Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].C(O)C.[CH3:6][N:7]([CH3:20])[C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13](OC)=[O:14])=[O:9]>O>[OH:14][CH2:13][C:12]1[CH:11]=[C:10]([CH:19]=[CH:18][CH:17]=1)[C:8]([N:7]([CH3:20])[CH3:6])=[O:9]
Reactant: COC(=O)c1cccc(C(=O)N(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(C)C(=O)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Under ice cooling, sodium borohydride (264 mg, 6.97 mmol) was added to an ethanol (15 ml) solution of methyl 3-(N,N-dimethylcarbamoyl)benzoate (289 mg, 1.39 mmol). The temperature of the resulting mixture was allowed to rise back to room temperature and then, stirring was conducted at 50° C. for 14 hours. After the reaction mixture was cooled back to room temperature, it was ice cooled. Sodium borohydride (264 mg, 6.97 mmol) was added and the mixture was stirred at 50° C. for 6 hours. The reaction mixture was ice cooled, and then added with water, followed by concentration under reduced pressure. The residue thus obtained was added with water, followed by extraction with methylene chloride. The extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column, and the fraction obtained from the methanol:methylene chloride (=1:30) eluate was concentrated under reduced pressure, whereby the title compound (196 mg, 79%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][N:4]=[C:3]1[N+:8]([O-:10])=[O:9].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[K].CC(C)([O-])C>C(O)C>[CH3:1][N:2]1[C:6]([CH:7]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][N:4]=[C:3]1[N+:8]([O-:10])=[O:9]
Reactant: O=Cc1ccccc1
Reactant: Cc1cnc([N+](=O)[O-])n1C
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CCO
Product: Cn1c(C=Cc2ccccc2)cnc1[N+](=O)[O-]
Yield: 16 %

Procedure:
A mixture of 7.2 g. of 1,5-dimethyl-2-nitroimidazole, 41.2 ml. of benzaldehyde and 7.9 g. of potassium dazole, tert-butoxide in 300 ml. of ethanol is refluxed for 35 minutes under nitrogen. The residue, which is obtained by evaporation of the reaction mixture under vacuum, is extracted with ethyl ether and filtered. The ethyl ether solution after concentration yields an oily residue which is chromatographed through 300 g. of silica gel by eluting with chloroform. After evaporation of the solvent under vacuum at 40° C., an oily residue is obtained which crystallizes on standing. After washing with a small amount of methyl ethyl ketone, 1.9 g. (16%) of a product which melts at 170°-180° C. is obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].CN(C)C=O.[F:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([N+:35]([O-:37])=[O:36])[CH:29]=1>O>[F:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:8][CH2:9][CH2:10][N:11]2[C:15](=[O:16])[C:14]3[C:13](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]2=[O:21])=[C:30]([N+:35]([O-:37])=[O:36])[CH:29]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccc(F)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 4 h
Yield: 100.4 %

Procedure:
Potassium carbonate (10.8 g, 78.1 mmol) and N-(3-bromopropyl)phthalimide (12.1 g, 45.1 mmol) were added to a N, N-dimethylformamide (DMF) solution (80 ml) of 4-fluoro-2-nitrophenol (6.0 g, 38.2 mmol), and the mixture was stirred at 60° C. for 4 hours. After the reaction mixture was cooled to room temperature, water (200 ml) was added, and the reaction mixture was then cooled with ice. The precipitated insoluble matter was collected by filtration. After being washed with water (50 ml×3), the substance remaining in the filter was air-dried, giving 13.2 g of powdery pale yellow 2-[3-(4-fluoro-2-nitrophenoxy)propyl]isoindole-1,3-dione (yield: 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CC=C(c2c[nH]c3c(F)cc(F)cc23)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(C3=CCN(C)CC3)c3cc(F)cc(F)c32)cc1

Procedure:
(8.8 mg, 54%); from 5,7-difluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4g, 10 mg, 0.04 mmol) and 4-methylphenylsulfonyl chloride (11.4 mg, 0.06 mmoles) with 1M NaN(TMS)2 (60 μL, 0.06 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: [CH2:1]([CH:8]1[NH:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]I>CN(C=O)C.O>[CH2:1]([CH:8]1[N:12]([CH3:25])[C:11](=[O:13])[N:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[C:9]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(Cc2ccccc2)C(=O)N1c1cc(F)ccc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2cc(F)ccc2F)C(=O)C1Cc1ccccc1
Reaction time: 1 h
Yield: 56.8 %

