Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([OH:13])=O)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][N:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>ClCCl.CN(C=O)C>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:11]([C:8]3[S:7][C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=4[CH:9]=3)=[O:13])=[CH:35][N:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C(O)c1cc2c(Cl)cccc2s1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3cc4c(Cl)cccc4s3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 4-chloro-benzo[b]thiophene-2-carboxylic acid (98 mg, 0.462 mmol), CH2Cl2 (5 mL), and a catalytic amount of DMF was stirred under Ar, and oxalyl chloride (2M in dichloromethane, 600 μL, 1.20 mmol) was dripped into the mixture over 5 min. The mixture was stirred at room temperature and after 1.0 hr the reaction was concentrated to dryness. Benzene was added and the solution was evaporated to dryness again. The white-yellow solid was re-dissolved in 5 mL of CH2Cl2 and dripped, under Ar, into a solution of 4-(5-amino-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (134 mg, 0.462 mmol), and triethylamine (102 μL, 1.0 mmol) in 5 mL of dichloromethane. The reaction was stirred at room temperature for 0.5 hr and then concentrated and the residue was taken up in 50 mL of EtOAc and washed with 50 mL of saturated ammonium chloride, brine and dried over anhydrous sodium sulfate. The EtOAc solvent was removed and the product was triturated with diethyl ether and hexanes (1:1 ratio), followed by filtration, to afford the product, 4-{5-[(4-chloro-benzo[b]thiophene-2-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester, as a pale green solid (80 mg, 38% yield). LCMS for C23H25ClN4O3S calcd. (m/e) 472, observed 471 (M−H).
Reaction SMILES: [CH:1]([Li])([CH2:3][CH3:4])[CH3:2].[F:6][C:7]1[C:12](F)=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:8]=1[F:17].C(=O)=O.CC(C)=O>C1CCCCC1>[CH:1]([C:12]1[C:11]([F:14])=[C:10]([F:15])[C:9]([F:16])=[C:8]([F:17])[C:7]=1[F:6])([CH2:3][CH3:4])[CH3:2]
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Reactant: [Li]C(C)CC
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCCCC1
Product: CCC(C)c1c(F)c(F)c(F)c(F)c1F

Procedure:
A solution of sec-butyl lithium (350 ml; 12% in cyclohexane) was added over a period of 1 hour to a stirred mixture of hexafluorobenzene (80 g) in cyclohexane (750 ml) at a temperature of 0° C. On warming the reaction above 0° C. a violently exothermic reaction took place which was brought under control by external cooling (Cardice-acetone). The reaction mixture was subsequently brought to room temperature (no further reaction occurred) and was quenched with water (600 ml). The organic layer was separated, washed with dilute hydrochloric acid (2N; 2×200 ml) and water (2×200 ml) and dried over anhydrous magnesium sulphate and distilled through a 15 cm vigreux column. The fraction distilling at 160°-170° C. was collected to give sec-butylpentafluorobenzene (50.3 g), b.p. 162°-164° C. (760 mm), in the form of a colourless liquid. Hexafluorobenzene is a known compound and is readily available.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[CH2:12]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]>CCCCCC>[CH2:12]([N:16]([CH2:17][CH2:18][CH2:19][CH3:20])[C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[O:11])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNCCCC
Reactant: Cc1ccc(N=C=O)c(C)c1
Solvent: CCCCCC
Product: CCCCN(CCCC)C(=O)Nc1ccc(C)cc1C

