 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (1.54 mL, 0.0103 mol). The resulting mixture was stirred at 60° C. overnight, then evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 50% EtOAc in hexanes, to give the desired product (2.36 g, 73%). LCMS (M+H) 316.1.
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH2:10](Br)[CH:11]=[CH2:12]>CN(C=O)C>[CH2:12]([O:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCC(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl hydroxyacetate was added dropwise to a slurry of NaH (1.1 eq) in DMF at 0° C. and the resulting mixture was stirred at RT for 2 h. After cooling to 0° C., allylbromide (1.1 eq) was added dropwise via syringe and the reaction mixture was stirred at RT for 2 h, quenched by careful addition of sat. aq. NH4Cl and partitioned between Et2O and brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give the title compound as pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 5.91 (m, 1H), 5.30 (dd, J 17.2, 1.5, 1H), 5.24 (dd, J 10.6, 0.6, 1H), 4.23 (q, J 2.1, 2H), 4.10 (d, J 5.7, 2H), 4.08 (s, 2H), 1.29 (t, J 7.08, 3H).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:19]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]4[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=4)[C:29]([OH:31])=O)=[N:18][CH:17]=[N:16][C:15]=3[S:14][CH:13]=2)=[CH:8][CH:7]=1.[NH2:35][NH2:36]>O1CCCC1>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:20]3[C:19]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]4[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=4)[C:29]([NH:35][NH2:36])=[O:31])=[N:18][CH:17]=[N:16][C:15]=3[S:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: O=C(O)c1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Reactant: NN
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: NNC(=O)c1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
Thionyl chloride (13 mg, 0.11 mmol) was added to a solution of 3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)benzoic acid (43 mg, 0.10 mmol) in tetrahydrofuran (2.0 mL) with stirring at 70° C. Stirring continued for one hour at 70° C. and then the mixture was cooled to 25° C. and added to a solution of hydrazine (32 mg, 1.0 mmol) in tetrahydrofuran (2.0 mL). The reaction was stirred at room temperature for one hour and the solvent was then removed in vacuo. The residue was dissolved in ethyl acetate (30 mL), washed with of aqueous sodium bicarbonate solution (20 mL), concentrated, and purified by column chromatography over silica gel using 2% methanol in ethyl acetate as eluant to give 22 mg (50%) of 3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)benzohydrazide as a white solid. MS [M+H] 439.2, 1H NMR (CDCl3) δ (ppm) 8.65 (s, 1H), 7.50-7.35 (m, 2H), 7.32-7.21 (m, 3H), 7.18 (s, 1H), 7.10-6.97 (m, 2H), 6.94 (d, J=2.7 Hz, 1H), 4.59 (t, J=6.9 Hz, 2H), 4.11 (s, 2H), 3.74 (t, J=6.0 Hz, 2H), 2.09 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12](=O)[CH2:13][C:14]([O:16]CC)=O.FC(F)(F)C([O-])=O.[CH2:27]([O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([C@@H:38]([NH2+:40][NH2:41])[CH3:39])=[CH:34][CH:33]=1)=[O:31])[CH3:28]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[C:12]1[CH2:13][C:14](=[O:16])[N:40]([C@H:38]([C:35]2[CH:36]=[CH:37][C:32]([C:30]([O:29][CH2:27][CH3:28])=[O:31])=[CH:33][CH:34]=2)[CH3:39])[N:41]=1
Reactant: CCOC(=O)c1ccc([C@H](C)[NH2+]N)cc1
Reactant: CCOC(=O)CC(=O)c1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Product: CCOC(=O)c1ccc([C@H](C)N2N=C(c3cc(C(F)(F)F)ccc3F)CC2=O)cc1

Procedure:
Ethyl 3-[2-fluoro-5-(trifluoromethyl)phenyl]-3-oxopropanoate (3 g, 9.7 mmol) and {(1S)-1-[4-(ethoxycarbonyl)phenyl]ethyl}hydrazinium trifluoroacetate (2.64 g, 8.2 mmol) were heated in dry acetonitrile (150 ml) to 85° C. for 8 hr. Solvent was evaporated and the residue purified by flash column chromatograph (SiO2, 25% ethyl acetate in hexanes) to give ethyl 4-((1S)-1-{3-[2-fluoro-5-(trifluoromethyl)phenyl]-5-oxo-4,5-dihydro-1H-pyrazol-1-yl}ethyl)benzoate as a white solid. NMR (500 MHz, CDCl3) δ: 1.38 (t, J=7.1, 3H); 1.82 (d, 7.2 Hz, 3H); 3.81 (dd, J=3 Hz, 23.9 Hz, 1H); 3.87 (dd, J=3 Hz, 23.9 Hz, 1H); 4.36 (q, J=7.1 Hz, 2H); 5.60 (q, J=7.2 Hz, 1H); 7.25 (t, J=9.5 Hz, 1H); 7.51 (d, J=8.4 Hz, 2H): 7.66 (br, 1H); 8.03 (d, J=8.4 Hz, 2H); 8.25 (dd, J=1.8 Hz, 6.4 Hz, 1H). MS C21H18F4N2O3
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:11]=1[C:12]([CH2:14][CH2:15][C:16](OC)=[O:17])=O)([CH3:4])([CH3:3])[CH3:2].O.[NH2:27][NH2:28]>>[C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:11]=1[C:12]1[CH2:14][CH2:15][C:16](=[O:17])[NH:27][N:28]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CCC(=O)c1cc(C)ccc1OCC(O)CNC(C)(C)C
Reactant: NN
Solvent: O
Product: Cc1ccc(OCC(O)CNC(C)(C)C)c(C2=NNC(=O)CC2)c1

