Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:18]1[C:30]2[CH:29]([CH2:31][O:32][C:33]([N:35]3[CH2:39][CH2:38][CH2:37][C@H:36]3[C@H:40]([O:46][CH3:47])[C@@H:41]([CH3:45])[C:42](O)=[O:43])=[O:34])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C.C(OCC)(=O)C>[CH:27]1[C:28]2[CH:29]([CH2:31][O:32][C:33]([N:35]3[CH2:39][CH2:38][CH2:37][C@H:36]3[C@H:40]([O:46][CH3:47])[C@@H:41]([CH3:45])[C:42]([NH:2][C@H:3]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:43])=[O:34])[C:30]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: CO[C@H]([C@@H](C)C(=O)O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO[C@H]([C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 78.8 %

Procedure:
To a stirring solution of tert-butyl L-phenylalaninate, hydrochloride salt (1.67 g, 6.5 mmol, 1.0 eq.) and #119 (5.9 g, 6.5 mmol, 1.0 eq.) in 50 mL of dichloromethane and 5 mL of DMF, HATU (2.9 g, 7.9 mmol, 1.2 eq.) was added followed by Hunig's base (5.6 mL, 32 mmol, 5.0 eq.). The reaction was allowed to stir at room temperature for 45 minutes. Reaction was reduced down, diluted with ethyl acetate, washed with 0.5 N HCl and brine before being concentrated down onto silica. Silica chromatography was then performed (Gradient: 0%-25% acetone in heptane) producing #120 (3.14 g, 79%) as a white yellow solid. LC-MS (Protocol Q): m/z 613.1 [M+H+] retention time=2.37 minutes.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C(OC([NH:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:28][CH:29]1[CH2:33][CH2:32][N:31]([C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([CH3:16])[C:10]=2[F:15])[CH2:30]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(F)c(N2CCC(N)C2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110 %

Procedure:
A mixture of 0.70 g (2.50 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.56 g (3.00 mmol) of 3-(t-butoxycarbonyl)aminopyrrolidine, 0.76 g (7.52 mmol) of triethylamine, and 25 ml of acetonitrile was refluxed for 4.5 hours, then stirred at room temperature overnight. The solids were filtered and washed with acetonitrile and ether. The crude product was dissolved in 20 ml of 6N hydrochloric acid and 20 ml of acetic acid and was stirred at room temperature for three hours. The solution was concentrated to an oil which was triturated with 2:1 ether:isopropanol. The solids were filtered and washed with ether to give 0.95 g of the title compound as the hydrochloride salt, mp >300° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:20]O>>[CH3:20][O:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)CCCc1ccccc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)CCCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Initially charge 705 mg (3.37 mmol) of 4-(2-nitrophenyl)butanoic acid in 7 ml of methanol, cool to 0° C. and add 0.26 ml (3.54 mmol) of thionyl chloride dropwise. Warm the mixture slowly to RT and stir overnight. To complete the reaction, add an approx. 20% excess of thionyl chloride and stir the mixture at RT for a further 5 h. After concentration under reduced pressure, stir the residue in a little methanol and filter off the resulting solid. 700 mg (95.5% of theory) of the target product are obtained as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]([CH2:22][NH2:23])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl.N1C=CC=CC=1>[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][NH:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC[C@@H]1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.6 %

Procedure:
C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine hydrochloride (0.5 gms, 1.41 mmole) was dissolved in 20 mL methylene chloride and 0.5 mL pyridine, and the mixture was cooled in an ice bath. Methanesulfonyl chloride (0.16 g, 1.41 mmol) was added dropwise, and the reaction mixture was stirred for five minutes at ice bath temperature, then allowed to warm to room temperature. The reaction mixture was quenched by addition of water, and was extracted with methylene chloride. The organic layer was washed with water, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give 0.39 g of (R)—N-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-methanesulfonamide, M+H=398.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[C:30]([O:34][C:35]([NH:37][C:38]1[CH:43]=[C:42]([I:44])[CH:41]=[C:40]([I:45])[CH:39]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:37]([C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])[C:38]2[CH:39]=[C:40]([I:45])[CH:41]=[C:42]([I:44])[CH:43]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(I)cc(I)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCN(C(=O)OC(C)(C)C)c2cc(I)cc(I)c2)c1CCC(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.7 %

