Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]#[C:18][CH2:19][CH2:20][CH2:21]Cl)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[Na+].[I-:24]>CC(=O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][I:24])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccc(Cl)cc1)N1CCC(C#CCCCCl)CC1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=C(Oc1ccc(Cl)cc1)N1CCC(C#CCCCI)CC1
Temperature: 80 °C

Procedure:
A solution of 733 mg (2.15 mmol) of 4-(5-Chloro-pent-1-ynyl)-piperidine-1-carboxylic acid 4-chloro-phenyl ester in 20 ml butan-2-one was treated with 650 mg of NaI (4.3 mmol) and heated at 80° C. for 48 h. Evaporation gave crude 4-(5-Iodo-pent-1-ynyl)-piperidine-1-carboxylic acid 4-chloro-phenyl ester, which was used directly for the next step, MS: 431 (M, 1Cl).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[C:15](O)(=[O:25])[C:16]1[CH:24]=[CH:23][C:22]2[O:21][CH2:20][O:19][C:18]=2[CH:17]=1.C(P(C#N)(CC)=O)C.Cl>O.C(N(CC)CC)C.CN(C)C=O>[C:15]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:6][CH:7]=1)(=[O:25])[C:16]1[CH:24]=[CH:23][C:22]2[O:21][CH2:20][O:19][C:18]=2[CH:17]=1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: Nc1ccc(C2SC(=O)NC2=O)cc1
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(c2ccc(NC(=O)c3ccc4c(c3)OCO4)cc2)S1
Reaction time: 2 h
Yield: 61.4 %

Procedure:
Into 20 ml of dimethylformamide were dissolved 1.00 g of 5-(4-aminophenyl)thiazolidine-2,4-dione and 0.80 g of piperonylic acid, and, after added 1.12 g of diethylphosphoryl cyanide and then 0.50 g of triethylamine at 0° C., the mixture was stirred for 1 hour as it was. Thereafter, the reaction mixture was brought to room temperature and stirred for 2 hours. Then, it was poured into 200 ml of water and, after made acidic with hydrochloric acid, the crystals deposited were collected by filtration. These were recrystallized from ethanol to obtain 1.05 g of title compound.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][NH2:8])=[CH:5][N:6]=1.CS[C:11](=[N:14][N+:15]([O-:17])=[O:16])[NH:12][CH3:13]>C(O)C>[Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][C:11]([NH:12][CH3:13])=[N:14][N+:15]([O-:17])=[O:16])=[CH:5][N:6]=1
Reactant: CNC(=N[N+](=O)[O-])SC
Reactant: NCc1cnc(Cl)s1
Solvent: CCO
Product: CNC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Yield: 71.3 %

Procedure:
A mixture of 0.48 g of 2-chloro-5-thiazolemethanamine, 0.31 g of S-methyl-N-methyl-N'-nitroisothiourea prepared by the method described in the Journal of Medical Chemistry., 1977, Vol. 20, No. 7, P. 905 and 3 ml of ethanol was heated under reflux for 6 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Solvent: Chloroform/Methanol =20/1) to obtain 0.37 g of the title compound as crystals. This compound is No. 8 in Table 1. m.p.: 151.0°-153.0° C.
Reaction SMILES: [I:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=O.S(Cl)([Cl:12])=O>>[I:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([Cl:12])=[O:9]
Reactant: O=C(O)c1ccoc1I
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccoc1I
Temperature: 70 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To 2-iodofuran-3-carboxylic acid (6.21 g, 26.1 mmol) was added thionyl chloride (20 ml, 274 mmol). The solution was heated while stirring to 70° C. for 5 h. The mixture was reduced in vacuo and the residue azeotroped with toluene (2×30 ml) to afford the crude title compound (6.69 g, 100%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[NH:4][CH2:5][C:6]#[CH:7].N1C=CC=CC=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>O1CCCC1>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[N:4]([C:24]([C:20]1[O:19][CH:23]=[CH:22][CH:21]=1)=[O:25])[CH2:5][C:6]#[CH:7]
Reactant: C#CCNc1c(C)cccc1C
Reactant: O=C(Cl)c1ccco1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C#CCN(C(=O)c1ccco1)c1c(C)cccc1C
Yield: 88.8 %