Procedure:
Methyl 3-[2-(3-t-butylamino-2-hydroxypropoxy)-5-methylbenzoyl]propionate was cyclised with hydrazine hydrate in a similar manner to the procedure described in Example 2 (ii) to give 6-[2-(3-t-butylamino-2-hydroxypropoxy)-5-methylphenyl]-4,5-dihydro-3(2H)-pyridazinone, m.p. 126°-127.5°. The hydrochloride had m.p. 206.5°-209.5°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.I[CH:10]([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH:10]([CH3:12])[CH3:11])[CH:7]=1
Reactant: CC(C)I
Reactant: Oc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cc(Br)ccc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To a solution of 5-bromopyridin-2-ol (1 g, 5.75 mmol) in DMF (10 mL) were added 2-iodopropane (4.9 g, 28.75 mmol) and K2CO3 (4 g, 28.75 mmol). The mixture was stirred at rt overnight. The mixture was diluted with water (20 mL) extracted with EtOAc (3×25 mL), the combined organic phase was washed with brine, dried over Na2SO4, concentrated and purified by prep TLC to give 5-bromo-1-isopropylpyridin -2(1H)-one (380 mg, 31%). 1H NMR (CDCl3): 1.35 (d, 6H), 5.65-5.75 (m, 1H), 6.48 (d, 1H), 7.30 (m, 1H), 7.41 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.[Cl-].[CH3:14][C:15]1[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=1[CH:17]=[N+:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([CH:17]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:16]2[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=2[CH3:14])[CH:3]=1
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: Cc1ccccc1C=[N+]1CCOCC1
Agent: [Cl-]
Product: Cc1ccccc1C(c1cc(Cl)c2ccccc2c1O)N1CCOCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-chloro-1-naphthol and 4-(2-methyl-benzylidene)-morpholin-4-ium chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][NH:9]2)=[CH:4][C:3]=1[F:18].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][OH:28]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][N:9]2[CH2:26][CH2:27][OH:28])=[CH:4][C:3]=1[F:18]
Reactant: CCOC(=O)c1c[nH]c2cc(Cl)c(F)cc2c1=O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCO)c2cc(Cl)c(F)cc2c1=O
Temperature: 110 °C
Yield: 67 %

Procedure:
A solution of 8.1 g of 7-chloro-3-ethoxycarbonyl-6-fluoro-4-oxo-1,4-dihydro-quinoline and 8.2 g of potassium carbonate in 70 cm3 of DMF was agitated and heated at 110° C. for 1 hour. After cooling to 60° C., 15 of 2-bromo-ethanol were added to the reaction mixture and it was agitated and heated at 110° C. for 4 hours. After evaporation of the solvent under reduced pressure, 100 cm3 of water were added to the residue and the aqueous mixture was extracted with chloroform (4×100 cm3). The combined organic extracts were washed with water (2×100 cm3), dried over Na2SO4, filtered and then evaporated to dryness. The residue was recrystallised from ethanol (150 cm3). 6.75 g of 7-chloro-6-fluoro-3-ethoxycarbonyl-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline, m.p. 202° C., were obtained; yield 67%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][C@H:16]([CH3:18])[N:15]([CH3:19])[C@H:14]([CH3:20])[CH2:13]1)[NH:8][CH2:7][CH2:6]2.C[Al](C)C.[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]([C:42](OC)=[O:43])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:13][C@H:14]([CH3:20])[N:15]([CH3:19])[C@H:16]([CH3:18])[CH2:17]1)[N:8]([C:42]([C:35]1[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:32]([CH:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[CH:33][CH:34]=1)=[O:43])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1N1C[C@@H](C)N(C)[C@@H](C)C1)NCC2
Reactant: COC(=O)c1ccc(C2CCN(C)CC2)c2ccccc12
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1C[C@@H](C)N(C)[C@@H](C)C1)N(C(=O)c1ccc(C3CCN(C)CC3)c3ccccc13)CC2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 35.3 %

