Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[NH:21][C:22](=[O:25])[CH2:23]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[NH:21][C:22](=[O:25])[CH2:23][N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1
Reactant: O=C(CCl)Nc1cccc(Cl)c1Cl
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.4 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(2,3-dichlorophenyl)-2-chloroacetamide (48 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure the residue purified by preparative HPLC to provide 9 mg (16%) of the desired product as a trifluoroacetic acid salt. 1H NMR (500 MHz, DMSO-d6) δ 2.62 (t, J=4 Hz, 4H), 3.23 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.55 (t, J=6 Hz, 1H), 7.68 (m, 2H), 7.88 (m, 2H), 8.12 (d, J=5 Hz, 1H), 10.12 (s, 1H); MS (ESI/APCI+) m/e 365 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[N:9]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=4)=[CH:30][CH:29]=3)[CH:10]=[C:11]([C:13]3[CH:27]=[CH:26][C:16]([O:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:15][CH:14]=3)[N:12]=2)[CH2:3][CH2:2]1.[CH:42](=O)[CH3:43].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:42]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[N:9]([C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]4[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=4)=[CH:32][CH:33]=3)[CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:26][CH:27]=3)[N:12]=2)[CH2:3][CH2:2]1)[CH3:43]
Reactant: CC=O
Reactant: CCN(CC)CCCOc1ccc(-c2cn(-c3ccc(Oc4ccc(Cl)cc4)cc3)c(CC3CCNCC3)n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)CCCOc1ccc(-c2cn(-c3ccc(Oc4ccc(Cl)cc4)cc3)c(CC3CCN(CC)CC3)n2)cc1
Temperature: 25 °C

Procedure:
[3-(4-{2-(Piperidine-4-ylmethyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine (Example 539) (0.1 mmol) was treated in anhydrous DCM (2 ml) with acetaldehyde (1.2 eq.) followed by addition of Na(OAc)3BH (1.5 eq.). The reaction mixture was stirred at rt. Crude product was extracted into EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concenterated in vacuo to give desired product, which was purified by column chromatography on silica gel to afford 49 mg of Example 540.
Reaction SMILES: C(S(N1CCC(C2[C:20]3[C:15](=[C:16]([C:33](N)=O)[CH:17]=C(C4SC(CNCC(C)CC)=CC=4)C=3)[NH:14]C=2)CC1)(=O)=O)C.[CH:36]([C:38]1[S:42][C:41]([B:43]([OH:45])[OH:44])=[CH:40][CH:39]=1)=O.C[C@@H](N)C(C)C.[BH3-]C#N.[Na+]>>[CH3:20][C@@H:15]([NH:14][CH2:36][C:38]1[S:42][C:41]([B:43]([OH:45])[OH:44])=[CH:40][CH:39]=1)[CH:16]([CH3:33])[CH3:17]
Reactant: CCC(C)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Reactant: O=Cc1ccc(B(O)O)s1
Agent: CC(C)[C@@H](C)N
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)[C@@H](C)NCc1ccc(B(O)O)s1

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [(1R)-1,2-dimethylpropyl]amine (28 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 20.5 mg of the title compound (30%).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:15]2=[CH:16][CH:17]=[N:18][CH:19]=[C:14]2[C:5]2[C:6]([OH:13])=[CH:7][C:8]([CH:10]([CH3:12])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:21].[N:22]1([CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:21].[CH3:20][C:2]1([CH3:1])[C:15]2=[CH:16][CH:17]=[N:18][CH:19]=[C:14]2[C:5]2[C:6]([O:13][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:7][C:8]([CH:10]([CH3:12])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCCCC1
Reactant: CC(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CC(C)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-iso-propyl-10-[4-(piperidino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-iso-propyl-5H-[1]benzopyrano[3,4-d]pyridine and γ-piperidinobutyric acid hydrochloride in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: [H][H].[C:3]1([CH:9]([CH3:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1C=CC=CC=1>[C:3]1([CH:9]([CH3:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:4]=[CH:3][CH3:8]
Reactant: [H][H]
Solvent: c1ccccc1
Solvent: CC(C)c1ccccc1
Product: C=CC

