Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]3[N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[N:18]=[CH:19][C:12]2=3)=[O:10])[C:6]=1[CH3:7].[Li+].CC([N-]C(C)C)C.[CH2:39]=[O:40]>C1COCC1>[Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH:8]([CH2:39][OH:40])[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]3[N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[N:18]=[CH:19][C:12]2=3)=[O:10])[C:6]=1[CH3:7]
Reactant: C=O
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(C(F)(F)F)nn1C(CO)C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
To a mixture of 2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]ethanone (0.100 g, 0.23 mmol) in THF (3 ml) at −78° C. was added LDA (0.15 mL, 0.3 mmol, 2 M in THF). After stirred for 10 min at −78° C., dry paraformaldehyde (0.020 g, 0.66 mmol, suspended in THF) was added. The mixture was then warmed to rt for 8 min, quenched with sat. NH4Cl. The mixture was partitioned between EtOAc (50 mL) and brine (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to yield the desired product (0.060 g, 56%). 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.43 (dd, J=8.4, 4.6 Hz, 2H), 7.17 (dd, J=8.8, 8.4 Hz, 2H), 5.40 (t, J=5.4 Hz, 1H), 4.90 (s, 1H), 4.30 (m, 1H), 4.20 (m, 1H), 3.71 (m, 1H), 3.29 (m, 1H), 2.79 (m, 2H), 2.28 (s, 3H), 1.95 (m, 2H); MS: (ES) m/z calculated for C20H18ClF4N5O2 [M+H]+ 472.1, found 472.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][NH:7]1.CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:35])[O:33][CH3:34]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][N:7]1[C:32]([O:33][CH3:34])=[O:35]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2cc(F)cc(C(F)(F)F)c2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2cc(F)cc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
To a solution of methyl 2-(3-fluoro-5-(trifluoromethyl)benzyl)piperidine-4-carboxylate (4.10 g, 12.84 mmol) in DCM (50 mL) cooled in an ice-bath was added DIPEA (3.5 mL, 20.09 mmol) followed by methyl carbonochloridate (1.112 mL, 14.12 mmol). After completed addition the reaction mixture was stirred at room temperature for 2 h. The solvents were evaporated and the residue partitioned between ethyl acetate and 3.8 M HCl. After phase separation the organic layer was washed with brine, then dried over MgSO4 and evaporated to yield crude dimethyl 2-(3-fluoro-5-(trifluoromethyl)benzyl)piperidine-1,4-dicarboxylate (4.94 g, 102%) as a pale yellow oil. MS m/z 378 (M+H)+
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[C:14]([NH2:19])[C:13]3[N:20]=[C:21]([CH2:26][O:27][CH2:28][CH3:29])[N:22]([CH2:23][CH2:24][CH3:25])[C:12]=3[C:11]=2[CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C.CO>[NH2:19][C:14]1[C:13]2[N:20]=[C:21]([CH2:26][O:27][CH2:28][CH3:29])[N:22]([CH2:23][CH2:24][CH3:25])[C:12]=2[C:11]2[CH:10]=[C:9]([OH:8])[CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(OCc4ccccc4)cc3c21
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CCCn1c(COCC)nc2c(N)nc3ccc(O)cc3c21
Yield: 61.5 %

Procedure:
A dispersion of 8-benzyloxy-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (22.0 g, 56.3 mmol) and 10% palladium on carbon (7.5 g) in 50:50 ethanol/methanol (300 mL) was shaken under hydrogen pressure on a Parr apparatus at 50 psi (3.4×105 Pa) for three days. The reaction mixture was filtered to remove the catalyst, which was washed with hot ethanol/methanol (3 L). The filtrate was concentrated under reduced pressure. The resulting solid was triturated with methanol and isolated by filtration to provide 10.4 g of 4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol as an off-white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[C:22]([C:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH:24]=3)=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:14][CH:13]=1)=[O:11].C(O)(=O)C>[Pd].O1CCCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:11])[C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[C:22]([CH:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]3)=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:32][CH:33]=1
Reactant: CC(=O)N1CC=C(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)N1CCC(c2cccnc2Oc2ccc(C(O)c3nc4ccccc4[nH]3)cc2)CC1
Reaction time: 16 h

Procedure:
1-(4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (0.42 g, 0.96 mmol), acetic acid, glacial (0.11 mL, 1.92 mmol) and palladium on carbon, 10% (0.20 g, 0.19 mmol) were suspended in tetrahydrofuran (10 mL) in a pressure reactor. The mixture was hydrogenated at 50 psi for 16 h. The catalyst was filtered off and washed with THF. To the solution was added palladium on carbon, 10% (0.204 g, 0.192 mmol) and acetic acid, glacial (0.111 mL, 1.916 mmol) and the mixture was hydrogenated at 50 psi for another 24 h. The mixture was filtered through celite and washed with THF. The solvent was removed under reduced pressure and the residue was partitioned between DCM and saturated NaHCO3. The organic layer was dried and concentrated to give 1-(4-(2-(4-((1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)phenoxy)pyridin-3-yl)piperidin-1-yl)ethanone as off-white solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>C(Cl)Cl>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[N:4]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[N:3]=2)=[CH:23][CH:22]=1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ccc(-c2nn(C3CCCCO3)c3ccc(C#N)cc23)cc1
Yield: 76.8 %

Procedure:
A flask was charged with 300 mg (0.98 mmol) of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile, 223 mg (1.47 mmol, 1.50 equiv.) of 4-methoxyphenylboronic acid, 80.3 mg (0.098 mmol, 0.100 equiv.) of [1,1′-bis (diphenylphosphino)-ferrocene}dichloropalladiuin (II) complex with dichloromethane (Aldrich), 1.04 g (4.90 mmol, 4.98 equiv.) of powdered potassium phosphate (K3PO4), and 4.90 mL of anhydrous 1,2-dimethoxyethane (DME). The mixture was refluxed under nitrogen for 19 h. The mixture was diluted with CH2Cl2, washed with 2× sat. aq. NaHCO3, and dried (Na2SO4). The crude material was purified by silica gel chromatography using 20-30% EtOAc in hexanes affording the title compound (251 mg, 77% yield): ES-MS (m/z) 334 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[C:16]3[N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[I-].[Na+].C(N(CC)CC)C.[CH3:36][O:37][CH2:38][CH2:39]Br>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[C:16]3[N:19]3[CH2:24][CH2:23][N:22]([CH2:39][CH2:38][O:37][CH3:36])[CH2:21][CH2:20]3)=[CH:11][CH:10]=2)=[O:7])=[CH:25][CH:26]=1
Reactant: O=C(Nc1ccc2cccc(N3CCNCC3)c2c1)c1ccc(Cl)cc1
Reactant: COCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCCN1CCN(c2cccc3ccc(NC(=O)c4ccc(Cl)cc4)cc23)CC1

Procedure:
A mixture of 7-(4-chlorobenzamido)-1-(1-piperazinyl)-naphthalene (0.15 g, 0.41 mmol, product of example 12), sodium iodide (0.064 g, 0.431 mmol), triethylamine (0.164 mL, 0.431 mmol) and 2-bromoethyl methyl ether (0.040 mL, 0.431 mmol) in acetonitrile (7 mL) was refluxed overnight. The reaction was cooled and concentrated at reduced pressure. The residue was taken up in methylene chloride and washed with 1N sodium hydroxide and brine, dried, concentrated onto silica gel and flash chromatographed (1×2.5 inches). Elution proceeded as follows: 50% ethyl acetate hexane (100 mL) and 75% ethyl acetate/hexane (100 mL), nil; 75% ethyl acetate/hexane (100 mL) and ethyl acetate (150 mL), 0.121 g (69%) of 7-(4-chlorobenzamido)-1-(4-methoxyethyl-1-piperazinyl)-naphthalene as an oil. This oil was converted to the HCl salt from an ether solution. An amorphous white powder hydrochloride salt of the title compound was obtained. mp 134°-148° C. 1H NMR δ 8.54 (br s, 1 H), 8.05 (br s, 1 H), 7.84 (long range coupled t, J=9 Hz, 3 H), 7.66 (dd, J -2, 9 Hz, 1 H), 7.55-7.43 (m, 3 H), 7.36 (t, J=8 Hz, 1 H), 7.11 (dd, J=1, 7.5 Hz, 1 H), 3.57 (t, J=5.5 Hz, 2H), 3.38 (s, 3 H), 3.19 (br s, 4 H), 2.83 (br s, 4 H), 2.70 (t, J=5.5 Hz, 2 H). Analysis calculated for C24H26ClN3O2 ·2HCl·1.5H2O: C, 55.02; H, 5.96; N, 8.02. Found: C, 55.53; H, 6.31; N, 7.78.
Reaction SMILES: S(C)C.[C:4]1([S:10]([N:13]2[C:23]3[C:24]4[C:15]([CH2:16][NH:17][C:18](=O)[C:19]=4[CH:20]=[CH:21][CH:22]=3)=[CH:14]2)(=[O:12])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1>[C:4]1([S:10]([N:13]2[C:23]3[C:24]4[C:15]([CH2:16][NH:17][CH2:18][C:19]=4[CH:20]=[CH:21][CH:22]=3)=[CH:14]2)(=[O:12])=[O:11])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1NCc2cn(S(=O)(=O)c3ccccc3)c3cccc1c23
Solvent: CSC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc2c3c(cccc31)CNC2
Reaction time: 5 h