Procedure:
5-Benzyl-3-(2,5-difluorophenyl)imidazolidine-2,4-dione (2.0 g, 6.62 mmol) in DMF (10 mL) was added dropwise to a suspension of sodium hydride (166 mg, 6.95 mmol) in DMF (5 mL) at 0° C. The solution was stirred for 1 hour; then methyl iodide (0.62 mL, 9.9 mmol) was added and the mixture was stirred for 5 hours, then diluted with water and extracted with ethyl acetate (3×). The combined extracts were washed with brine (saturated), dried (over MgSO4), filtered and concentrated to give 1.19 grams of 5-benzyl-3-(2,5-difluorophenyl)-1-methylimidazolidine-2,4-dione, as an oil (compound 1 under Table A).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.[CH3:14][C:15]1[CH:16]=[C:17]([P:24]([C:26]2[CH:31]=[C:30]([CH3:32])[C:29]([O:33][CH3:34])=[C:28]([CH3:35])[CH:27]=2)Cl)[CH:18]=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22]>C1COCC1.CC(OC)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:24]([C:26]1[CH:31]=[C:30]([CH3:32])[C:29]([O:33][CH3:34])=[C:28]([CH3:35])[CH:27]=1)[C:17]1[CH:16]=[C:15]([CH3:14])[C:20]([O:21][CH3:22])=[C:19]([CH3:23])[CH:18]=1
Reactant: COc1c(C)cc(P(Cl)c2cc(C)c(OC)c(C)c2)cc1C
Reactant: Brc1ccccc1I
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COc1c(C)cc(P(c2cc(C)c(OC)c(C)c2)c2ccccc2Br)cc1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 9.67 g (34.2 mmol) of 1-bromo-2-iodobenzene in 30 ml of THF are added dropwise, at −78° C., 17.6 ml (37.6 mmol) of an isopropylmagnesium chloride solution (2 molar in THF). The mixture is stirred at a temperature between −30° C. and −40° C. for a further 1 hour, then cooled again to −78° C., and a solution of 12.66 g (37.6 mmol) of bis(3,5-dimethyl-4-methoxyphenyl)chlorophosphine in 10 ml of THF and 10 ml of TBME is added. The cooling is removed and the reaction mixture is stirred at room temperature overnight. The resulting solution is admixed with 50 ml of water and extracted with water/TBME. The organic phases are collected and dried over sodium sulphate, and the solvent is distilled off under reduced pressure on a rotary evaporator. The crude product is purified by chromatography (silica gel 60; eluent=1:1 heptane/ethyl acetate). The desired product is obtained in the form of white crystals in a yield of 76%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:20]=[CH:19][C:14]([O:15][CH2:16][CH2:17]O)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.S(Cl)([Cl:23])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:20]=[CH:19][C:14]([O:15][CH2:16][CH2:17][Cl:23])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCCOc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Product: ClCCOc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1

Procedure:
2-[4-(6-Bromo-3H-imidazo[4,5-b]pyridin-2-yl)phenoxy]ethanol (2.0 g, 6 mmol) was dissolved and refluxed in thionyl chloride (30 ml) for 3 h. The excess thionyl chloride was evaporated off and the residue was co-evaporated twice with toluene affording the title product in quantitative yield.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].[CH3:20][O:21][C:22]1([O:42][CH3:43])[CH:41]=[CH:40][C:25]([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:24][CH2:23]1>N1C=CC=CC=1>[CH3:43][O:42][C:22]1([O:21][CH3:20])[CH:23]=[CH:24][C:25]([C:26]([CH:17]([OH:18])[CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:19])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:40][CH2:41]1
Reactant: COC1(OC)C=CC(C(Cl)(c2ccccc2)c2ccccc2)=CC1
Reactant: OCCOCCOCCOCCOCCOCCO
Solvent: c1ccncc1
Product: COC1(OC)C=CC(C(c2ccccc2)(c2ccccc2)C(O)COCCOCCOCCOCCOCCO)=CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.1 %