Procedure:
A stainless steel reaction tube with a glass-coated inside was filled with 0.1 g of a carrier molded into 0.5 to 1.0 mm in size, and a pretreatment was carried out in a stream of gaseous hydrogen of 80 ml/min in rate for three hours. 1 μl of cumene was injected into the tube at a reaction temperature of 200° C. to obtain the cracking ratios (mol %) of cumene to propylene and benzene.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10](=[O:19])[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:9])(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>ClCCl>[F:21][C:22]([F:27])([F:26])[C:23]([O-:25])=[O:24].[CH2:12]([NH:11][C:10]([C@@H:8]([NH3+:7])[CH3:9])=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]([NH3+])C(=O)NCc1ccccc1
Product: O=C([O-])C(F)(F)F
Reaction time: 4 h

Procedure:
To a solution of ((S)-1-benzylcarbamoyl-ethyl)-carbamic acid tert-butyl ester (180 mg, 0.645 mmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.500 mL, 6.73 mmol). The reaction mixture was stirred for 4 h. The reaction mixture was then concentrated in vacuo to afford (S)-1-benzylcarbamoyl-ethyl-ammonium trifluoro-acetate, m/z 179.2 [M+1]+.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3](O)=O.[N-:8]=[N+:9]=[N-:10].[Na+].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[Mg]Br.[OH-].[NH4+]>C(Cl)(Cl)Cl>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:2]1([N:8]=[N+:9]=[N-:10])[CH2:3][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)C(Cl)(Cl)Cl
Reactant: Br[Mg]c1cccs1
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: [N-]=[N+]=NC1(c2cccs2)CCCCC1
Temperature: 10 °C
Reaction time: 48 h

Procedure:
Trichloracetic acid (31.9 g, 195 mmoles) is dissolved in chloroform (200 ml). Sodium azide (8.45 g, 130 mmoles) is added and the medium is cooled down to 10° C. The alcohol obtained in Stage 17a (11.8 g, 65 mmoles) dissolved in chloroform (50 ml) is added dropwise. The reaction medium is agitated for 48 hours whilst maintaining the temperature at 10-12° C. A solution of ammonium hydroxide (10%) is then added until neutralisation, then the aqueous phase is extracted with dichloromethane (3×100 ml). The organic phase is washed with water (200 ml), dried over Na2SO4 and concentrated to dryness. In this way, a brown oil is obtained which is then used without further purification.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH2:8]([O:15][C:16]([N:18]1[CH2:24][C:23]2[CH:25]=[C:26]([O:32][CH3:33])[C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:22]=2[NH:21][C:20](=[O:34])[CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.I[CH2:36][CH3:37]>CCCCCC>[CH2:8]([O:15][C:16]([N:18]1[CH2:24][C:23]2[CH:25]=[C:26]([O:32][CH3:33])[C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:22]=2[N:21]([CH2:36][CH3:37])[C:20](=[O:34])[CH2:19]1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCI
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CN(C(=O)OCc1ccccc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCN1C(=O)CN(C(=O)OCc2ccccc2)Cc2cc(OC)c([N+](=O)[O-])cc21
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution of Sodium hydride (0.135 g, 0.00338 mol;) and N,N-Dimethylformamide (40 mL, 0.5 mol;) was added at 5° C. 7-Methoxy-8-nitro-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid benzyl ester (1.00 g, 0.00269 mol) and stirred for 1 hour at room temperature. Iodoethane (0.286 mL, 0.00358 mol) was added and stirred for 3 hours. The solvent was evaporated and the residue taken up in water and ethyl acetate, separated, washed, dried and evaporated to a give a gum. Trituration with hexane gave 1-Ethyl-7-methoxy-8-nitro-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-carboxylic acid benzyl ester as a red solid (1.01 g). (94%). Mp 55-56° C. LCMS (m/e) 400 (M+1); 1H-NMR (DMSO, 400 MHz) δ 8.02 (s, 1H), 7.58 (s, 1H), 7.50-7.30, (br, 5H), 5.15 (s, 2H), 4.56-4.48 (br, 2H), 3.94 (s, 3H), 3.91-3.84 (m, 4H), 1.05-1.01 (t, 3H, J=7.07 Hz).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[F:5][CH:6]([F:15])[O:7][C:8]1[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1.BrBr.O>C(O)(=O)C>[F:15][CH:6]([F:5])[O:7][C:8]1[N:13]=[C:12]2[S:1][C:2]([NH2:3])=[N:14][C:11]2=[CH:10][CH:9]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(OC(F)F)nc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2ccc(OC(F)F)nc2s1
Temperature: 25 °C
Yield: 36.1 %

