Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]6[CH:45]=[CH:46][CH:47]=[CH:48][C:43]6=[N:42][C:41]=5[CH3:49])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]6[CH:45]=[CH:46][CH:47]=[CH:48][C:43]6=[N:42][C:41]=5[CH3:49])=[O:59])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4c(C)nc5ccccn45)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4c(C)nc5ccccn45)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(2-methylimidazol[1,2-a]pyridin-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (0.80 g) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.43 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., sodium thiosulfate solution was added to the mixture at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetatehexane 3:1→ethyl acetate), and was recrystallized from ethyl acetate-diisopropylether, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(2-methylimidazol[1,2-a]pyridin-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 163) (456.5 mg) as yellow crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](O)=O)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2].[NH2:21][C:22](=[N:42][OH:43])[C:23]1[CH:24]=[CH:25][C:26]([F:41])=[C:27]([CH:40]=1)[CH2:28][N:29]([CH3:39])[CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:43][N:42]=[C:22]([C:23]3[CH:24]=[CH:25][C:26]([F:41])=[C:27]([CH:40]=3)[CH2:28][N:29]([CH3:39])[CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:21]=2)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2]
Reactant: CN(CCC(=O)OC(C)(C)C)Cc1cc(C(N)=NO)ccc1F
Reactant: CCc1ccccc1-c1ccc(C(=O)O)cc1COC
Product: CCc1ccccc1-c1ccc(-c2nc(-c3ccc(F)c(CN(C)CCC(=O)OC(C)(C)C)c3)no2)cc1COC

Procedure:
The title compound was prepared following procedure described for example 141, step 1, but starting from Intermediate 36 (162.20 mg; 0.60 mmol) and Intermediate 63 (185.47 mg; 0.57 mmol), the crude mixture was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1) to afford the title compound as a colorless oil. 1H NMR (CDCl3) δ 8.42 (d, J=1.4 Hz, 1H), 8.23 (dd, J=7.1, 1.4 Hz, 1H), 8.17 (dd, J=7.9, 1.8 Hz, 1H), 8.12-8.08 (m, 1H), 7.41-7.10 (m, 6H), 4.27-4.17 (m, 2H), 3.66 (br s, 2H), 3.33 (s, 3H), 2.08 (t, J=7.0 Hz, 2H), 2.52-2.31 (m, 4H), 2.28 (s, 3H), 1.45 (s, 9H), 1.05 (t, J=7.5 Hz, 3H). LC/MS (Method B): 560.5 (M+H)+. HPLC (Method A) Rt 5.14 min (Purity: 94.0%).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.C(O)(=O)C.[BrH:18]>>[Br:18][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1
Reactant: O=C1CCc2ccc(CO)cc2N1
Reactant: Br
Solvent: CC(=O)O
Product: O=C1CCc2ccc(CBr)cc2N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
500 mg of 7-(hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one (2.82 mmol, 1 eq.) were dissolved in 1.77 ml of 33% hydrogen bromide in glacial acetic acid (31.0 mmol, 11 eq.) under nitrogen atmosphere and stirred at room temperature for 30 minutes. The reaction mixture was partitioned between aq. saturated sodium hydrogen carbonate solution and dichloromethane/isopropanol 4+1. The aqueous layer was extracted three times with dichloromethane/isopropanol 4+1. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo. The crude product was purified by flash chromatography to yield 175 mg (0.66 mmol, 23.3%) of the analytically pure target compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH2:10][Cl:11])=[CH:5][C:4]=1[CH3:12].[CH2:13]([O:15][P:16]([O:20]CC)[O:17][CH2:18][CH3:19])[CH3:14]>>[Cl:11][CH2:10][C:6]1[CH:5]=[C:4]([CH3:12])[C:3]([CH2:2][P:16]([O:17][CH2:18][CH3:19])([O:15][CH2:13][CH3:14])=[O:20])=[CH:8][C:7]=1[CH3:9]
Reactant: Cc1cc(CCl)c(C)cc1CCl
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cc(C)c(CCl)cc1C)OCC
Temperature: 130 °C

