Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:8][CH2:9][C:10]([OH:12])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[NH:22][CH2:21][CH2:20][CH2:19]2.CCN=C=NCCCN(C)C>C1COCC1.CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([S:8][CH2:9][C:10]([N:22]2[C:23]3[C:18](=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:13])[CH2:19][CH2:20][CH2:21]2)=[O:12])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CSc1ncccc1Cl
Reactant: Cc1cccc2c1NCCC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cccc2c1N(C(=O)CSc1ncccc1Cl)CCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 33 %

Procedure:
To a solution of (3-chloro-pyridin-2-ylsulfanyl)-acetic acid (19, 0.27 g, 1.3 mmol) in 12 mL of dry THF at 0° C. was added neat 8-methyl-1,2,3,4-tetrahydroquinolin (0.20 g, 1.3 mmol) followed by addition of DMAP (0.19 g, 1.6 mmol) and EDCI (0.31 g, 1.6 mmol). The reaction was stirred for 20 h at room temperature under N2. The reaction mixture was diluted with 50 mL of CH2Cl2, washed with H2O, 10% citric acid, NaHCO3 (saturated), brine, dried over Na2SO4 and concentrated. The crude was purified by column chromatography (hexanes/EtOAc) to give 0.15 g (33% yield) of the target 20 as an off-white solid. MS (APCI) m/z: 333.1 (100%, [M+H]+, 186.0 (35%, [M−147+H]+; HPLC purity: 100%; Anal. Calcd. for C17H17ClN2OS: C, 61.34; H, 5.15; N, 8.42; Cl, 10.65; S, 9.63. Found: C, 61.04; H, 5.28; N, 8.36; Cl. 10.78; S, 9.68.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11]([O:13][C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=O)[CH:10]=1.[NH2:16][CH:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1>C(O)CCC>[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[CH:17]([N:16]1[C:11](=[O:13])[C:9]3[CH:10]=[CH:1][CH:2]=[C:3]4[C:8]=3[C:7](=[CH:6][CH:5]=[CH:4]4)[C:14]1=[O:15])[CH2:18]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Solvent: CCCCO
Product: O=C1c2cccc3cccc(c23)C(=O)N1C1CN2CCC1CC2
Yield: 83.7 %

Procedure:
A solution of 1,8-naphthalic anhydride (1.9 g, 9.6 mmol) and (RS)-3-amino-1-azabicyclo[2.2.2]octane (1.2 g, 9.5 mmol) in n-butanol (100 mL) was stirred for 3 hours at reflux temperature and the solution concentrated to dryness. Purification of the remaining solid by column chromatography (silica-gel; 5-10% gradient methanol in CH2Cl2 and approximately 1% aqueous NH4OH) gave (RS)-2-(1-azabicyclo[2.2.2]oct-3-yl)-2,3-dihydro-1H-benz[de]isoquinoline-1,3-dione (2.45 g, 7.95 mmol), m.p. 206°-207° C.
Reaction SMILES: [OH:1][C@H:2]([C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH:3]=[CH2:4].C(N(C(C)C)CC)(C)C.[CH3:30][O:31][CH2:32][CH2:33][O:34][CH2:35]Cl>C(Cl)Cl>[CH3:30][O:31][CH2:32][CH2:33][O:34][CH2:35][O:1][C@H:2]([C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[CH:3]=[CH2:4]
Reactant: C=C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C[C@H](OCOCCOC)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.1 %