Procedure:
A stirred solution of D3 (58 mg, 0.21 mmole) in toluene (5 ml) under argon was treated with 2M trimethylaluminium in toluene (0.13 ml, 0.25 mmole), then stirred at room temperature for 0.75 h. A solution of D9 (60 mg, 0.21 mmole) in toluene (5 ml) was added and the mixture was heated under reflux for 3.5 h, then allowed to cool to room temperature. The mixture was added to a 5 g silica gel column and eluted with 0-10% MeOH/DCM to afford a yellow oil. This was further purified by preparative plate TLC on silica gel eluting with 9:1:0.1 DCM/MeOH/0.88 NH3 to afford the title compound as a white solid (39 mg, 35%). MH+ 527.
Reaction SMILES: [F:1][C:2]([F:13])([CH:10]([F:12])[F:11])/[CH:3]=[CH:4]/[C:5]([O:7]CC)=[O:6].[OH-].[Na+]>C(O)C.O>[F:1][C:2]([F:13])([CH:10]([F:11])[F:12])/[CH:3]=[CH:4]/[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)/C=C/C(F)(F)C(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)/C=C/C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Ethyl (E)-4,4,5,5-tetrafluoropent-2-enoate (15.9 g, 0.08 mol) was dissolved in ethanol (30 ml), 4M NaOH was added (15 ml) and the mixture was stirred at room temperature overnight. The mixture was diluted with water, washed with ethylacetate, acidified with 1M HCl and extracted with ethyl acetate. The organic extract was dried over magnesium sulfate, the solvent was removed under reduced pressure. 12.8 g of a colourless oil were obtained (0.074 mmol, 93%). MS (ESI) m/z=170.9 [M−1]−.
Reaction SMILES: Cl[C:2]1(Cl)[C:8](=[O:9])[CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([O:17][CH3:18])[CH2:15][CH3:16]>C(O)(=O)C.[Zn]>[CH3:18][O:17][CH:14]([CH2:15][CH3:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH:6]1[CH2:5][CH2:4][CH:3]2[CH:7]1[C:8](=[O:9])[CH2:2]2
Reactant: CCC(CCCCC1CCC2C1C(=O)C2(Cl)Cl)OC
Agent: [Zn]
Solvent: CC(=O)O
Product: CCC(CCCCC1CCC2CC(=O)C12)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Zinc (3 g) is added to a stirred solution of 6,6-dichloro-2(5-methoxyhept-1-yl)bicyclo[3.2.0]heptan-7-one {7,7-dichloro-4(5-methoxyheptyl)bicyclo[3.2.0]heptan-6-one} (2 g, 6 moles) in acetic acid (100 ml) under a nitrogen atmosphere. The solution is stirred at room temperature for one hour, then refluxed for 13 hours, after which time the mixture is filtered through a sintered glass funnel and the ether solution dried over anhydrous sodium sulfate. The solvent is removed under vacuum, leaving the crude product. Chromatography on silica gel yields 2-(5-methoxyhept-1-yl)bicyclo[3.2.0]heptan-7-one {4-(5-methoxyheptyl) bicyclo[3.2.0]heptan-6-one} (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.[Cl:17][S:18](O)(=[O:20])=[O:19].[Cl-].[Ca+2].[Cl-]>>[Cl:17][S:18]([C:7]1[C:6]2[C:5](=[O:16])[C:4]3[C:13](=[CH:14][CH:15]=[C:2]([Cl:1])[CH:3]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(O)Cl
Reactant: O=c1c2ccccc2oc2ccc(Cl)cc12
Agent: [Ca+2]
Agent: [Cl-]
Product: O=c1c2cc(Cl)ccc2oc2cccc(S(=O)(=O)Cl)c12
Temperature: 120 °C

Procedure:
80 g (0.347 moles) of 2-chloroxanthone (DHAR, J. Chem. Soc. 117, 1068) are suspended in 210 ml of chlorosulfonic acid (368.1 g; 3.16 moles) in a 500 ml one neck flask provided with refluxing coolant and calcium chloride valve. The mixture is slowly heated in an oil bath up to 120° C. under magnetic stirring. It is maintained at 120°-130° C. until the gas development ceases (2-3 h). The cool reaction mixture is carefully dropwise added to a becker containing ground ice under mechanical stirring. A heavy crystalline product is separated which is filtered on Buchner and washed with iced H2O. It is dried in air. There are obtained 112 g (98%) of raw 2-(chlorosulfonyl-7-chloroxanthone. After TLC monitoring (silica gel F245 ; toluene, acetic acid 14:1, visualizer UV) the product is used as such for the next reaction.