Procedure:
A solution of 4.89 g. of 2,4-dimethylphenylisocyanate in 100 ml. of hexane is added to a solution of 3.48 g. of di(n-butyl)amine in 150 ml. of hexane and the solution is stirred at room temperature for 2 hours and then evaporated. The residual solid is recrystallized from pentane to yield 1,1-di-(n-butyl)-3-(2,4-dimethylphenyl)urea, m.p. 48°-50° C.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7](Br)=[CH:8][S:9][C:4]2=[CH:3][CH:2]=1.[Li]CCCC.[C:16](=[O:18])=[O:17]>CCOCC>[S:9]1[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: Brc1csc2ccccc12
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(O)c1csc2ccccc12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
3-bromothianaphthene (1.63 g, 7.65 mmol) was dissolved in anhydrous ether (30 ml) and n-BuLi (2.5 M, 3.5 ml, 8.65 mmol) was added to the solution at −78° C. The mixture was stirred at −78° C. for 10 min, and then the reaction solution was slowly added to an excessive amount of dry ice dissolved in anhydrous ether (140) under nitrogen conditions. The mixture was heated to room temperature for 1 hour, and then stirred at room temperature for another 2 hours. After the reaction was completed, the product was washed, filtered, and dried to obtain benzo[b]thiophene-3-carboxylic acid (805 mg, 4.51 mmol).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:22][NH2:23])=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[CH:24](O)=O>O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:5]2[N:4]([CH:24]=[N:23][N:22]=2)[N:3]=1
Reactant: O=CO
Reactant: NNc1nnc(Cl)c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Solvent: O
Product: Clc1ccc(-c2c(Cl)nn3cnnc3c2-c2ccc(Cl)cc2)cc1
Temperature: 120 °C
Yield: 91 %

Procedure:
To a round bottom flask was added 3-chloro-4,5-bis(4-chlorophenyl)-6-hydrazinylpyridazine (3.0 gm, 8.2 mmol) and formic acid (15 ml). The reaction was heated at 120° C. for 2 hrs. The reaction mixture was cooled to rt, poured into water (100 ml) and solid precipitated. The solid was collected by filtration to give product 6-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine as a grey solid (2.8 gm, 91% yield). LCMS (M+H)=376.9; 1HNMR (CDCl3, 400 Hz): 9.16 (1H, s), 7.38-7.40 (4H, m), 7.37 (2H, d), 7.15 (2H, d).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[C:11]([OH:22])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[CH3:34][C:35]1([C:40](Cl)=[O:41])[CH2:38][CH:37]([CH3:39])[CH2:36]1>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[CH2:17][CH:18]([CH3:19])[CH3:20])=[C:11]([O:22][C:40]([C:35]2([CH3:34])[CH2:38][CH:37]([CH3:39])[CH2:36]2)=[O:41])[CH:10]=1)=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)CC(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1O
Reactant: CC1CC(C)(C(=O)Cl)C1
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CC(C)CC(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1OC(=O)C1(C)CC(C)C1

