Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](OCC)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:29])[N:27]=2)[CH2:22]1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: C[Al](C)C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(C)(C)[Si](OC1CN(c2nc(C(=O)N3CCOCC3)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (1.0 g, 2.14 mmol) (obtained as described in Reference Example 2(1)) in benzene (50 ml) was added a solution of 0.67M morpholine-trimethylaluminium in benzene (6.42 ml) at room temperature under an atmosphere of nitrogen. The reaction mixture was heated under reflux for 2 hours. After checking the completion of the reaction, 10% aqueous acetic acid solution (50 ml) and ethyl acetate (100 ml) were added to the reaction mixture in an ice bath, and then the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1→1:3) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-morpholinocarbonyl-1,3-thiazol-2-yl)azetidine (1.05 g, yield 97%) as a pale brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.7 %

Procedure:
To a solution of (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (11 g, 57 mmol) and triethylamine (17.3 g, 171 mmol) in tetrahydrofuran (180 ml) was added methanesulfonyl chloride (9.8 g, 85.5 mmol) at 5° C. The mixture was stirred for 3 hours at room temperature, poured into water, and extracted with ethyl acetate. The organic extract was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford (S)-3-methanesulfonyloxypyrrolidine-1-carboxylic acid tert-butyl ester (16.9 g, quant.) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:14][N:15]=[C:16]=[S:17]>C(OCC)C>[CH3:14][NH:15][C:16](=[S:17])[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CN=C=S
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Agent: CCOC(=O)C(=O)c1csc(=N)[nH]1
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1csc(NC(=S)NC)n1
Reaction time: 5 h

Procedure:
A mixture of ethyl 2-(2-amino-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (20 g.) and methyl isothiocyanate (73 g.) was stirred for 5 hours at 90° to 95° C. After the reaction, to the reaction mixture was added diethyl ether. The precipitates were collected by filtration, washed with diethyl ether and then dried to give ethyl 2-[2-[3-(methyl)thioureido]-1,3-thiazol-4-yl]glyoxylate, which can be represented as ethyl 2-[2-[3-(methyl)thioureido]-2,3-dihydro-1,3-thiazol-4-yl]glyoxylate, (21.3 g.), mp. 121° to 123° C.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.Cl.[C:9]([C@@H:12]1[CH2:16][C@H:15]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14][NH:13]1)(=[O:11])[NH2:10].[OH-].[Na+]>O1CCOCC1>[C:9]([C@@H:12]1[CH2:16][C@H:15]([S:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:14][N:13]1[CH3:5])(=[O:11])[NH2:10]
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc(CS[C@@H]2CN[C@H](C(N)=O)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)N(C)C2)cc1
Reaction time: 1 h

Procedure:
10.86 ml of dimethyl sulfate were added to a solution of 30 g of (2S,4S)-2-carbamoyl-4-(4-methoxybenzylthio)pyrrolidine hydrochloride in a mixture of 36 ml of 20% w/v aqueous solution of sodium hydroxide and 470 ml of dioxane, and the resulting mixture was stirred at a temperature of between 22° C. and 23° C. for 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was extracted with 2 liters of ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solution was then concentrated by evaporation under reduced pressure, until crystals emerged, and then 400 ml of diisopropyl ether were added to the mixture and the crystals which precipitated were collected by filtration, to give 23 g of the title compound as crystals, melting at 113°-114° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.[S:18]([CH2:22][CH2:23][C:24](O)=[O:25])(=[O:21])(=[O:20])[NH2:19].C(Cl)CCl.C1C=C2N=NN(O)C2=CC=1.O>CN(C=O)C>[NH2:19][S:18]([CH2:22][CH2:23][C:24]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:12]=1)=[O:25])(=[O:21])=[O:20]
Reactant: NS(=O)(=O)CCC(=O)O
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: NS(=O)(=O)CCC(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.5 %

Procedure:
To a solution of (3-quinoxalin-2-ylphenyl)amine (120 mg, 0.545 mol) and 3-sulfamoylpropanoic acid (100 mg, 0.654 mmol) in dry DMF (3 mL), EDC (115 mg, 0.6 mmol) and HOBt hydrate (92 mg, 0.6 mmol) were added and the reaction mixture stirred at room temperature for 24 hrs. The solvent was evaporated in vacuo (45° C., 0.1 mbar) and the residue was triturated with DCM (10 mL) and filtered. The solid was triturated with hot acetonitrile, filtered hot and dried to afford 3-(aminosulfonyl)-N-[3-(2-quinoxalinyl)phenyl]propanamide (78 mg, 40%). LCMS calculated for C17H16N4O3S (M+H): 357.41. found 357.24. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.41 (1H, br.), 9.50 (1H, s), 8.53 (1H, m), 8.15 (2H, m), 8.02 (1H, m), 7.94-7.80 (3H, m), 7.55 (1H, m), 6.88 (2H, br.), 3.35 (2H, t, J=7.2 Hz), 2.85 (2H, t, J=7.2 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].CN(C)[CH:13]=[O:14]>>[CH3:13][O:14][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CN(C)C=O
Reactant: O=C(O)CCCCCCBr
Product: COCCCCCCC(=O)O

