Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[O:12])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>O>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:11]([C:4]1[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:2]([NH:1][C:24](=[O:26])[CH3:25])[N:3]=1)=[O:12]
Reactant: Nc1nc(C(=O)c2cccs2)c2sccc2n1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1nc(C(=O)c2cccs2)c2sccc2n1
Temperature: 25 °C
Yield: 61 %

Procedure:
A mixture of 2-aminothieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone (0.07 g, 0.27 mmol), anhydrous pyridine (3 mL) and acetyl chloride (0.15 g, 1.88 mmol) was refluxed for 24 h, cooled to room temperature, poured into water (30 mL) and extracted with EtOAc (2×30 mL). The organic phase was washed with 1-M HCl (2×25 mL) and saturated brine (25 mL), dried (MgSO4) and concentrated in vacuo to give a yellow solid which was purified by chromatography (SiO2; heptane-EtOAc (2:1)] to give the title compound (50 mg, 58%) as a yellow solid.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[N:13]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14]1.CI>C1COCC1>[CH3:1][C:15]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:16][CH2:17][CH2:18][N:13]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:14]1
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Temperature: -30 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a flame-dried round bottom flask under Argon atmosphere was added THF (100 mL), then it was cooled to −30° C. To this cold solvent were added n-butyllithium (40.1 ml, 64.1 mmol), and diisopropylamine (10.80 ml, 76 mmol) drop wise. The resultant solution was stirred at −25° C. for 1 hour. To the above solution 1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (15 g, 58.3 mmol) in THF (20 mL) was added drop wise at −78° C. (maintain temperature <−70° C.). After the addition, the reaction was stirred at −70° C. for 1 h, and then methyl iodide (4.74 mL, 76 mmol) was added drop wise. This reaction mixture was stirred at same temperature for 1 h, then slowly warmed to RT and stirred for 16 h. The reaction mixture was quenched with sat. aq. NH4Cl (50 mL), extracted with EtOAc (2×200 mL), the combined organics extracts was washed with sat. NH4Cl (100 mL), brine (50 mL), dried (Na2SO4) and concentrated to get crude compound. The crude residue was purified by ELSD ISCO on 120 g silica column, eluted the compound around 20% ethyl acetate in hexanes, the pure fractions were collected and concentrated to give desired product 1-tert-butyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate (15.14 g, 52.5 mmol, 90% yield) as a colorless oil. Anal. Calcd. for C14H25NO4 m/z 271.3, found: 172.2 (M-Boc+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 4.13 (q, J=7.0 Hz, 2 H), 3.82 (d, J=13.5 Hz, 1 H), 3.46-3.38 (m, 1 H), 3.32-3.19 (m, 1 H) 3.13 (d, J=13.2 Hz, 1 H) 2.07-1.97 (m, 1 H) 1.60-1.50 (m, 2 H) 1.48-1.40 (m, 10 H), 1.25 (t, J=7.15 Hz, 3 H), 1.15 (s, 3 H)
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[C:8]1[CH:9]=[C:10]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[H-].[Na+]>CN(C)C=O>[CH:1]1([C:12]2[CH:11]=[C:10]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:9]=[CH:8][C:13]=2[O:14][CH3:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)ncn2-c1ccc(OC)c(O)c1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)ncn2-c1ccc(OC)c(C2CCCC2)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of (800 mg, 5.3 mmoles) cyclopentyl bromide, (1.6 g, 5.3 mmoles) methyl 1-(3-hydroxy-4-methoxyphenyl)-1H-benzimidazole-5-carboxylate and 251 mg of 50% sodium hydride in 10 ml of dimethylformamide was stirred at 100° C. for 30 minutes. The reaction was cooled, poured onto H2O and extracted with ethyl acetate. The ethyl acetate layer was dried and evaporated to give 2 g of crude product. Purification on silica gel with CH2Cl2 gave 1.1 g of methyl 1-(3-cyclopentyl-4-methoxyphenyl)-1H-benzimidazole-5-carboxylate. M.P.: 129°-131°.
Reaction SMILES: CC(C)([O-])C.[Li+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:10]=1[C:25](=[O:27])[CH3:26].[C:28](=S)=[S:29].IC.[CH3:33][S:34]([CH3:36])=O>C(OCC)(=O)C.O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:10]=1[C:25](=[O:27])[CH:26]=[C:33]([S:29][CH3:28])[S:34][CH3:36]
Reactant: S=C=S
Reactant: COc1ccc(COc2cccc(OC)c2C(C)=O)cc1
Reactant: CS(C)=O
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(COc2cccc(OC)c2C(=O)C=C(SC)SC)cc1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a mixture of lithium tert-butoxide (602.4 g, 7.52 mol) in anhydrous DMSO (11.0 L) under a nitrogen atmosphere is added 1-(2-methoxy-6-(4-methoxybenzyloxy)phenyl)ethanone (1000.0 g, 3.49 mol). The resulting mixture is stirred 30 min and CS2 (259 mL, 4.296 mol) is slowly added over 1 to 1.5 h while maintaining the internal temperature below 30° C. After stirring for at least one hour at ambient temperature, iodomethane (1000 g, 7.045 mol) is added slowly while maintaining the internal temperature below 30° C. The resulting mixture is stirred at ambient temperature for 30 min to one hour. Reaction completion is confirmed by HPLC. The resulting reaction mixture is cooled, followed by extractive work up with water and ethyl acetate. The resulting organic portion is concentrated to provide a slurry which is filtered and washed with ethyl acetate (1 L), followed by methyl t-butyl ether (2×1 L). The isolated solid is dried at 40° C. in a vacuum oven to provide 1057 g (77%) of the title compound. mp 93-94° C.; ES/MS m/z 391.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:14](OC(C1C(N)SC2=CC=CC=12)=O)C.S(Cl)(Cl)=O>CO>[CH3:14][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: CCOC(=O)C1=C2C=CC=C2SC1N
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 15 h