Procedure:
Following a procedure similar to that described in Example 13A above, when 3-hydroxy-4-(isovaleryloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with 1,3-dimethylcyclobutanecarbonyl chloride there is obtained 3-(1,3-dimethylcyclobutanecarbonyloxy)-4-(isovaleryloxy)-phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloric salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 13B, there is obtained 3-(1,3-dimethylcyclobutanecarbonyloxy)-4-(isovaleryloxy)-alpha-(tert-butylaminomethyl)-benzyl alcohol hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:5][S:4][CH:3]=1.O=P(Cl)(Cl)Cl.CN([CH:21]=[O:22])C>>[CH:21]([C:3]1[S:4][CH:5]=[C:6]([CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[C:2]=1[CH3:1])=[O:22]
Reactant: Cc1cscc1C1CCCCC1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C2CCCCC2)csc1C=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of 3-methyl-4-cyclohexylthiophene (3 g, 17 mmol) in DMF (10 mL) was added 10 mL of a solution prepared from DMF and POCl3 (4:1, v:v). The temperature was maintained at about 0° C. during the addition. The reaction mixture was then stirred overnight at room temperature, and poured into ice water. After neutralization with 25% NaOH solution to pH˜8, the product was extracted with dichloromethane. The solvent was evaporated to afford the crude product 2-formyl-3-methyl-4-cyclohexylthiophene as a solid which was purified by column chromatography (dichloromethane-petroleum ether (1:3)) (2.85 g, yield: 83%). 1H NMR (CDCl3) δ 10.07 (s, 1, CHO), 7.28 (s, 1, thienyl-H), 2.58 (m,1,cyclohexyl methane), 2.53 (s, 3,CH3),1.89 and 1.37 m, 10, cyclohexyl).
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C:9]1([CH3:16])[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CN=C1.O>CN(C=O)C>[CH3:1][C:2]([Si:5]([CH3:7])([CH3:6])[O:15][C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:16])([CH3:4])[CH3:3]
Reactant: Cc1ccccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Add TBDMSCl (4.6 g, 30.5 mmol) to a solution of o-cresol (3 g, 28 mmol) and imidazole (2.08 g, 30.5 mmol) in 25 ml of dry DMF and stir at room temperature. After 7 h, pour the reaction into H2O and extract with hexane twice. Combine the organic layers, wash with H2O, dry over Na2SO4, filter and concentrate under reduced pressure to give a residue. Purify the residue by column chromatography on silica gel eluting with hexane to afford pure (1,1-dimethylethyl)dimethyl(2-methylphenoxy)silane as colourless oil. Add AIBN (330 mg, 1.98 mmol) to a solution of NBS (3.87 g, 21.76 mmol) and (1,1-dimethylethyl)dimethyl(2-methylphenoxy)silane (4.4 g, 19.78 mmol) in 100 ml of CCl4 and stir at reflux for 6 h. Concentrate the solvent under reduced pressure, add hexane and filter the solid. Wash the hexane with a saturated aqueous solution of NaHCO3 and H2O. Dry the organic phase over Na2SO4, filter and concentrate under reduced pressure to obtain [2-(bromomethyl)phenoxy](1,1-dimethylethyl)dimethylsilane as colourless oil.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[N:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.[F:24][CH2:25][CH:26](O)[CH2:27][F:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:24][CH2:25][CH:26]([O:23][C:20]1[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=1)[CH2:27][F:28]
Reactant: OC(CF)CF
Reactant: Oc1ccncc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FCC(CF)Oc1ccncc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
Di-tert-butyl azodicarboxylate (719 mg, 3.12 mmol) was added in one portion to pyridin-4-ol (YY) (297 mg, 3.12 mmol), 1,3-difluoropropan-2-ol (100 mg, 1.04 mmol) and Polymer supported triphenylphosphine (1.89 mmol/g; 1016 mg, 3.12 mmol) in dichloromethane (10 mL) at 20° C. under air. The resulting suspension was stirred at 20° C. for 4 hours. The mixture was filtered and the solvent evaporated to a yellow oil. The reaction mixture was diluted with dichloromethane (25 mL), and washed sequentially with 2M NaOH (2×10 mL) and saturated brine (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. This was re-dissolved in dichloromethane (25 mL), and washed with 2M HCl (10 mL). The aqueous layer was basified with 2M NaOH and extracted with dichloromethane (×3). The combined organic layers were dried over MgSO4, filtered and evaporated to afford the desired compound as a viscous oil (90 mg, 50%); 1H NMR (400.132 MHz, CDCl3) δ 4.60-4.67 (2H, m), 4.71-4.76 (2H, m), 4.78-4.90 (1H, m), 6.92 (2H, d), 8.48 (2H, d); m/z (LC-MS, ESI+), RT=1.53 (M+H 174).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:16][C:17]1[C:22]([CH3:23])=[C:21](Cl)[N:20]=[C:19]([S:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:18]=1>C(O)C>[Cl:16][C:17]1[C:22]([CH3:23])=[C:21]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:20]=[C:19]([S:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:18]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)CSc1nc(Cl)c(C)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1nc(Cl)c(C)c(NCc2ccc(Cl)cc2)n1
Yield: 31.4 %

