Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]1[CH2:27][N:16]2[CH2:17][CH2:18][N:19]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:20][CH:15]2[CH2:14][CH2:13]1.[H-].[Na+].[CH3:30]I>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:30])[CH:6]=[C:5]2[CH2:11][CH:12]1[CH2:27][N:16]2[CH2:17][CH2:18][N:19]([C:21]3[N:22]=[CH:23][CH:24]=[CH:25][N:26]=3)[CH2:20][CH:15]2[CH2:14][CH2:13]1
Reactant: CI
Reactant: Fc1ccc2[nH]cc(CC3CCC4CN(c5ncccn5)CCN4C3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(CC2CCC3CN(c4ncccn4)CCN3C2)c2cc(F)ccc21
Temperature: 50 °C
Yield: 47.1 %

Procedure:
A flame-dried flask was charged with 0.103 g (0.28 mmol) of (7RS,9aSR)-7-(5-fluoro-1H-indol-3-yl)methyl-2-(pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Example 50), anhydrous DMF (1 mL) and 12 mg (0.30 mmol) of sodium hydride (60% oil dispersion). The suspension was treated with 0.019 mL (0.31 mmol) of methyl iodide and the mixture was heated at 50° C. for 16 h. The mixture was cooled to room temperature, concentrated in vacuo, and diluted with methylene chloride (25 mL) and water (25 mL), and the layers were separated. The organic phase was dried (sodium sulfate), filtered and evaporated to a solid residue. The solid was washed with ethyl acetate (2×), the ethyl acetate was evaporated to give 50 mg of the title compound. 1H NMR (CDCl3): δ 1.00–1.31 (m, 3H), 1.64–2.23 (m, 6H), 2.54–3.1 (m, 5H), 3.69 (s, 3H), 4.51–4.56 (m, 2H), 6.43 (dd, J=1 Hz, 1H), 6.83 (s, 1H), 6.93 (m, 1H), 7.15 (m, 2H), 8.27 (d, J=1 Hz, 2H). TLC Rf: 0.81 (90:10:1 methylene chloride:methanol:ammonium hydroxide).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Br[CH:10]([CH2:18][CH2:19]Br)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>O1CCCC1>[CH3:3][C:4]1[CH:5]=[N:6][N:7]([C:10]2([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:19][CH2:18]2)[CH:8]=1
Reactant: Cc1cn[nH]c1
Reactant: CC(C)(C)OC(=O)C(Br)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnn(C2(C(=O)OC(C)(C)C)CC2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
Into a 25 mL round bottom flask were added sodium hydride (60% dispersion in mineral oil, 164.3 mg, 4.1 mmol) and anhydrous tetrahydrofuran (8 mL). The mixture was cooled with an ice-water bath before a solution of 4-methylpyrazole (204.2 mg, 2.487 mmol) in anhydrous tetrahydrofuran (2 mL) was added. The mixture was stirred in the ice-water bath for 30 minutes before tert-butyl 2,4-dibromobutanoate (0.48 mL, 2.2 mmol) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes and then at room temperature for 18 h. The solvent was removed under reduced pressure and water and ethyl acetate were added to the residue. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (0-50% ethyl acetate in heptanes) to afford tert-butyl 1-(4-methyl-1H-pyrazol-1-yl)cyclopropanecarboxylate (218 mg, 44%). 1H NMR (400 MHz, CDCl3) δ 1.33 (s, 9H), 1.45-1.51 (m, 2H), 1.61-1.67 (m, 2H)H), 1.98-2.01 (m, 3H)H), 7.21 (s, 1H), 7.23-7.26 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:31][CH2:32][C@@H:33]4[CH2:37][CH2:36][CH2:35][O:34]4)[C:17]4[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.Cl>CO>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:31][CH2:32][C@@H:33]4[CH2:37][CH2:36][CH2:35][O:34]4)[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(NC[C@@H]4CCCO4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Agent: Cl
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(NC[C@@H]4CCCO4)n2)CNCC3)cc1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
(S)-tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-((tetrahydrofuran-2-yl)methylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (75 mg, 0.15 mmol) was dissolved in methanol (3 mL). Hydrochloric acid (4.51 μL, 0.15 mmol) was added and the reaction mixture was stirred at 75° C. for 1 h. The solvent was evaporated under reduced pressure and the crude (S)-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (55.0 mg, 91%) was used as such in the subsequent step. MS (ES+) m/z 406.3 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:48])[C:10]([NH:12][NH:13][C:14]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:18]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)[C:17](=[O:35])[N:16]([CH2:36][C:37]2[C:38]([CH3:47])=[N:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=2)[N:15]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:1]([O:8][C@@H:9]([C:10]1[N:15]2[N:16]([CH2:36][C:37]3[C:38]([CH3:47])=[N:39][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:41][CH:42]=3)[C:17](=[O:35])[C:18]([C:27]3[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=3)=[C:19]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C:14]2=[N:13][N:12]=1)[CH3:48])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(NNC(=O)[C@@H](C)OCc2ccccc2)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc([C@@H](C)OCc3ccccc3)n21
Temperature: 120 °C
Reaction time: 3 h
Yield: 43.6 %