Procedure:
5-Chloro-2-nitro-benzoic acid (compound A′) (5.0 g) was dissolved in methanol (150 ml). Thionyl chloride (9.5 ml) was added to the solution at 0° C., and the mixture was heated under reflux with stirring for 15 hr. After the completion of the reaction, distilled water was added thereto at 0° C., and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with distilled water and saturated brine, was dried over sodium sulfate, and was then concentrated to give 5-chloro-2-nitro-benzoic acid methyl ester as a useful intermediate (12.9 g, yield 92%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[C@@H:15]4[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]4[C@@H:13]([CH2:21][OH:22])[O:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:32][C@@H:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34]1>C(O)CCC>[C@@H:33]1([NH:32][C:2]2[C:3]3[CH:10]=[CH:9][N:8]([C@H:11]4[C@@H:15]5[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]5[C@@H:13]([CH2:21][OH:22])[O:12]4)[C:4]=3[N:5]=[CH:6][N:7]=2)[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34]1
Reactant: N[C@H]1CCc2ccccc21
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1ccc2c(Cl)ncnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1ccc2c(N[C@H]3CCc4ccccc43)ncnc21

Procedure:
A solution of [(3aR,4R,6R,6aR)-6-(4-Chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-methanol (574 mg, 1.76 mmol), diisopropylethylamine (1.2 mL, 7.04 mmol) and (S)-(+)-1-aminoindane (680 μL, 5.27 mmol) in n-butanol 3.3 mL) was divided into two portions and each portion was microwave irradiated at 190° C. for 900 s. The solvent was removed in vacuo and the combined crude portions were purified by silica gel chromatography (0 to 5% MeOH/CH2Cl2) to afford 460 mg (62% over two steps) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[C:13]=2[O:25][CH3:26])[CH:7]=[CH:6][C:5]=1[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[F:35].O.O.[OH-].[Li+]>CO.C1COCC1>[CH3:1][C:2]([CH3:37])([CH3:36])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:13]=2[O:25][CH3:26])[CH:7]=[CH:6][C:5]=1[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[F:35]
Reactant: CCOC(=O)CCc1ncnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(COc3ncnc(CCC(=O)O)c3OC)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.9 %

Procedure:
To a solution of ethyl 3-(6-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-methoxypyrimidin-4-yl)propanoate (1.13 g) in methanol (5.0 mL) and THF (10 mL) were added water (5.0 mL) and lithium hydroxide monohydrate (450 mg), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (330 mg) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[CH2:6][C:7]3([O:26][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:10][N:9](C(OC1C=CC=CC=1)=O)[CH2:8]3.[OH-].[K+].O>C(O)CC>[ClH:1].[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[CH2:6][C:7]3([O:26][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:10][NH:9][CH2:8]3
Reactant: O=C(Oc1ccccc1)N1Cc2ccccc2C2(Cc3ccc(Cl)cc3O2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCCO
Solvent: O
Product: Cl
Product: Clc1ccc2c(c1)OC1(CNCc3ccccc31)C2
Yield: 137.3 %