Procedure:
15.9 g (0.1 mol) of 2,6-dimethyl-N-propargylaniline and 8 g (0.1 mol) of pyridine were heated to the boil in 100 ml of tetrahydrofuran, and 13 g (0.1 mol) of furan-2-carboxylic acid chloride were added carefully. The reaction mixture was stirred under reflux for 15 minutes and then concentrated by distilling off the solvent in vacuo. The residue was taken up in methylene chloride and the methylene chloride mixture was washed with water. The organic phase was separated off, dried over sodium sulphate and concentrated. After triturating with petroleum ether, the residue crystallized. 22.5 g (89% of theory) of 2,6-dimethyl-N-(2-furoyl)-N-propargyl-aniline of melting point 109°-112° C. were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:13]([CH3:16])([O-:15])=[O:14].CN(C)C(=N)N(C)C>C(OCC)C.Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:16][N+:13]([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C=Cc1ccccc1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CCOCC
Product: COC(=O)CC(C[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 300 g of cinnamic acid methyl ester, 500 g of nitromethane and 39 g of tetramethylguanidine is allowed to stir at room temperature for 72 hours. The solution is diluted with diethyl ether and aqueous hydrochloric acid solution (1 N, 1 liter) is added. The organic layer is separated, dried over anhydrous magnesium sulfate, and evaporated to give 4-nitro-3-phenylbutanoic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:13][N:12]=1.C(OCC)(=O)C.[H][H]>C(O)(=O)C.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:13][N:12]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(/C=C/c2ccc(F)cc2F)nc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)c1ccc(CCc2ccc(F)cc2F)nc1
Yield: 94 %

Procedure:
2-[(E)-2-(2,4-difluorophenyl)vinyl]-5-(phenylsulfonyl)pyridine (Example 26, 0.52 g, 1.45 mmol) and palladium hydroxide (20% wt. Pd on carbon, 100 mg, 0.14 mmol) were stirred in acetic acid (10 mL) and ethyl acetate (5 mL) under a balloon of hydrogen for 3 hours. The catalyst was removed by filtration and the filtrate washed with 4N sodium hydroxide solution (×2). The aqueous layers were extracted with dichloromethane. The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give 2-[2-(2,4-difluorophenyl)ethyl]-5-(phenylsulfonyl)pyridine as a pale yellow solid (0.49 g, 94%). δH (500 MHZ, d6 DMSO): 9.02 (1H, s), 8.23 (1H, dd, J=2.2, 8.2 Hz), 7.99 (2H, d, J=7.4 Hz), 7.70 (1H, t, J=7.4 Hz), 7.63 (2H, t, J=7.7 Hz), 7.48 (1H, d, J=8.2 Hz), 7.27 (1H, q, J=8.0 Hz), 7.11 (1H, td, J=2.0, 9.9 Hz), 6.94 (1H, td, J=1.9, 8.6 Hz), 3.07 (2H, t, J=7.7 Hz), 2.97 (2H, t, J=7.7 Hz); m/z (ES+) 360 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[CH2:31]([OH:33])[CH3:32].Cl>CC(O)C>[CH2:31]([O-:33])[CH3:32].[ClH:1].[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: CCO
Agent: Cl
Agent: O=c1[nH]c2ccccc2n1CCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Solvent: CC(C)O
Product: CC[O-]