Procedure:
To the resultant compound from Example 6 (2.51 g, 8.84 mmol) in methylene chloride (20 ml) was added diisopropylethylamine (4.60 ml, 26.4 mmol) and methoxyethoxychloromethane (3.00 ml, 26.3 mmol). After stirring at room temperature for 24 h the mixture was concentrated, diluted with ethyl acetate, washed with 0.5M H3PO4, saturated NaHCO3 solution, then brine, dried over Na2SO4, and evaporated. Chromatography on silica gel with ethyl acetate/ hexane mixtures afforded 2.63 g (80%) of the desired product as an oil. EI-MS: M+ =371.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[C:16](=[S:19])[NH:17][N:18]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5].S(OC)(O[CH3:24])(=O)=O.[OH-].[Na+]>O>[CH3:24][S:19][C:16]1[N:8]2[C:9](=[O:15])[C:10]3[NH:11][CH:12]=[N:13][C:14]=3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]2=[N:18][N:17]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(=S)[nH]nc12
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(SC)nnc12
Yield: 85.1 %

Procedure:
A solution of 9-pentyl-3-thioxo-2,3,6,9-tetrahydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (1.90 g, 6.83 mmol), dimethyl sulfate (1.03 g, 8.19 mmol) and 1 M of sodium hydroxide in water (25 ml) was stirred at room temperature for 1 hour. The mixture was nutralized to pH=7. The solid formed was filtered and dried to provide the desired product (1.70 g, 85.2%). 1HNMR (300 MHz, CD3OD): δ 4.29 (t, J=7.2 Hz, 2H), 2.65 (s, 3H), 1.89 (m, 2H), 1.40 (m, 4H), 0.92 (m, 3H). LCMS calculated for: C12H17N6OS (M+H) 294.1; found: 294.1.
Reaction SMILES: [CH2:1]([S:11]([OH:14])(=[O:13])=[O:12])[CH2:2][S:3][S:4][CH2:5][CH2:6][S:7]([OH:10])(=[O:9])=[O:8].[OH-].[NH4+:16].CC(C)=O>O>[CH2:1]([S:11]([O-:14])(=[O:13])=[O:12])[CH2:2][S:3][S:4][CH2:5][CH2:6][S:7]([O-:10])(=[O:8])=[O:9].[NH4+:16].[NH4+:16]
Reactant: O=S(=O)(O)CCSSCCS(=O)(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=S(=O)([O-])CCSSCCS(=O)(=O)[O-]
Yield: 82 %

Procedure:
A solution of 2,2′-dithiobis ethane sulfonic acid (2.5 g, containing 9% water, 8.1 mmol) in water (1.0 mL) was titrated with ammonium hydroxide aqueous solution (28-30% concentration, Aldrich) until the pH of the reaction solution was adjusted to 7.0. Overall 2.6 mL of ammonium hydroxide was used. Acetone (200 mL) was added to the reaction solution to precipitate the product. The resulting white solid was isolated by filtration and dried under high vacuum to give 2.10 g of product (82% yield). The purity of the product was 98.2% from HPLC analysis.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: COC(=O)c1ccc(C)c(I)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(C#C[Si](C)(C)C)c1
Temperature: 50 °C

Procedure:
A mixture of methyl 3-iodo-4-methylbenzoate (2.0 g, 7 mmol), trimethylsilylacetylene (1.2 ml, 8 mmol), Pd(PPh3)4 (0.42 g, 0.3 mmol), CuI (0.137 g, 0.7 mmol) and diisopropylethylamine (2.5 ml, 11.4 mmol) in THF (20 ml) was heated at 50° C. for 12 hrs under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and filtered through a Celite® bed. The clear filtrate was concentrated and the residue purified by flash chromatography on silica gel (elution with 2% ethyl acetate in n-hexane) to provide methyl 4-methyl-3-[(trimethylsilyl)ethynyl]benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[C:12]=2[N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[C:23](Cl)(=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(N(CC)CC)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[C:12]=2[N:13]2[CH2:18][CH2:17][N:16]([C:23](=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:15][CH2:14]2)=[CH:6][CH:7]=1
Reactant: CCCCCCCCC(=O)Cl
Reactant: Clc1ccc(-c2oc3ccccc3c2N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCC(=O)N1CCN(c2c(-c3ccc(Cl)cc3)oc3ccccc23)CC1
Reaction time: 0.5 h