Procedure:
To a round bottom flask was added (R)-2-(benzyloxy)-N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)propanehydrazide (70 mg, 0.140 mmol), toluene (3 ml). The reaction was heated to 120° C. POCl3(0.3 ml) was then added and the reaction was stirred at 120° C. for additional 3 hr. The reaction was then cooled to rt and the solution was concentrated. The resulting residue was diluted with EtOAc (30ml). The organic solution was then extracted with saturated NaHCO3 (20 ml), water (20 ml) and saturated NaCl (20 ml). The organic solution was dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (4 g silica gel, 20%-50% EtOAc/Hex) to give product (R) -4-(3-(1-(benzyloxy)ethyl)-8-(4-chlorophenyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile as a white solid (40 mg, 44% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Br[CH2:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26]>>[Cl:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[CH2:18][NH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: Fc1cccc(Cl)c1CBr
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Product: O=c1[nH]c2ncccc2c2cc(NCc3c(F)cccc3Cl)ccc12
Yield: 5.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 458 using 70 (149 mg, 0.70 mmol) and 2-(bromo-methyl)-1-chloro-3-fluorobenzene (189 mg, 0.85 mmol) to provide 471 (14 mg, 6% yield) as a white powder. LC-MS (M+H=355, obsd.=355). 1H NMR (400 MHz, DMSO-D6) δ 11.53 (s, 1H), 8.64 (m, 1H), 8.45 (s, 1H), 8.01 (s, 1H), 7.99 (s, 1H), 7.50 (s, 2H), 7.43 (s, 2H), 7.30 (s, 1H), 6.97 (s, 1H), 4.55 (s, 2H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([NH:20][C:21]([C:23]1[N:24]=[C:25]([N:28]2[CH2:31][CH:30](OS(C)(=O)=O)[CH2:29]2)[S:26][CH:27]=1)=[O:22])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:37]([O-:40])(=[S:39])[CH3:38].[K+]>CN(C)C=O>[C:37]([S:39][CH:30]1[CH2:31][N:28]([C:25]2[S:26][CH:27]=[C:23]([C:21](=[O:22])[NH:20][CH:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[N:24]=2)[CH2:29]1)(=[O:40])[CH3:38]
Reactant: CC([O-])=S
Reactant: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)NC(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C)cs2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
To a solution of 1-{4-[2-(t-butyldimethylsilyloxy)-1-(t-butyldimethylsilyloxymethyl)-ethylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (1.56 g, 2.53 mmol) (obtained as described in Reference Example 39(6)) in dimethylformamide (78 ml) was added potassium thioacetate (1.73 g, 15.2 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (4:1→2:1) as the eluant to afford 3-acetylthio-1-{4-[2-(t-butyldimethylsilyloxy)-1-(t-butyldimethylsilyloxymethyl)-ethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (773 mg, yield 57%) as a pale brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O:13]CC)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.O1CCCC1.C(O)C.O.[OH-].[Li+]>O>[F:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cnc2cc(F)ccn12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cnc2cc(F)ccn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.8 %

Procedure:
Ethyl 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate (8.0 g; 44.4 mmol) was mixed with tetrahydrofuran (225 mL), ethanol (110 mL) and water (55 mL). Lithium hydroxide monohydrate (0.962 g; 22.9 mmol) was added. The mixture was stirred at ambient temperature for 16 hours. The mixture was concentrated under reduced pressure to remove tetrahydrofuran and ethanol. 2 N hydrochloric acid was added to the mixture to adjust to pH 3. A white precipitate formed which was collected by filtration and dried under high vacuum to give 7-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid as a white solid (6.3 g).
Reaction SMILES: [Cu]C#N.[Cl-].[Li+].I[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.[CH2:17](Br)[CH:18]=[CH2:19]>O1CCCC1.ClCCl.O>[CH2:19]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)[CH:18]=[CH2:17]
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C=CCBr
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: C=CCc1ccc(C(=O)OC)cc1
Temperature: 150 °C
Reaction time: 0.75 h

