Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[N:6][C:5]([Cl:10])=[C:4]([Cl:11])[N:3]=1.[CH2:12]([Mg]Cl)[CH:13]=[CH2:14].[Cl-].[NH4+]>O1CCCC1.CCOCC>[NH2:1][C:2]1[C:7]([CH:8]([OH:9])[CH2:14][CH:13]=[CH2:12])=[N:6][C:5]([Cl:10])=[C:4]([Cl:11])[N:3]=1
Reactant: C=CC[Mg]Cl
Reactant: Nc1nc(Cl)c(Cl)nc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(O)c1nc(Cl)c(Cl)nc1N
Reaction time: 0.25 h

Procedure:
In 4 ml of tetrahydrofuran and 4 ml of ether there was dissolved 288 mg (1.5 mMol) of 2-amino-5,6-dichloro-3-formylpyrazine prepared as in Example 1, Step B, after which the reaction mixture was cooled in a dry-ice/acetone bath, followed by addition of 2-propenyl magnesium chloride (1.5 ml). The reaction mixture was stirred for 15 minutes, an ammonium chloride solution was then added, followed by stirring for 15 minutes at room temperature, after which ether was added. The resulting aqueous layer was extracted twice with ether, and the combined extracts and ether layer were washed well with water, dried, and the solvent evaporated. The remaining material was passed through a silica gel column and eluted with dichloromethane to obtain the product (120 mg).
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1([S:15]/[CH:16]=[C:17]2/[C:18](=[O:23])[O:19][CH2:20][CH2:21][CH2:22]/2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C(Cl)Cl>[OH:19][CH2:20][CH2:21][CH2:22]/[C:17](=[CH:16]\[S:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)/[C:18]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:23]
Reactant: O=C1OCCC/C1=C\Sc1ccccc1
Reactant: Nc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Nc1ccccc1)/C(=C/Sc1ccccc1)CCCO
Reaction time: 0.08 h
Yield: 90.1 %

Procedure:
6.4 ml of diethylalumiun chloride (1 mol/1 of hexane solution) was added to 10 ml of methylene chloride solution including 0.6 g of aniline at room temperature. After stirring for 5 minutes, methylene chloride solution including 1.28 g of (E)-3-(phenylthiomethylene)tetrahydro-2H-pyran-2-one was dropped into the resulting solution. After stirring at room temperature for 2 hours, the solution was added with 10% hydrochloric acid, then stirred at room temperature for 30 minutes. The solution was extracted with ethyl acetate, and the organic layer was washed with brine, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.64 g of the title compound.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:9][C:10]([C:12]1[CH:16]=[C:15]([CH2:17][CH2:18][OH:19])[O:14][N:13]=1)=[O:11])[CH3:8].[CH:20]1[CH:25]=[CH:24][C:23]([O:26][C:27](Cl)=[S:28])=[CH:22][CH:21]=1>ClCCl>[CH2:7]([O:9][C:10]([C:12]1[CH:16]=[C:15]([CH2:17][CH2:18][O:19][C:27]([O:26][C:23]2[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=2)=[S:28])[O:14][N:13]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1cc(CCO)on1
Reactant: S=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(CCOC(=S)Oc2ccccc2)on1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
Pyridine (2,4 g, 31 mmol) was added to a stirred solution of 5-hydroxyethylisoxazole-3-carboxylic acid ethyl ester (4.75 g, 26 mmol) (prepared analogously to Example 64 part a) in dichloromethane (150 ml) under nitrogen at room temperature. The mixture was cooled to 0° C. and phenyl chlorothionoformate (5.3 g, 31 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 h and at room temperature for 2 h, then diluted with dichloromethane (200 ml) and washed with water (×2). The organic layer was dried (MgSO4) and evaporated in vacuo. Flash chromatography of the residue on silica gel, eluting with 20% ethyl acetate/hexane, gave the title-compound (6.7 g, 81%), 1H NMR (250 MHz, CDCl3) δ 1.43 (3H, t, J=7.1 Hz, CH3), 3.37 (2H, t, J=6.3 Hz, CH2), 4.46 (2H, q, J=7.1 Hz, CH2), 4.83 (2H, t, J=6.3 Hz, CH2), 6.60 (1H, s, Ar—H), 7.08-7.11 (2H, m, 2 of Ar—H), 7.29 (1H, m, Ar—H), 7.38-7.46 (2H, m, 2 of Ar—H); MS (ES30) m/e 322 [MH]+, m/e 168 [MH−154]+.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[CH3:9][O:10][CH2:11][CH2:12][NH2:13]>C(O)C>[C:1]([CH2:3][C:4]([NH:13][CH2:12][CH2:11][O:10][CH3:9])=[O:6])#[N:2]
Reactant: COCCN
Reactant: CCOC(=O)CC#N
Solvent: CCO
Product: COCCNC(=O)CC#N
Temperature: 25 °C

