Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.Br[C:11]1[CH:12]=[C:13]([Cl:17])[CH:14]=[CH:15][CH:16]=1>CN(C)C=O.C(O)C.[Cu]>[Cl:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1
Reactant: Clc1cccc(Br)c1
Reactant: Cc1ccc(O)cn1
Agent: [Cu]
Agent: [K]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2cccc(Cl)c2)cn1

Procedure:
3 g of a potassium salt of 5-hydroxy-2-methylpyridine, 3.83 g of m-bromochlorobenzene and 200 mg of a copper powder were suspended in 8 ml of dimethylformamide, followed by allowing the mixture to react in a nitrogen gas stream at 130° C. for 13 hours while stirring. The reaction mixture was diluted with 40 ml of ethanol and filtered. The filtrate was immediately concentrated, and 80 ml of chloroform was added to the residue. The mixture was washed with a 0.01 N aqueous sodium hydroxide solution. The chloroform layer was washed with water, dried with anhydrous sodium sulfate and dried to solidify to obtain 2.96 g of oily 5-(m-chlorophenoxy)-2-methylpyridine.
Reaction SMILES: [CH:1]1([N:4]([CH:26]2[CH2:28][CH2:27]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]([NH2:22])=[S:21])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Cl[CH2:30][C:31](=O)[C:32]([CH3:35])([CH3:34])[CH3:33]>>[C:32]([C:31]1[N:22]=[C:20]([NH:19][C:12]2[N:11]=[C:10]3[N:23]([CH2:24][CH3:25])[C:7]([C:5]([N:4]([CH:1]4[CH2:2][CH2:3]4)[CH:26]4[CH2:27][CH2:28]4)=[O:6])=[CH:8][C:9]3=[C:14]3[N:15]([CH3:18])[CH:16]=[N:17][C:13]=23)[S:21][CH:30]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)C(=O)CCl
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(N)=S)nc21
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C(C)(C)C)cs3)nc21

Procedure:
Prepared from N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2B) and 1-chloro-3,3-dimethylbutan-2-one using the same procedure as reported for 2.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.B(O)(O)[C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1.CCOCC>C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC.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>[N+:8]([C:7]1[C:2]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
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: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: Cc1ccc(-c2ncccc2[N+](=O)[O-])cc1
Yield: 81.4 %

Procedure:
A stirred mixture of 2-chloro-3-nitropyridine (10.6 g), p-tolylboronic acid (19.69 g) and tetrakis(triphenylphosphine)palladium (O) (0.16 g) in 2N sodium carbonate solution (100 ml) and dimethoxyethane (100 ml) was heated to reflux under nitrogen. After 64 h the mixture was cooled then filtered through hyflo eluting with more dimethoxyethane. The filtrate was evaporated in vacuo to give an oil which was redissolved with ether (300 ml) and washed with 5N sodium hydroxide solution (300 ml). The aqueous portion was further extracted with ether (300 ml×2). The combined organic extracts ware washed with water (200 ml), 1N hydrochloric acid (2×100 ml) and saturated brine. were dried (MgSO4) and evaporated in vacuo. The resultant crystalline solid was triturated with hexane to give the title compound as a yellow crystalline solid (11.66 g). T.l.c.(Hexanelethylacetate (2:1)), Rf 0.52,
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11]([O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19](I)[CH:18]=1)([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>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>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:24])[CH:22]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)c1cccc(I)c1
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: [K+]
Solvent: COCCOC
Product: Cc1ccc(-c2cccc(C(=O)OC(C)(C)C)c2)cc1
Yield: 78.2 %

Procedure:
A mixture of 4-methylphenylboronic acid (0.65 g, 4.3 mmol), t-butyl-3-iodobenzoate (0.87 g, 2.86 mmol), K2CO3 (0.59 g, 4.3 mmol), and (Ph3P)4 Pd (0.17 g, 0.14 mmol) in DME (15 mL) was degassed and flushed with N2 before being brought to reflux for 2 h. Following a standard aqueous/EtOAc work-up, the residue was triturated with 1:10 EtOAc/hexane. The excess boronic acid was removed by filtration, and the filtrate was concentrated to give an oil which was purified by flash chromatography (hexane) to give an oil (0.6 g). This material (≈60% pure) was used as such for the next step.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:12][CH2:13][C:14]([CH3:16])=O.Cl.O1CCOCC1>CC(O)=O>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:14]([CH3:16])=[C:13]2[CH2:12][C:11]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CCC(C)=O
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1c(C)[nH]c2ccc(Br)cc12
Yield: 70.9 %