Procedure:
A 100 mL flask containing copper(I) cyanide (0.85 g, 9.54 mmol) and lithium chloride (0.81 g, 19.08 mmol) was placed under vacuum and heated to 150° C. for 90 minutes, and then cooled to room temperature. A 500 mL flask containing a solution of methyl 4-iodobenzoate (12.5 g, 47.7 mmol) in tetrahydrofuran (75 mL) under argon was cooled to −25° C. and isopropylmagnesium chloride-lithium chloride complex (49.1 mL, 1 M, 49.1 mmol) was added over 16 minutes while the internal temperature was maintained at below −20° C. After 45 minutes, the copper(I) cyanide and lithium chloride were dissolved in tetrahydrofuran (20 mL) with sonication, and the resulting solution was transferred to the clear, orange reaction mixture via cannula. After an additional 25 minutes, allyl bromide (4.13 mL, 47.7 mmol) was added over 10 min while the reaction temperature was kept below −15° C., and then the reaction was kept at −5° C. for 24 hours. 60 mL of 9:1 NH4Cl(sat):NH3(sat) was then added, followed by 50 mL of water and 200 mL dichloromethane. The layers were separated, and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were washed with 100 mL water and then diluted with 100 mL dichloromethane and 100 mL chloroform. The organic layer was washed with 150 mL brine, dried over MgSO4 and Na2SO4, filtered, and concentrated to yield an oil and a solid. The oil was filtered through a cotton plug and the entire flask was then rinsed with hexanes (4×2 mL); these rinses were combined with the oil after filtering through cotton. Concentration of this solution yielded the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.Cl.[CH:12]([C:15]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[C:17]([CH:24]([CH3:26])[CH3:25])[C:16]=1[S:27]([NH:30][NH2:31])(=[O:29])=[O:28])([CH3:14])[CH3:13]>CO>[CH:24]([C:17]1[CH:18]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:20]=[C:15]([CH:12]([CH3:13])[CH3:14])[C:16]=1[S:27]([NH:30][N:31]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH3:9])(=[O:28])=[O:29])([CH3:25])[CH3:26]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN)c(C(C)C)c1
Reactant: CC(=O)c1ccc(C)cc1
Agent: Cl
Solvent: CO
Product: CC(=NNS(=O)(=O)c1c(C(C)C)cc(C(C)C)cc1C(C)C)c1ccc(C)cc1
Yield: 86.4 %

Procedure:
1-(4-Methylphenyl)ethanone (2.28 g) and concentrated hydrochloric acid (1 ml) were added to a stirred solution of 2,4,6-triisopropyl benzenesulphonylhydrazine (5 g) in methanol (20 ml). The resulting mixture was stirred until a dense white precipitate formed. The precipitate was removed by filtration and washed with cold methanol to yield 1-(4-methylphenyl)ethanone 2,4,6-triisopropylbenzenesulphonylhydrazone (6 g) as a fine white crystalline solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH:2]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:1]
Reactant: CCOC(=O)c1nc2ccccn2c1CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCOC(=O)c1nc2ccccn2c1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
A solution of 1.2 g (5.45 mmol) of ethyl 3-(hydroxymethyl)-imidazolo[1,2-a]pyridine-2-carboxylate in 50 mL dichloromethane is treated with 1.75 g (15.0 mmol) of N-methylmorpholine N-oxide, 2.5 g powdered 4A molecular sieves and 180 mg (0.5 mmol) tetrapropylammonium perruthenate. The mixture is stirred at room temperature for 2 hr and applied directly to a column of silica. The column is eluted with 10% methanol in dichloromethane to afford 1.09 g (92%) ethyl 3-formyl-imidazolo[1,2-a]pyridine-2-carboxylate.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.O1CCOCC1.[OH-].[Na+]>O>[O:16]1[CH2:15][CH:14]1[CH2:12][O:11][C:1]1[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2c1CC=CC2
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C1=CCc2c(cccc2OCC2CO2)C1