Procedure:
2,5-Bis(chloromethyl)-p-xylene (25 mmol) and triethylphosphite (10 mmol) were combined and heated to 130° C. under a nitrogen atmosphere for 24 hours. The reaction mixture was chromatographed on silica gel (175 gm). The column was eluted with dichloromethane until the excess starting material eluted. The eluting solvent was then changed to 5% ethanol/dichloromethane whereupon the product eluted The appropriate fractions were pooled and concentrated on a rotatory evaporator to give the product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16])[N:8]([CH3:17])[CH:7]=[C:6]2[C:18]1[N:26](S(C2C=CC(C)=CC=2)(=O)=O)[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16])[N:8]([CH3:17])[CH:7]=[C:6]2[C:18]1[NH:26][C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=1
Reactant: COCCOc1cc2c(cc1OC)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Product: COCCOc1cc2c(cc1OC)c(-c1cc3cccnc3[nH]1)cn2C
Yield: 46.5 %

Procedure:
2-[5-Methoxy-6-(2-methoxyethoxy)-1-methyl-1H-indol-3-yl]-1H-pyrrolo[2,3-b]pyridine is prepared by following the procedure described in example 89a, but using 0.102 g of 2-[5-methoxy-6-(2-methoxyethoxy)-1-methyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine and 0.80 ml of 5N potassium hydroxide. After purification by flash-pack chromatography (silica, 92.5/7.5 by volume dichloromethane/methanol as eluents, argon), 0.033 g of 2-[5-methoxy-6-(2-methoxyethoxy)-1-methyl-1H-indol-3-yl]-1H-pyrrolo[2,3-b]pyridine is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([P+:3]([CH2:8]O)([CH2:6]O)[CH2:4]O)O.[Cl-:10].[NH2:11][C:12]([NH2:14])=[O:13]>>[Cl-:10].[NH:11]([CH2:8][P+:3]([CH2:1][NH:11][C:12]([NH2:14])=[O:13])([CH2:4][NH:11][C:12]([NH2:14])=[O:13])[CH2:6][NH:11][C:12]([NH2:14])=[O:13])[C:12]([NH2:14])=[O:13]
Reactant: OC[P+](CO)(CO)CO
Reactant: NC(N)=O
Agent: [Cl-]
Product: NC(=O)NC[P+](CNC(N)=O)(CNC(N)=O)CNC(N)=O
Yield: 100.9 %