Procedure:
A mixture of 4-bromophenylhydrazine hydrochloride (2.23 g, 10 mmol) and ethyl levulinate (1.58 g, 11 mmol) in 10 mL HOAc was heated to reflux for 20 h. The HOAc was removed under vaccum. The residue was dissolved in 10 mL EtOH. A solution of HCl in dioxane (12 mmol, 4M solution) was added. The mixture was heated to reflux for 4 h. The mixture was concentrated under vacuum and the residue was purified by flash chromatography on silica gel, eluting with 20% EtOAc in hexane to afford 2.1 g (78%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=2)[NH2:13])=[CH:6][C:5]=1[OH:19])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:27]([CH2:31][CH2:32][C:33](Cl)=[O:34])([O:29][CH3:30])=[O:28].Cl>O1CCCC1>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:13][C:33](=[O:34])[CH2:32][CH2:31][C:27]([O:29][CH3:30])=[O:28])[CH:14]=[CH:15][CH:16]=2)=[CH:6][C:5]=1[OH:19])(=[O:3])[CH3:2]
Reactant: COC(=O)CCC(=O)Cl
Reactant: CC(=O)c1ccc(OCc2cccc(N)c2)cc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCC(=O)Nc1cccc(COc2ccc(C(C)=O)c(O)c2)c1
Temperature: 25 °C
Yield: 53 %

Procedure:
A solution of 3-[(4-acetyl-3-hydroxyphenoxy)methyl]aniline (3.4 g prepared as in Example 1B) and triethylamine (1.62 g) in tetrahydrofuran (40 ml) is cooled to -78° C. under nitrogen. To this solution is added 3-carbomethoxypropanoyl chloride (2 g, neat), dropwise. The reaction is left to warm to room temperature overnight, then poured onto 10% HCl and extracted with ether. The extracts are washed with saturated brine, and then dried over MgSO4, and concentrated on a rotary evaporator. The residue is dissolved in a minimum amount of acetone, to which several drops of ether are added and then stored at 0° C. Filtration gives 2.6 g (53% yield) of product, m.p. 121°-123° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:15][C:9]1[C:10]([CH:13]=[O:14])=[CH:11][NH:12][C:8]=1[C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=Cc1c[nH]c(-c2cccnc2F)c1
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1c[nH]c(-c2cccnc2F)c1Cl
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 44.4 %

Procedure:
5-(2-Fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (610 mg) was dissolved in N,N-dimethylformamide (20 mL), N-chlorosuccinimide (641 mg) was added and the mixture was stirred at 80° C. for 40 min. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:2→1:1) to give the title compound as a colorless powder (yield 320 mg, 44%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=3)[S:10][C:5]=2[C:4](=[O:21])[NH:3]1.[BH4-].[Na+]>C(O)C.CO>[CH3:1][C:2]1([CH3:22])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][N:12]=3)[S:10][C:5]=2[C:4](=[O:21])[NH:3]1
Reactant: CC1(C)NC(=O)c2sc(-c3ccnc(S(C)(=O)=O)n3)cc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC1(C)NC(=O)c2sc(-c3ccncn3)cc2N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.1 %