Procedure:
To a cooled solution of 15 g. (0.1 m.) of 5,8-dihydro-1-naphthol and 13.2 g. (0.14 m.) of epichlorohydrin in 38 ml. of p-dioxane, a cold solution of 4.9 g. of sodium hydroxide in 10 ml. of water is added dropwise. The mixture is refluxed three hours, cooled, and extracted with benzene. The benzene extract is washed with water, dried (MgSO4) and evaporated in vacuo to give 1-(2,3-epoxypropoxy)-5,8-dihydronaphthalene. Distillation of the crude oil at 1.2 mm., b.p. 139°-140°, gives a colorless liquid; λliq.max. film 1250, 910, 840 cm-1 (characteristic epoxy bands), CDCl3 4.13 (-C/H=C/H-), 2.5 - 3.5 (aromatic protons).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH3:12][C:13]([CH3:18])([CH3:17])[CH:14]([NH2:16])[CH3:15]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:16][CH:14]([CH3:15])[C:13]([CH3:18])([CH3:17])[CH3:12])=[S:11]
Reactant: Fc1ccc(N=C=S)c(F)c1
Reactant: CC(N)C(C)(C)C
Solvent: ClCCl
Product: CC(NC(=S)Nc1ccc(F)cc1F)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
To a solution of 2,4-difluoro-phenyl isothiocyanate (1.00 g, 5.84 mmol) in dichloromethane (20 mL) at room temperature was added (±) 3,3-dimethyl-2-aminobutane (1.02 mL, 7.6 mmol) and the reaction was stirred overnight at room temperature. The mixture was concentrated in vacuo and the resulting residue was triturated with diethyl ether and filtered to afford 1.34 g (84%) of 1-(2,4-difluoro-phenyl)-3-(1,2,2-trimethyl-propyl)-thiourea as a white solid which was used without further purification.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16](=O)[NH:17][CH:18]=[N:19]3)=[CH:14][C:13]=2[O:23][CH3:24])[CH2:4][CH2:3]1.CN(C=O)C.S(Cl)([Cl:33])=O>C1(C)C=CC=CC=1>[Cl:33][C:16]1[C:15]2[C:20](=[CH:21][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:5]3[CH2:6][CH2:7][S:2](=[O:25])(=[O:1])[CH2:3][CH2:4]3)=[C:13]([O:23][CH3:24])[CH:14]=2)[N:19]=[CH:18][N:17]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCS(=O)(=O)CC1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCS(=O)(=O)CC1
Yield: 52 %

Procedure:
7-(3-(1,1-Dioxothiomorpholino)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (4.2 g, 11.4 mmol) was suspended in thionyl chloride (45 ml) and DMF (0.1 ml) then heated at reflux for 2.5 hours. The residue was diluted with toluene, the thionyl chloride was evaporated under vacuum, the residue was then azeotroped with toluene three times. The residue was taken up in water and basified (pH8) with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with dichloromethane (×4), the organic layer was washed with water and brine then filtered through phase separating paper. The organic layer was concentrated under vacuum to give an orange solid. The solid was flash chromatographed on silica eluting with dichloromethane and methanol (95/5). The relevant fractions were combined and evaporated to give a solid which was triturated with ether then filtered and dried to give 4-chloro-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline (2.27 g, 52%).
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].Br[C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=1.[Mg].[Cl-].[NH4+]>CCOCC.C1COCC1>[F:15][C:10]1[CH:9]=[C:8]([CH:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5])[CH:13]=[C:12]([F:14])[CH:11]=1
Reactant: CCCCC=O
Reactant: Fc1cc(F)cc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCC(O)c1cc(F)cc(F)c1
Yield: 116 %

Procedure:
A solution of pentanal (19.0 g, 0.22 mol) in dry ether (75 ml) was added dropwise to a stirred solution of the Grignard reagent at room temperature, under dry nitrogen, prepared from 1-bromo-3,5-difluorobenzene (50.2 g, 0.26 mol) and magnesium (7.25 g, 0.30 mol) in dry THF (100 ml). The stirred mixture was heated under reflux for 2 h, cooled and a saturated solution of ammonium chloride (300 ml) was added. The product was extracted into ether (twice), and the combined ethereal extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo to give a pale-orange liquid (51.1 g) which was distilled to yield a colourless liquid. Smaller quantities of crude product were purified by column chromatography (silca gel/dichloromethane) to yield a colourless liquid (92%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][NH:12][OH:13])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(Cl)Cl>[CH2:6]([O:5][P:4]([CH2:9][CH2:10][CH2:11][N:12]([OH:13])[C:14](=[O:16])[CH3:15])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(CCCNO)OCC
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCOP(=O)(CCCN(O)C(C)=O)OCC
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 112.4 %