Procedure:
0.5 g (4.42 mmol) Ethyl cyanoacetate and 0.37 g (4.86 mmol) 2-methoxyethylamine are dissolved in 10 ml ethanol and stirred at reflux overnight. After cooling down to room temperature, the solvent is removed in vacuo and the product is crystallised from ethanol/diethylether.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[S:9]([C:13]1[CH:14]=[C:15]([NH:19][C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH:16]=[CH:17][CH:18]=1)(=[O:12])(=[O:11])[NH2:10].C(N(CC)CC)C.CS(O)(=O)=O>CN(C)C1C=CN=CC=1.C(#N)C.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:10][S:9]([C:13]1[CH:14]=[C:15]([NH:19][C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12])=[O:7]
Reactant: O=C(Cl)c1ccco1
Reactant: CN(C)C(=O)Nc1cccc(S(N)(=O)=O)c1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)C(=O)Nc1cccc(S(=O)(=O)NC(=O)c2ccco2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
6.1 g of 2-furancarboxylic acid chloride and 0.1 g of 4-dimethylaminopyridine are added to a suspension of 10.1 g of 1-(3-sulfamoylphenyl)-3,3-dimethylurea in 60 ml of acetonitrile. 9.5 g of triethylamine are added dropwise to that mixture at room temperature. The reaction mixture is stirred for 15 hours at room temperature and for one hour at 60° C. After the mixture has cooled, 4.5 g of methanesulfonic acid are added dropwise thereto and the mixture is taken up in 1 liter of water. The oil that separates out crystallises after a short time. The crystals are separated off, washed with methanol and dried, yielding 11.3 g of 1-[3-(N-2-furylcarbonylsulfamoyl)-phenyl]-3,3-dimethylurea, m.p. 216°-217° C. (with decomposition).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1.[CH3:28][NH:29][CH3:30]>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:29]([CH3:30])[CH3:28])[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CNC
Solvent: c1ccncc1
Product: CN(C)c1c(F)c(N)c2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c2c1Cl
Temperature: 25 °C
Reaction time: 96 h
Yield: 81 %

Procedure:
5-Amino-1-(6-amino-3, 5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg) and an aqueous solution (about 50%; 170 mg) of dimethylamine were added to pyridine (500 mg), and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, and ethanol (1 ml) was added to the residue. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (86 mg) as a yellow powder.
Reaction SMILES: C[C@@H:2]([C@@H:9]1[C@@]2(C)CC[C@@H]3[C@@]4(C)CC[C@@H](O)C[C@H]4[C@@H](O)C[C@H]3[C@@H]2CC1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[O:30]1C=[CH:34][CH2:33][CH2:32][CH2:31]1.CO>O1CCOCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH:8]1[O:7][CH:5]1[CH2:4][CH2:3][CH2:2][CH2:9][O:6]1
Reactant: C1=COCCC1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](O)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: C1COCCO1
Product: C1CCC(OC2CCCCO2)OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 245.3 %

Procedure:
To a solution of 100.0 g (0.2557 mole) of methyl hyodeoxycholate and 5.68 g of p-toluenesulfonic acid in 2000 ml of p-dioxane was added 153.7 g (1.62 mole, 148.6 ml) of dihydropyran over a period of 30 min under argon atmosphere. After stirring overnight at room temperature, the pH of the solution was adjusted to approximately pH 8 by the addition of 55 ml of 50/50 methanol/29% ammonium hydroxide. The solution was concentrated to a yellow oil under reduced pressure and the residue stirred in heptane 4 hr, then filtered to remove the precipitated p-toluenesulfonic acid. The filtrate was heated with charcoal, filtered, and evaporated to yield 116.8 g (80%) of the di-tetrahydropyranyl ether as a colorless viscous oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]#[C:22][CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[C:19]([O:36][CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]#[C:22][CH:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)=[C:19]([O:36][CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1C#CC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1C#CC1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}ethynyl)piperidine-1-carboxylate (0.0982 g, 0.197 mmol) in methylene chloride (5 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-(piperidin-4-ylethynyl)benzofuran-3(2H)-one (0.0392 g, 50%).
Reaction SMILES: Br[CH:2]([CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])[C:3]([CH3:12])([CH3:11])[CH:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[O-]CC.[Na+].Cl>O1CCCC1>[Cl:15][C:14]([Cl:16])([Cl:17])[CH:13]=[CH:2][C:3]([CH3:12])([CH3:11])[CH:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C)C(C)(C)C(Br)CC(Cl)(Cl)Cl
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C(C)(C)C=CC(Cl)(Cl)Cl
Reaction time: 5 h
Yield: 74.8 %