Procedure:
To the solution of 56 g of 1-(2-p-chlorophenyl-3-benzofuryl)piperazine in 25.2 g of triethylamine and 500 ml of methylene chloride, 31.7 g of pelargonic acid chloride in 300 ml of methylene chloride are added while stirring at 0° for 1/2 hour and stirring is continued for 15 hours. The mixture is washed successively with 1 N-hydrochloric acid, 2 N-aqueous sodium hydroxide and saturated aqueous sodium chloride, dried and evaporated to yield the 1-(2-p-chlorophenyl-3-benzofuryl)-4-pelargonylpiperazine as an oil showing in the 1R-spectrum characteristic bands at 1640 and 812 cm-1.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=O)[N:9]=1)(=[O:3])[CH3:2].[CH:12]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13]>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=[CH:14][CH:12]=[O:13])[N:9]=1)(=[O:3])[CH3:2]
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Nc1nc(C=O)cs1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc(C=CC=O)cs1
Yield: 64.8 %

Procedure:
A mixtuxe of 2-acetylamino-4-formylthiazole (6.05 g), formylmethylidenetriphenylphosphorane (10.82 g) and chloroform (360 ml) was refluxed for 4 hours. The precipitates were collected by filtration and washed with chloroform to give 2-acetylamino-4-(2-formylvinyl)thiazole (4.52 g).
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][NH2:17])=[N:14][CH:15]=2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].O=[C:19]1[CH2:23][S:22][CH2:21][CH:20]1[C:24](OC)=[O:25]>>[C:1]([C:5]1[N:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:24](=[O:25])[C:20]4[CH2:21][S:22][CH2:23][C:19]=4[NH:17]3)=[N:14][CH:15]=2)[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CSCC1=O
Reactant: CC(C)(C)c1noc(-c2ccc(NN)nc2)n1
Product: CC(C)(C)c1noc(-c2ccc(-n3[nH]c4c(c3=O)CSC4)nc2)n1
Yield: 36.4 %

Procedure:
According to the process described in Example 1, starting with 0.6 g of 5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-2-hydrazinylpyridine and 0.41 g of methyl 4-oxotetrahydrothiophene-3-carboxylate, 0.32 g of 2-[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)pyridin-2-yl]-1,2,4,6-tetrahydro-3H-thieno[3,4-c]pyrazol-3-one is obtained in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[S:5][C:6]=1[CH2:7][CH2:8][O:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH2:19][CH2:20][CH3:21])=[CH:15][NH:16]2)=[CH:12][CH:11]=1.Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].[H-].[Na+]>>[C:37]([O:36][C:34](=[O:35])[CH2:33][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([O:9][CH2:8][CH2:7][C:6]3[S:5][C:4]([C:22]4[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=4)=[N:3][C:2]=3[CH3:1])[CH:18]=2)[C:14]([CH2:19][CH2:20][CH3:21])=[CH:15]1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CCCc1c[nH]c2cc(OCCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCCc1cn(CC(=O)OC(C)(C)C)c2cc(OCCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc12