Procedure:
A stirred mixture of 4.2 g of p-chlorobenzylamine, 3.18 g of sodium carbonate and 8.4 g of (4,6-dichloro-5-methyl-2-pyrimidinylthio)acetic acid, ethyl ester in 100 ml of ethanol was heated under reflux for 4 hr. The reaction mixture was filtered and water was added to the filtrate to start precipitation. The collected solid was recrystallized from benzenepetroleum ether to give 3.6 g of product, mp. 114°-117°C.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([OH:24])[N:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:32]([O:39][C:40](=[O:44])[C@@H:41](Br)[CH3:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:31])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([O:24][C@@H:41]([C:40]([O:39][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:44])[CH3:42])[N:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:20]=2)=[O:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Reactant: C[C@H](Br)C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O[C@H](C)C(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1.75 g 4-{2-[(5-Hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester in 10 ml DMF were added 990 mg (S)-2-bromo-propionic acid benzyl ester (prepared by standard benzylation procedure using (S)-2-bromopropionic acid and benzyl alcohol/p-TsOH) and 2.67 g cesium carbonate. After stirring at room temperature for 12 h the solution was diluted with 100 ml ethyl acetate and extracted with aqueous LiCl (4% w/w), 0.1 M HCl and aqueous NaHCO3. The crude product obtained after evaporation of the solvent was pure enough for the following reactions. Yield: 2.1 g
Reaction SMILES: O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O.O.[OH:20][CH:21]1[CH2:26][CH2:25][CH:24]([CH:27]([C:32]([O:34][CH3:35])=[O:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:23][CH2:22]1>C(OCC)C>[O:20]=[C:21]1[CH2:26][CH2:25][CH:24]([CH:27]([C:28]([O:30][CH3:31])=[O:29])[C:32]([O:34][CH3:35])=[O:33])[CH2:23][CH2:22]1
Reactant: COC(=O)C(C(=O)OC)C1CCC(O)CC1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)C(C(=O)OC)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
At 5° C., a mixture of 22.7 g of sodium dichromate dihydrate, 17 ml of concentrated sulfuric acid and 113 ml of water was added dropwise to a solution of 47.7 g of dimethyl (4-hydroxycyclohexyl)malonate in 250 ml of diethyl ether. The mixture was stirred at room temperature for 4 hours, the organic phase was separated off and the aqueous phase was once more extracted with diethyl ether. The combined organic phases were dried and concentrated to give the title product as a yellow oil which was used without any further purification for the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([F:12])[F:11])=[CH:6][C:5]=1[NH2:13].[I:15]I>CCO.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([I:15])[C:7]([CH:10]([F:12])[F:11])=[CH:6][C:5]=1[NH2:13]
Reactant: COC(=O)c1ccc(C(F)F)cc1N
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COC(=O)c1cc(I)c(C(F)F)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of 2-amino-4-difluoromethyl-benzoic acid methyl ester (1.98 g, 9.84 mmol) in EtOH (75 mL) were added Ag2SO4 (3.08 g, 1 equiv) and I2 (2.50 g, 1 equiv) and the resulting mixture was stirred at r.t. for 1 hour. The mixture was filtered through a pad of celite and washed with EtOH. The solution was concentrated in vacuo and then diluted with AcOEt. The organic phase was washed with sat. aq NaHCO3, 1M aq Na2S2O3 and brine and dried (Na2SO4). The solution was concentrated in vacuo to afford the title compound as an off-white solid (2.9 g, 90% yield). ES-MS: m/z 369.2 [M+CH3CN+H]+, rt 5.87 min.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])[CH2:3][CH2:4][CH:5]1[O:10][CH2:9][CH2:8][CH2:7][O:6]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O.O>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:2]([CH2:3][CH2:4][CH:5]1[O:6][CH2:7][CH2:8][CH2:9][O:10]1)=[O:1]
Reactant: OC(CCC1OCCCO1)c1ccc(Cl)cc1Cl
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCC1OCCCO1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.4 %

Procedure:
A mixture of 2-[3-hydroxy-3-(2,4-dichlorophenyl)prop-1-yl]-1,3-dioxane (2.91 g) and pyridinium dichromate (6.96 g) in dry dimethylformamide (DMF: 20 ml) was stirred at room temperature for 7 hours. The reaction mixture was diluted with water (100 ml) and extracted with diethyl ether. The extracts were washed with water, dried over magnesium sulphate, and concentrated under reduced pressure to give 2-[2-(2,4-dichlorobenzoyl)ethyl]-1,3-dioxane (2.7 g, 93%) as an orange oil, IR (film): 1700 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:22])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11]S(=O)(=O)[NH:9]2)=[CH:4][CH:3]=1.C1(O)C=CC=CC=1>Br.C(O)(=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]([NH2:11])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([NH2:9])[CH3:22])=[CH:14][CH:15]=1
Reactant: CC1(c2ccc(Cl)cc2)NS(=O)(=O)NC1c1ccc(Cl)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: CC(=O)O
Product: CC(N)(c1ccc(Cl)cc1)C(N)c1ccc(Cl)cc1
Temperature: 130 °C
Reaction time: 0.67 h
Yield: 50.8 %