Procedure:
To acetic acid (10 mL) cooled in an ice bath was added potassium thiocyanate (3.18 g, 32.8 mmol) and 6-(difluoromethoxy)pyridin-3-amine (1 g, 4.1 mmol). The reaction was cooled in an ice-salt bath until the reaction temperature reached <0° C. A solution of bromine (0.65 mL, 12.7 mmol) in acetic acid (3 mL) was added dropwise over 2 hours at a rate that maintained the reaction temperature <0° C. This gave a very thick mixture. After the addition was complete, the mixture was left to stir and allowed to slowly warm to room temperature overnight. After stirring overnight, water (5 mL) was added and the mixture was heated to 85° C. in an oil bath. This mixture was then filtered while still hot. The yellow filter cake was returned to the reaction flask, and an additional 5 mL acetic acid was added. The mixture was heated again to 85° C., and then filtered while still hot. The combined filtrates were cooled in an ice bath and neutralized to pH 8 with concentrated ammonium hydroxide. A yellow precipitate formed which was then collected by filtration. This crude material was purified by column chromatography (12-100% ethyl acetate/hexanes) to afford 5-(difluoromethoxy)thiazolo[5,4-b]pyridin-2-amine (321 mg, 1.48 mmol, 36.1% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.64-7.81 (m, 2 H), 6.92 (d, J=8.53 Hz, 1 H). MS (LC/MS) R.T.=1.66; [M+H]+=218.10.
Reaction SMILES: [C:1]1(=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([CH2:11][C:12]([OH:14])=[O:13])[CH2:2]1.[CH2:16](O)[CH3:17]>C1C=CC=CC=1>[CH2:16]([O:13][C:12](=[O:14])[CH2:11][CH:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[O:15])[CH2:2]1)[CH3:17]
Reactant: CCO
Reactant: O=C(O)CC1CC(=O)c2ccccc2C1
Solvent: c1ccccc1
Product: CCOC(=O)CC1CC(=O)c2ccccc2C1
Yield: 100 %

Procedure:
A solution of 28.3 g of 2-(1,2,3,4-tetrahydro naphthalene 1-one 3-yl)acetic acid (VIII) in 150 ml of ethanol, 30 ml of 7 N hydrochloric ethanol and 150 ml of benzene is brought to reflux for 8 hours. Then the solvents are evaporated, the residue is taken up in ether, washed with water, dried on sodium sulfate, filtered and the filtrate evaporated. 38 g (Yield ~100%) of 2-(1,2,3,4-tetrahydro naphthalene 1-one 3-yl)acetic acid ethyl ester are obtained, the NMR spectrum of which has the following characteristics: δppm=7.8 to 8.1, m (aromatic H at 8); 7.2 to 7.6, m (aromatic H at 5, 6 and 7); 4.15, q (COO--CH2); 2.4 to 3, m (7 H: protons at 2,3,4 and CH2 --CO--O--); 1.25, t (CH3).
Reaction SMILES: [C:1](Cl)(=[O:14])[O:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.[NH:16]1[CH2:21][CH:20]=[CH:19][CH2:18][CH2:17]1.C([O-])(O)=O.[Na+]>C1COCC1.O>[N:16]1([C:1]([O:2][CH2:3][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=2)=[O:14])[CH2:21][CH2:20][CH:19]=[CH:18][CH2:17]1
Reactant: C1=CCNCC1
Reactant: O=C(Cl)OCc1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccc2ccccc2c1)N1CC=CCC1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
Naphthalen-2-ylmethyl carbonochloridate (11.00 g, 49.85 mmol) was dissolved in THF (25 mL) and this was added dropwise to a cooled (0° C.) solution of 1,2,3,6-tetrahydropyridine (3.79 ml, 41.5 mmol) and NaHCO3 (4.18 g, 49.8 mmol) in water (88 mL). A precipitate formed in the reaction immediately, therefore after the addition, additional THF (63 mL) was added to solubilize the reaction mixture. The solution was removed from the bath and warmed to ambient temperature for 16 hours. The reaction was concentrated in vacuo then methylene chloride was added. The mixture was separated, the aqueous layer was washed with methylene chloride, and the combined organics were dried over Na2SO4 and concentrated in vacuo to provide the desired product as an oil (11 g).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH3:13][O:14][C:15]1[C:20]([F:21])=[C:19](F)[C:18]([N+:23]([O-:25])=[O:24])=[C:17]([F:26])[C:16]=1[F:27]>CN(C)C=O>[CH3:13][O:14][C:15]1[C:16]([F:27])=[C:17]([F:26])[C:18]([N+:23]([O-:25])=[O:24])=[C:19]([N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])[C:20]=1[F:21]
Reactant: COc1c(F)c(F)c([N+](=O)[O-])c(F)c1F
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: COc1c(F)c(F)c([N+](=O)[O-])c(N2C(=O)c3ccccc3C2=O)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
4.62 g (0.025 mole) of potassium phthalimide were added to a solution of 5.41 g (0.024 mole) of 4-methoxy-2,3,5,6-tetrafluoro-1-nitrobenzene (XXXIII) in 100 ml of dimethylformamide, and the mixture was stirred at room temperature for 3 hours. At the end of this time, the solvent was removed by evaporation under reduced pressure, the residue was dissolved in toluene, and the solution was washed with water, dried and concentrated by evaporation under reduced pressure to give an oily substance. This oily substance was subjected to silica gel column chromatography eluted with toluene, to afford 5.07 g of 4-methoxy-2-phthalimido-3,5,6-trifluoro-1-nitrobenzene (XXXIV) as pale yellow powdery crystals.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH3:8][O:9][Si:10]([CH2:15][CH2:16][CH2:17][Cl:18])([O:13][CH3:14])[O:11][CH3:12]>C(OCC)(=O)C>[Cl-:18].[CH3:8][O:9][Si:10]([CH2:15][CH2:16][CH2:17][N+:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:1][CH3:2])([O:13][CH3:14])[O:11][CH3:12]
Reactant: CCN(CC)CC
Reactant: CO[Si](CCCCl)(OC)OC
Solvent: CCOC(C)=O
Product: CC[N+](CC)(CC)CCC[Si](OC)(OC)OC
Product: [Cl-]