Procedure:
Reaction of 80% THPC (23.82 g, 0.1 mol) with urea (24.02 g, 0.4 mol), following Example 3, gave 36.18 g (100.8%) of tetrakis(ureidomethyl)phosphonium chloride (I, R=R'=R"=H, X=Cl) as a colorless, brittle glass, identical (31P NMR) to the product of Example 11.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH:6]1[C:19]2[C:10](=[CH:11][C:12]3[C:17]([C:18]=2[CH:20]=O)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[CH:16]1[C:17]2[C:12](=[CH:11][C:10]3[C:19]([C:18]=2[CH2:20][NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:13]=[CH:14][CH:15]=1
Reactant: NCCCO
Reactant: O=Cc1c2ccccc2cc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OCCCNCc1c2ccccc2cc2ccccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a stirred solution of 3-amino -1-propanol, 15a (0.87 g, 11.65 mmol) in 25% MeOH/CH2Cl2 (20 mL), was added a solution of aldehyde 8 (2.00 g, 9.7 mmol) in 25% MeOH/CH2Cl2 (15 mL) under N2. The mixture was stirred at room temperature overnight until the imine formation was complete (monitored by NMR). The solvent was removed in vacuo, the solid residue dissolved in 50% MeOH/CH2Cl2 (40 mL) and the solution was cooled to 0° C. NaBH4 (29.1 mmol) was added in small portions to the solution and the mixture was stirred at rt overnight. The solvent was removed in vacuo, the solid residue dissolved in CH2Cl2 (40 mL) and washed with 10% aq. Na2CO3 solution (3×30 mL). The CH2Cl2 layer was separated, dried over anhydrous Na2SO4, filtered and removed in vacuo to give an oily residue. The oil was purified by flash column chromatography (6% MeOH/CHCl3) to yield the product 14a as a pale yellow thick oil (78%), Rf=0.3 (6% MeOH/CHCl3); 1H NMR (CDCl3) δ 8.39 (s, 1H), 8.27 (d, 2H), 7.99 (d, 2H), 7.52 (m, 2H), 7.45 (m, 2H), 4.71 (s, 2H), 3.79 (t, 2H), 3.09 (t, 2H), 1.74 (q, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[CH3:46][C:47]1([OH:51])[CH2:50][NH:49][CH2:48]1>CN(C=O)C>[OH:51][C:47]1([CH3:46])[CH2:50][N:49]([C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:13]([CH3:15])[CH3:14])[CH2:48]1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1(O)CNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(C)(O)C1
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
(S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic acid (5.30 g, 24.4 mmol), and TBTU (9.40 g, 29.3 mmol) was mixed in DMF (50 mL). To the mixture was NMM (6.70 mL, 60.99 mmol) added. After 30 min at rt was 3-methylazetidin-3-ol hydrochloride (3.01 g, 24.39 mmol) added. The resultant mixture was stirred at rt over night. The mixture was concentrated and the residue dissolved in DCM (200 mL). The organic phase was washed with NaHCO3 (saturated, 2×150 mL) and brine (150 mL), filtered through a phase separator and concentrated under reduced pressure to give the title compound (7.00 g, quant. yield). The obtained crude product was used without further purification. 1H NMR (400 MHz, CD3OD) δ 0.76-1.07, 1.31-1.56, 1.78-2.04, 2.55-2.73, 3.64-3.98, 4.04-4.42, 6.52-6.84.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C-:30]#[N:31].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[C:30]([CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:31]
Reactant: ClCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 38.6 %

Procedure:
A suspension of 350 mg of 4-chloromethyl-5-((Z)-2-tritylthioethen-1-yl)thiazole, prepared in step a) in Example 2, in 7 ml of DMF was cooled in ice, and 94 mg of sodium cyanide was added to the cooled suspension under an argon atmosphere. The mixture was stirred at room temperature for 2.5 hr, and brine was then added to the reaction solution. The mixture was extracted twice with ethyl acetate, and the organic layers were combined, followed by washing with brine. The washed organic layer was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to give 132 mg of the title compound.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[CH:8]=[O:9]>C1COCC1.Cl[Ti](Cl)(Cl)Cl>[Br:4][C:5]1[CH:6]=[C:7]([CH:8]([OH:9])[CH3:1])[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1
Reactant: O=Cc1cc(Br)cc([N+](=O)[O-])c1
Reactant: C[Mg]Br
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A solution of TiCl4 (9.48 g, 50 mmol) and methylmagnesiumbromide (20.80 ml, 52 mmol, 2.5 M solution in THF) in THF (400 ml) was stirred at −30° C. when 3-bromo-5-nitro-benzaldehyde (9.20 g, 40 mmol) was added as solid. The mixture was stirred for 1 h at −30° C. As the reaction was not complete, the reaction was cooled to −78° C. and 0.65 eq. methylmagnesium bromide and 0.625 eq. TiCl4 were added and stirring was continued at −30° C. This procedure was repeated again to add 0.325 eq. methylmagnesium bromide and 0.313 eq. TiCl4. After complete conversion the reaction was cooled to −78° C. and quenched by addition of 500 ml cold water. 500 ml dichloromethane were added and the reaction was allowed to warm to r.t. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The organic phases were washed with water and brine, combined and dried over Na2SO4. Volatiles were removed under reduced pressure. The crude product was purified by automated column chromatography (cyclohexane/ethyl acetate) yielding the title compound as yellowish oil. 1H-NMR (360 MHz, CDCl3): 8.20 (s, 1H), 8.10 (s, 1H), 7.78 (s, 1H), 4.95 (q, 1H), 1.45 (d, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[C:11]([CH:13]=[N:14][O:15][CH2:16][CH2:17][OH:18])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:20]1[CH:52]=[CH:51][C:23]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]2=[O:50])=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[C:11]([CH:13]=[N:14][O:15][CH2:16][CH2:17][O:18][C:20]3[CH:52]=[CH:51][C:23]([CH2:24][CH:25]4[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:26]4=[O:50])=[CH:22][CH:21]=3)[CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCON=Cc1cncc(-c2ccccc2)c1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1SC(Cc2ccc(OCCON=Cc3cncc(-c4ccccc4)c3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 72.8 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 354 mg of 2-(3-phenyl-5-pyridylmethyleneaminooxy)ethanol (prepared as described in Preparation 11), 510 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 383 mg of triphenylphosphine and 255 mg of diethyl azodicarboxylate, 550 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:21][N:22]=[C:23]=[O:24]>C(Cl)Cl>[CH3:21][NH:22][C:23]([O:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)=[O:24]
Reactant: CN=C=O
Reactant: OCCSc1cccc2nccn12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)OCCSc1cccc2nccn12
Yield: 85.2 %