Procedure:
To a mixture of the 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (3.6 g, 7.6 mmol), N-tert-butoxycarbonyl-3,5-diiodoaniline (2.8 g, 6.3 mmol) in DMF (60 mL) was added NaH (60% dispersion in mineral oil), (504 mg, 12.6 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with EtOAc (120 mL), then washed with brine. The organic phase was dried over Na2SO4 and evaporated under reduced pressure. Purification by Isco chromatography (Gradient of 20 minutes from hexanes to Hexanes/EtOAc 80%) afforded the title compound (3.3 g, 60%) as a light yellow oil. HR-ES(+): calculated for C34H47N1O7I2 (M+Na)+ 858.1334, found 858.1325.
Reaction SMILES: [C:1]1([C:9]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[CH:14][CH:13]=2)=O)[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.Cl.[NH2:21][OH:22].[OH-].[Na+]>CO.O>[C:1]1([C:9](=[N:21][OH:22])[CH2:11][C:12]2[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1
Reactant: NO
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(CC(=NO)c2ccc(OC)cc2)cc1
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
Desoxyanisoin (98%, 52.2 g., 0.2 mole) and hydroxylamine hydrochloride (15.3 g., 0.22 mole) are slurried in a mixture of methanol (300 ml) and water (200 ml) and sodium hydroxide (16 g., 0.4 mole) is added slowly. The mixture is stirred for 15 minutes, then placed in a hot water bath (70° C.) and stirred an additional hour. Methanol is then added to the hot mixture until solution is almost complete, the mixture is filtered and concentrated to remove most of the methanol, then cooled with the addition of ice-water. Filtered, dissolved the resulting solid in ethyl acetate, extracted with brine. Dried the organic layer (Na2SO4), filtered and concentrated to obtain 53.5 g (98.5%) of the oxime as a yellow solid.
Reaction SMILES: Cl[O-].[Na+].[OH:4][N:5]=[CH:6][CH2:7][O:8][CH:9]([C:13]1([CH3:16])[CH2:15][CH2:14]1)[CH2:10][CH:11]=[CH2:12].C(N(CC)CC)C>ClCCl.O>[CH3:16][C:13]1([C@@H:9]2[O:8][CH2:7][C:6]3=[N:5][O:4][CH2:12][C@@H:11]3[CH2:10]2)[CH2:15][CH2:14]1
Reactant: C=CCC(OCC=NO)C1(C)CC1
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1([C@H]2C[C@H]3CON=C3CO2)CC1