Procedure:
3.0 g of triethylamine and 18 g of ethyl acetate were charged into a 100 mL flask to be dissolved. While stirring the resultant mixed solution with a magnetic stirrer, to the mixed solution, a solution in which 8.8 g of trimethoxysilylpropyl chloride was dissolved in 24 g of ethyl acetate was gradually added at room temperature in a nitrogen atmosphere. The reaction mixture was refluxed over 3 days and therefrom, ethyl acetate was distilled off under reduced pressure. The resultant concentrate was dropped into 100 mL of diethyl ether and therefrom, triethylamine and trimethoxysilylpropyl chloride as by-products were removed. This purification was repeated three times and then remaining diethyl ether was distilled off under reduced pressure, followed by dissolving the resultant concentrate in methanol to obtain a 30% methanol solution of trimethoxysilylpropyltriethylammonium chloride.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12].C(N(C(C)C)CC)(C)C>CN(C=O)C.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>[CH3:14][Si:13]([C:11]#[C:12][C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)([CH3:16])[CH3:15]
Reactant: Brc1cnc2cccnn12
Reactant: C#C[Si](C)(C)C
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: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cnc2cccnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A mixture of 3-bromoimidazo[1,2-b]pyridazine (36.78 g, 0.186 mol; prepared according to Stanovnik, B. et al. Synthesis (1981), 12, 987-989), ethynyltrimethylsilane (21.89 g, 0.223 mol), Pd(PPh3)4 (10.73 g, 9.29 mmol), Cul (5.30 g, 0.028 mol), and diisopropylethylamine (32.4 mL, 0.279 mol) in 150 mL of DMF was stirred at ambient temperature, under an atmosphere of N2, for 1 h. The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 0-5% MeOH/DCM) to provide 28.46 g of product.
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:7]=[C:8](/[CH:12]=[CH:13]/[CH2:14][N:15]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[C:23]([C:34](=[O:36])[NH2:35])[CH:22]=2)[S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH:9]=[CH:10][CH:11]=1)(=[NH:5])[NH2:4].CO[C:39]1[CH2:40][CH2:41][CH2:42][N:43]=1.N1CCCC1=O.Cl>C(O)C.O.C(N(CC)CC)C>[ClH:1].[ClH:1].[C:3]([C:6]1[CH:7]=[C:8](/[CH:12]=[CH:13]/[CH2:14][N:15]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]3[CH2:33][CH2:32][N:31]([C:39]4[CH2:40][CH2:41][CH2:42][N:43]=4)[CH2:30][CH2:29]3)=[C:23]([C:34](=[O:36])[NH2:35])[CH:22]=2)[S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH:9]=[CH:10][CH:11]=1)(=[NH:4])[NH2:5]
Reactant: COC1=NCCC1
Reactant: CCS(=O)(=O)N(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCNCC2)c(C(N)=O)c1
Agent: Cl
Agent: O=C1CCCN1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCS(=O)(=O)N(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCN(C3=NCCC3)CC2)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 147 %

Procedure:
To a solution of N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[3-carbamoyl-4-(piperidin-4-yloxy)phenyl]ethanesulfonamide dihydrochloride (0.68 g) obtained in example 100(a) in ethanol (15 ml) were added successively 5-methoxy-3,4-dihydro-2H-pyrrole (0.36 g), which was prepared from 2-pyrrolidinone according to the method described in Org. Prep. Proced. Int., 24, 147 (1992), and triethylamine (0.85 ml) at room temperature and the resulting mixture was allowed to stand at room temperature overnight. At the end of this time, to the reaction mixture were furthermore added successively 5-methoxy-3,4-dihydro-2H-pyrrole (0.19 g) and triethylamine (0.34 ml) at room temperature, and the resulting mixture was stirred at room temperature for 5 hours and then evaporated in vacuo. Subsequently, to the residue obtained were successively added ethanol (10 ml) and a 4N solution of hydrogen chloride in dioxane (4 ml), and the resulting mixture was evaporated in vacuo. The residue obtained was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: 10% acetonitrile/water). To the amorphous solid obtained was added 1N hydrochloric acid (8 ml) and the resulting mixture was evaporated to dryness in vacuo. The residue obtained was dissolved in water and then lyophilized to afford the title compound (0.56 g, yield: 73%) as a pale brown amorphous solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].C(N(CC)CC)C.O>C(OCC)C>[S:8]([O:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: CCOC(=O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)COS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of ethyl glycolate (500 mg, 4.8 mmol) and tosyl chloride (915 mg, 4.8 mmol) in anhydrous diethyl ether (2 ml) at 0° C. was treated dropwise with triethylamine (1.34 ml, 9.6 mmol). The temperature was maintained at 0° C. with stirring for a further 2 h. After this time, water was added and the phases separated. The aqueous phase was extracted with fresh diethyl ether. The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo. The crude product was purified by column chromatography over silica gel (Rf=0.29, 25% ethyl acetate in hexane) affording the tosylate 2 as a colorless oil which solidified on standing as a white solid (868 mg, 70%). [This procedure was repeated on 2× scale (1.8 g, 73%)]. δH (400 MHz, CDCl3) 1.22-1.27 (3H, m, CH3), 2.46 (3H, s, ArCH3), 4.16-4.22 (2H, m, CH2CH3), 4.58-4.59 (2H, m, OCH2), 7.36 (2H, d, J=8.2 Hz, ArH), 7.84 (2H, d, J=8.2 Hz, ArH); δc (100.6 MHz, CDCl3) 14.2, 21.9, 62.1, 64.9, 128.3, 130.1, 132.9, 145.5, 166.2; MS (ES+) 276.0 (100%, [M+H2O]+) (ion not detected in ES−).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([N:14]=[C:15]=[S:16])=[O:13])[CH3:10].C(N(CC)CC)C>O1CCCC1>[C:12]([NH:14][C:15](=[S:16])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O:11][CH2:9][CH3:10])=[O:13]
Reactant: CCOC(=O)N=C=S
Reactant: OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)NC(=S)OCc1ccccc1
Yield: 71.6 %

Procedure:
A mixture of 162 g of benzyl alcohol and 196 g of ethoxycarbonyl isothiocyanate and 1 ml of triethylamine in 1 liter of tetrahydrofuran was refluxed for 24 hours and was concentrated to dryness. The residue was washed with petroleum ether and isopropyl ether to obtain 256 g of benzyl N-carbethoxy-thiocarbamate melting at 96° C.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[NH2:11][OH:12].C(Cl)Cl>O.C(Cl)(Cl)Cl>[CH2:7]([O:6][C:4](=[O:5])[C:3](=[N:11][OH:12])[CH2:2][Br:1])[CH3:8]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(CBr)=NO

Procedure:
Ethyl bromopyruvate (5.0 mL, 39.8 mmol) was added to hydroxylamine hydrochloride (2.52 g, 36.2 mmol) in H2O (10 mL) and CHCl3 (10 mL). The reaction mixture was capped and stirred overnight at 23° C. at which time CH2Cl2 and H2O were added, the layers separated, the organics dried over Na2SO4, and the volatiles removed on a rotary evaporator to yield 7.58 g (100%) of as a white solid. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.26 (t, J=7.12 Hz, 3 H) 4.20 (s, 2 H) 4.24 (m, 2 H) 13.19 (s, 1 H).