Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[NH2:11][OH:12].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[C:3]([CH:8]=[N:11][OH:12])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ncccc1F
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1ncccc1F
Temperature: 0 °C
Yield: 77 %

Procedure:
Combine 3-fluoropyridine-2-carboxaldehyde (3.00 g, 0.024 mol) with hydroxylamine hydrochloride (1.70 g, 0.026 mol) and ice (50 g) in an ethanol/water (30 mL/30 mL) mixture. Add aqueous sodium hydroxide (2.46 g, 0.06 mol, in 25 mL of water) dropwise and stir for 4 h near ambient temperature. Adjust the mixture to approx. pH 7.0 with aqueous hydrochloric acid and extract with diethyl ether. Dry over sodium sulfate and concentrate in vacuo. Elute the resulting residue over silica gel using methanol/dichloromethane to give 2.59 g (77%) of the desired oxime as an off white solid. MS(ES): (M+1)+ 140.9, 142.0 m/z.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH:23]([C:30](=O)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=O)=[CH:15][CH:14]=2)[N:10]=1.C([O-])(=O)C.[NH4+:43].C(O)(=O)C>C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]3[O:22][C:23]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:43]=3)=[CH:15][CH:14]=2)[N:10]=1
Reactant: COC(=O)CCC(OC(=O)Cc1ccc(OCc2nc(-c3ccco3)oc2C)cc1)C(=O)c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)CCc1oc(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1-c1ccccc1
Yield: 77.3 %

Procedure:
A mixture of methyl 4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]phenyl]acetoxy-5-oxo-5-phenylpentanoate (1.49 g), ammonium acetate (777 mg) and acetic acid (5 ml) was refluxed for 3 hrs. After cooling, ethyl acetate was added to the reaction mixture. The obtained ethyl acetate solution was washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[2-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-4-phenyl-5-oxazolyl]propionate (1.11 g, yield 77%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[F:18][C:19]([F:32])([O:23][C:24]1[CH:25]=[C:26]([CH2:30]Br)[CH:27]=[CH:28][CH:29]=1)[CH:20]([F:22])[F:21].O>COCCOC>[F:1][C:2]1[CH:7]=[C:6]([C:8](=[O:15])[CH:9]([CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:19]([F:18])([F:32])[CH:20]([F:21])[F:22])[CH:25]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)CC(=O)c1ccnc(F)c1
Reactant: FC(F)C(F)(F)Oc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (3.80 g, 18.2 mmol) in carbon tetrachloride (50 ml) were added N-bromosuccinimide (3.54 g, 19.9 mmol) and 2,2′-azobis(isobutyronitrile) (136 mg, 0.83 mmol), and the mixture was heated under reflux for 4 hrs. After cooling, the reaction solution was filtered, and the filtrate was concentrated to give ethyl 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To a solution of ethyl 3-(2-fluoropyridin-4-yl)-3-oxopropionate (3.5 g, 16.6 mmol) in 1,2-dimethoxyethane (35 ml) was added sodium hydride (60% in oil, 0.66 g, 16.6 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene prepared earlier in 1,2-dimethoxyethane (5 ml), and the mixture was stirred at room temperature for 1 hr. The reaction solution was poured into water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1) to give ethyl 3-(2-fluoropyridin-4-yl)-3-oxo-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate (4.78 g, 69%) as a colorless oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=1.C(N(CC)CC)C.[Cl:25][C:26]1[N:31]=[CH:30][C:29]([CH:32]=[CH:33][C:34](O)=[O:35])=[CH:28][CH:27]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C1COCC1.CCOC(C)=O>[Cl:25][C:26]1[N:31]=[CH:30][C:29]([CH:32]=[CH:33][C:34]([NH:2][CH2:3][C:4]2[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=2)=[O:35])=[CH:28][CH:27]=1
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Reactant: O=C(O)C=Cc1ccc(Cl)nc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(Cl)nc2)cc(F)c1NS(C)(=O)=O
Reaction time: 0.17 h
Yield: 23.4 %