Procedure:
2.8 g (0.013 mol) 3-(N-hydroxyamino)-propylphosphonic acid diethylester are dissolved in 30 ml methylene chloride and added drop by drop with cooling with ice to 2.65 g (0.026 mol) acetic anhydride. The reaction mixture is stirred for 30 minutes at 0-5° C. and for a further 1.5 hours at room temperature. After concentration under reduced pressure until a yellow oily radical is achieved, this oily residue is taken up in 15 ml methanol and 5 ml water, adjusted to pH 8 with 2 n NaOH and stirred for a further 1.5 hours at room temperature. Methanol is removed under reduced pressure and the resultant solution is adjusted to pH=5 with concentrated HCl. The yellow solution is extracted repeatedly with methylene chloride (1×30 ml, 2×10 ml in each case), the combined CH2Cl2 phases are dried over MGSO4 and the solvent is removed at room temperature under reduced pressure. 3.7 g of a yellow oil are obtained which are freed from adhering volatile substances in the entire diaphragm pump vacuum. 2.78 g yellow oil remain.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][NH:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=O)=[CH:2]1>C1(C)C=CC=CC=1>[CH3:17][N:14]1[CH2:15][CH2:16][CH:11]([C:9]2[C:2]3[S:1][CH:5]=[CH:4][C:3]=3[CH2:6][CH2:7][N:8]=2)[CH2:12][CH2:13]1
Reactant: CN1CCC(C(=O)NCCc2ccsc2)CC1
Solvent: Cc1ccccc1
Product: CN1CCC(C2=NCCc3ccsc32)CC1

Procedure:
1-Methylpiperidine-4-carboxylic acid (2-thiophen-3-yl-ethyl)-amide (1.2 g) POCl3 (1.22 ml) were reacted in toluene (50 ml) exactly as described in example 4. 1.1 g of [7-(1-Methylpiperidin-4-yl)-4,5,-dihydrothieno[2,3-c]pyridine was isolated identified by NMR and MS: M+=234.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH2:4][OH:5].I[CH2:12][CH2:13][CH3:14].[C:15]([OH:22])(=[O:21])/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19].[CH2:23]([C@@H:25]1[CH2:30][NH:29][CH2:28][CH2:27][N:26]1[C:31](OCC1C=CC(OC(F)F)=CC=1)=[O:32])C>>[C:15]([OH:22])(=[O:21])/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19].[CH3:23][C@@H:25]1[CH2:30][NH:29][CH2:28][CH2:27][N:26]1[C:31]([O:5][CH2:4][C:3]1[CH:6]=[C:7]([O:10][CH2:12][CH2:13][CH3:14])[CH:8]=[CH:9][C:2]=1[F:1])=[O:32]
Reactant: CC[C@@H]1CNCCN1C(=O)OCc1ccc(OC(F)F)cc1
Reactant: CCCI
Reactant: OCc1cc(O)ccc1F
Agent: O=C(O)/C=C/C(=O)O
Product: CCCOc1ccc(F)c(COC(=O)N2CCNC[C@H]2C)c1

Procedure:
(R)-2-Fluoro-5-propoxybenzyl 2-methylpiperazine-1-carboxylate fumarate was prepared from 2-fluoro-5-hydroxybenzyl alcohol, 1-iodopropane and (R) 1-chlorocarbonyl-2-methyl-4-tert-butoxycarbonylpiperazine according to the methods described for Examples 54 and 96 to give the product as a white solid (26.4%); melting point 162.6–162.7° C.; NMR δH (400 MHz, DMSO-d6) 0.963(3H, t, J 7.5 Hz), 1.173(3H, d, J 7.0 Hz), 1.709(2H, m), 2.582(1H, m), 2.801(2H, bs), 2.991(2H, bm), 3.731(1H, bdd), 3.895(2H, t, J 6.5 Hz), 4.142(1H, bm), 5.077(2H,q), 6.556(2H, s), 6.931(2H, m) and 7.126(1H, t, J 9.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH3:19])[C:7](=[O:18])[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.CC([O-])(C)C.[K+].[N:28](OC(CC)(C)C)=[O:29]>C(O)(C)(C)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH3:19])[C:7](=[O:18])[C:8](=[N:28][OH:29])[C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: CN1C(=O)CC(=O)N(c2ccccc2)c2cc(Cl)ccc21
Reactant: CCC(C)(C)ON=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cn1c(=O)c(=NO)c(=O)n(-c2ccccc2)c2cc(Cl)ccc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
3 g of 7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione were suspended in 30 ml of tert-butanol and 1.12 g of potassium tert-butylate were added in small fractions. While maintaining the temperature at 20° C. with a water bath, 2.3 ml of tert-amyl nitrite were added and the solution thickened and a precipitate formed. After standing for 16 hours at ambient temperature, the precipitate formed was separated off (potassium salt of the oxime) and dissolved in 20 ml of water and acidified by acetic acid. The precipitate formed was extracted and the organic phase was washed with water, dried and concentrated to obtain 2.8 g of the expected product (yield=85%) melting at approx. 50° C.