Procedure:
To a solution of hexaethylene glycol (8.46 grams, 30 mmoles) in 250 ml dry pyridine, a solution of 4,4-dimethoxytrityl chloride (3.38 grams, 10 mmoles) in 50 ml dry pyridine was added dropwise at room temperature. The resulting solution was stirred at room temperature for additional 5 hours. The solvent was then evaporated to dryness, and the residue was extracted with 200 ml ethylacetate/200 ml 5% sodium bicarbonate solution, washed twice with water and twice with brine solution. The obtained organic layer was dried over anhydrous sodium sulfate, evaporated and purified by silica gel column chromatography using 5% methanol in dichloromethane, 0.5% pyridine. The resulting 4,4-dimethoxytrityl-hexaethylene glycol compound (5.23 grams, 89% yield) migrated with Rf=0.29.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][N:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:20]4)[C:14]([F:29])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.N[C@@H:31]1CCCC[C@H]1CNC1C(F)=CN=C(C2C3C(=NC=C(Cl)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)N=1.CS(Cl)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][CH2:31][C@H:20]4[NH:21][S:25]([CH3:28])(=[O:26])=[O:27])[C:14]([F:29])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)N1CCC[C@@H](CNc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC[C@@H]4CCCC[C@H]4N)n3)c3cc(Cl)cnc32)cc1
Agent: CS(=O)(=O)Cl
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1CNc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F

Procedure:
Sulfonamide 557 was prepared according to the procedure for compound 36 (Scheme 12B) using N-((trans-2-aminocyclohexyl)methyl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine, 14f, and methane sulfonyl chloride, afforded desired product, 557, as a racemic mixture of trans isomers.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH2:22]1[C:24]2([CH2:28][CH2:27][NH:26][CH2:25]2)[CH2:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:23]1[C:24]2([CH2:28][CH2:27][N:26]([C:12]([C:10]3[CH:9]=[CH:8][C:7]([N:15]4[CH2:18][C:17]([F:20])([F:19])[CH2:16]4)=[C:6]([O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[N:11]=3)=[O:14])[CH2:25]2)[CH2:22]1
Reactant: C1CC2(CC2)CN1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCC2(CC2)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 5-azaspiro[2.4]heptane hydrochloride (3659-21-0) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=364.5 [MH+].
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7](C2N=CNN=2)[C:8]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].[CH:27]([NH2:30])([CH3:29])[CH3:28]>O1CCOCC1>[C:1]([NH:4][C:5]1[N:6]=[C:7]([NH:30][CH:27]([CH3:29])[CH3:28])[C:8]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(=O)Nc1nc(-c2nc[nH]n2)c2nc(-c3ccc(F)cc3)ccc2n1
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(NC(C)C)c2nc(-c3ccc(F)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
To a suspension of the 2-acetamido-4-(1,2,4-triazolyl)-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine of example 2 (70 mg) in dioxane (5 ml) was added isopropylamine (0.4 mmol). The reaction was stirred at room temperature for 24 hours. The solvents were evaporated in vacuo, yielding the crude title compound which was purified by preparative TLC on silica, using a mixture of methanol and dichloromethane, in a ratio of 10:90 as mobile phase, thus providing the title compound in 73% yield. The pure title compound was characterized by its mass spectrum as follows: MS (m/z): 340 ([M+H]+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:6]([O:8][CH3:9])=[O:7].[H][H]>CO.C1COCC1.[C].[Pd]>[NH2:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N)c(OC)c1
Temperature: 25 °C
Yield: 104.1 %

Procedure:
10% palladium-carbon (containing 50% water, 15 g) was added to a solution of methyl 3-methoxy-4-nitrobenzoate (150 g) in methanol (600 mL) and THF (300 mL), and the reaction solution was stirred at a hydrogen pressure of 0.9 MPa at 50° C. to 64° C. for 6.5 hours. The reaction solution was left to cool to room temperature and then filtered through celite. The resulting filtrate was concentrated under reduced pressure to obtain 134 g of the title compound. The property values corresponded to the reported values (CAS #41608-64-4).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12]>>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: CC(C)CC(=O)Cl
Product: COc1ccc(C(=O)CC(C)C)cc1
Yield: 96 %