Procedure:
A solution of 737 mg of ethyl 4-bromo-6,6,6-trichloro-2,3,3-trimethylhexanoate in 20 ml of anhydrous tetrahydrofuran was cooled to 0°. To the cold solution was added 163 mg of sodium ethoxide and the mixture was stirred for 5 hours. The cooled mixture was poured into cold 1N hydrochloric acid and extracted with diethyl ether. The ether extract was washed successively with water, saturated aqueous sodium bicarbonate and aqueous sodium chloride, then dried over magnesium sulfate. The dried ether extract was distilled to give 430 mg (75% yield) of ethyl 6,6,6-trichloro-2,3,3-trimethyl-4-hexenoate, b.p. 92°-95°/0.2 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH2:16])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[BH4-].[Na+]>CO>[OH:6][CH:5]([C:4]1[CH:13]=[CH:14][C:15]([NH2:16])=[C:2]([NH2:1])[CH:3]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(C(O)c2ccccc2)cc1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
3,4-Diaminobenzophenone (5.79 g, 27 mmol) was dissolved in MeOH (80 mL) and cooled to 0° C. A solution of NaBH4 (4.12 g, 109 mmol) in MeOH (30 mL) was added dropwise over 10 min. The mixture was stirred for 2 hours and concentrated to dryness. The residue was dissolved in EtOAc and washed with NaHCO3 (3×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to afford the title compound (5.3 g, 90%): 1HNMR (400 MHz, CDCl3) δ 5.6-5.65 (1H, s), 6.6-6.7 (3H, m), 7.2-7.45 (5H, m).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][O:23][CH3:24])[C:16]=1[C:25](=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][O:23][CH3:24])[C:16]=1[C:25](=[CH2:1])[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C(=O)c1c(OCOC)cccc1OCOC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C(=O)OCC)c1c(OCOC)cccc1OCOC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 79.3 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (3.13 g, 8.75 mmol) in dry tetrahydrofuran (30 ml) at 0° C. KHMDS (1.745 g, 8.75 mmol) was slowly added and the reaction mixture was stirred for 15 minutes at 0° C. and for 45 minutes at room temperature. The reaction mixture was cooled to 0° C. and a solution of ethyl (2,6-bis{[(methyloxy)methyl]oxy}phenyl)(oxo)acetate (Reference Intermediate 209, 1.74 g) in dry tetrahydrofuran (10 mL) was slowly added and the reaction mixture was stirred for 2 hours at 0° C. The reaction was quenched with an aqueous saturated solution of ammonium chloride (10 ml), diluted with water (20 ml) and extracted with ethyl acetate (2×50 ml). The organic layer was dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 8:2 as eluents affording the title compound as a colourless oil (1.37 g).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](CC(=O)C)=[O:7])=[CH:4][N:3]=1.[CH3:14][C:15](C)=[O:16]>>[CH2:15]([O:16][C:6]([C:5]1[CH:12]=[CH:13][C:2]([CH3:1])=[N:3][CH:4]=1)=[O:7])[CH3:14]
Reactant: CC(C)=O
Reactant: CC(=O)CC(=O)c1ccc(C)nc1
Product: CCOC(=O)c1ccc(C)nc1