Procedure:
A solution of 1 part of 5-chloro-1-{1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one in 40 parts of ethanol is acidified with 2-propanol, previously saturated with gaseous hydrogen chloride. While cooling, the formed hydrochloride salt is allowed to crystallize, yielding 1 part (83%) of 5-chloro-1-{1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one hydrochloride ethanolate; mp. 231.7° C.
Reaction SMILES: [F:1][C:2]1[C:25]([NH:26][C:27]([NH:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[O:28])=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](OCC2C=CC=CC=2)=[O:12])[C@H:7]([CH3:21])[CH2:6]1.CCN(CC)CC.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.[NH:57]1[CH2:60][CH2:59][CH2:58]1>CO.C1COCC1.[Pd]>[N:57]1([C:11]([N:8]2[CH2:9][CH2:10][N:5]([CH2:4][C:3]3[C:2]([F:1])=[C:25]([NH:26][C:27]([NH:29][C:30]4[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=4)=[O:28])[CH:24]=[CH:23][CH:22]=3)[CH2:6][C@H:7]2[CH3:21])=[O:12])[CH2:60][CH2:59][CH2:58]1
Reactant: C1CNC1
Reactant: Cc1ccc(NC(=O)Nc2cccc(CN3CCN(C(=O)OCc4ccccc4)[C@H](C)C3)c2F)cn1
Agent: [Pd]
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(NC(=O)Nc2cccc(CN3CCN(C(=O)N4CCC4)[C@H](C)C3)c2F)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 25.6 %

Procedure:
To a solution of (R)-benzyl 4-(2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)-2-methylpiperazine-1-carboxylate (7.0 g, 14.3 mmol, 1.0 equiv) in MeOH (50 mL) was added 10% Pd/C (approx. 5 g). The resulting suspension was stirred and sparged with hydrogen gas using a balloon and needle. After 1 h, reaction was complete, as determined by LCMS. The mixture was filtered through a pad of Celite, and the celite pad was washed with additional methanol. The mixture was concentrated in vacuo, and 2.55 g (7.14 mmol) of the resulting residue was dissolved in dry THF (35 mL). To this room temperature solution was added Et3N (4.0 mL, 28.6 mmol, 4.0 equiv), followed by 4-nitrophenyl chloroformate (1.58 g, 7.85 mmol, 1.1 equiv). After 15 min, the reaction was complete, as judged by LCMS. Azetidine (530 μL, 7.85 mmol, 1.1 equiv) was added by syringe. After 1 h, additional azetidine (265 μL, 3.9 mmol, 0.5 equiv) and Et3N (500 μL, 3.6 mmol, 0.5 equiv) were added by syringe, and the reaction mixture was heated to 60° C. overnight. The reaction was the allowed to cool to room temperature, and the solvent was removed in vacuo. The residue was dissolved in EtOAc and washed three times with 1 N NaOH, and once with brine. The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography on silica gel (20% MeOH/DCM) provided (R)-1-(3-((4-(azetidine-1-carbonyl)-3-methylpiperazin-1-yl)methyl)-2-fluorophenyl)-3-(6-methylpyridin-3-yl)urea as a white foam (885 mg, 28%). LCMS m/z (APCI)=441.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1C=C[C:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:16](=[O:17])[C:15]([CH2:18][O:19]S(C)(=O)=O)=[CH:14][C:13]([C:24]3[CH:25]=[CH:26][C:27]4[O:31][CH2:30][CH2:29][C:28]=4[CH:32]=3)=[N:12]2)=[CH:4][CH:3]=1.[O:33]1C2C=CC(C3C=C(C(OC)=O)C(=O)NN=3)=CC=2CC1.ClC1C=CC=CC=1CCl>>[C:18]([C:15]1[C:16](=[O:17])[N:11]([CH2:10][C:9]2[CH:8]=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1])[N:12]=[C:13]([C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH2:30][CH2:29][C:28]=3[CH:32]=2)[CH:14]=1)([OH:33])=[O:19]
Reactant: COC(=O)c1cc(-c2ccc3c(c2)CCO3)n[nH]c1=O
Reactant: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(CCCc2ccc(Cl)cc2)c1=O
Agent: ClCc1ccccc1Cl
Product: O=C(O)c1cc(-c2ccc3c(c2)CCO3)nn(Cc2ccccc2Cl)c1=O

Procedure:
The general procedure of Example 1 (3) was carried out by use of 6-(2,3-dihydro-1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one and 2-chlorobenzyl chloride, to thereby yield the title compound as yellow needle-like crystal (yield: 75.0%).
Reaction SMILES: [CH:1](=[O:12])[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.C[Si]([C:17]#[N:18])(C)C>[N+](C)([O-])=O.[I-].[Zn+2].[I-]>[NH2:18][CH2:17][CH:1]([C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1)[OH:12]
Reactant: COc1ccc(C=O)cc1OC
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(O)CN)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a stirred solution of veratraldehyde(16.6 g) and zinc iodide (50 mg) in anhydrous nitromethane (200 ml) was added trimethylsilyl cyanide (12 g) dropwise under nitrogen. After the resulting mixture was stirred at room temperature for 1 hour, the solvent was removed under reduced pressure. Anhydrous tetrahydrofuran (50 ml) was added to the residue, and the resulting mixture was added under ice cooling to a suspension of lithium aluminum hydride (3.9 g) in anhydrous tetrahydrofuran (200 ml). After that, the resulting mixture was stirred for 1 hour at room temperature. Water was added to the reaction mixture, insoluble matter was filtered off, and the solvent was then removed under pressure from the filtrate. Chloroform (300 ml) was added to the residue. The resulting mixture was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The thus-obtained residue was purified by a silica gel column, whereby the title compound (10.8 g, yield: 54.8%) was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[C:16](=[O:17])[CH:10]([CH2:11][N:12]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][Mg]Cl>C(OCC)C>[CH2:18]([N:12]1[CH2:11][CH:10]2[C:16]([OH:17])([CH3:25])[CH:14]([CH2:15][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9]2)[CH2:13]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1C2CN(Cc3ccccc3)CC1CN(Cc1ccccc1)C2
Reactant: C[Mg]Cl
Solvent: CCOCC
Product: CC1(O)C2CN(Cc3ccccc3)CC1CN(Cc1ccccc1)C2
Reaction time: 0.33 h
Yield: 60 %

Procedure:
A solution of 3,7-dibenzyl-3,7-diazabicyclo[3.3.1]nonane-9-one (from step (i) above; 2.05 g; 6.4 mmol) in diethyl ether (15 mL) was added to a stirred solution of methyl magnesium chloride (12.8 mmol) in diethyl ether (8 mL) over 80 minutes. The reaction mixture was subsequently stirred for 20 minutes and then quenched with HCl (1 M). The aqueous layer was separated, concentrated and partitioned between EtOAc and NaOH (2 M). The organic layer was separated and subsequently treated with ion exchange resin (Amberlyst IRA 400), the solvent removed and the residue subjected to column chromatography (hexane:EtOAc; 1:1 with NH3 sat. MeOH; gradient 0-32%) to give the sub-tide compound as a diastereoisomeric mixture in a 60% yield.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=[S:9])[CH:5]=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1CCC(N)CC1)=O)([CH3:13])([CH3:12])[CH3:11].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[C:10]([O:14][C:15](=[NH:17])[N:3]1[CH2:2][CH2:8][CH:6]([NH2:7])[CH2:5][CH2:4]1)([CH3:13])([CH3:12])[CH3:11].[CH3:1][C:2]1[N:7]=[C:6]([CH:8]=[S:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: Cc1nccc(C=S)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=N)N1CCC(N)CC1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
2-Methylthiopyrimidine-4-carboxaldehyde (1.51 g, 9.8 mmol), 1-t-butoxycarbonyl-4-aminopiperidine (Mach R. H., et al., J. Med. Chem. 1993 36, 3707) (2.1 g, 10.5 mmol), MgSO4 (ca 2 g) and CH2Cl2 (75 mL) were combined and stirred at 23° C. for 16 h. Filtration and concentration of the filtrate afforded the title compound as a yellow oil: 1H NMR (CDCl3) δ8.57 (d, 1), 8.27 (s, 1), 7.58 (d, 1), 4.05 (m, 2), 3.55 (m, 1), 3.00 (m, 2), 2.60 (s, 3), 1.75 (m, 4), 1.48 (s, 9).
Reaction SMILES: FC(F)(F)C(O)=O.O[C:9]1([CH2:22][CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1>ClCCl>[CH3:26][C:24]1([CH3:25])[CH2:23][CH2:22][C:9]2([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[O:27]1
Reactant: CC(C)(O)CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCC2(CCNCC2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
Trifluoroacetic acid (10 mL) was added to a solution of 1,1-dimethylethyl 4-hydroxy-4-(3-hydroxy-3-methylbut-1-yl)-1-piperidinecarboxylate (Description 80, 3.9 g, 13.57 mmol) in dichloromethane (10 mL) and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3(Aq.) (90:10:1) to give the title compound (2.04 g, 89%). m/z (ES+) 170 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14]CC)=[O:13])=[CH:5]2.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([OH:14])=[O:13])=[CH:5]2
Reactant: CCOC(=O)c1cnc2ccc(Cl)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cnc2ccc(Cl)cc2c1
Yield: 82.7 %

Procedure:
Ethyl 6-chloroquinoline-3-carboxylate (0.19 g, 0.81 mmol) was saponified by treatment with dioxane (10 ml) and 10% aqueous sodium hydroxide (10 ml) at reflux for 3 hours. The dioxane was removed under vacuo; the aqueous solution remaining was acidified with HCl. The precipitated product was collected and washed with water to isolate 6-chloroquinoline-3-carboxylic acid as an off-white solid (0.14 g, 0.67 mmol). 1H NMR [(CD3OD), 300 MHz]: δ 9.35 (s, 1H), 8.95 (s, 1H), 8.17 (s, 1H), 8.1 (d, 2H), 7.87 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:11][CH2:10][C:9](=O)[CH:8]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH2:7]1)[CH3:2]>O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:7][C:8]2[S:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[C:9]=2[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CC1CCC(=O)C(Sc2cccc(Cl)c2)C1
Solvent: O
Product: CCOC(=O)CC1CCc2c(sc3cccc(Cl)c23)C1

Procedure:
To 200 g. of polyphosphoric acid contained in a 1-l. three-necked flask, provided with a stirrer and condenser was added 8.0 g. of 3-(3-chlorophenylthio)-4-oxocyclohexaneacetic acid ethyl ester. The mixture was heated on a steam bath for 90 minutes and then poured into a mixture of 200 g. of ice and 200 ml. of water with stirring, which was continued until the dark oily complex was decomposed and a light yellow color appeared. The product was extracted twice with 200 ml. of ether. The ether extract was washed twice with 50 ml. of water and then with 50 ml. of saturated sodium bicarbonate solution. The solution was dried over anhydrous potassium carbonate and then filtered. The ether was removed on a steam bath in a rotary evaporator at atmospheric pressure, and the residue was distilled at reduced pressure. At 205°-220°/2 mm. a yield of 3.3 g. of 9-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethyl ester was obtained.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[C:6]([OH:11])(=[O:10])[C:7]([CH3:9])=O>O>[C:3]([NH:2][N:1]=[C:7]([CH3:9])[C:6]([OH:11])=[O:10])(=[S:4])[NH2:5]
Reactant: NNC(N)=S
Reactant: CC(=O)C(=O)O
Solvent: O
Product: CC(=NNC(N)=S)C(=O)O
Temperature: 70 °C