Procedure:
A mixture of 6-chloro-2'-phenoxycarbonylspiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (25.0 g), potassium hydroxide (25 g) and water (25 ml) in n-propanol (250 ml) is heated under reflux for four hours. Removal of the solvent under reduced pressure yields a solid which is stirred with water (500 ml) and extracted with ether. The combined ether extract is washed with 3 N hydrochloric acid and basified with saturated sodium carbonate solution. The material which separates is extracted with ether, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the solvent is removed to yield product as a solid (13.5 g, 78%). A 4.0 g portion of the solid is dissolved in ether and converted to the product hydrochloride salt (4.3 g). An analytical sample is twice recrystallized from ethyl acetate/methanol, mp 238°-239° (dec).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:16]=[C:11]3[C:10]([CH3:23])=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:23][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)[CH:16]=2)[NH:8][N:9]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(-c4cnn(C)c4)cnc32)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2ncc(-c3cnn(C)c3)cc12
Temperature: 50 °C

Procedure:
To a solution of 1-(4-methoxybenzyl)-3-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridine (107) (60 mg, 0.179 mmol) dissolved in chloroform (10 mL) was added trifluoroacetic acid (5 mL) and the reaction mixture was heated at 50° C. for 12 h. After completion of the reaction the solvents were removed and diluted with cold water, pH was adjusted to 8 and the aqueous phase extracted with chloroform two times. The organic layer was washed with brine solution and dried over sodium sulphate and the solvents were removed. The crude was passed through 100-200 mesh silica gel eluting the compound at 80% ethyl acetate in hexane as pale yellow solid 3-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridine 108 (30 mg).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[OH:9])=[N+:2]=[N-:3].N1C=CC=CC=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17].[N+](C1C=CC(S(O)(=O)=O)=CC=1)([O-])=O>C(Cl)Cl>[N:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[O:9][S:25]([C:22]1[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=1)(=[O:26])=[O:27])=[N+:2]=[N-:3]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: [N-]=[N+]=N[C@@H]1CCC[C@H]1O
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: [N-]=[N+]=N[C@@H]1CCC[C@H]1OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 84.2 %