Procedure:
The 6-methylnicotinoyl-acetone which is mentioned as the starting substance in Example 6, can be obtained in a known manner from α-picoline-5-carboxylic acid ethyl ester and acetone, or from 5-acetyl-α-picoline (prepared in accordance with Angew. Ch. 67, page 398) and ethyl acetate: 270 g of 5-acetyl-α-picoline, 5 1 of anhydrous toluene, 387 g. of ethyl acetate and 537 g of potassium tert.-butylate are stirred at 40° for 20 hours and the mixture is subsequently decomposed by means of a mixture of 3 1 of ice water and 288 ml of acetic acid. 283.5 g of 6-methylnicotinoyl-acetone, boiling point 108°-117° /0.2 mm Hg, which rapidly crystallises and, after recrystallisation from ligroin, melts at 57°-58°, is obtained in the usual manner from the toluene solution.
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.[Cl:8][C:9]1[C:10]([CH2:23]O)=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:19][N:20]([CH3:22])[CH3:21].CS(Cl)(=O)=O.[C-]#N.[K+]>C(Cl)Cl.O>[Cl:8][C:9]1[C:10]([CH2:23][C:1]#[N:3])=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:19][N:20]([CH3:22])[CH3:21]
Reactant: CN(C)Cc1cccc2cc(Cl)c(CO)cc12
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CN(C)Cc1cccc2cc(Cl)c(CC#N)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.4 %

Procedure:
Triethylamine (0.12 ml, 0.87 mmol, 2.0 equiv) was added to a solution of (3-chloro-8-dimethylaminomethyl-naphthalen-2-yl)-methanol (109 mg, 0.44 mmol) in CH2Cl2 (1.5 ml). At −25° C., a solution of methanesulfonyl chloride (0.05 ml, 0.66 mmol, 1.5 equiv) in CH2Cl2 (1.5 ml) was then added dropwise. After 15 minutes at 0° C., cold water (4° C., 10 ml) was added, and the mixture was extracted with CH2Cl2 (2×40 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude mesylate was dissolved in N,N-dimethylformamide (2 ml) and treated at 0° C. with potassium cyanide (39 mg, 0.60 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 2 hours, until TLC analysis indicated complete conversion. After dilution with water (50 ml), the mixture was extracted with CH2Cl2 (2×200 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (hexane/EtOAc 100:0 to 80:20) afforded the title compound (54 mg, 48%, mixture of 2 regioisomers). The regioisomers could be separated by preparative HPLC. Data for (3-chloro-8-dimethylaminomethyl-naphthalen-2-yl)-acetonitrile: 1H NMR (400 MHz, CDCl3): δ=8.20 (s, 1H), 8.04 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.72 (d, J=6.6 Hz, 1H), 7.55 (dd, J=8.4/6.6 Hz, 1H), 4.59 (s, 2H), 3.96 (s, 2H), 2.78 (s, 6H). MS (ES+): 259 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].O[Li].O>CC(O)C.O>[C:9]([O:8][C:6](=[O:7])[CH2:5][CH:4]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:3]([OH:17])=[O:2])([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)CC(C)C
Agent: [Li]O
Solvent: CC(C)O
Solvent: O
Product: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Yield: 76.5 %

Procedure:
2-Isobutylsuccinic acid-4-t-butyl ester-1-methyl ester (11.1 g, 45.4 mmol) and LiOH.H2O (2.0 g, 47.7 mmol) are stirred in 180 mL of 3:1 IPA/H2O at room temperature overnight. The reaction mixture is extracted with Et2O (3×25 mL). The aqueous phase is acidified to pH=4, with saturated KH2PO4 and extracted with Et2O (3×50 mL). The Et2O is dried over MgSO4, and evaporated to give 8.0 g (77% yield) of 2-isobutyl-succinic acid-4-t-butyl ester as an oil. NMR (H1, 400 MHz, CDCl3) δ 0.9 (6H, m); δ 1.3 (1H, m); δ 1.4 (9H, s); δ 1.6 (2H, m); δ 2.3 (1H, dd); δ 2.6 (1H, dd); δ 2.8 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH2:11][C:12]#[N:13])[C:7]=2[CH:14]=1.Cl.[NH2:16][OH:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH2:11][C:12](=[N:16][OH:17])[NH2:13])[C:7]=2[CH:14]=1
Reactant: COc1ccc2onc(CC#N)c2c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2onc(CC(N)=NO)c2c1
Yield: 76.6 %