Procedure:
To a solution of 2,2-dimethyl-6-[2-(methylsulfonyl)pyrimidin-4-yl]-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (0.034 g, 0.10 mmol) in ethanol (2 mL) and methanol (15 mL) was added sodium borohydride (0.092 g, 2.4 mmol) in four portions over 20 min, and the reaction was stirred at room temperature for 15 h. Then, the reaction mixture was concentrated, the residue was dissolved in water (15 mL), and the solution was extracted with 75:25 ethyl acetate/tetrahydrofuran (2×40 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated, and the residue was purified by flash chromatography (silica gel, ethyl acetate to 90:10 ethyl acetate/methanol) to give the title compound (0.012 g, 46%) as a yellow solid:
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13](O)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:22][CH2:23][C:24]1[C:25](=[O:37])[NH:26][C:27]([CH3:36])=[CH:28][C:29]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13]([NH:22][CH2:23][C:24]3[C:25](=[O:37])[NH:26][C:27]([CH3:36])=[CH:28][C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3]
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccncc3)nc21
Reactant: Cc1cc(-c2ccccc2)c(CN)c(=O)[nH]1
Product: Cc1cc(-c2ccccc2)c(CNC(=O)c2cc(-c3ccncc3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 11 from 1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (150 mg, 0.531 mmol) and 3-(aminomethyl)-6-methyl-4-phenyl-2(1H)-pyridinone (133 mg, 0.531 mmol). The product was collected as a white solid, 0.041 g (15%). LCMS E-S (M+H)=479.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (d, J=6.82 Hz, 6H) 2.23 (s, 3H) 4.23-4.27 (m, 2H) 5.33-5.42 (m, 1H) 6.02-6.04 (m, 1H) 7.35-7.42 (m, 1H) 7.43 (s, 4H) 8.23-8.26 (m, 1H) 8.34-8.39 (m, 2H) 8.41-8.42 (m, 1H) 8.84-8.88 (m, 2H) 8.91-8.96 (m, 1H) 11.91 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:6]([CH2:21][O:22][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:5]([CH:40]([CH3:42])[CH3:41])[N:4]=1.[CH3:43]I.[H-].[Na+]>O1CCCC1.O>[CH3:43][O:1][CH2:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:6]([CH2:21][O:22][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:5]([CH:40]([CH3:41])[CH3:42])[N:4]=1
Reactant: CCCCCc1c(CO)nc(C(C)C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1-c1ccc(F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCc1c(COC)nc(C(C)C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1-c1ccc(F)cc1
Temperature: 40 °C
Yield: 40 %

Procedure:
A mixture of the intermediate obtained in Example 200, Step B (0.1 g, 0.17 mmol), methyl iodide (0.013 mL, 1.2 equiv), and sodium hydride (8 mg of a 60% dispersion in mineral oil, 1.2 equiv) in tetrahydrofuran (1 mL) was heated at 40° C. for 3 h. The mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with saturated aqueous sodium chloride solution (3×10 mL). Silica gel chromatography provided a colorless solid (40 mg, 40%). 1H NMR (300 MHz, CDCl3): δ 7.41 (m, 6H), 7.32 (m, 4H), 7.06 (m, 4H), 4.62 (s, 2H), 4.27 (s, 2H), 3.48 (s, 3H), 3.15 (sept, 6.6 Hz, 1H), 2.36 (m, 2H), 1.27 (m, 2H), 1.18 (d, 6.6 Hz, 6H), 1.12 (m, 2H), 1.00 (s, 9H), 0.87 (m, 2H), 0.78 (t, 6.6 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][C:4]=1[C:15]#[C:16][C:17]1([OH:25])[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1)=[O:2].CO.[BH4-].[Na+]>O>[OH:2][CH2:1][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][C:4]=1[C:15]#[C:16][C:17]1([OH:25])[CH:22]2[CH2:21][CH2:20][N:19]([CH2:24][CH2:23]2)[CH2:18]1
Reactant: COC(=O)CCc1ccc(C#CC2(O)CN3CCC2CC3)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CCc1ccc(C#CC2(O)CN3CCC2CC3)c(CO)c1
Reaction time: 8 h
Yield: 27.7 %