Procedure:
An aqueous solution of sodium hypochlorite (6.15% solution, 65 mL, 51 mmol) was added drop-wise over 24 minutes to a solution of N-hydroxy-2-{[1-(1-methylcyclopropyl)but-3-en-1-yl]oxy}ethanimine (C55) (6.54 g, 36 mmol) and triethylamine (280 mg, 2.7 mmol) in dichloromethane (64 mL) that was immersed in a room temperature water bath. The rate of addition was adjusted to maintain the internal temperature of the reaction between 19.5° C. and 22.8° C. After completion of the addition, the reaction mixture was diluted with water (50 mL) and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo (300 mbar, 40° C.). Silica gel chromatography (Gradient: 0% to 10% ethyl acetate in petroleum ether) provided the product as a white solid. Yield: 3.84 g, 21.2 mmol, 57%. The indicated relative stereochemistry of compound C56 was assigned based on nuclear Overhauser enhancement studies, which revealed an interaction between the methine protons on carbons 3a and 5. LCMS m/z 182 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 4.73 (d, J=13.2 Hz, 1H), 4.64 (dd, J=10.4, 8.0 Hz, 1H), 4.14 (d, J=14.1 Hz, 1H), 3.81 (dd, J=11.6, 8.0 Hz, 1H), 3.44-3.39 (m, 1H), 2.82 (d, J=12.8 Hz, 1H), 2.21-2.15 (m, 1H), 1.76 (q, J=11.9 Hz, 1H), 1.05 (s, 3H), 0.55-0.51 (m, 1H), 0.44-0.41 (m, 2H), 0.40-0.39 (m, 1H).
Reaction SMILES: C(Cl)(=O)CCCCC([Cl:8])=O.OCCCCCCCCCCCCCCC[C:27]([O:29][CH:30]([O:32][C:33](=[O:50])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]CCCCCCCCCO)C)=[O:28]>C(Cl)(Cl)Cl>[Cl:8][C:27]([O:29][CH2:30][O:32][C:33](=[O:50])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:28]
Reactant: O=C(Cl)CCCCC(=O)Cl
Reactant: CC(OC(=O)CCCCCCCCCCCCCCCO)OC(=O)CCCCCCCCCCCCCCCO
Solvent: ClC(Cl)Cl
Product: O=C(Cl)OCOC(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 415.4 %

Procedure:
In a three-necked round bottomed flask equipped with a reflux condenser, a glass gas inlet tube and a pressure equalizing dropping funnel was placed freshly distilled adipoyl chloride (2.60 ml, 17.50 mmol) dissolved in absolute chloroform (15 ml). The temperature was raised to ca. 50° C. and under a gentle stream of nitrogen through the solution, a solution of ethylidene bis(16-hydroxyhexadecanoate) (1.0g, 1.75 mmol) in absolute chloroform (30 ml) was added dropwise and left at this temperature a further 3 hours after addition. The mixture was then cooled to room temperature and quickly transferred into a 50 ml round bottomed flask equipped for distillation under reduced pressure. Chloroform was first distilled off at normal pressure, then oil-pump vacuum was established and excess adipoyl chloride distilled off at ca. 75° C., 5 mbar pressure, leaving the residual title compound (1.56 g).
Reaction SMILES: C[N:2]1C=CC(C(=O)C)=N1.Cl.FC1C=CC=CC=1CNN.C([O:24][C:25]1[C:30]([F:31])=[CH:29]C=[C:27]([C:32]2[CH:36]=[C:35]([C:37]3[CH:41]=[CH:40][O:39][N:38]=3)[N:34]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[F:49])[N:33]=2)[N:26]=1)(=O)C.C(OC(=O)C(F)=C[O-])C.[Na+]>N1C=CC=N1.C(O)C>[F:31][C:30]1[C:25]([OH:24])=[N:26][C:27]([C:32]2[CH:36]=[C:35]([C:37]3[CH:41]=[CH:40][O:39][N:38]=3)[N:34]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[F:49])[N:33]=2)=[N:2][CH:29]=1
Reactant: CC(=O)c1ccn(C)n1
Reactant: CC(=O)Oc1nc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)ccc1F
Agent: CCOC(=O)C(F)=C[O-]
Agent: Cl
Agent: NNCc1ccccc1F
Solvent: CCO
Product: Oc1nc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)ncc1F