Procedure:
The title compound was prepared by the method of Example 1 using 7-bromoheptanoic acid (50 g, 239 mmol) instead of 12-bromoundecanoic acid and dimethylformamide (300 mL) instead of methanol as the solvent. Concentration afforded the title compound (30 g) as a pale yellow liquid and the structure verified by NMR.
Reaction SMILES: FC1(F)CC[N:5](C(C2C=CC(C(F)(F)F)=CC=2)CN)[CH2:4]C1.[CH3:22][C:23]1[N:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:22][C:23]1[N:28]=[CH:27][C:26]([CH:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:4][NH2:5])=[CH:25][CH:24]=1
Reactant: Cc1ccc(C=O)cn1
Reactant: C1COCCN1
Reactant: NCC(c1ccc(C(F)(F)F)cc1)N1CCC(F)(F)CC1
Product: Cc1ccc(C(CN)N2CCOCC2)cn1

Procedure:
This compound was prepared using a method analogous to that of 2-(4,4-difluoropiperidin-1-yl)-2-(4-(trifluoromethyl)phenyl)-ethanamine (A.2.18), 6-methyl-pyridine-3-carboxaldehyde replacing 4-(trifluoromethyl)benzaldehyde and morpholine replacing 4,4-difluoropiperidine HCl.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1.C(OC(=O)C)(=O)C>C(O)(=O)C>[N+:1]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:5][N:6]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2[nH]ncc2c1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Nitric acid (2 mL) was added to a stirred solution of indazole (5.0 g, 42 mmol) in acetic acid (40 mL) at 0° C. The resulting mixture was stirred at RT for 30 min. Acetic anhydride (6 mL) was added in one portion and the mixture was stirred at RT overnight. The solvent was removed under reduced pressure and the residue was purified by chromatography to give 3-nitro-1 H-indazole (3.4 g, 49% yield). 1H NMR (400 MHz, DMSO-d4): δ 14.46 (s, 1 H), 8.12 (m, 1 H), 7.76 (m, 1 H), 7.57 (m, 1 H), 7.48 (m, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl.[OH-:16].[Na+]>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:8][CH:7]([OH:10])[CH2:14][O:15][C:13]2[CH:11]=[CH:9][C:4]([N+:1]([O-:2])=[O:16])=[CH:5][CH:6]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: [OH-]
Reactant: ClCC1CO1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCC(O)COc2ccc([N+](=O)[O-])cc2)cc1
Yield: 80.6 %