Procedure:
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (78.3 mg, 0.272 mmol) was suspended in THF and treated with triethylamine (30 mg, 0.299 mmol) and then the resulting mixture was stirred for 10 mins. 3-(6-chloro-pyridin-3-yl)-acrylic acid (50 mg, 0.272 mmol) was added to the reaction mixture followed by DMTMM (82 mg, 0.299 mmol) after 10 mins. The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, sat'd NaHCO3 (×2), brine, and then dried over anhyd. Na2SO4, filtered and concentrated under reduced pressure. The crude residue was recrystallized (CH2Cl) to yield the title compound (26 mg, 23%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[CH2:30]([N:32]([CH2:37][CH3:38])[S:33](Cl)(=[O:35])=[O:34])[CH3:31]>C(N(CC)CC)C>[CH2:30]([N:32]([CH2:37][CH3:38])[S:33]([N:23]1[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]2[CH:26]=[CH:27][C:14]([NH:13][C:7]3[C:6]4[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[CH:15][CH:16]=2)[CH2:21][CH2:22]1)(=[O:35])=[O:34])[CH3:31]
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: CCN(CC)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCN(CC)S(=O)(=O)N1CCN(C(=O)c2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1

Procedure:
In the manner given in Example 14, 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine is reacted with diethylsulfamoyl chloride, in the presence of triethylamine to give 1-[(diethylamino)sulfonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10]1[NH:11][C:12]2[CH:18]=[C:17]([C:19](Cl)=[O:20])[CH:16]=[CH:15][C:13]=2[N:14]=1.[NH2:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27]([CH3:34])=[CH:28][C:29](=[O:33])[O:30]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.O>CCOC(C)=O>[CH3:34][C:27]1[C:26]2[C:31](=[CH:32][C:23]([NH:22][C:19]([C:17]3[CH:16]=[CH:15][C:13]4[N:14]=[C:10]([C:4]5[C:3]([CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=5[CH3:9])[NH:11][C:12]=4[CH:18]=3)=[O:20])=[CH:24][CH:25]=2)[O:30][C:29](=[O:33])[CH:28]=1
Reactant: Cc1cccc(C)c1-c1nc2ccc(C(=O)Cl)cc2[nH]1
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1-c1nc2ccc(C(=O)Nc3ccc4c(C)cc(=O)oc4c3)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of 2-(2,6-dimethylphenyl)-3H-benzoimidazole-5-carbonyl chloride HCl salt (from Example 1-247) (160 mg) and 7-amino-4-methyl-chromen-2-one (87 mg) was added DIPEA (0.27 mL). The resulting solution was stirred at room temperature for 18 h. The mixture was partioned between water and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was purified by an amino column using hexanes/ethyl acetate (1:4) and gave 2-(2,6-dimethylphenyl)-3H-benzoimidazole-5-carboxylic acid (4-methyl-2-oxo-2H-chromen-7-yl)-amide as a white solid; MS (ESI)m/z 424 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH2:25].CCN(CC)CC.Cl[C:34](=[O:39])[C:35]([O:37][CH3:38])=[O:36]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH:25][C:34](=[O:39])[C:35]([O:37][CH3:38])=[O:36]
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Reactant: COC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=O)NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added Et3N (0.141 mL, 1 mmol) and methyl 2-chloro-2-oxoacetate (0.09 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20% EtOAc in hexane) afforded the title compound as a solid (0.12 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.48 (m, 1H). 7.43 (m, 3H), 7.38 (m, 1H), 7.23 (s, 1H), 6.55 (d, J=16.0 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.60 (d, J=4.4 Hz, 2H), 4.18 (m, 1H), 3.85 (s, 3H); ESIMS m/z 512.22 ([M−H]−); IR (thin film) 1740, 1701, 1114, 808 cm−1.