Procedure:
3-[2-(2-formyl-4-(2-methoxycarbonylethyl)phenyl]ethynyl]quinuclidin-3-ol (575 mg) was stirred with methanol (25 ml) at ambient temperature under an atmosphere of argon. Sodium borohydride (329 mg) was added portionwise over 5 minutes to the reaction mixture and stirring continued at ambient temperature overnight. Water (25 ml) was added and the mixture was extracted with ethyl acetate (25 ml). The organic phase was separated, washed with saturated aqueous sodium carbonate (3×25 ml), water (3×25 ml), dried (MgSO4) and evaporated. The residue was purified by elution through silica gel (10 g Bond elut column) with a gradient of 0-30% methanol in dichloromethane to give 3-[2-(2-hydroxymethyl-4-(2-methoxycarbonylethyl)phenyl)ethynyl]quinuclidin-3-ol (160 mg) as a solid, m.p. 35.8° C.; microanalysis, found: C, 69.2; H, 7.5; N, 3.9% C20H25NO4 0.2 H2O requires: C, 69.2; H, 7.38; N, 4.04%; NMR(CDCl3): 1.4(1H,m), 1.66(1H,m), 2.02(3H,m), 2.62(2H,t), 2.8(3H,m), 2.95(2H,t), 3.03(1H,d), 3.27(1H,d), 3.66(3H,s), 4.75(2H,s), 7.07(1H,m) and 7.3(2H,m); m/z 344 (M+H).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].Br[C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[CH3:12]>CO>[CH3:1][O:2][C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[CH3:12]
Reactant: C[O-]
Reactant: Cc1nc(N)sc1Br
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1sc(N)nc1C
Temperature: 0 °C

Procedure:
Sodium methoxide was freshly prepared by dissolving 0.408 g (17.7 mmol) of sodium metal in 25 mL of abs. MeOH. After cooling to 0° C., 5-bromo-4-methyl-thiazol-2-ylamine (1.00 g, 5.18 mmol) was added and the cooling bath removed. After 15 Min., TLC indicated the absence of starting material. The reaction mixture was poured onto crashed ice/NH4Cl, twofold extracted with ethyl acetate, washed with water, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/ethyl acetate=1/1), yielded 0.441 g of the title compound as brown oil; it should be stored at −28° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].Cl[CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16]>CN(C)C=O>[CH2:8]([O:7][C:1](=[O:6])[CH:2]([C:3](=[O:4])[CH3:5])[CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)=CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC=C(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 58.4 %

Procedure:
To a solution of 26.05 g ethyl acetoacetate in 150 ml of dimethylformamide, 8.30 g 60% sodium hydride were added portionwise over 1 hour while the temperature rose to 60° C. After cooling down to room temperature, a solution of 24.8 g 1-chloro-3-methyl-2-butene in 50 ml of dimethylformamide was dropped in. Then the mixture was stirred at room temperature for 2.5 hours. The mixture was quenched with water and extracted with ether. The combined organic phase was dried, filtered and evaporated to dryness. The resulting yellow oil was purified by distillation to yield 23.16 g of a colourless oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][N:6]1[C:10](=[O:11])[CH2:9][S:8][C:7]1=[S:12])(=[O:4])=[O:3].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH:17]=O.CC([O-])=O.[Na+]>CO>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:9]2[S:8][C:7](=[S:12])[N:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:10]2=[O:11])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)NN1C(=O)CSC1=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)NN1C(=O)C(=Cc2ccc(Cl)c(Cl)c2)SC1=S
Reaction time: 24 h
Yield: 54.5 %

Procedure:
3-(Methanesulfonylamino)-4-oxo-2-thionothiazolidine 269 mg (1.19 mmol, 1.0 equiv) was dissolved in 3 mL MeOH followed by the addition of 208 mg 3,4-dichlorobenzaldehyde (1.19 mmol, 1.0 equiv) and 10 mg NaOAc (0.119 mmol, 0.1 equiv). The solution was allowed to stir for 24 hours, at which time the yellow solid was removed by filtration. The solid was washed (4×MeOH) and dried under vacuum to give the 248 mg of the product as a yellow solid (0.649 mmol, 55%). 1H NMR (DMSO, 400 MHz) δ 8.01 (d, J=1.0 Hz, 1 H), 7.95 (s, 1 H), 7.84 (d, J=8.4 Hz, 1 H), 7.63 (dd, J=2.1, 8.4 Hz, 1 H), 3.28 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:12](Cl)(=O)C>CO>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1
Reactant: Nc1cccc(CC(=O)O)c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)Cc1cccc(N)c1

