Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:14])[NH:6]2.[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>CO>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:20]/[C:16]1[NH:15][CH:19]=[CH:18][CH:17]=1)/[C:5](=[O:14])[NH:6]2
Reactant: O=Cc1ccc[nH]1
Reactant: O=C1Cc2c(ccc([N+](=O)[O-])c2F)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Product: O=C1Nc2ccc([N+](=O)[O-])c(F)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,3-dihydro-4-fluoro-5-nitro-2H-indol-2-one (400 mg, 2.04 mmol) (Starting Material 10) in MeOH (4 mL), was successively added at room temperature pyrrole-2-carboxaldehyde (220 mg, 2.25 mmol) (Aldrich) and tetrabutyl ammonium hydroxide (4.5 mL, 1.0 M solution in MeOH)(Aldrich). The mixture was stirred at r.t. for 12 h, then quenched with 1N HCl. The yellow precipitate was collected by suction filtration, washed with water and dried in a vacuum oven. (Yield 510 mg, 92%).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([CH2:17][NH:18][CH3:19])[C:10]=1[O:11][C@H:12]1[CH2:16][CH2:15][O:14][CH2:13]1)[NH2:7].C(N(CC)C(C)C)(C)C.[CH2:29]([O:36][C:37]([O:39]N1C(=O)CCC1=O)=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[NH2:7][C:6]1[CH:5]=[C:4]([F:3])[C:10]([O:11][C@H:12]2[CH2:16][CH2:15][O:14][CH2:13]2)=[C:9]([CH:8]=1)[CH2:17][N:18]([CH3:19])[C:37](=[O:39])[O:36][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CNCc1cc(N)cc(F)c1O[C@H]1CCOC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc(N)cc(F)c1O[C@H]1CCOC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To 39A (640 mg, 2.043 mmol), N,N-diisopropylethylamine (1.424 ml, 8.17 mmol) in DMF (10 ml), was added N-(benzyloxycarbonyloxy) succinimide (560 mg, 2.248 mmol). The mixture was stirred at rt for 1 h, quenched with water, extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography to give 39B (540 mg, 1.442 mmol, 70.6% yield). MS (ESI) m/z: 375.2 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[CH2:26]=[O:27]>O.O1CCCC1>[CH2:22]([Sn:17]([CH2:26][OH:27])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23][CH2:24][CH3:25]
Reactant: C=O
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC[Sn](CO)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 197.2 %