Procedure:
In ethanol (20 ml) was dissolved 5-methoxy-1,2-benzisoxazole-3-acetonitrile (2.0 g) and thereto was added a solution of hydroxylamine hydrochloride (0.88 g) and sodium carbonate (1.34 g) in water (10 ml). After heating the mixture on water bath at 70° to 80°C for 3 hours, ethanol was distilled off under a reduced pressure. To the residue was added water and the precipitated crystallines were separated by filtration, washed with water and dried to give the desired compound (1.8 g), which was recrystallized from ethanol. m.p. 180° to 183°C.
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])([C:4](=[O:6])[CH3:5])[CH3:3].[BH4-].[Na+]>CO>[OH:6][CH:4]([CH3:5])[C:2]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:1])[CH3:3]
Reactant: CC(=O)C(C)(C)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)C(C)(C)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a solution of tert-butyl 2-methyl-3-oxobutan-2-ylcarbamate (2.36 g, 11.73 mmol) in MeOH (30 mL) at 0° C. was added portion wise NaBH4 (0.887 g, 23.45 mmol). Cold bath was removed and the reaction was stirred for 1 hour. HCl solution (1 M, 0.2 mL) was then added cautiously to quench the reaction. The reaction mixture was then concentrated and diluted with EtOAc (50 mL) and water (10 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organics were then dried (Na2SO4) and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography (10-50% EtOAc-Hexanes) to afford the desired product as a white solid (2.12 g). LCMS m/z 204.1 (M+H)+, Rt 0.69 min.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-trifluoromethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-trifluoromethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1.Br[CH2:15][CH2:16][CH3:17].CC(N1CCCC(C(C)=O)=C1)C>>[CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[N:9]([CH2:15][CH2:16][CH3:17])[CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1
Reactant: CCCBr
Reactant: CC1(C)CC(=O)C2=C(C1)NCCC2
Agent: CC(=O)C1=CN(C(C)C)CCC1
Product: CCCN1CCCC2=C1CC(C)(C)CC2=O

Procedure:
7,7-Dimethyl-1,2,3,4,7,8-hexahydro-quinolin-5 (6H)-one [prepared by the method of Grob and Kiefer, Helv. Chim Acta., 48 799, (1964)]was reacted with 1-bromopropane according to the procedure of Part (b) of Example 1 to give 7,7-dimethyl-1,2,3,4,7, 8-hexahydro-1-propyl-quinolin-5(6H)-one (17) as an oil.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[C:22]1([CH2:28][CH2:29][CH:30]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1CCCCC1>C(O)C>[C:22]1([CH2:28][CH2:29][CH:30]=[C:18]2[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]3[N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=3)[C:19]2=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Reactant: O=CCCc1ccccc1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1SC(=CCCc2ccccc2)C(=O)N1CCCCSc1cccc2nccn12

Procedure:
To a solution of 1.61 g (5.0 mmol) of 3-[4-(imidazo-[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 1.34 g (10 mmol) of 3-phenylpropionaldehyde in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/4) to yield 2.27 g (quant, brown oily substance) of the desired product.
Reaction SMILES: [CH3:1][C:2]([S:5](/[N:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1)=[O:6])([CH3:4])[CH3:3].C[Si](C)(C)[C:18]([F:21])([F:20])[F:19]>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.C1C=CC([Si-](F)(F)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:4][C:2]([S:5]([NH:7][CH:8]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1)[C:18]([F:21])([F:20])[F:19])=[O:6])([CH3:1])[CH3:3]
Reactant: Cc1cccc(/C=N/S(=O)C(C)(C)C)n1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: F[Si-](F)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc(C(NS(=O)C(C)(C)C)C(F)(F)F)n1
Temperature: -78 °C

Procedure:
A solution of 2-methyl-N-[(1E)-(6-methylpyridin-2-yl)methylene]propane-2-sulfinamide (0.33 g, 1.48 mmol) in THF (6 mL) was added to a dry flask containing TBAT (0.88 g, 1.63 mmol) and the solution was cooled to −78° C. under a nitrogen atmosphere. To this was added trimethyl(trifluoromethyl)silane (0.26 mL, 1.78 mmol) and the reaction was warmed to −20° C. for 2 hours. The reaction was quenched with ammonium chloride solution and partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo. Purification by flash chromatography (5-40% ethyl acetate/hexane) gave 2-methyl-N-[2,2,2-trifluoro-1-(6-methylpyridin-2-yl)ethyl]propane-2-sulfinamide. LC-MS EIMS: m/z 295.1 [M+H]+.