Procedure:
(3-Amino-phenyl)-acetic acid methyl ester was prepared by reacting 3-aminophenylacetic acid with acetyl chloride in MeOH to afford the corresponding methyl ester, HCl salt, (3.09 g, 15.324 mmol). The ester was dissolved in DMF (5 ml) with DIEA (2.67 ml, 15.324 mmol) and cooled to 0° C. To this solution was added dropwise a 0° C. solution of DMF (5 ml) containing 2,4-dichloro-1,3,5-triazine (2.297 g, 15.324 mmol) and DIEA (2.67 ml, 15.324 mmol). The reaction was stirred at ODC for 15 min and then at RT for 1 h. The reaction mix was diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed 4 times with brine and dried over Na2SO4. The crude was concentrated down and dried under reduced pressure, giving [3-(4-chloro-[1,3,5]triazin-2-ylamino)-phenyl]-acetic acid methyl ester (4.3 g, 100%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:17][CH2:16][CH:15]([O:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.O.NN>C(O)C>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:13][CH2:14][CH:15]([O:18][NH2:19])[CH2:16][CH2:17]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Yield: 92.5 %

Procedure:
A solution of 2-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yloxy)isoindoline-1,3-dione (4.85 g, 10.0 mmol) and hydrazine monohydrate (550 mg, 11.0 mmol) in ethanol (30 ml) was stirred at room temperature for 30 minutes. The resulting solid was filtered off and concentrated in vacuo. The residue was triturated with diethyl ether (80 ml), and the resulting solid was filtered off again and concentrated in vacuo to give O-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl)hydroxylamine (3.00 g, 93%) as a white solid: LCMS: 325 [M+1]+.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.[CH3:28][NH:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]1>ClC(Cl)C.O1CCCC1>[OH:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([N:29]([CH3:28])[C:8]([NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)=[O:27])[CH2:31][CH2:32]1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: CN[C@H]1CC[C@H](O)CC1
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)N(C)[C@H]3CC[C@H](O)CC3)nc12

Procedure:
From (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-carbamic acid phenyl ester with trans-4-Methylamino-cyclohexanol in dichloroethane and tetrahydrofuran. ES-MS m/e (%): 422 (M+H+, 100).
Reaction SMILES: Cl.[NH2:2][OH:3].O=[C:5]([CH3:25])[CH2:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=12.C(=O)([O-])[O-].[K+].[K+].CO>O>[OH:3][N:2]=[C:5]([CH3:25])[CH2:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=12
Reactant: NO
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)=O)=C21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)=NO)=C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: 5.8 g of hydroxylamine hydrochloride are added to the mixture of 15 g of 1-(2-oxopropyl)-3,4,5,5a,6,7-hexahydro-9-methoxy-2H-naphth[1,2-d]-azepin-2-one, 6.2 g of powdered potassium carbonate, 120 ml of methanol and 10 ml of water. It is refluxed for three hours and stirred at room temperature overnight. The suspension is evaporated, the residue is suspended in 200 ml of chloroform-water (3:1) and filtered off, to yield the 1-(2-hydroxyiminopropyl)-3,4,5,5a,6,7-hexahydro-9-methoxy-2H-naphth[1,2-d]azepin-2-one melting at 216°-218°.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.[F-].[K+].[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[C:37]=[O:38].O>C1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([C:37]([NH:36][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[Br:29])=[O:38])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([C:22]#[N:23])([CH3:24])[CH3:25])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C=Nc1ccccc1Br
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(C(=O)Nc3ccccc3Br)c3cnc4ccc(Br)cc4c32)cc1

Procedure:
To a suspension of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 0.050 g, 0.12 mmol) and potassium fluoride (0.010 g, 0.18 mmol) in dry benzene (6 ml) was added 1-bromo-2-isocyanatobenzene (0.036 g, 0.12 mmol) at RT. The reaction was stirred at reflux temperature for 6 hours. The reaction mixture was cooled and poured into cold water, extracted with ethyl acetate (2×20 ml). Organic layer was washed with water dried over sodium sulfate and concentrated. The crude product was crystallized in ethyl acetate\pet ether to obtain the title compound. Yield: 0.017 g (22%); 1H NMR (DMSO-d6, 300 MHz): δ 11.82 (s, 1H), 8.78 (s, 1H), 7.90 (d, 1H, J=9 Hz), 7.81 (d, 2H, J=8.1 Hz), 7.61-7.65 (m, 3H), 7.28 (d, 1H, J=8.1 Hz), 6.95-7.05 (m, 2H), 6.74 (d, 1H, 7.8 Hz), 6.41 (t, 1H, 7.2 Hz), 1.79 (s, 6H); MS: m/z 606 (M+).