Procedure:
SMe2 (205 μL, 2.2 mmol) was added dropwise over 5 min. to a refluxing mixture of 1-(phenylsulfonyl)-3,4-dihydropyrrolo[4,3,2-de]isoquinolin-5(1H)-one, Intermediate 2, (225 mg, 0.72 mmol) in dry THF (10 mL) with continuous reflux for 2.5 h. Additional two portions BH3:SMe2 (100 μL×2) were added (2.5 h reflux between the additions). Reflux was continued for 5 h after the last addition, then room temperature over night. The reaction was quenched by addition of HCl in MeOH (1.25 M, 4 mL) and reflux 1 h. The solvent was evaporated and the crude mixture was extracted with DCM (×2) and sat. Na2CO3(aq). The organic layers were combined, dried and concentrated. Purification was performed by flash column chromatography (3-5% MeOH in DCM) which gave 66 mg of the title compound as a beige solid. MS m/z 299 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:7][C:8]=2[O:18][CH3:19])[O:3]1>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:25])[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:7][C:8]=2[O:18][CH3:19])[O:3]1
Reactant: CCCCCc1cc(OC)c2c(c1)OC(C)(C)C=C2c1ccncc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCc1cc(OC)c2c(c1)OC(C)(C)CC2c1ccncc1

Procedure:
2,2-Dimethyl-5-methoxy-7-n-pentyl-4-(4-pyridyl)-2H-chromene (3.90g.) was hydrogenated for 4.5 hours at 20° C and 30 p.s.i. in ethanol (100 ml) in the presence of 5% palladium on charcoal (0.50g.). The solution was filtered and evaporated to dryness under reduced pressure to yield 2,2-dimethyl-5-methoxy-7-n-pentyl-4-(4-pyridyl) chroman as a yellow oil (3.90g.). (This compound was also prepared in low yield via treatment of 2,2-dimethyl-7-n-pentyl-4-(4-pyridyl) chroman-5-ol with 1) sodium hydride and 2) iodomethane in benzene).
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:37][S:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:36])=[O:35])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: NS(=O)(=O)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccccc2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and benzene sulfonamide in accordance with Procedure 1, Method A described hereinabove. Yield (76%); 1H NMR (CDCl3) δ 8.41 (br. s, 1H), 8.08 (d, J=8.4 Hz, 2H), 7.65–7.07 (m, 16H), 6.86 (d, J=8.4 Hz, 2H), 6.23 (d, J=15.7 Hz, 1H), 2.46 (q, J=7.3 Hz, 2H), 0.92 (t, J=7.3 Hz, 3H); ESI m/z: 492 (M−H−, 100%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([OH:29])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>N1C=CC=CC=1>[CH3:30][S:31]([O:29][C@@H:10]([CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])(=[O:33])=[O:32]
Reactant: CCCCCCCCCCCCCCCCOC[C@H](O)CO[Si](C)(C)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOC[C@@H](CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-1-(tert-butyldimethylsilyloxy)-3-(hexadecyloxy)propan-2-ol (1 eq) in pyridine (0.5 M) at 0° C., was added MsCl (2 eq). The reaction was stirred at 0° C. for 1 h and quenched by H2O. The aqueous phase was extracted with DCM. The combined organic phases were washed with H2O, and the aqueous phase was back extracted with DCM. The combined organic phases were washed with saturated NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-15% EtOAc/Hex to give (S)-1-(tert-butyldimethylsilyloxy)-3-(hexadecyloxy)propan-2-yl methanesulfonate as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=O.[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[SH:13]>CN(C)C=O.ClCCl>[Cl:1][CH2:2][C:3]1[S:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1S
Solvent: CN(C)C=O
Solvent: ClCCl
Product: ClCc1nc2ccccc2s1
Reaction time: 18 h
Yield: 65 %

Procedure:
Chloroacetyl chloride (81.6 ml) is added dropwise to a solution composed of 2-aminothiophenol (112 ml, 1.04 mol), dichloromethane (1.2 l) and three drops of dimethylformamide, while the temperature is kept below 40° C. After stirring for 18 hours, the precipitate formed is filtered off by suction and then dissolved in a minimum amount of water. This aqueous phase is extracted with pentane and the extracts are concentrated under vacuum at room temperature, giving 120 g (65%) of a flaky solid.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([O:32][CH2:33][C:34]2[CH:39]=[CH:38]C=[CH:36][CH:35]=2)[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]4=[O:31])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:40]1C=CC(CCl)=CC=1>CN(C=O)C>[N:40]1[CH:36]=[CH:35][C:34]([CH2:33][O:32][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]4=[O:31])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=[CH:39][CH:38]=1
Reactant: O=C1c2ccccc2CN1C1CCN(c2ccc(C(OCc3ccccc3)c3ccccc3)cc2)CC1
Reactant: ClCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2CN1C1CCN(c2ccc(C(OCc3ccncc3)c3ccccc3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a suspension of sodium hydride (55.3 mg, 1.38 mmol) in DMF (5 mL) at 0° C. was added dropwise a solution of Example 293 Part A compound (500 mg, 1.26 mmol) in DMF (8 mL). The reaction was stirred at 0° C. for 30 min. A solution of 4-picolyl chloride (175 mg, 1.38 mmol) in DMF (1 mL) was added dropwise to the reaction at 0° C. The reaction was stirred at 0° C. for 1 h then warmed to RT overnight. The reaction was quenched with saturated ammonium chloride solution (2 mL). Ethyl acetate (200 mL) was added to the reaction, and the organic layer was washed with water (2×100 mL), brine (2×100 mL) and dried over MgSO4. Purification was performed by flash chromatography on silica gel (100 g), loaded and eluted with 70% EtOAc in hexane. Pure fractions were combined and evaporated to give title compound (320 mg, 52%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:12])([CH3:11])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].CS(O[CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=O)=O.[H-].[Na+]>CN(C=O)C>[CH2:24]([O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:1][CH2:2][C:3]([CH3:12])([CH3:11])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CS(=O)(=O)OCCOCCOCc1ccccc1
Reactant: CC(C)(C)OC(=O)C(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)COCCOCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of tert-butyl 3-hydroxy-2,2-dimethylpropanoate (353 mg, 2.03 mmol) and 2-(2-(benzyloxy)ethoxy)ethyl methanesulfonate (47) (500 mg, 1.82 mmol) in DMF (6 mL) at 0° C. was added NaH (60 wt % in oil) (109 mg, 2.73 mmol), and the reaction mixture was allowed to stir at RT for 30 min. The reaction mixture was quenched with sat. NH4Cl (aq.) (1 mL) diluted with water (20 mL) and washed with EtOAc (4×20 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (12 g, 0-40% Et2O in isohexane) to afford tert-butyl 3-(2-(2-(benzyloxy)ethoxy)ethoxy)-2,2-dimethylpropanoate (48) (619 mg, 96%) as a colourless oil: m/z 375 (M+Na)+ (ES+). 1H NMR (400 MHz, CDCl3) δ: 7.32-7.25 (m, 5H), 4.54 (s, 2H), 3.66-3.56 (m, 8H), 3.41 (s, 2H), 1.40 (s, 8H), 1.10 (s, 6H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]#[N:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Ni]>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH2:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1CN(Cc2ccccc2)CCO1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: NCC1CN(Cc2ccccc2)CCO1
Reaction time: 12 h
Yield: 72.7 %

Procedure:
4-benzylmorpholine-2-carbonitrile 2c (0.80 g, 4 mmol) was dissolved in 30 mL of methanol followed by the addition of Raney nickel (0.50 g), filled with hydrogen two times and the resulting solution was stirred for 12 hours, filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (4-benzylmorpholin-2-yl)methanamine 2d (0.60 g) as a colorless oil liquid, which was used in the next step without further furification.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:5]([CH3:15])=[C:6]([CH3:14])[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1.[CH:16]([OH:19])([CH3:18])[CH3:17]>CN(C=O)C>[CH:16]([O:19][C:4]1[C:5]([CH3:15])=[C:6]([CH3:14])[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1)([CH3:18])[CH3:17]
Reactant: CC(C)O
Reactant: Cc1c(Cl)nn2c(N)nnc2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(OC(C)C)nn2c(N)nnc2c1C

Procedure:
Isopropanol (27 ml) was deprotonated analogously to W1.056 with sodium hydride (1.3 g) and reacted with 6-chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.006a, 1 g), dissolved in isopropanol (10 ml) and DMF (10 ml), and worked up. 847 mg of the title compound were isolated in sufficient purity.
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][CH2:7][C:8]1[S:9][CH:10]=[C:11]([CH3:13])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.CN(C)[CH:29]=[O:30]>>[Si:5]([O:6][CH2:7][C:8]1[S:9][C:10]([CH:29]=[O:30])=[C:11]([CH3:13])[CH:12]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:15])[CH3:14]
Reactant: CN(C)C=O
Reactant: Cc1csc(CO[Si](C)(C)C(C)(C)C)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)sc1C=O

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 10 (10b) using t-butyl(dimethyl) [(4-methyl-2-thienyl)methoxy]silane (2.5 g, 10 mmol) that was obtained in Example 11 (11a), 1.6 M solution of n-butyllithium in hexane (7.8 mL, 12 mmol), and N,N-dimethylformamide (1.6 mL, 21 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 5:95) as the eluent to afford the title compound (2.5 g) in a yield of 89% as a pale yellowish oily product.
Reaction SMILES: [CH:1]([C:3]1[S:4][C:5]2[NH:6][C:7](=[O:16])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[N:15]=1)=[CH2:2].[CH3:17][NH:18][CH3:19]>C(Cl)Cl.CO>[CH3:17][N:18]([CH3:19])[CH2:2][CH2:1][C:3]1[S:4][C:5]2[NH:6][C:7](=[O:16])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[N:15]=1
Reactant: C=Cc1nc2c([nH]c(=O)c3ccccc32)s1
Reactant: CNC
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCc1nc2c([nH]c(=O)c3ccccc32)s1
Temperature: 65 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
To a suspension of 2-vinyl-4H-1,3-thiazolo[5,4-c]isoquinolin-5-one (0.05 g, 0.22 mmol) and CH2Cl2/methanol (6 ml; 1/1) was added dimethylamine (0.33 ml of 2M solution in THF, 0.66 mmol). After stirring at 65° C. for 48 hours, the reaction mixture was concentrated under reduced pressure and purified by flash-chromatography (CH2Cl2/methanol, 90/10). Recrystallization from methanol/diethyl ether yielded 0.038 g (a 63% yield) of the title compound as a white solid. m.p. 236-240° C. (dec.); 1H NMR (400 MHz, DMSO) δ 2.85 (s, 6H, (CH2)2N(CH3)2), 3.52-3.56 (m, 4H, (CH2)2N(CH3)2), 7.56-7.59 (m, 1H, Ar), 7.84-7.87 (m, 1H, Ar), 8.19-8.26 (m, 2H, Ar), 12.37 (bs, NH); 13C NMR (100.6 MHz, DMSO) δ 29.71, 44.26, 56.79, 124.03, 125.74, 128.69, 129.79, 133.45, 134.44, 135.15, 158.51, 162.72.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:15])(=O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:15][C:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:1]([OH:11])=[CH:2][CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Oc1cccc2c1CCCC2
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc(Cl)c2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.5 %

Procedure:
A solution of 37 grams (0.25 mole) of 5,6,7,8-tetrahydronaphthol in 200 ml of carbon tetrachloride was treated dropwise with stirring with 33.8 grams (0.25 mole) of sulfuryl chloride at room temperature. When addition was complete the reaction mixture slowly brought to boiling over a 1 hour period and held there at reflux for 30 minutes. After cooling to ambient temperature the reaction mixture was washed with 10 percent aqueous sodium carbonate and then with water. After drying over calcium chloride the carbon tetrachloride solution was distilled to give a portion, b.p. 110-112/0.25 mm, which was recrystallized from hexane to give 8 grams (17.5 percent) of product, m.p. 58°-59°C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[C:5]=2[CH2:4][CH2:3]1.[BH4-].[Na+]>C(O)C>[OH:1][CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[C:5]=2[CH2:4][CH2:3]1
Reactant: N#Cc1cccc2c1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cccc2c1CCC2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a stirred suspension of 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile (1.0 equiv, 0.4M) and silica gel (catalytic) in ethanol at 0° C. was added NaBH4 (1/3 equiv). The reaction was allowed to warm up to room temperature and stirred for 2 h. The Solvent was removed under reduced pressure and the product purified by CC in hexane/EtOAc (5:5) to offer 1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile in 80% yield.