Procedure:
In analogy to the procedure described in example 3 a], 6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-3-propyl-1H-indole was reacted with tert-butyl bromoacetate in the presence of sodium hydride to obtain (6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-3-propyl-indol-1-yl)-acetic acid tert-butyl ester as colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:28])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][NH:2][C:3](=[O:28])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:16][CH:15]=1)[NH2:5]
Reactant: CNC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
N-Boc-O-benzyl tyrosine methylamide (5.29 g, 13.8 mmol) was taken up in CH2Cl2 (100 ml). To the solution at 0° C. TFA (10 ml) was added dropwise and the solution allowed to warm to ambient temperature. After 4 hours the solvent and TFA were removed under vacuum. Any remaining TFA was quenched with saturated NaHCO3 solution (100 ml). The reaction mixture was extracted using CH2Cl2 (100 ml) and washed with saturated NaHCO3 solution (100 ml) and brine (100 ml). The CH2Cl2 layer was dried over Na2SO4 and the solvent was removed under vacuum to give a white solid, which was recrystallised from ethyl acetate/hexane to yield the title compound as a white crystalline solid (3.35 g, 85.4%).
Reaction SMILES: [N:1]1(CCOC2C=CC(NC(N)=O)=CC=2)CCCC1.[N:19]([C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1)=[C:20]=[S:21]>C(Cl)Cl.CO>[CH3:34][N:31]1[CH2:30][CH2:29][N:28]([C:25]2[CH:24]=[CH:23][C:22]([NH:19][C:20]([NH2:1])=[S:21])=[CH:27][CH:26]=2)[CH2:33][CH2:32]1
Reactant: CN1CCN(c2ccc(N=C=S)cc2)CC1
Reactant: NC(=O)Nc1ccc(OCCN2CCCC2)cc1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(c2ccc(NC(N)=S)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The title compound is prepared as described in Example 1 for [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-urea but using 1-(4-isothiocyanato-phenyl)-4-methyl-piperazine and stirring the reaction mixture at RT for 17 h. Title compound: ES-MS: 251.0 [M+H]+; major peak at tR=3.56 min (System 1); Rf=0.27 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[C:9](=[CH:12]N3CCOCC3)[CH2:8][CH2:7][C:5]=2[N:6]=1.[N+]([O-])(O)=O.[N:23]1([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[NH:37])=[CH:31][CH:30]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[OH-].[Na+]>COCCO>[CH3:1][C:2]1[S:3][C:4]2[C:10]3[N:38]=[C:36]([NH:35][C:32]4[CH:31]=[CH:30][C:29]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[CH:34][CH:33]=4)[N:37]=[CH:12][C:9]=3[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: Cc1nc2c(s1)C(=O)C(=CN1CCOCC1)CC2
Reactant: N=C(N)Nc1ccc(N2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O=[N+]([O-])O
Product: Cc1nc2c(s1)-c1nc(Nc3ccc(N4CCOCC4)cc3)ncc1CC2
Yield: 2.1 %

Procedure:
A mixture of 2-methyl-6-morpholin-4-ylmethylene-5,6-dihydro-4H-benzothiazol-7-one (200 mg, 7.6 mmol), N-(4-morpholin-4-yl-phenyl)-guanidine nitrate (215 mg, 7.6 mmol), NaOH (30 mg, 7.6 mmol), and 2-methoxyethanol (2 mL) was heated under reflux for 20 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (5% MeOH:CH2Cl2), followed by crystallisation from EtOAc gave the pure title product as dark orange crystals (60 mg, 21%): mp 236-237° C. Anal. RP-HPLC: tR 13.4 min (0-60% MeCN, purity 100%). 1H-NMR (DMSO-d6): δ 9.26 (s, 1H, NH), 8.20 (s, 1H, Py-H), 7.58 (d, 2H, J 9.2, Ph-H), 6.84 (d, 2H, J 9.2, Ph-H), 3.70 (t, 4H, J 4.8, 2×CH2), 2.99 (t, 4H, J 4.8, 2×CH2), 2.90 (m, 4H, CH2—CH2), 2.66 (s, 3H, CH3).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:22]([CH:24]1[O:26][CH2:25]1)Br>CC(CC)=O>[O:26]1[CH2:25][CH:24]1[CH2:22][O:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5]
Reactant: BrCC1CO1
Reactant: COC(=O)CCC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)CCC(=O)c1ccccc1OCC1CO1
Yield: 104.7 %