Procedure:
A solution of (±)-trans-2-azido-cyclopentanol (1.27 g, 10.0 mmol) (Zhang, Z. da; Scheffold, R. Helv. Chim. Acta 1993, 76, 2602) in CH2Cl2 (14 mL) at 0° C. was treated successively with pyridine (0.88 mL, 10.9 mmol) and 4-nitro-benzenesulfonyl chloride (2.22 g, 10.0 mmol) and allowed to warm to room temperature slowly. The reaction was stirred for 4 d, during which additional pyridine (0.9 mL, 11 mmol) and 4-nitro-benzenesulfonic acid (2.2 g, 10 mmol) was added, and partitioned between CH2Cl2 and 1 N HCl. The aqueous phase was extracted with CH2Cl2 and the extracts were washed with saturated NaHCO3, dried and concentrated. Chromatography of the residue with 10:1–4:1 hexanes:EtOAc gave the product (2.63 g, 84%) as a yellow oil: 1H NMR δ 1.61–1.90 (m, 4H), 2.00–2.16 (m, 2H), 3.96 (m, 1H), 4.72 (m, 1H), 8.14 (m, 2H), 8.43 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:38]=[CH:37][C:14]([O:15][C:16]2[C:21]([F:22])=[C:20]([F:23])[C:19]([C:24]3[C:29]([F:30])=[C:28]([F:31])[C:27](F)=[C:26]([F:33])[C:25]=3[F:34])=[C:18]([F:35])[C:17]=2[F:36])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:39]([C:42]1[C:47](F)=[C:46]([F:49])[C:45]([OH:50])=[C:44]([F:51])[C:43]=1[F:52])([O-:41])=[O:40].C(=O)([O-])[O-:54].[K+].[K+].C(=O)([O-])O.[K+]>CS(C)=O>[N+:39]([C:42]1[C:43]([F:52])=[C:44]([F:51])[C:45]([O:50][C:27]2[C:28]([F:31])=[C:29]([F:30])[C:24]([C:19]3[C:20]([F:23])=[C:21]([F:22])[C:16]([O:15][C:14]4[CH:37]=[CH:38][C:11]([C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[O:10])=[CH:12][CH:13]=4)=[C:17]([F:36])[C:18]=3[F:35])=[C:25]([F:34])[C:26]=2[F:33])=[C:46]([F:49])[C:47]=1[OH:54])([O-:41])=[O:40]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1c(F)c(F)c(O)c(F)c1F
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(F)c(F)c3F)c(F)c2F)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(Oc4c(F)c(O)c([N+](=O)[O-])c(F)c4F)c(F)c3F)c(F)c2F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
50 g of 4-(4-benzyloxycarbonylphenoxy)nonafluoro-biphenyl prepared as described in Example 3 (0.092 mol) and 19.4 g of 4-nitrotetrafluorophenol prepared as described in Example 4 (0.092 mol) are dissolved in 400 ml of dimethyl sulfoxide. 25 g of potassium carbonate (0.184 mol) are added in portions to the solution. The mixture is then stirred at room temperature for 24 hours and then heated at 60° C. for 24 hours, and 10 g of potassium hydrogencarbonate (0.1 mol) are then added. The reaction solution is ten cooled to room temperature and filtered through a fluted filter. The crude product is washed by shaking with 300 ml of ethyl acetate and 700 ml of water, and the organic phase is washed three times with water and evaporated in a rotary evaporator until the reaction product precipitates out. The reaction product is then recrystallized from a mixture of ethyl acetate and n-hexane (volume ratio 1:1) and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 92%).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[CH2:6]([NH2:10])[CH2:7][CH2:8][CH3:9].[N+](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N-]>O1CCCC1>[CH2:6]([N:10]1[CH:1]([CH2:2][CH2:3][CH3:4])[CH:13]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:7][CH2:8][CH3:9]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCCCN
Reactant: CCCC=O
Solvent: C1CCOC1
Product: CCCCN1C(CCC)C1C(=O)OCC
Temperature: -5 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
A small amount of a molecular sieve was added to a mixture of 0.5 mmol of n-butyraldehyde, 0.5 mmol of butylamine, 1 mmol of ethyl diazoacetate, 0.025 mmol of di-l-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir2Cl2(cod)2], and 0.5 ml of tetrahydrofuran. The resulting mixture was stirred at −5° C. in an argon atmosphere for 3 hours to yield 1-butyl-2-ethoxycarbonyl-3-propylaziridine in a yield of 74%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C.CN(C)C1C=CN=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:10])[CH:5]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: Nc1nc(C(=O)O)cc(-c2ccco2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(C(=O)NCc2ccccc2)cc(-c2ccco2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 35.3 %

Procedure:
A solution of 2-amino-6-(2-furyl)pyrimidine-4-carboxylic acid (103 mg, 0.5 mmol) in DMF (2 mL) was treated with benzylamine (59 mg, 0.55 mmol), EDCl (104 mg, 0.54 mmol) and 4-dimethylaminopyridine (66 mg, 0.54 mmol), stirred at room temperature for 17 h, poured into water (25 mL) and extracted with EtOAc (2×25 mL). The combined organic phase was washed with water (25 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; isopropyl ether:EtOAc, (100:0-0:100)] to give the title compound (52 mg, 40%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].Cl.N([O-])=O.[Na+].[N-:19]=[N+:20]=[N-].[Na+]>O.ClCCl>[CH3:13][O:12][C:8]1[CH:7]=[C:5]([N:6]=[N+:19]=[N-:20])[CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(N)cc(OC)c1OC
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(N=[N+]=[N-])cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
3,4,5-Trimethoxyaniline (1.83 g; 10 mmol) is added to a 100 mL flask containing water (20 mL) and HCl (conc. aqueous solution, 5 mL). The solution is chilled to 0° C. and a solution of sodium nitrite (830 mg; 12 mmol) in water (5 mL) is added. The solution is stirred at 0° C. for 30 minutes, and then a solution of sodium azide (1.3 g; 20 mmol) in water (5 mL) is added. After another 30 minutes of stirring, dichloromethane is added (20 mL) and the organic phase was collected and filtered through a plug of silica, dried over magnesium sulfate and the solvent was evaporated to give approximately two grams of 3,4,5-trimethoxyphenyl azide.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([NH2:18])=[O:17])[C:3]1=[O:23].C(Cl)(=O)[C:25](Cl)=[O:26]>ClCCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([N:18]=[C:25]=[O:26])=[O:17])[C:3]1=[O:23]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc2c(cn1)cc(-c1cc(C(N)=O)ccc1C)c(=O)n2C
Solvent: ClCCCl
Product: Cc1cc2c(cn1)cc(-c1cc(C(=O)N=C=O)ccc1C)c(=O)n2C