Procedure:
This compound was generated exploiting General Procedure A-I from 1-(1-methyl-1H-pyrazol-3-yl)ethanone (1.67 g, 13.45 mmol) in the initial Claisen condensation, and using (2-fluorobenzyl)hydrazine hydrochloride (2.38 g, 13.45 mmol) in the pyrazole formation step (72%, two steps). The ester was then carried on to the corresponding amidine, again, as outlined in General Procedure A-I. The amidine (213 mg, 0.714 mmol) was cyclized via treatment with sodium 3-ethoxy-2-fluoro-3-oxoprop-1-en-1-olate (446 mg, 2.86 mmol) in ethanol (5.0 mL)—stirring at 90° C. for 14 hour. The solvent was removed in vacuo, and purification by silica gel chromatography (0-10% methanol in DCM) provided a mixture of the desired compound and a side-product. The mixture was then subjected to reverse-phase preparative HPLC which afforded Compound 92 (20 mg, 7.6% yield) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17](OC)=[O:18])[N:12]3[C:21]=2[CH:22]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:27]=1[CH2:28][NH2:29].[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:27]=1[CH2:28][N:29]1[C:17](=[O:18])[C:13]2[N:12]3[C:21](=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=2)[CH2:22]1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COC(=O)c1cccc2nc(-c3ccc(C#N)cc3)c(C=O)n12
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CN2Cc3c(-c4ccc(C#N)cc4)nc4cccc(n34)C2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a solution of (B1) in MeOH (0.2 M), 2,4-dimethoxybenzylamine (1.2 eq.) and Ti(iPrO)4 (2.0 eq.) were added and the reaction mixture was stirred at RT for 2 h. Then, NaBH3CN (1.5 eq.) was added and stirring was continued for 24 h. The solvent was reduced in vacuo and the residue pardoned between sat. aq. NaHCO3 and DCM. The aqueous phase was separated and extracted several times with DCM. The combined organic extracts were washed with brine and dried (Na2SO4). Evaporation of the solvent gave a residue which was purified by flash column on silica using a gradient of EtOAc/Petroleum ether from 50:50 to 70:30 to yield (55%) the title compound as a yellow powder. 1H NMR (600 MHz, DMSO-d6, 330K) δ 7.94 (2H, d, J=8.6 Hz), 7.90 (2H, d, J=8.6 Hz), 7.72 (1H, d, J=9.0 Hz), 7.47 (1H, d, J=7.0 Hz), 7.35 (1H, dd, J=8.4, 7.0 Hz), 7.23 (1H, d, J=8.3 Hz), 6.61 (1H, d, J=2.0 Hz), 6.48 (1H, dd, J=8.3, 2.0 Hz), 5.38 (2H, s), 4.72 (2H, s), 3.86 (3H, s), 3.74 (3H, s). MS (ES+) C25H20N4O3 requires: 424, found: 425 (M+H)+.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].Br[C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1>O>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: Oc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2F)cn1
Temperature: 60 °C
Yield: 55.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.11 g, 2.7 mmol) was mixed with 3-5 ml of dry dimethylformamide and 2-fluorophenol (0.24 ml, 2.7 mmol) was added to the stirred suspension. When the gas evolution was ceased the reaction mixture was heated at stirring at 60° C. and 5-bromo-2-nitropyridine (0.5 g, 2.5 mmol) was added to the reaction mixture in one portion. The reaction mixture was stirred at 60° C. for about 12 hours. The reaction mixture was then mixed with 50 ml of water and extracted into methylene chloride (3×20 ml). Organic extract was washed with water and brine, dried over magnesium sulfate and concentrated by rotary evaporation. The resulting mixture was purified by column chromatography on silica (30 g, EtOAc/hexane 1:3) to give 326 mg (57% yield) of desired product.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=2)[NH:6][CH:5]=1)#[N:2].CN.[C:21](OCC)(=O)C.CC(O)C.O>C(O)C.[Pd]>[CH3:21][NH:2][CH2:1][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][NH:14][S:15]([CH3:18])(=[O:16])=[O:17])[CH:11]=2)[NH:6][CH:5]=1
Reactant: CS(=O)(=O)NCc1ccc2[nH]cc(CC#N)c2c1
Reactant: CCOC(C)=O
Agent: [Pd]
Agent: CN
Solvent: CC(C)O
Solvent: O
Solvent: CCO
Product: CNCCc1c[nH]c2ccc(CNS(C)(=O)=O)cc12

Procedure:
A solution of N-[[3-(cyanomethyl)-1H-indol-5-yl]methyl]methanesulphonamide (0.04 g) in absolute ethanol (10 ml) containing methylamine in ethanol, (33%, 0.5 ml) was hydrogenated at room temperature and pressure over palladium on charcoal (10%, 50% aqueous paste, 0.05 g). After 60 h TLC Silica, ethyl acetate/2-propanol/water/0.88 ammonia (25:15:2) showed one major basic spot Rf 0.4, identical to authentic product (see Example 2)
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:18][CH:17]([CH2:19][N:20]([CH3:26])[CH:21]2[CH2:25][CH2:24][O:23][CH2:22]2)[CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:18][CH:17]([CH2:19][N:20]([CH3:26])[CH:21]2[CH2:25][CH2:24][O:23][CH2:22]2)[CH2:16]1
Reactant: CN(CC1CN(C(=O)OC(C)(C)C)C1)C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CC1CNC1)C1CCOC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.6 %

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of 3-{[methyl(tetrahydrofuran-3-yl)amino]methyl}azetidine-1-carboxylic acid tert-butyl ester (257 mg, 0.95 mmol) in dichloromethane (12 mL). The resulting reaction mixture was stirred at RT for 1.5 h. The solvents were reduced in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM to afford (Azetidin-3-ylmethyl)methyl(tetrahydrofuran-3-yl)amine as colourless oil (140 mg, 86%). 1H NMR (400 MHz, CDCl3): δ 3.94 (1H, td, J=8.62, 4.35 Hz), 3.84 (1H, dd, J=8.76, 6.50 Hz), 3.76-3.65 (3H, m), 3.62 (1H, dd, J=8.76, 6.50 Hz), 3.38 (2H, t, J=7.31 Hz), 3.09-3.07 (1H, m), 2.99-2.88 (1H, m), 2.64 (1H, dd, J=12.50, 7.22 Hz), 2.53 (1H, dd, J=12.50, 7.22 Hz), 2.15 (3H, s), 2.01 (1H, dtd, J=12.34, 7.72, 3.21 Hz), 1.83 (1H, dtd, J=12.35, 8.40, 6.96 Hz)
Reaction SMILES: C(OCC)C.Cl.[CH2:7]([O:14][NH2:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].[CH2:18]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1)[CH2:19][CH2:20][CH3:21]>O>[CH2:7]([O:14][NH:15][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:18][CH2:19][CH2:20][CH3:21])=[CH:23][CH:24]=1)=[O:30])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NOCc1ccccc1
Reactant: CCCCc1ccc(N=C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCCCc1ccc(NC(=O)NOCc2ccccc2)cc1
Yield: 82.1 %

Procedure:
Diethyl ether (10 mL) was added to a suspension of O-benzylhydroxylamine hydrochloride (0.82 g, 5.1 mmol) in water (1 mL). A solution of sodium hydroxide (0.23 g, 5.8 mmol) in water (1 mL) was added and the mixture was stirred for several minutes. The aqueous layer was removed by pipette and extracted with diethyl ether (3 mL). The ether extract was added to the reaction flask. 4-Butylphenyl isocyanate (0.90 g, 5.1 mole) was added to the reaction flask via pipette in a single portion. A mild reflux occurred. The reaction mixture was allowed to stir at ambient temperature for 15 minutes then purified by flash chromatography (silica gel; 1:4 ethyl acetate:hexanes) to provide 1.25 g of 1-benzyloxy-3-(4-butylphenyl)urea as a fluffy white solid, m.p. 90.6°-91.4° C.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1[CH:13]=[CH:12][C:10](N)=[CH:9][CH:8]=1)([CH3:4])[CH3:3].N([O-])=O.[Na+].[I-:18].[K+]>Cl>[CH3:1][Si:2]([C:5]#[C:6][C:7]1[CH:13]=[CH:12][C:10]([I:18])=[CH:9][CH:8]=1)([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)C#Cc1ccc(N)cc1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Product: C[Si](C)(C)C#Cc1ccc(I)cc1
Reaction time: 1 h
Yield: 90.8 %