Procedure:
To a solution of 5-[2-(hydroxy)ethylthio]imidazo[1,2-a]pyridine (971 mg, 5 mmoles) and trietylamine (0.91 ml, 6.53 mmoles) in methylene chloride (40 ml) was added methyl isocyanate (0.65 ml, 11 mmoles) under ice-cooling with stirring and the mixture was stirred at room temperature for 12 hours. The reaction mixture was washed with saturtated saline and dried over anhydrous magnesium sulfater. After the solvent was distilled off, the residue was purified by column chromatography (eluent: methanol/chloroform=1:20) to obtain 1.07 g of the desired product (85.2%, colorless crystals).
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33](=[O:42])[CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)=[S:31])=[CH:25][C:24]=3[F:43])[CH:14]=2)=[N:11][CH:12]=1>C(O)(=O)C>[F:43][C:24]1[CH:25]=[C:26]([NH:29][C:30]([NH:32][C:33](=[O:42])[CH2:34][C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)=[S:31])[CH:27]=[CH:28][C:23]=1[O:22][C:19]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:14]=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([CH:2]=[O:1])=[CH:12][N:11]=3)[S:21][C:20]=12
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Solvent: CC(=O)O
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1
Temperature: 90 °C
Yield: 66.1 %

Procedure:
To a solution of 80% acetic acid (104 mL AcOH/26 mL water) was added 32 (4.01 g, 6.48 mmol). The reaction mixture was heated at 90° C. overnight, cooled to r.t., to form a precipitate which was collected by filtration to afford intermediate 33 (2.4 g, 66% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.51 (s, 1H), 11.86 (s, 1H), 10.14 (s, 1H), 9.14 (s, 1H), 8.66 (d, J=5.6 Hz, 1H) 8.59 (s, 1H), 8.54 (d, J=8.0 Hz, 1H), 8.40 (d, J=8.4 Hz, 1H), 8.07 (d, J=12.8 Hz, 1H), 7.58 (s, 2H), 7.38 (t, J=7.2 Hz, 2H), 7.19 (t, J=8.6 Hz. 2H), 6.83 (d, J=5.6 Hz, 1H), 3.84 (s, 2H). MS (m/z): 560.9 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.Br[C:16]1[CH:17]=[CH:18][C:19]([NH2:23])=[N:20][C:21]=1[F:22].CCN(CC)CC>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:21]1[N:20]=[C:19]([NH2:23])[CH:18]=[CH:17][C:16]=1[C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]=2[CH:8]=1
Reactant: COc1ccc2oc(B(O)O)cc2c1
Reactant: Nc1ccc(Br)c(F)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc2oc(-c3ccc(N)nc3F)cc2c1
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 50.3 %