Procedure:
A suspension of rac-(3R*,4S*)-3,4-bis(4-chlorophenyl)-3-methyl-1,2,5-thiadiazolidine-1,1-dioxide (3.71 g, 10.4 mmol) and phenol (4.86 g, 52 mmol) in 48% hydrobromic acid (13.56 mL) and acetic acid (46.44 mL) was stirred at 130° C. for 40 min (reaction progress monitored by TLC), then allowed to cool to room temperature. The crude reaction mixture was partitioned between ethyl acetate and water, and the aqueous phase washed twice with ethyl acetate. The aqueous phase was then made basic by the slow addition of solid sodium hydroxide (60 g; CARE! Exothermic) and extracted with diethyl ether (3×500 mL). The combined ethereal extracts were washed with 2M sodium hydroxide (100 mL), then dried over anhydrous sodium sulfate (with a few pellets of solid sodium hydroxide) and evaporated to give the title compound (1.56 g). This material was carried forward to the next step without any further purification.
Reaction SMILES: Cl.[C:2]([CH2:4][C:5](=[NH:10])[O:6][CH2:7][CH2:8][CH3:9])#[N:3].[N:11]#[C:12]N>>[C:12]([N:10]=[C:5]([O:6][CH2:7][CH2:8][CH3:9])[CH2:4][C:2]#[N:3])#[N:11]
Reactant: N#CN
Reactant: CCCOC(=N)CC#N
Agent: Cl
Product: CCCOC(CC#N)=NC#N
Yield: 72.2 %

Procedure:
3.25 g of n-propyl cyanoacetimidate hydrochloride and 1.26 g of cyanamide were treated with the same manner as in Example 1 and 2.18 g of oily n-propyl N-cyanocyanoacetimidate was obtained (yield 72.1%). The structure of this compound was confirmed by IR and NMR. Analysis calculated for C7H9N3O C 55.62, H 6.00, N 27.80, found C 54.80, H 6.27, N 27.13.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([NH:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[O:39])=[CH:32]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N(CC)CC)C.O>C1COCC1.C(OCC)(=O)C>[OH:6][CH2:7][CH2:8][N:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([NH:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[O:39])=[CH:32]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCc1c[nH]c2ccccc12)Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(CN(CCO)CCc3c[nH]c4ccccc34)cc2)c1)NOC1CCCCO1
Reaction time: 17 h

Procedure:
(E)-3-{1-[4-({[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (compound B 14) (120 mg, 0.169 mmol) is dissolved in THF (20 ml). Then it is added tetrabutylammonium fluoride (203 μl, 0.203, 1M in THF) and triethylamine (47 μl, 0.338 mmol) and the mixture is stirred for 17 hours. After addition of water (50 ml) and extraction with ethyl acetate the organic phase is dried over sodium sulfate, filtrated and evaporated. The crude product is purified by a silica gel flash chromatography using dichloromethane-methanol eluent.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:24][C:25]2[N:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:28][C:29]=2[CH3:30])[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:24][C:25]2[N:26]=[C:27]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[O:28][C:29]=2[CH3:30])[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccccc2OCc2nc(-c3ccccc3)oc2C)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccccc2OCc2nc(-c3ccccc3)oc2C)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (1.09 g), 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (10 ml), and ethanol (10 ml) was stirred at room temperature for two hours, diluted with 1 N hydrochloric acid (5 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (834 mg, yield: 82%) was obtained. This was recrystallized from ethanol-hexane. Melting point: 127–128° C.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:14]1([CH2:20][C:21](Cl)=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O=P(Cl)(Cl)Cl>>[CH2:20]([C:21]1[O:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(Cc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol), TEA (0.153 ml; 1.1 mmol), phenylacetylchloride (170 mg, 0.145 ml, 1.1 mmol) and POCl3 (0.5 ml; 5.5 mmol) as described in method 1; yield: 0.026 mg (9.4%); MS m/z: 277.4 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 4.34 (s, 2H); 7.25-7.28 (m, 1H); 7.29-7.38 (m, 4H); 7.83 (d, 1H, 3J=8.7 Hz); 7.91 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 8.19-8.20 (m, 1H); 8.85 (s, 1H); HPLC (METHOD [A]): rt 11.17 min (100%)