Procedure:
As shown in the following Reaction 2, 250 mg (1.32 mmol) of 4-trimethylsilylethynylaniline obtained in A of Example 1-1 was melted in 3 mL of hydrochloric acid at the temperature of 0° C., and 94 mg (1.37 mmol, 1.04 eq) of sodium nitrite was added thereto, and then the reaction solution was stirred for 1 hour. After completion of stirring, 280 mg (1.69 mmol, 1.28 eq) of potassium iodide was added to the reaction solution, and then the reaction solution was stirred at room temperature for 12 hours. Next, the reaction solution was extracted with ether 2 times and 1 time with 1M sodium chloride aqueous solutions 1 time. The organic solvent layer was dehydrated with magnesium sulfate, filtered, and then distilled under reduced pressure. The compound distilled under reduced pressure was purified with an alumina column chromatography (mobile phase: hexane) to obtain 360 mg of 4-trimethylsilylethynyl iodobenzene with the yield of 92%. NMR data of the obtained compound is as follows. [1H NMR (400 MHz, CDCl3): δ 0.23-0.27 (m, 9H), 7.16 (d, 2H), 7.69 (d, 2H)].
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]2[N:15]=[C:16]([O:19][CH2:20][CH2:21][CH2:22][S:23](=[N:25][C:26]#[N:27])[CH3:24])[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1.S([O-])(O[O-])(=O)=[O:29].[K+].[K+].C(=O)([O-])[O-].[K+].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.O.C(O)C.CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]2[N:15]=[C:16]([O:19][CH2:20][CH2:21][CH2:22][S:23](=[N:25][C:26]#[N:27])([CH3:24])=[O:29])[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1
Reactant: CS(CCCOc1ccc2ncc(-c3cc4ccccc4o3)n2n1)=NC#N
Reactant: O=S(=O)([O-])O[O-]
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(CCCOc1ccc2ncc(-c3cc4ccccc4o3)n2n1)=NC#N
Yield: 93.9 %

Procedure:
25 mL methanol were added to 1 g (2.64 mmol) [(3-{[3-(1-benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}propyl)(methyl)-lambda4-sulfanylidene]-cyanamide in 20 mL dichloromethane. To the clear solution 25 mL ethanol were added. 6.614 g (5.27 mmol) potassium peroxymonosulfate were dissolved in 24 mL water. 2.186 g (15.82 mmol) potassium carbonate were dissolved in 16 mL water and transferred to the potassium peroxymonosulfate solution. This solution was added in 40 min under vigorous stirring. After 19 h 200 mL dichloromethane and 50 mL of a saturated sodium thiosulfate solution was added and stirred for a few minutes. The layers were separated and the aqueous phase was extracted three times with 50 mL dichloromethane. The combined organic layers were dried over sodium sulfate, and concentrated. This residue was dissolved in 20 mL dichloromethane and 25 mL methanol. To the clear solution 25 mL ethanol were added. 6.61 g (5.27 mmol) potassium peroxymonosulfate were dissolved in 24 mL water. 2.19 g (15.85 mmol) potassium carbonate were dissolved in 16 mL water and transferred to the potassium peroxymonosulfate solution. This solution was added in 15 minutes under vigorous stirring. After 4 hours 200 mL dichloromethane and 30 mL of a saturated sodium thiosulfate solution was added and stirred for a few minutes. The layers were separated and the aqueous phase was extracted once with 50 mL dichloromethane. The combined organic layers were dried over sodium sulfate, and concentrated to yield 0.98 g (94%) of a yellow solid.