Procedure:
5-Methoxybenzofuran boronic acid (230 mg, 1.20 mmol), 5-bromo-6-fluoro-pyridin-2-ylamine (191 mg, 1.00 mmol), Pd(PPh3)2Cl2 (16.8 mg, 0.024 mmol) and Et3N (317 μL, 2.27 mmol) were mixed in EtOH (10 mL) in a microwave vial. The reaction mixture was stirred at 140° C. for 15 minutes in a microwave reactor. The volatiles were then removed under reduced pressure, the residue was suspended in water and the product was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification of the crude product by flash column chromatography using 25% ethyl acetate in hexane gave 6-fluoro-5-(5-methoxy-benzofuran-2-yl)-pyridin-2-ylamine (130 mg) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ: 8.05-8.21 (m, 1 H) 7.36 (d, J=8.59 Hz, 1 H) 7.03 (d, J=1.95 Hz, 1 H) 6.97 (d, J=3.12 Hz, 1 H) 6.86 (dd, J=8.78, 2.54 Hz, 1 H) 6.45 (d, J=6.63 Hz, 1 H) 4.66 (br. s., 2 H) 3.86 (s, 3 H)
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:18](=[O:19])[CH:17]=[N:16][C:15]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[N:23][C:14]1=2)C1C=CC=CC=1>C(OCC)(=O)C.ClCCl.[O-2].[O-2].[Mn+4]>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:18](=[O:19])[CH:17]=[N:16][C:15]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[N:23][C:14]1=2
Reactant: COc1ccc2ncc(=O)n(CCCCOCc3ccccc3)c2n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CCCCO)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.9 %

Procedure:
To a solution of 4-[4-(benzyloxy)butyl]-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (847 mg, 2.5 mmol) in ethyl acetate (20 ml) 20% palladium hydroxide (400 mg) was added and the catalytic hydrogenation was carried out at room temperature for 90 minutes. After removing the catalyst by filtration, the solvent was removed under reduced pressure, the obtained residue was dissolved in dichloromethane (20 ml) to which manganese dioxide (1.09 g, 12.5 mmol) was then added, and the mixture was stirred overnight at room temperature. After removing manganese dioxide by filtration, the solvent of the filtrate was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to yield 548 mg (88%) of the title compound in the form of a light brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]([OH:17])([CH3:16])[CH:14]=[CH2:15])[CH2:11][O:10]C1(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(=O)(O)[O-].[Na+]>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:12]([CH2:11][OH:10])[C:13]([OH:17])([CH3:16])[CH:14]=[CH2:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(C)(O)C1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CC(C)(O)C(CO)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a solution of 4-(1-hydroxy-1-methyl-allyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (compound of formula II, 3.3 g, 12.1 mmol, prepared as in Ageno, G.; Banfi, L.; Cascio, G.; Guanti, G.; Manghisi, E.; Riva, R.; Rocca, V. Tetrahedron, 1995, 29, 8121) in 100 ml of methanol was added p-toluenesulfonic acid monohydrate (0.215 g, 1.1 mmol). After stirring for about 30 minutes at a temperature of about 20° C. to about 25° C., the mixture was diluted with saturated aqueous sodium bicarbonate and was concentrated in vacuo. The residue was diluted with water and was extracted 3 times into ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford 2.8 g of (2-Hydroxy-1-hydroxymethyl-2-methyl-but-3-enyl)-carbamic acid tert-butyl ester (compound of formula III) as a colorless syrup.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22](=[CH:28]O)[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22](=[CH:28][NH:16][C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:15][CH:14]=3)[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1
Reactant: Nc1ccc(OCCN2CCCCC2)cc1
Reactant: O=C1Nc2cc(F)ccc2C1=CO
Product: O=C1Nc2cc(F)ccc2C1=CNc1ccc(OCCN2CCCCC2)cc1
Yield: 70 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-piperidin-1-yl-ethoxy)-phenylamine (737 mg, 1.2 equiv.) and 6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.79 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (745 mg, 70%).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:17])[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:17])[CH2:6]1
Reactant: [N-]=[N+]=NCC1CCN(c2ccccc2)C(=O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCC1CCN(c2ccccc2)C(=O)C1
Reaction time: 1 h

Procedure:
4-(Azidomethyl)-1-phenylpiperidin-2-one (0.37 g, 1.3 mmol) was dissolved in tetrahydrofuran (10 mL) and treated with triphenylphosphine (0.36 g, 1.4 mmol, 1.05 equiv). After stirring for 1 hour, the mixture was treated with water (1 mL) and stirred for 14 hours. The mixture was dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.