Procedure:
To a mixture of thiosemicarbazide (2) (4.55 g, 50.0 mmol) in water (90 mL) was added pyruvic acid (1) (4.40 g, 50.0 mmol). The mixture was heated at 70° C. for 20 min (while a white solid precipitated). After cooling to room temperature, the white solid was collected by filtration, washed with water and dried in air to give 2-(2-carbamothioylhydrazono)propanoic acid (3).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]([F:10])([F:9])[F:8])=[N:4][NH:5][CH:6]=1.[CH2:11]=[O:12]>CC(C)=O>[Br:1][C:2]1[C:3]([C:7]([F:10])([F:9])[F:8])=[N:4][N:5]([CH2:11][OH:12])[CH:6]=1
Reactant: C=O
Reactant: FC(F)(F)c1n[nH]cc1Br
Solvent: CC(C)=O
Product: OCn1cc(Br)c(C(F)(F)F)n1
Temperature: 140 °C
Reaction time: 5 h
Yield: 85.1 %

Procedure:
The mixture of 3.38 g of 4-bromo-3-(trifluoromethyl)-1H-pyrazole and 0.66 g of paraformaldehyde was stirred at 140° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. Hexane was added to the residue obtained by concentration of the filtrate under reduced pressure, as a result, a crystal was formed. The crystal was collected to obtain 3.28 g of 4-bromo-3-(trifluoromethyl)-1H-pyrazole-1-ylmethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:20])[CH:3]=1.[OH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:27]=[CH:28][C:23]([CH2:22][OH:21])=[CH:24][CH:25]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:20])[CH:3]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Cc1cc(Cl)ccc1/C=C/C(=O)c1ccc(=O)n(C)c1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: C1=CCCC=CCC1
Solvent: O
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(CO)cc1

Procedure:
In analogy to example 203, step 1, 5-[(E)-3-(4-chloro-2-methyl-phenyl)-acryloyl]-1-methyl-1H-pyridin-2-one (example 323, step 3) was reacted with 4-(hydroxymethyl)phenyl-boronic acid in the presence of chloro(1,5-cyclooctadiene)rhodium(I) dimer and sodium hydrogencarbonate in 1,4-dioxane and water at 60° C. to give the title compound as a yellow foam, MS (ESI+): m/z=396.1 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][OH:28])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][O:28][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Yield: 100 %

Procedure:
Stir a solution of 2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-ethanol (293 mg, 0.78 mmol) and methane sulfonyl chloride (68 μL, 0.81 ml) in dried pyridine (5 mL) for 2 hours. Remove the pyridine in vacuo and recover the residue with chloroform. Wash the organic layer with saturated sodium bicarbonate and dry over sodium sulfate to give the desired subtitled intermediate as a white foam (425 mg, 100%). MS ES+ m/e 451.1 (M+1).
Reaction SMILES: [B][B][B][B][B][B][B][B][B][B].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](=O)[CH3:27]>CO>[CH3:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[NH:11][CH:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH3:19])[CH3:27]
Reactant: Cc1cccc(N)c1
Reactant: CC(=O)c1ccccc1C
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: Cc1cccc(NC(C)c2ccccc2C)c1
Reaction time: 20 h

Procedure:
To a flame-dried 100 mL round-bottom flask equipped with a magnetic stirring bar was added 260 mg of decaborane (260 mg, 2.1 mmol), dry methanol (52 mL), m-toluidine (780 μL, d=0.989 g/mL, 7.2 mmol), and 2′-methylacetophenone (1 mL, d=1.014 g/mL, 7.6 mmol), and the mixture stirred and monitored by TLC (product Rf=0.43-0.44 in 50% dichloromethane/hexanes). The solution gradually changed color from brown to pale yellow and the reaction proceeded. After 20 hours, the solution was colorless, decaborane (115 mg, 0.941 mmol) was added, at which time the solution became pale yellow again. Another portion of decaborane (103 mg, 0.843 mmol) was added after 4 days, and the reaction stirred an additional six days. After completion, the solvent was evaporated, the residue redissolved, loaded onto a short 2.5 inch columns of silica gel and eluted with 5% ethyl acetate/hexanes. The eluent was collected and concentrated, and the crude product purified by flash chromatography using a slow gradient of 10% dichloromethane/hexanes to 20% dichloromethane/hexanes. Fractions were combined and concentrated to give the desired product ZZZ (1.29 g, 79.6%) as colorless oil.