Procedure:
A solution of 1 g (7.2 mmol) of 4-nitrophenol, 0.28 ml (3.6 mmol) of epichlorohydrin, and 0.16 g (3.96 mmol) of sodium hydroxide in 2 ml of dimethylformamide was heated at 110° C. for 1 h. The solvent was removed in vacuo, and the residue was purified by flash chromatography using chloroform to give 0.97 g (81%) of the desired compound (Rf 0.42, 40% ethyl acetate in chloroform). 1H NMR (CDCl3) δ 2.54 (d, 5 Hz, 1H), 4.28 (dd, J=10, 6 Hz, 2H), 4.29 (dd, J=10, 5 Hz, 2H), 4.50 (br sextet, J=6 Hz, 1H), 7.0-7.05 (m, 4H), 8.2-8.3 (m, 4H). Mass spectrum (M+NH4)+ =352.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[CH3:22][CH:23]1[O:28][CH:27]([CH3:29])[CH2:26][N:25]([C:30]2[CH:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=2)[CH2:24]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:36][C:33]3[CH:32]=[CH:31][C:30]([N:25]4[CH2:26][CH:27]([CH3:29])[O:28][CH:23]([CH3:22])[CH2:24]4)=[CH:35][N:34]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21]
Reactant: CC1CN(c2ccc(N)nc2)CC(C)O1
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CC(C)OC(C)C4)cn3)ncc12
Temperature: 25 °C
Yield: 25.8 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.70 mmol) and 5-(2,6-dimethyl-morpholin-4-yl)-pyridin-2-ylamine (0.668 g, 3.73 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was collected by filtration and washed on the funnel with toluene (3×10 mL) to give 6-bromo-8-cyclopentyl-2-[5-(2,6-dimethyl-morpholin-4-yl)-pyridin-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one as a brown solid (0.358 g, 27.3%). MS (APCI) Calc'd for M+1: 513.2. Found: 513.1. Anal. Calc'd for C24H29BrN6O2: C, 56.14; H, 5.69; N, 16.37. Found: C, 55.90; H, 5.62; N, 16.10.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][N:16]=1.[NH2:21][C:22]1[CH:23]=[C:24]2[CH2:39][C:29]3([C:37]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:38])[CH2:28][C:25]2=[N:26][CH:27]=1.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[O:1]=[C:2]1[N:6]([CH2:7][C:8]([NH:21][C:22]2[CH:23]=[C:24]3[CH2:39][C:29]4([C:37]5[C:32](=[N:33][CH:34]=[CH:35][CH:36]=5)[NH:31][C:30]4=[O:38])[CH2:28][C:25]3=[N:26][CH:27]=2)=[O:10])[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][N:16]=1
Reactant: O=C(O)Cn1c(=O)n(-c2ccncn2)c2ccccc21
Reactant: Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1c(=O)n(-c2ccncn2)c2ccccc21)Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (2-oxo-3-pyrimidin-4-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid (62 mg, 0.23 mmol, described in Intermediate 8), (±)-3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol, described in Intermediate 4), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([Br:24])[CH:23]=[C:18]3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH2:25])[CH:10]=1.N1C=CC=C[CH:27]=1.[CH3:32][N:33](C)[S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([Br:24])[CH:23]=[C:18]3[N:17]=[CH:16]2)[CH:12]=[C:11]([N:25]([CH3:27])[S:34](=[O:36])(=[O:35])[NH:33][CH3:32])[CH:10]=1
Reactant: c1ccncc1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(Br)cnc32)c1
Solvent: ClCCl
Product: CNS(=O)(=O)N(C)c1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(Br)cnc32)c1
Reaction time: 16 h
Yield: 55 %

Procedure:
To a solution of N-(2′,4′-difluoro-5-((6-bromo)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)amine (3.0 g, 7.48 mmol) in DCM (10 ml) was added pyridine (3 ml, 37.9 mmol, 2 eq.) followed by dimethylsulfamoyl chloride (1.6 g, 11.22 mmol, 1.5 eq.). The mixture was stirred for 16 h and quenched and extracted as in Example 1(d). The solvent was distilled off to afford the crude product which was purified by preparative HPLC to give the title product in 55% yield (2.1 g).
Reaction SMILES: CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.B.CSC.[CH2:26]([O:33][C:34]1[C:39]2[NH:40][C:41](=[O:43])[S:42][C:38]=2[C:37]([C:44](=[O:47])[CH2:45][Br:46])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.C1COCC1>[CH2:26]([O:33][C:34]1[C:39]2[NH:40][C:41](=[O:43])[S:42][C:38]=2[C:37]([C@@H:44]([OH:47])[CH2:45][Br:46])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)sc12
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Solvent: CSC
Solvent: C1CCOC1
Product: O=c1[nH]c2c(OCc3ccccc3)ccc([C@@H](O)CBr)c2s1
Reaction time: 72 h
Yield: 69.8 %