Reaction SMILES: [BH4-].[Na+].Cl[CH2:4][C:5]([C:7]1[CH:8]=[N:9][C:10]([N:13]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH3:19])=[CH:11][CH:12]=1)=[O:6].[NH2:20][C@@H:21]([CH3:24])[CH2:22][OH:23].C(Cl)Cl>O1CCCC1.O>[CH3:19][C:14]1[N:13]([C:10]2[N:9]=[CH:8][C:7]([CH:5]([OH:6])[CH2:4][NH:20][C@@H:21]([CH3:24])[CH2:22][OH:23])=[CH:12][CH:11]=2)[C:17]([CH3:18])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C)n1-c1ccc(C(=O)CCl)cn1
Reactant: C[C@H](N)CO
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C)n1-c1ccc(C(O)CN[C@@H](C)CO)cn1
Temperature: 15 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Water (15.0 L) was added to a suspension of sodium borohydride (4.11 Kg, 109 mol) in tetrahydrofuran (140 L) at 15° C. and the resulting solution stirred at 15° C. A solution of 2-chloro-1-[6-(2,5-dimethylpyrrol-1-yl)pyridin-3-yl]ethanone (30.0 Kg, 120.6 mol) in tetrahydrofuran (100 L) and water (15 L) was added over 40 minutes maintaining the temperature below 30° C. The resulting solution was stirred for 60 minutes at 15° C. When all the 2-chloro-1-[6-(2,5-dimethylpyrrol-1-yl)pyridin-3-yl]ethanone was consumed the reaction mixture was treated with concentrated HCl (27% w/w, 47 Kg) over 80 minutes maintaining the temperature below 30° C. The mixture was cooled to 15° C. and NaOH (34% w/w, 79 Kg) was added over 60 minutes maintaining the temperature below 30° C. The mixture was then granulated at 20° C. overnight. When all the chloroalcohol intermediate was consumed, the aqueous phase was separated. DCM (150 L) and water (140 L) were added and the mixture was stirred before allowing the phases to separate. The organic phase was washed with water (2×30 L). (S)-(+)-2-amino-1-propanol (17.2 Kg, 229 mol) and tetrahydrofuran (15 L) were added over 20 minutes. The equipment was set for distillation and DCM was replaced by tetrahydrofuran to give a final volume of 160 litres. The reaction mixture was left at reflux overnight. After cooling to room temperature, DCM (150 L) was added and the mixture was washed with water (3×30 L). The equipment was set for distillation and the tetrahydrofuran and DCM were replaced by acetonitrile to give a final volume of 84 litres. ααα-trifluorotoluene (300 L) was added over 60 minutes, the mixture was cooled to 5° C. over 8 hours and granulated at 5° C. for 6 hours. The product was collected by filtration, washed with ααα-trifluorotoluene (2×30 L) and dried at 45° C. under vacuum overnight. Yield=65% (22.7 Kg) δH (CDCl3, 300 MHz) 1.10 (3H, t), 2.10 (6H, s), 2.7-3.2 (3H, m), 3.45 (1H, m), 3.70 (H, dd), 4.85 (1H, m), 5.90 (2H, s), 7.20 (1H, d), 7.90 (1H, dd), 8.60 (1H, d) ppm. MS m/z 290 (MH+). The intermediate epoxide was characterised as δH (CDCl3, 300 MHz) 2.10 (6H, s), 2.90 (1H, dd), 3.25 (1H, dd), 4.00 (1H, dd), 5.90 (2H, s), 7.20 (1H, d), 7.70 (1H, dd), 8.40 (1H, d) ppm. MS m/z 215 (MH+).
Reaction SMILES: [C:1]1(=[O:14])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][NH:2]1.[H-].[Na+].Cl[CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C.C(OCC)(=O)C>[C:21]1([CH2:20][O:19][CH2:18][N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]3[C:1](=[O:14])[NH:2][CH2:3][CH2:4][C:5]2=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCOCc1ccccc1
Reactant: O=C1NCCc2[nH]c3ccccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1NCCc2c1c1ccccc1n2COCc1ccccc1
Reaction time: 0.08 h

Procedure:
a solution of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (1.12 g) in dry DMF (60 ml) was treated with sodium hydride (60% dispersion in oil; 480 mg) and the resulting mixture was stirred under nitrogen until effervescence ceased. The mixture was then cooled to 0° and benzyl (chloromethyl) ether (10% w/v solution in DMF; 0,835 ml) was added over 10 min. Stirring was continued for a further 5 min and then water (10 ml) was added. The reaction mixture was concentrated in vacuo to give an oil which was dissolved in ethyl acetate (100 ml) and washed with water (3×100 ml). The organic phase was dried and adsorbed onto FCC silica. Purification by FCC eluting with System A (150:8:1) gave the title compound 1.1 g), m.p. 133°-135°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:56]=[CH:55][CH:54]=[CH:53][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][CH2:41]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[C-:57]#[N:58].[K+]>CN(C)C=O.[OH-].[Na+]>[C:57]([CH2:41][CH2:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[O:33][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:53]=[CH:54][CH:55]=[CH:56][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19]1)#[N:58]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: [C-]#N
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCC#N)cc1
Temperature: 25 °C

Procedure:
A solution of 0.20 g of tert-butyl 4-{4-[3-(2-methoxybenyloxy)propoxy]phenyl}-3-(2-{2-[2-(toluene-4-sulphonyloxy)ethyl]phenoxy}ethoxy)piperidine-1-carboxylate (Example 26b) and 0.33 g of potassium cyanide in 4 ml of N,N-dimethylformamide is stirred at 65° C. over 10 hours. The reaction mixture is cooled to room temperature, diluted with 0.1N NaOH and extracted with tertbutyl methyl ether (2×) and ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.44 (1:1 EtOAc-heptane); Rt=6.02.
Reaction SMILES: CS([C:4]1[S:5][C:6]2[CH:12]=[C:11]([CH2:13][C:14]3[N:18]4[N:19]=[C:20]([C:23]#[N:24])[CH:21]=[CH:22][C:17]4=[N:16][CH:15]=3)[CH:10]=[CH:9][C:7]=2[N:8]=1)=O.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[OH:32][C@@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]1[NH:25][C:4]1[S:5][C:6]2[CH:12]=[C:11]([CH2:13][C:14]3[N:18]4[N:19]=[C:20]([C:23]#[N:24])[CH:21]=[CH:22][C:17]4=[N:16][CH:15]=3)[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: CS(=O)c1nc2ccc(Cc3cnc4ccc(C#N)nn34)cc2s1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc2ncc(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)n2n1
Temperature: 135 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
A mixture of 3-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrile (300 mg, 0.9 mmol), (1R,2R)-2-aminocyclohexanol (293 mg, 2.5 mmol) and DIEA (219 mg, 1.7 mmol) in NMP (16 mL) was stirred at 135° C. overnight. The mixture was cooled to rt and water (40 mL) was added. The mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrile as a brown solid (100 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ 8.40 (d, J=9.3 Hz, 1H), 7.87-7.84 (m, 2H), 7.70 (d, J=9.3 Hz, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.13 (dd, J=1.5, 8.1 Hz, 1H), 4.72 (d, J=5.1 Hz, 1H), 4.36 (s, 2H), 3.54-3.51 (m, 1H), 3.39-3.36 (m, 1H), 2.06-2.02 (m, 1H), 1.90-1.86 (m, 1H), 1.65-1.59 (m, 2H), 1.31-1.17 (m, 4H). LCMS (ESI) m/z 405 (M+H)+.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[Y:6].[O-2:7].[Y+3].[O-2].[O-2].[Y+3]>>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Y+3:6].[O-2:7].[Y+3:6].[O-2:2].[O-2:2].[Y+3:6]
Reactant: O=P(O)(O)O
Reactant: [Y]
Agent: [O-2]
Agent: [Y+3]
Product: O=P([O-])([O-])[O-]

Procedure:
Generally, a 75 to 85 weight percent solution of phosphoric acid is added to the slurry over a period of about 15 minutes to about 90 minutes as the slurry is continuously agitated and maintained at a temperature that typically ranges between about 20° C. and about 70° C. The amount of the phosphoric acid added to the slurry is usually about 1.5 molar percent less than the amount of the yttrium compound present in the slurry. When the yttrium compound used is yttrium oxide, the reaction takes place to form yttrium phosphate, minor amounts of yttrium oxide, minor amounts of surface adsorbed phosphoric acid and water. The yttrium phosphate formed comprises approximately 95.5 percent of the solids portion in the slurry.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[C:11]([O:19][CH3:20])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH2:30][Cl:31]>S1(CCCC1)(=O)=O>[Cl:31][CH2:30][CH2:29][CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[C:11]([O:19][CH3:20])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc2c(=O)[nH]c(-c3ccc(O)cc3)nc12
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: COc1cccc2c(=O)[nH]c(-c3ccc(OCCCCl)cc3)nc12
Temperature: 25 °C

Procedure:
2.7 gm (10 mmols) of 2-(4-hydroxy-phenyl)-8-methoxy-3,4-dihydro-quinazolin-4-one were dissolved in 30 ml of sulfolane and reacted with 1.5 gm (10 mmols+10%) of potassium carbonate. The resulting clear solution was admixed with 2.7 ml of 1-bromo-3-chloro-propane, and the mixture was stirred at room temperature until the reaction was complete. The reaction mixture was then poured into ice water, the aqueous mixture was extracted with ethyl acetate, and the combined organic extracts were dried over sodium sulfate and evaporated. A colorless oil was obtained, which crystallized upon cooling.
Reaction SMILES: [Cl:1][C:2]1[C:3](S(C)=O)=[N:4][C:5]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([NH2:17])=[O:16])[CH2:10]2)=[N:6][CH:7]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH:45][C:46](=[O:49])[CH:47]=[CH2:48]>CO.C(Cl)(Cl)Cl>[C:46]([NH:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[NH:38][C:3]1[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([NH2:17])=[O:16])[CH2:10]2)[N:4]=1)(=[O:49])[CH:47]=[CH2:48]
Reactant: C=CC(=O)Nc1ccccc1N
Reactant: CS(=O)c1nc(N[C@@H]2CCC[C@H](C(N)=O)C2)ncc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CO
Product: C=CC(=O)Nc1ccccc1Nc1nc(N[C@@H]2CCC[C@H](C(N)=O)C2)ncc1Cl
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of Intermediate 3 (1.4 g, 4.43 mmol) in 0.04 M PTSA/1,4-dioxane (12 mL, 0.106 mmol) was added N-(2-aminophenyl)acrylamide (1.72 g, 6.64 mmol), and the reaction mixture was stirred at 70° C. for 1 h. After completion of the reaction (TLC System: 5% methanol/chloroform, (Rf): 0.5), the reaction mixture was concentrated and diluted with water (30 mL), and the precipitate was filtered, washed with saturated sodium bicarbonate solution (15 ml) and dried to afford the desired compound as a white solid. (1.1 g, 59.7%). 1H NMR (400 MHz, DMSO-d6) δ 1.21-1.26 (m, 3H), 1.26-1.32 (m, 2H), 1.67-1.69 (m, 2H), 1.76-1.79 (m, 2H), 2.05 (m, 1H), 5.79 (d, 1H J=11.4 Hz), 6.28-6.32 (d, 1H J=16.9 Hz), 6.46-6.52 (dd, 1H J=10.2 Hz and 17 Hz), 6.64 (br s, 1H), 7.14 (br s, 1H), 7.22-7.27 (m, 2H), 7.43 (d, 1H J=7.4 Hz), 7.74 (d, 1H J=7.8 Hz), 8.01 (s, 1H), 8.86 (br s, 1H), 10.15 (s, 1H). MS m/z: 415.2 (ES+, M+H).
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].Cl[C:24]([O:26][CH2:27][Cl:28])=[O:25]>ClCCl>[C:24](=[O:25])([O:22][CH2:21][CH2:20][CH:17]1[CH2:18][CH2:19][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH2:15][CH2:16]1)[O:26][CH2:27][Cl:28]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCOC(=O)OCCl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine (3.22 ml) was added to an ice-cold solution of 2-(1-(tert-butoxycarbonyl)-4-piperidyl)-ethanol (7.6 g) in dichloromethane (33 ml) followed by chloromethyl chloroformate (3.23 ml) at such a rate that the temperature was kept below 10° C. After stirring overnight at room temperature the reaction mixture was washed twice with 0.5 M HCl followed by water and aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered and evaporated in vacuo to yield the title compound as a colourless oil.
Reaction SMILES: [CH3:1][CH:2]([C:5]1[C:17]([OH:18])=[C:16]2[C:8]([CH:9]3[CH:14]([CH:15]2[NH:19][CH3:20])[CH2:13][CH2:12][CH2:11][CH2:10]3)=[C:7]([CH3:21])[CH:6]=1)[CH:3]=[CH2:4].Cl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1>N1C=CC=CC=1>[CH3:1][CH:2]([C:5]1[C:17]([OH:18])=[C:16]2[C:8]([CH:9]3[CH:14]([CH:15]2[N:19]([CH3:20])[C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=2)[CH2:13][CH2:12][CH2:11][CH2:10]3)=[C:7]([CH3:21])[CH:6]=1)[CH:3]=[CH2:4]
Reactant: O=C(Cl)c1cccnc1
Reactant: C=CC(C)c1cc(C)c2c(c1O)C(NC)C1CCCCC21
Agent: Cl
Solvent: c1ccncc1
Product: C=CC(C)c1cc(C)c2c(c1O)C(N(C)C(=O)c1cccnc1)C1CCCCC21
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.2 %

Procedure:
To 1.5 ml of pyridine were added 1.0 g of 7-(1-methyl-2-propenyl)-8-hydroxy-5-methyl-9-methylamino-1,2,3,4,4a,9a-hexahydrofluorene and 0.7 g of nicotinoylchloride hydrochloride, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated and then extracted with chloroform. The chloroform layer was washed with water, dried with sodium sulfate and then concentrated. The residue was purified by a silica gel column chromatography (eluent: ethyl acetate) and then recrystallized from ethyl acetate-n-hexane to obtain 0.7 g of 7-(1-methyl-2-propenyl)-8-hydroxy-5-methyl-9-(N-methyl-N-nicotinoylamino)- 1,2,3,4,4a,9a-hexahydrofluorene having a melting point of 183°-184° C. and of colorless powdery crystal.