Procedure:
3-(1,7-Dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylbenzamide 30 (310 mg, 1 mmol) is heated with oxalyl chloride (1 mL) in 1,2-dichloroethane (2 mL) at reflux for 2 h. Solvent is evaporated to give 31 as a white solid which is used without purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])=[C:5]([O:15][CH3:16])[CH:4]=1.[OH:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].[OH-].[K+]>CN(C)C=O.CO>[CH3:16][O:15][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])[CH2:2][O:17][N:18]1[C:22](=[O:23])[C:21]2[C:20](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]1=[O:28]
Reactant: CCC#CCOc1ccc(CCl)cc1OC
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CCC#CCOc1ccc(CON2C(=O)c3ccccc3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Chloromethyl-2-methoxy-1-pent-2-ynyloxy-benzene (28 g, 0.12 mol) and N-hydroxyphthalimide (19.5 g, 0.12 mol) are dissolved in 180 ml of N,N-dimethylformamide. The reaction mixture is heated to +70° C. and potassium hydroxide (24 ml of a 5 M solution in methanol, 0.12 mol) is added at this temperature. The reaction is stirred for 1 hour at +70° C., subsequently cooled to room temperature and poured on water. This mixture is stirred for one further hour and filtered. The resulting crystalls are washed with water and recrystallized from methanol/acetone (8:1) to yield 2-(3-methoxy-4-pent-2-ynyloxy-benzyloxy)-isoindole-1,3-dione as colourless crystalls.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([NH:20]/[C:21](/[NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[N:22]\[C:23](=[O:34])[C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[NH:17][N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:36]([NH:35]/[C:21](/[NH:20][C:18]1[NH:17][N:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH:19]=1)=[N:22]/[C:23](=[O:34])[C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: [H][H]
Reactant: CC(C)(C)N/C(=N/C(=O)c1ccc(C(F)(F)F)cc1)Nc1cc(-c2ccc(OCc3ccccc3)cc2)n[nH]1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)N/C(=N/C(=O)c1ccc(C(F)(F)F)cc1)Nc1cc(-c2ccc(O)cc2)n[nH]1
Yield: 68.1 %

Procedure:
(Z)—N-(((3-(4-(Benzyloxy)phenyl)-1H-pyrazol-5-yl)amino)(tert-butylamino)methylene)-4-(trifluoromethyl)benzamide (150 mg) was dissolved in methanol (10 mL) and the solution was degassed with nitrogen. To the solution was added 10% palladium on carbon (30 mg, 0.1 equiv). The mixture was subjected to hydrogen gas at 60 psi pressure in a Parr shaker. The reaction was checked periodically for completion. Upon completion, the reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo to provide the crude product, which was purified by silica chromatography (9:1 to 55:45 hexanes:EtOAc) to provide the title compound (85 mg, 68% yield).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]([S:23]([C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[O:34][CH3:35])(=[O:25])=[O:24])[C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[N:13]=1)(C)(C)C>C(Cl)Cl.Cl.O1CCOCC1>[CH3:35][O:34][C:27]1[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:26]=1[S:23]([N:8]([CH2:7][C:6]([OH:36])=[O:5])[C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[N:13]=1)(=[O:24])=[O:25]
Reactant: COc1ccc(OC)c(S(=O)(=O)N(CC(=O)OC(C)(C)C)c2nc(-c3ccc(C(C)C)cc3)cs2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(OC)c(S(=O)(=O)N(CC(=O)O)c2nc(-c3ccc(C(C)C)cc3)cs2)c1

Procedure:
{(2,5-Dimethoxy-benzenesulfonyl)-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-amino}-acetic acid was prepared following general procedure G1 using a solution of {(2,5-dimethoxy-benzenesulfonyl)-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-amino}-acetic acid tert-butyl ester (96.8 mg, 0.182 mmol) in DCM (3 mL) and 4 N HCl solution in dioxane (2.5 mL) followed by trituration in hexanes to give {(2,5-Dimethoxy-benzenesulfonyl)-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-amino}-acetic acid. 1H-NMR (400 MHz, CDCl3): 7.64 (d, 2H), 7.55 (d, 1H), 7.09-7.26 (m, 3H), 6.87 (d, 1H), 4.85 (s, 2H), 3.82 (s, 3H), 3.66 (s, 3H), 2.92 (sept, 1H), 1.25 (d, 6H); LCMS m/z: 477 (M+1)+.