Procedure:
In the first and second steps, after anisole (2) is reacted with isovaleryl chloride to afford 1-(4-methoxy-phenyl)-3-methyl-butan-1-one (3), the compound (3) is reacted with bromine, sulfuryl chloride, N-bromosuccinimide or copper bromide, to prepare 2-bromo-1-(4-methoxy-phenyl)-3-methyl-butan-1-one (4). At this time, the reaction temperature is preferably maintained in the range from −10 to 40° C., and the reaction solvent is selected from polar solvents, including dichloromethane, acetonitrile, ethylacetate, lower alcohols such as methanol, ethanol or isopropanol, ethers such as tetrahydrofuran or 1,4-dioxane, dimethylformamide, or dimethylsulfoxide, and mixtures thereof. Among the materials reacting with the compound (3) in the second step, bromine is preferably used because it is inexpensive and increases the yield (yield: 96% or more).
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([CH2:7][C@@:8]23[CH2:15][C@H:14]([NH2:16])[CH2:13][N:12]2[C:11](=[O:17])[N:10]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:9]3=[O:26])=[CH:5][CH:4]=1)#[N:2].[C:29](OC(=O)C)(=[O:31])[CH3:30]>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C@@:8]23[CH2:15][C@H:14]([NH:16][C:29](=[O:31])[CH3:30])[CH2:13][N:12]2[C:11](=[O:17])[N:10]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:9]3=[O:26])=[CH:27][CH:28]=1)#[N:2]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc(C[C@@]23C[C@H](N)CN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Solvent: C1CCOC1
Product: CC(=O)N[C@@H]1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)[C@]2(Cc2ccc(C#N)cc2)C1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a solution of (5S,7S)-5-(4-cyanobenzyl)-3-(3,5-dichlorophenyl)-7-amino-1,3-diazabicyclo[3.3.0]octane-2,4-dione (78.5 mg) in THF (5 mL) was added acetic anhydride (1.0 mL). The reaction mixture was stirred for 2 hours at 45° C., and the mixture was concentrated and purified by preparative thin-layer chromatography (silica gel; CH2Cl2) to afford the titled compound (84 mg). MS (m/z) 478.8 (MNa+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.Cl.[NH:18]([C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[NH2:19]>C(O)CCC>[ClH:1].[N:21]1[CH:22]=[CH:23][CH:24]=[N:25][C:20]=1[N:18]1[C:12](=[O:14])[C:3]2=[CH:4][NH:5][C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[C:2]2=[N:19]1
Reactant: NNc1ncccn1
Reactant: CCOC(=O)c1cnc2ccncc2c1Cl
Agent: Cl
Solvent: CCCCO
Product: O=c1c2c[nH]c3ccncc3c-2nn1-c1ncccn1
Temperature: 25 °C

Procedure:
A solution of 1.75 g of ethyl 4-chloro-1,6-naphthyridine-3-carboxylate and 1.17 g of 2-hydrazinopyrimidine hydrochloride (prepared according to Yakugakuzasshi, 1953, 73, 598) in 60 ml of n-butanol is refluxed for 3 hours. The resultant slurry is cooled to room temperature and filtered. Collected solid is washed with ethanol, then with ether to yield 2-(2-pyrimidyl)-pyrazolo[4,3-c][1,6]naphthyridin-3(5H)-one hydrochloride, m.p. above 350°; IR (KBr) 782, 791, 820, 830, 871 cm-1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(S)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(F)cc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-fluoro-thiophenol.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[I:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[O:22])[CH3:21].[CH2:23]1[CH2:28][CH2:27][CH:26]([CH:29]=[O:30])[CH2:25][CH2:24]1>C1COCC1>[CH:26]1([CH:29]([OH:30])[CH2:21][C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[I:13])=[O:22])[CH2:27][CH2:28][CH2:23][CH2:24][CH2:25]1
Reactant: O=CC1CCCCC1
Reactant: CC(=O)c1ccccc1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(CC(O)C1CCCCC1)c1ccccc1I
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 77.4 %