Procedure:
A well stirred mixture of methyl 3-(2-hydroxybenzoyl)-propionate (63.3 g, 0.3 mole), potassium carbonate (48.4 g, 0.35 mole). epibromohydrin (117 ml, 1.4 mole), and dry ethyl methyl ketone (2000 ml) was heated under reflux for 28 hours. Evaporation of the filtered solution under reduced pressure gave methyl 3-[2-(2,3-epoxypropoxy)benzoyl]propionate (83 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH:19]([CH3:21])[CH3:20])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:22](N=C(N(C)C)N(C)C)([CH3:25])([CH3:24])[CH3:23].BrCC(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:23][CH:22]([CH3:25])[CH3:24])[C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH:19]([CH3:21])[CH3:20])=[CH:14][N:13]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Reactant: Cc1cc(C(C)C)cnc1NS(=O)(=O)c1ccc(F)cc1
Solvent: CC#N
Solvent: CC(C)CBr
Product: Cc1cc(C(C)C)cnc1N(CC(C)C)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
4-fluoro-N-(5-isopropyl-3-methylpyridin-2-yl)benzenesulfonamide (127 mg, 0.41 mmol) was dissolved in acetonitrile (3 mL) and to this solution was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.09 mL, 0.41 mmol). The mixture was allowed to stir at room temperature for 30 minutes, 1-bromo-2-methylpropane (0.09 mL, 0.83 mmol) was then added to the mixture and the reaction vessel sealed and heated by microwaves to 150° C. for 1 hour. The reaction mixture was concentrated in vacuo and the crude product extracted to the organic phase of an aqueous workup between ethyl acetate and water. The organic phase was then passed through a hydrophobic frit, concentrated in vacuo and purified by mass directed autoprep (formic acid modifier) to give the title compound (73 mg). LCMS (2 min, formic) Rt 1.44 min, m/z (ES+) 365 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]#[C:19][CH2:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1)#[CH:2].[CH2:28]([NH:30][CH2:31][CH2:32][OH:33])[CH3:29]>>[CH2:28]([N:30]([CH2:22][CH2:21][CH2:20][C:19]#[C:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[CH:2])=[CH:4][CH:5]=1)[CH:10]=[CH:11]2)[CH2:31][CH2:32][OH:33])[CH3:29]
Reactant: CCNCCO
Reactant: C#Cc1ccc(-n2ccc3cc(C#CCCCOS(C)(=O)=O)ccc32)cc1
Product: C#Cc1ccc(-n2ccc3cc(C#CCCCN(CC)CCO)ccc32)cc1

Procedure:
In analogy to example 5.5, Methanesulfonic acid 5-[1-(4-ethynyl-phenyl)-1H -indol-5-yl]-pent-4-ynyl ester and 2-ethylaminoethanol were converted to yield 2-(Ethyl-{5-[1-(4-ethynyl-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-amino)-ethanol as light yellow viscous oil, MS: 371 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:13]Br)=[C:4]([CH2:11]Br)[C:5]([F:10])=[C:6]([F:9])[C:7]=1[F:8].[NH2:15][C@H:16]([C:20]([OH:22])=[O:21])[CH:17]([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[OH-].[K+]>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]2[C:3]=1[CH2:13][N:15]([CH:16]([CH:17]([CH3:19])[CH3:18])[C:20]([OH:22])=[O:21])[CH2:11]2
Reactant: Fc1c(F)c(F)c(CBr)c(CBr)c1F
Reactant: CC(C)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)C(C(=O)O)N1Cc2c(F)c(F)c(F)c(F)c2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3,4,5,6-tetrafluoro-1,2-bis(bromomethyl)benzene (3 g, 9 mmol), valine (1 g, 9 mmol), potassium carbonate (2.8 g) and 25 ml THF/HMPT (1:1) is stirred for about 24 hours at RT (the reaction is followed by TLC). The reaction mixture is then diluted with 100 ml aqueous 10% KOH and extracted three times with ether. The aqueous phase is acidified to about pH 3 with aqueous HCl and extracted thoroughly with ether. The organic layer is washed with water, dried and solvent removed under vacuum to give 2-(4,5,6,7-tetrafluoro-2-isoindolinyl)-3-methylbutanoic acid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.OS(O)(=O)=O.[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1>O1CCOCC1>[Cl:2][C:3]1[C:4]2[NH:9][C:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][C:19]=3[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: NNc1ccccc1Cl
Reactant: CN1CCC(=O)CC1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CN1CCc2[nH]c3c(Cl)cccc3c2C1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 30.9 %