Procedure:
To a mixture of diisopropylamine (62 mL, 0.44 mol) and tetrahydrofuran (1000 mL) were added dropwise n-butyl lithium (2.6 M n-hexane solution, 100 mL, 0.26 mol) and n-butyl lithium (1.6 M n-hexane solution, 95 mL, 0.15 mol) at −78° C., and then the reaction mixture was stirred for 30 minutes. To this mixture was added dropwise tributyltin hydride (100 mL, 0.37 mol) at −78° C., and then the reaction mixture was stirred for 60 minutes at 0° C. The reaction mixture was cooled to −78° C., after which paraformaldehyde (13 g, 0.15 mol) was added to the reaction mixture. The reaction mixture was slowly raised to room temperature, and then the reaction mixture was stirred overnight at room temperature. To the reaction mixture were water, an ammonium chloride aqueous solution, and diethyl ether, and the organic layer was separated. The organic layer was washed first with a saturated sodium hydrogencarbonate aqueous solution and then with saturated aqueous sodium chloride. The organic layer was separated, and was concentrated under a reduced pressure. The residue was purified by neutral silica gel column chromatography (heptane:diethyl ether=4:1) to obtain the title compound (95 g, 80%).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=[O:28].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=[O:28])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NN1CCCCC1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NN1CCCCC1=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.7 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added 1-aminopiperidin-2-one 256 (31 mg, 0.27 mmol),), HOBt (38 mg, 0.27 mmol), DMAP (32 mg, 0.27 mmol) and EDCl (53 mg, 0.27 mmol). The mixture was stirred at room temperature for 48 h and purified by column to afford 257 as foam (55 mg, 82%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Br[CH2:8][C:9]1[CH:13]=[C:12]([CH3:14])[O:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2[CH:13]=[C:12]([CH3:14])[O:11][N:10]=2)[CH:6]=1
Reactant: Cc1cc(CBr)no1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Cn2cc(I)cn2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
4-Iodo-1H-pyrazole (0.826 g, 4.26 mmol) (1), 3-(bromomethyl)-5-methylisoxazole (0.75 g, 4.26 mmol) and potassium carbonate (1.18 g, 8.52 mmol) were added to dry DMF (8 ml) and stirred at room temperature for 16 h. The reaction was diluted with ethyl acetate (20 ml) and washed with water, brine and dried. The organic solution was concentrated in vacuo and the residue purified by flash silica chromatography (20% ethyl acetate in hexane). The pure fractions provided the title compound as a white powder (0.7 g, 56.8%). 1H-NMR (500 MHz, CDCl3) 2.4 (s, 3H), 5.33 (s, 2H), 5.92 (s, 1H), 7.51 (s, 1H), 7.55 (s, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][CH:25]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:33].C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30][Br:33])=[CH:26][CH:25]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: BrC(Br)(Br)Br
Reactant: O=C(NC1CC1)c1cn(-c2cccc(-c3ccc(CO)cc3)c2)c2ncccc2c1=O
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(NC1CC1)c1cn(-c2cccc(-c3ccc(CBr)cc3)c2)c2ncccc2c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of N-cyclopropyl-1-[3-(4-hydroxymethylphenyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Example 16, carbon tetrabromide (2 eq), and diphos (0.6 molareq) in methylene chloride (15 ml/mmol) was stirred at room temperature for 3 hours. The mixture was concentrated at room temperature and chromatographed on silica gel eluting with a 1:1 mixture of ethyl acetate and methylene chloride to afford the N-Cyclopropyl-1-[3-(4-bromomethylphenyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound.
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].C(O)(=O)C.[Br:21]Br>C(OCC)C.C(Cl)Cl>[Br:21][CH2:14][C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:2]([F:16])([F:1])[CH:3]([F:4])[F:5])[CH:8]=1)=[O:15]
Reactant: BrBr
Reactant: CC(=O)c1cccc(OC(F)(F)C(F)F)c1
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(CBr)c1cccc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
1-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]ethanone (6.1 g, 25.8 mmol) was dissolved in diethyl ether (36.9 mL), and acetic acid (44.4 mL, 775 mmol) was added, followed by bromine (1.397 mL, 27.1 mmol). The reaction was stirred at 25° C. for 3 hours, then was diluted with DCM and extracted with saturated sodium bicarbonate solution. The combined organic layers were dried with anhydrous MgSO4, filtered, and concentrated. The crude product was purified on a silica gel column with a 340 g cartridge, using a 10% EtOAc/Hexanes isocratic mobile phase. 2-Bromo-1-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]ethanone (5 g, 15.87 mmol) was obtained. 1H NMR (400 MHz, CDCl3) 84.45 (s, 2H), 5.96 (t, J=53, 2.7 Hz, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.55 (t, J=7.9 Hz, 1H), 7.83 (s, 1H), 7.91 (d, J=7.7 Hz, 1H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].C(=O)([O-])O.[Na+].[Cl-].[Na+]>COCCOC.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>[S:5]1[CH:6]=[C:2]([C:12]2[CH:13]=[CH:14][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=2)[N:3]=[CH:4]1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: COCCOC
Solvent: O
Product: O=Cc1ccc(-c2cscn2)cc1
Yield: 85 %

Procedure:
To a solution of 4-bromothiazole (see The Journal of Organic Chemistry, 71, 3754 (2006)) (1.31 g, 7.98 mmol) in 1,2-dimethoxyethane (38.0 ml) were added 4-formylphenylboronic acid (1.45 g, 9.67 mmol), sodium hydrogencarbonate (2.00 g, 23.8 mmol) and water (19 ml), which was deaerated under reduced pressure, followed by argon substitution. Tetrakis(triphenylphosphine)palladium (270 mg, 0.234 mmol) was then added, followed by heating to reflux for 16 hours under argon atmosphere. After completion of the reaction, a saturated aqueous sodium chloride solution was added to the reaction solution, followed by extraction with chloroform. The separated organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=4:1 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (1.29 g) as a slightly yellow solid. (Yield: 85%)
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7](Br)=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[N:12]1([CH2:18][CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>CO.C(Cl)Cl.O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:20][CH2:19][CH2:18][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:5]2=[N:4][CH:3]=1
Reactant: NCCN1CCOCC1
Reactant: Brc1cncc2ncc(Br)n12
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: O
Product: Brc1cnc2c(NCCN3CCOCC3)nccn12
Temperature: 70 °C
Yield: 14 %

Procedure:
To a solution of 3,5-dibromo-imidazo[1,2-a]pyrazine (D) (200 mg, 0.72 mmol) in methanol (3.6 ml) was added (2-morpholin-4-yl-ethyl)-amine (2.5 eq.) and diisopropylethylamine (DIPEA) (0.383 ml, 4.5 mmol). The mixture was heated at 70° C. overnight. The mixture was then cooled to rt, diluted with DCM and water. The organic layer was washed with brine, dried and concentrated. The residue was purified on a silica gel column to give 34 mg (yield 14%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH2:19]O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH2:19][Cl:23])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2c(c1)c(CO)nn2Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)c(CCl)nn2Cc1ccccc1
Temperature: 25 °C
Yield: 47.3 %

Procedure:
To a solution of (1-benzyl-5-methoxy-1H-indazol-3-yl)methanol (18 g; 0.07 mol) in chloroform (200 ml) stirred at room temperature was slowly added thionyl chloride (15.8 g; 0.13 mol). Once the addition was complete, the solution was refluxed for 24 hours. The reaction was then stopped by cooling the mixture to room temperature and evaporating off the solvent under reduced pressure. The residue was then taken up several times in toluene and concentrated under reduced pressure. The crude residue obtained was purified by crystallization from hexane to give 9.5 g of 1-benzyl-3-(chloromethyl)-5-methoxy-1H-indazole with a melting point of 78-80° C.
Reaction SMILES: [CH3:1][C:2]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:15])([CH3:5])[CH2:3][OH:4].[H-].[Na+].I[CH3:19]>CN(C)C=O>[CH3:19][O:4][CH2:3][C:2]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:15])([CH3:1])[CH3:5]
Reactant: Cc1cc2ccccc2n1C(C)(C)CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC(C)(C)n1c(C)cc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution of 2-methyl-2-(2-methyl-1H-indol-1-yl)propan-1-ol (780 mg, 3.8 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added sodium hydride (919 mg, 38.3 mmol) at 0° C. The resultant reaction mixture was allowed to stirred at 0° C. for 1 h. Iodomethane (5.4 g, 38.3 mmol) was added dropwise at 0° C., And then the resulting reaction mixture was allowed to stir for 3 hours at room temperature. The reaction mixture was quenched with water. The pH was adjusted to around 6 by progressively adding 2N hydro chloride below 0° C., extracted with acetic ester (50 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph on silica gel eluted with (petrol ether/acetic ester 10:1→5:1) to give 1-(1-methoxy-2-methylpropan-2-yl)-2-methyl-1H-indole (800 mg, 96%) as a light yellow oil. LCMS (M+H+) m/z: calcd. 217.15. found 217.9.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([S:18][C:19]2[N:23]4[CH:24]=[C:25]([C:28]5[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=5)[CH:26]=[CH:27][C:22]4=[N:21][N:20]=2)=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:35][CH2:36][OH:37].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:33][N:31]1[CH:32]=[C:28]([C:25]2[CH:26]=[CH:27][C:22]3[N:23]([C:19]([S:18][C:14]4[CH:15]=[C:16]5[C:11](=[CH:12][CH:13]=4)[N:10]=[CH:9][C:8]([N:1]4[CH2:7][CH2:6][CH2:5][N:4]([CH2:35][CH2:36][OH:37])[CH2:3][CH2:2]4)=[CH:17]5)=[N:20][N:21]=3)[CH:24]=2)[CH:29]=[N:30]1
Reactant: Cn1cc(-c2ccc3nnc(Sc4ccc5ncc(N6CCCNCC6)cc5c4)n3c2)cn1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3nnc(Sc4ccc5ncc(N6CCCN(CCO)CC6)cc5c4)n3c2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.3 %

Procedure:
A mixture of 3-(1,4-Diazepan-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline (Example 19—see in Table below) (15 mg, 0.033 mmol), 2-bromoethanol (12.33 mg, 0.099 mmol) and K2CO3 (9.08 mg, 0.066 mmol) in DMF (0.5 ml) was stirred at rt for 24 hr. The mixture was purified by prep-HPLC to give the title compound (6 mg, yield 36%). [Method 1D]
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]3[CH3:21])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:22]([C:25]1[S:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])[CH3:23]>>[CH3:21][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][N:15]1[CH2:14][CH2:13][CH2:12][NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:28]3[S:29][C:25]([C:22](=[O:24])[CH3:23])=[CH:26][CH:27]=3)=[CH:3][N:4]=2)[N:7]=1
Reactant: CC1CCCCN1CCCNc1ccc2ncc(Br)n2n1
Reactant: CC(=O)c1ccc(B(O)O)s1
Product: CC(=O)c1ccc(-c2cnc3ccc(NCCCN4CCCCC4C)nn23)s1
Yield: 71 %

Procedure:
The reaction of 3-bromo-N-(3-(2-methylpiperidin-1-yl)propyl)imidazo[1,2-b]pyridazin-6-amine with (5-acetylthiophen-2-yl)boronic acid, under the Suzuki coupling condition described in example 5.6.19, afforded the desired compound in 71% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 (d, J=6.57 Hz, 3H) 1.45-1.59 (m, 1H) 1.67-1.96 (m, 5H) 2.13-2.31 (m, 2H) 2.60 (s, 3H) 2.74 (dd, J=10.86, 4.80 Hz, 1H) 2.83-2.95 (m, 1H) 3.11 (br. s., 1H) 3.17-3.31 (m, 1H) 3.34-3.46 (m, 1H) 3.53-3.72 (m, 2H) 6.72 (d, J=9.85 Hz, 1H) 7.56 (d, J=4.04 Hz, 1H) 7.64-7.73 (m, 2H) 7.94 (s, 1H); LRMS (ESI) m/e 398.0 [(M+H)+, calcd for C21H27N5OS 397.0].
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[C:16](F)[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CCCCO.CS(C)=O>[CH2:1]([NH:8][C:9]1[N:17]=[C:16]([NH:31][C@H:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H](N)C(O)C(C)(C)C
Reactant: CC(C)n1cnc2c(NCc3ccccc3)nc(F)nc21
Solvent: CS(C)=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](Nc1nc(NCc2ccccc2)c2ncn(C(C)C)c2n1)C(O)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of benzyl-(2-fluoro-9-isopropyl-9H-purin-6-yl)-amine (40 mg, 1 eq, 0.14 mmol) in n-BuOH/DMSO (5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.12 mL, 4.9 eq, 0.69 mmol) followed by (3RS,4R)-4-amino-2,2-dimethyl-hexan-3-ol (69 mg, 3.4 eq, 0.48 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×50 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with hexane:ether:MeOH (50:50:0→50:50:2) to afford the title compound as a white solid; Yield: 13 mg (23%).(55% de 4R,3S: 45% de 4R,3R). 1H-NMR (d-CDCl3, 250 MHz): δ 1.00-1.04 (m, 12H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 1.56+1.58 (2×d, 6H, J=6.63+6.79 Hz, —CH(CH3)2), 1.63-1.87 (m, 2H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.57 (d, 1H, J=1.42 Hz, —NHCH(CH2CH3) CH(C(CH3)3)OH), 3.73-3.87 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 4.57-4.70 (m, 1H, —CH(CH3)2), 4.77-4.86 (m, 2H, —HNCH2-Bz), 5.22-5.36+5.93-6.09 (2×m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 7.25-7.44 (m, 6H, 5×Bz-H+HNCH2-Bz), 7.53 (s, 1H, —N═CH—N). FABMS m/z (relative intensity): 411 ([M+H]+, 90), 323 (100). Accurate Mass (M+H): Actual: 411.2872, Measured: 411.2860.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1([F:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[O:21]1[CH2:24][C:23](=O)[CH2:22]1.C([BH3-])#N>O1CCCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:17]([NH2:20])(=[O:18])=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1([F:16])[CH2:15][CH2:14][N:13]([CH:23]2[CH2:24][O:21][CH2:22]2)[CH2:12][CH2:11]1
Reactant: NS(=O)(=O)c1ccc(OCC2(F)CCNCC2)c(Cl)c1
Reactant: O=C1COC1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(OCC2(F)CCN(C3COC3)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 322C (830 mg) in tetrahydrofuran (15 mL) and acetic acid (5 mL) was added oxetan-3-one (163 mg) and MP-cyanoborohydride (2.38 mmol/g, 1.9 g). The mixture was stirred at room temperature overnight. The reaction was then filtered and the filtrate was concentrated under vacuum. The residue was slurried in ether and the solid product was collected by filtration.
Reaction SMILES: [CH2:1]([C:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H][H]>C1(C)C=CC=CC=1>[CH2:1]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCC1=CCC(c2cccc(F)c2)CC1
Reactant: [H][H]
Solvent: Cc1ccccc1
Product: CCCCCCCC1CCC(c2cccc(F)c2)CC1

Procedure:
The compound (11) was dissolved in a mixed solvent of toluene (150 ml) and Solmix A-11 (150 ml), and 0.86 g of Pd/C(NX type) was added thereto. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed and then the solvent was distilled off. The residue obtained was purified with a fractional operation by means of column chromatography using heptane as the eluent and silica gel as the stationary phase powder, and further purified by means of recrystallization from Solmix A-11, and dried, giving 44.7 g of 4-heptyl-1-(3-fluorophenyl)-cyclohexane (12). The yield based on the compound (12) was 75.8%.
Reaction SMILES: [H-].[Na+].[CH3:3]S(I)(C)(C)=O.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14]>CS(C)=O>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]1[CH2:3][O:14]1
Reactant: COc1ccccc1C=O
Reactant: CS(C)(C)(=O)I
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccccc1C1CO1
Temperature: 40 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
Into a 1000-mL 3-necked round-bottom flask was placed DMSO (400 mL) and sodium hydride (7 g, 175.00 mmol, 1.19 equiv, 60%). This was followed by the addition of S,S-dimethylmethanesulfinyl iodide (38 g, 172.67 mmol, 1.18 equiv). The mixture was stirred for 1 h at 40° C. To this was added a solution of 2-methoxybenzaldehyde (20 g, 146.90 mmol, 1.00 equiv) in DMSO (100 mL) dropwise with stirring at 15° C. The resulting solution was stirred for 1 h at room temperature. The reaction was then quenched by the addition of 400 mL of NH4Cl (aq.). The resulting solution was extracted with 1000 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1000 mL of H2O. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification afforded 14 g (63%) of 2-(2-methoxyphenyl)oxirane as a yellow oil.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCCCCCCCCCCC.NC(N)=[O:24].C(=O)(O)[O-].[Na+].OO>O.S([O-])([O-])(=O)=O.[Mn+2]>[CH:1]12[O:24][CH:2]1[CH2:3][C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC(N)=O
Reactant: C1=Cc2ccccc2C1
Agent: [Mn+2]
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CCCCCCCCCCCC
Solvent: O
Product: c1ccc2c(c1)CC1OC21
Yield: 99 %

Procedure:
To a mechanically stirred solution of indene (0.01 mol), dodecane (0.001 mol), urea (0.208 mol), sodium bicarbonate (0.003 mol) and manganese sulphate (0.1 mmol) in 10.0 ml of water at 20° C. is added 30% aqueous hydrogen peroxide (0.4 mol) in three equal portions over a period of 3 hours. After 10 hours the reaction mixture was extracted with 4×5 ml diethyl ether. The combined organic layer was dried over anhydrous sodium sulphate. Removal of solvent yielded indene oxide in >99% yield with selectivity 95%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([F:30])([F:29])[F:18])[CH:9]=2)=[O:4]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Product: COC(=O)c1c(O)c2ccc(-c3ccccc3C(F)(F)F)cc2sc1=O

Procedure:
4-Hydroxy-2-oxo-7-(2-trifluoromethyl-phenyl)-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5e) under conditions analogous to Example 7(a) using 2-trifluoromethyl-phenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.376 (d, 1H), 7.783-7.295 (m, 6H), 4.024 (s, 3H).