Procedure:
To a solution of diisopropylamine (1.6 mL, 11.1 mmol) in THF (38 mL) at 0° C. was added n-BuLi (4.1 mL, 10.2 mmol) under an atmosphere of N2. After 30 min the solution was cooled to −30° C. and a solution of 1-(2-iodophenyl)ethanone (2.27 g, 9.23 mmol) in THF (6 mL) was added dropwise to the mixture and was stirred for 45 min at −30° C. The mixture was cooled to −78° C. and cyclohexylcarboxaldehyde (1.2 mL, 9.69 mmol) was added dropwise and the mixture was allowed to warm to −40° C. over 2 h. The reaction was quenched by the addition of saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography to afford the title compound as yellow oil (2.56 g, 78%). 1H NMR: 1.02-1.27 (m, 4H), 1.41-1.49 (m, 1H), 1.66-1.76 (m, 4H), 1.89 (d, 1H, J=12.4 Hz), 2.88 (d, 1H, J=3.2 Hz), 2.98 (dd, 1H, J=9.2 Hz, 17.2 Hz), 3.13 (dd, 1H, J=2.0 Hz, 17.2 Hz), 3.99-4.01 (m, 1H), 7.11-7.15 (m, 1H), 7.42 (d, 2H, J=4.4 Hz), 7.93 (d, 1H, J=8.0 Hz).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH2:2][OH:3].N1C=CN=C1.[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16]>CCOCC.CCCCCC>[C:15]([Si:19]([CH3:22])([CH3:21])[O:3][CH2:2][C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCCCOC(=O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCOC(=O)CO[Si](C)(C)C(C)(C)C

Procedure:
n-Butyl glycolate (231 g; 1.75 mol) and imidazole (345.1 g; 5.07 mol) are placed together at 0° C. The suspension obtained was treated portionwise with t-butyldimethylchlorosilane (303 g; 2.01 mol) during 1.5 hours. After 20 hours at room temperature the reaction mixture was diluted with ether/n-hexane 1:1 (1 l) and suction filtered. The crystals were rinsed thoroughly with ether/n-hexane hexane 1:1 (200 ml). The filtrate was washed in succession with water (2×700 ml) and saturated aqueous sodium chloride solution (500 ml), dried over magnesium sulphate and concentrated. The oil obtained was distilled over a Vigreux column (7.5 cm). Yield: 405 g (94%) as a colourless oil (b.p. 78° C./0.98 mmHg).
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.[CH:24]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][N:27]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.CO>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:24][C:26]3[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][N:27]=3)[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: COC(=O)c1ccc(C=O)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCCl
Product: O=C(O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.6 %

Procedure:
To a solution 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (130 mg, 0.398 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added methyl 6-formylnicotinate (86 mg, 0.518 mmol) and sodium triacetoxyborohydride (127 mg, 0.598 mmol), and the reaction mixture was stirred at room temperature for 18 h. The mixture was quenched with water (2 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated to give a crude product. The product was dissolved in methanol (2.000 mL) and sodium hydroxide (3M, 0.664 mL, 1.992 mmol) was added. The mixture was stirred at room temperature for 3 h and concentrated. The residue was treated with methanol and filtered. The filtrate was purified using reverse-phase HPLC under the acidic conditions to give 110 mg of product as pale yellow solid (HCl salt). MS: (M+H)+=366.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (m, 1H),1.54-1.73 (m, 3H), 1.98-2.12 (m, 3H), 2.59-2.72 (m, 1H), 2.94 (m, 4H), 3.45 (br. s., 2H), 4.54 (br. s., 2H), 7.16-7.25 (m, 3H), 7.27-7.35 (m, 2H), 7.81 (d, J=8.08 Hz, 1H), 8.38 (dd, J=8.08, 2.27 Hz, 1H), 9.12 (d, J=1.52 Hz, 1H), 9.78 (br. s., 2H), 10.72 (br. s., 1H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][N:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>CO>[S:4]1[C:5]2=[N:6][CH:7]=[CH:8][N:9]=[C:10]2[C:2]([NH:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:3]1
Reactant: Brc1nsc2nccnc12
Reactant: NCCCN
Solvent: CO
Product: NCCCNc1nsc2nccnc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-bromoisothiazolo[5,4-b]pyrazine in methanol (25 mL) was added 1,3-diaminopropane (6 mL). The reaction mixture was stirred at room temperature for 15 min, then heated to 50° C. After 1 h, the starting material was consumed as judged by LC-MS. The reaction mixture was concentrated under reduced pressure and then partitioned between ethyl acetate and brine. The aqueous layer was back-extracted twice with ethyl acetate and once with methylene chloride. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave N1-(isothiazolo[5,4-b]pyrazin-3-yl)propane-1,3-diamine (410 mg) as a yellow solid. 1H NMR (300 MHz, CDCl3-DMSO-d6): 8.62 (d, 1H), 8.54 (d, 1H), 2.66 (m, 4H), 2.49 (br s, 2H), 1.51 ppm (m, 2H). MW=209 confirmed by LC-MS, tr=2.51 min (Method Y) MH+=208-210.