Procedure:
A solution of [(R)-tetrahyro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c] [1,3,2]-oxazaborole] (22 μl of 1M in toluene) in dry THF(1 ml) was cooled to −5° C., stirring under nitrogen. Borane-methyl sulfide complex (2M solution in THF, 11 μl) was added and stirred for 10 min at −5° C. A solution of 4-(benzyloxy)-7-(bromoacetyl)-1,3-benzothiazol-2(3H)-one (47 mg) in dry THF (1.5 ml) was added dropwise and then another 66 μl of borane-methyl sulfide complex (2M solution in THF). The reaction mixture was left for 72 h at less than 5° C. and then partitioned between 2N HCl and ethyl acetate. The organic solution was dried (MgSO4), filtered and evaporated in vacuo. The residue was purified on a 5 g silica SPE cartridge, eluting with a stepped gradient of 10% to 25% ethyl acetate-cyclohexane mixtures to give the title compound (33 mg). LCMC RT=3.19 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH:13]=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:19]Br.N1(C2CCCCCCC2)CCCCCCN1>C(Cl)(Cl)(Cl)Cl.CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH:13]=[C:12]([Br:19])[C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1=CC(NC(=O)OC(C)(C)C)CC=C1
Reactant: BrBr
Agent: C1CCCC(N2CCCCCCN2)CCC1
Solvent: CC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C1=CC(NC(=O)OC(C)(C)C)CC=C1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2.53 g (10 m mole) of methyl 3-(tert-butoxycarbonylamino)-1,5-cyclohexadienecarboxylate in 40 ml of carbontetrachloride at 0° C. is treated dropwise with 1.60 g (10 m mole) of bromine. The solution is stirred at 25° C. for 12 hours, then evaporated under reduced pressure to afford the crude dibromide which is dissolved in 40 ml of acetone and treated with 1.2 g (10 m mole) of diazabicyclooctane for 12 hours at 25° C. The solvent is evaporated under reduced pressure, and the residue is treated with ether and water. The organic phase is dried and evaporated to afford methyl 3-tert-butoxycarbonylamino-6-bromo-1,5-cyclohexadienecarboxylate.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[C:17](=O)[CH3:18])(=[O:8])=[O:7].Cl.[CH3:24][O:25][C:26](=[O:31])[CH2:27][C:28](=[NH:30])[NH2:29].C[O-].[Na+]>CO>[CH3:24][O:25][C:26]([C:27]1[CH:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6]([CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])(=[O:8])=[O:7])[C:16]([N+:20]([O-:22])=[O:21])=[C:17]([CH3:18])[NH:29][C:28]=1[NH2:30])=[O:31]
Reactant: CC(=O)C(=Cc1ccccc1S(=O)(=O)CCCCCl)[N+](=O)[O-]
Reactant: COC(=O)CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1=C(N)NC(C)=C([N+](=O)[O-])C1c1ccccc1S(=O)(=O)CCCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.3 %

Procedure:
To a solution of 3.2 g of 4-{2-[(4-chlorobutyl)sulfonyl]phenyl}-3-nitro-3-buten-2-one in 25 ml of methanol in a 100 ml single-neck flask at 0° C. was added 1.41 g of amidino-acetic acid methyl ester hydrochloride, followed by 2.2 ml of 25% sodium methoxide in methanol. The mixture was warmed to room temperature and stirred overnight. After removal of the methanol, the residue was partitioned between water and dichloromethane. The organic layer was dried over magnesium sulfate and evaporated to give a crude product, which was purified via column chromatography on silica gel, eluting with 60:40 toluene:ethyl acetate. Recrystallization from isopropyl acetate provided 1.08 g of an orange product, m.p. 218° C. 1H-NMR (d6 -DMSO) δ 1.71-1 95(m,4H); 2.45(s,3H); 2.48-2.55(m,2H); 3.34(s,3H); 3.69(m,2H); 6.49(s,1H); 6.87(br s,2H); 7.33-7.44(m,2H); 7.56(t,1H,J=8 Hz); 7.79(d,1H,J=8 Hz); 9.51(br s,1H). Mass spectrum: 444 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Cl)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[CH:18][CH:17]=1
Reactant: ClCc1ccc(CCl)cc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(N2CCN(Cc3ccc(CCl)cc3)CC2)cc1
Temperature: 0 °C

Procedure:
To an aqueous solution (100 ml) of 1-(4-fluorophenyl)piperazine dihydrochloride was added an aqueous solution (50 ml) of sodium hydroxide (10 g) and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a white solid (ca. 20 g). A solution of this solid (1-(4-fluorophenyl)piperazine), α,α′-dichloro-p-xylene (20.0 g) and potassium carbonate in dimethylformamide (150 ml) was stirred at 75° C. for 2 hr and poured into ice water (500 ml). The mixture was extracted with ethyl acetate (400 ml×2). The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (developing solvent; ethyl acetate:hexane=1:3) and recrystallized from ethyl acetate-hexane to give the title compound (10.66 g) as white crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[O:18][CH2:19][CH2:20][CH2:21][S:22][CH3:23])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].ClC(Cl)C(O)=O>>[F:1][C:2]1[C:3]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH2:19][CH2:20][CH2:21][S:22][CH3:23])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CSCCCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: O=C(O)C(Cl)Cl
Product: CSCCCONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Yield: 79 %

Procedure:
The title compound was obtained by a procedure similar to that in Step C of Example 9. Namely, (E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsulfanyl-propoxyimino)-methyl]-benzamide was reduced with borane-pyridine complex in the presence of dichloroacetic acid to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsulfanyl-propoxyamino)-methyl]-benzamide (26.54 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: BrCc1ccncc1
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4ccncc4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 4-bromomethyl-pyridine gave the title compound.