Procedure:
To a suspension of 2-chlorophenyl hydrazine hydrochloride (19.7 g, 0.110 mol) in dioxane (190 mL) at RT was added conc. H2SO4 (8 mL, 0.150 mol) dropwise and the reaction mixture was stirred for 10 min. To this was added N-methyl-4-piperidone (17.53 g, 0.154 mol) and the reaction mixture was stirred at RT for 20 min, then heated at 80° C. for 4 h. The reaction was monitored by TLC. The solvent was evaporated and pH adjusted to pH 8-9 with saturated sodium bicarbonate solution. The product was extracted with EtOAc (3×300 mL). The combined organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by recrystallization (Ether/Hexane). The filtered solid was dried in vacuo to obtain 7.5 g of product as a brown solid. 1H NMR (CDCl3, freebase) d (ppm): 8.10 (bs, 1H), 7.30 (d, 1H), 7.10 (d, 1H), 7.0 (t, 1H), 3.62 (s, 2H), 2.90 (m, 2H), 2.82 (m, 2H), 2.38 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH2:12][CH2:13][NH:14][CH2:15][C:10]2=[N:9][N:8]=1.C(N(CC)C(C)C)(C)C.[CH3:25][Si:26]([CH3:41])([CH3:40])[CH2:27][CH2:28][O:29][C:30](ON1C(=O)CCC1=O)=[O:31]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH2:12][CH2:13][N:14]([C:30]([O:29][CH2:28][CH2:27][Si:26]([CH3:41])([CH3:40])[CH3:25])=[O:31])[CH2:15][C:10]2=[N:9][N:8]=1
Reactant: c1cnc(-c2nnc3n2CCNC3)cn1
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOC(=O)N1CCn2c(nnc2-c2cnccn2)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
To a solution of 3-(pyrazin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (1.0 g, 5.0 mmol) and N,N-diisopropylethylamine (1.7 mL, 9.9 mmol) in DMF (15 mL) was added 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione (1.5 g, 5.9 mmol). Stirred for 18 h and poured into ice cold brine (150 mL). Precipitate filtered and washed successively with water and ether to afford the desired product as a white solid (1.5 g, 89%). MS (ESI): mass calcd. for C15H22N6O2Si, 346.2; m/z found, 347.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 9.50 (d, J=1.4 Hz, 1H), 8.56 (d, J=2.5 Hz, 1H), 8.52-8.48 (m, 1H), 4.91 (s, 2H), 4.60-4.45 (m, 2H), 4.25-4.14 (m, 2H), 3.87 (t, J=5.3 Hz, 2H), 1.07-0.92 (m, 2H), 0.01-0.04 (m, 9H).
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[C:4](F)[C:3]=1[F:14].[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1(=O)OCCC1>[CH2:15]([O:22][C:4]1[C:5]([F:12])=[C:6]([F:11])[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[C:3]=1[F:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1c(F)c(F)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C1CCCO1
Product: O=[N+]([O-])c1c(F)c(F)c(OCc2ccccc2)c(F)c1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
21.3 g of pentafluoronitrobenzene (0.1 mol) and 12 g of benzyl alcohol (0.11 mol, i.e. a 10% excess) are dissolved in 200 ml of dry γ-butyrolactone in a three-neck flask fitted with stirrer. 30 g of potassium carbonate (0.22 mol) are then added in portions, and the mixture is stirred at room temperature for 24 hours. The reaction solution is then filtered via a fluted filter, and the crude product is extracted by shaking with 200 ml of ethyl acetate and 300 ml of water. The organic phase is washed three times with water, dried over sodium sulfate and evaporated to half in a rotary evaporator. The reaction product crystallizes from the initially viscous solution. The precipitated reaction product is then recrystallized from a mixture of methylene chloride and petrol ether (volume ratio 1:1) and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet.