Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](I)[CH2:2][CH2:3][CH2:4][CH3:5].[NH:7]1[CH2:12][CH:11]=[C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:8]1>CC(C)=O.[Ag]=O>[CH2:1]([N:7]1[CH2:8][CH:9]=[C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:11][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: CCCCCI
Agent: O=[Ag]
Solvent: CC(C)=O
Product: CCCCCN1CC=C(c2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5.18 g of silver oxide and then 20 ml of pentyl iodide were added to a solution of 10 g of 3-(1,2,3,6-tetrahydropyridin-4yl)-1H-indole in 100 ml of acetone and after stirring the mixture for 4 hours at room temperature, another 2.5 ml of pentyl iodide were added thereto. The mixture was stirred for one hour and was filtered and the filter was rinsed with a 1-1 methylene chloride-methanol mixture. The filtrate was evaporated to dryness under reduced pressure at 40° C. and the residue was chromatographed over silica gel. Elution was effected with a 7-2-1 chloroform-methanol-triethylamine mixture and the residue from evaporation of the solvents was extracted with 250 ml of refluxing ethanol. The organic extract was filtered and crystallization of the filtrate was effected at 0° to 5° C. to obtain 7.9 g of 3-(1-pentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole melting at about 180° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O1CCCC1>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc(Br)c1
Reactant: CCCCCCCCCCCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
A 4.87 g portion of magnesium was placed in a two-necked round bottom flask. The flask was flamed several times and 37.4 g of m-bromoanisole and 200 ml of tetrahydrofuran were added. As soon as the reaction stopped it was refluxed for 1 hour and then added to a boiling solution of 52.68 g of tetradecyl bromide in tetrahydrofuran. Then 10 ml of lithium cupric chloride was added and the mixture was refluxed for 1.25 hours, stirred at room temperature for 16 hours, quenched with water, washed with ammonium chloride solution, brine, dried and the solvent removed. The resulting oily residue was distilled in a Kugelrohr apparatus giving 52.4 g of the desired compound as a clear oil, B.P. (120°/0.5 mm).
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:26])[C:14]([CH3:25])([S:16]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH3:15])[O:9][N:8]=1)([CH3:6])[C:3]([OH:5])=[O:4].N12CCCN=C1CCCC[CH2:28]2.CI>C(#N)C>[CH3:28][O:4][C:3](=[O:5])[C:2]([CH3:1])([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:26])[C:14]([CH3:25])([S:16]([CH:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)(=[O:18])=[O:17])[CH3:15])[O:9][N:8]=1)[CH3:6]
Reactant: CC(C)(C(=O)O)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: CC#N
Product: COC(=O)C(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 78.7 %

Procedure:
2-Methyl-2-{5-[2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionylamino]-isoxazol-3-yl}-propionic acid (208 mg, 0.54 mmol) is suspended in acetonitrile (5 mL). 1,8-Diazabicyclo[5,4,0]undec-7-ene (0.096 mL, 0.64 mmol) is added and followed by the addition of methyl iodide (0.073 mL, 1.18 mmol). The reaction mixture is stirred at room temperature for 3.5 h. After this time, the reaction mixture is quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate twice. The combined organics are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (silica, eluent: DCM, MeOH) to provide 171 mg of the title compound. Yield: 79%; m/z 403 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH2:11].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C(O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]=[CH:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: COC(=O)c1cc(F)ccc1N
Solvent: CCO
Product: COC(=O)c1cc(F)ccc1N=Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 51.1 %

Procedure:
A mixture of 2-amino-5-fluoro-benzoic acid methyl ester (15 g, 89 mmol) and 3-bromo-benzaldehyde (16.4 g, 89 mmol) in ethanol (200 mL) was heated to reflux for 2 hours. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 2-{[1-(3-bromo-phenyl)-methylidene]-amino}-5-fluoro-benzoic acid methyl ester (15.3 g, 52%) as a white solid: LC/MS m/e calcd for C15H11BrFNO2 M+: 336.2, observed: 336.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:24][CH2:23][C:9]2[N:10]3[C:19]4[C:18]([C:8]=2[CH2:7]1)=[CH:17][CH:16]=[CH:15][C:14]=4[N:13]([CH3:20])[CH2:12][C:11]3([CH3:22])[CH3:21])=[O:5])[CH3:2].[BH3-]C#N.[Na+]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:24][CH2:23][CH:9]2[N:10]3[C:19]4[C:18]([CH:8]2[CH2:7]1)=[CH:17][CH:16]=[CH:15][C:14]=4[N:13]([CH3:20])[CH2:12][C:11]3([CH3:21])[CH3:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2c(c3cccc4c3n2C(C)(C)CN4C)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2C(C)(C)CN3C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl-1,1,3-trimethyl-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (69 mg, 0.21 mmol) in TFA (2 mL) at 0° C. was added NaBH3CN (53 mg, 0.84 mmol). The mixture was stirred at rt for 4 hours, and then removed the TFA by N2. About 10 mL of H2O was added and then was extracted with EtOAc (2×10 mL). The combined extracts were dried over magnesium sulfate and concentrated to afford ethyl-1,1,3-trimethyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate as an oil which was used for the next reaction (45 mg, 65%). MS [M+H]+330.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[CH:5]2.[C:17](#[N:19])C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[C:5]2[C:17]#[N:19]
Reactant: Clc1ccc2[nH]c(-c3cccnc3)cc2c1
Reactant: CC#N
Product: N#Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12

Procedure:
5-Chloro-2-pyridin-3-yl-1H-indole (Example 87) is processed according to the method described in Example 140, using acetonitrile instead of dichloromethane, to give 5-chloro-2-pyridin-3-yl-1H-indole-3-carbonitrile. 1H NMR (400 MHz, MeOD) δ ppm 7.36 (dd, J=8.6, 2.0 Hz, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.65-7.77 (m, 2H), 8.43 (dt, J=8.1, 2.0 Hz, 1H), 8.72 (d, J=4.8 Hz, 1H), 9.16 (s, 1H). HRMS (ESI) m/z 254.0495 [(M+H)+ calcd for C14H9ClN3: 254.0485].
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C1(C)C=CC(S(O[CH2:16][C:17]([I:21])=[C:18]([I:20])[I:19])(=O)=O)=CC=1>CN(C=O)C>[I:21][C:17](=[C:18]([I:20])[I:19])[CH2:16][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(S(=O)(=O)OCC(I)=C(I)I)cc1
Solvent: CN(C)C=O
Product: IC(I)=C(I)Cn1ccnc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 340 mg (5 mmoles) of imidazole in 5.0 ml of dry DMF were added 606 mg (1 mmole) of 3-p-toluenesulfonyloxy-1,1,2-triiodo-1-propene and the reaction was effected at 25° C. for 2 hours. The reaction mixture was poured into 20 ml of ice-water while stirring vigorously and the mixture was allowed to stand for a further one hour. The crystalline substance thus separated was recovered by filtration, washed with water and then dried. Yield 440 mg (96%), mp 127°-128° C. (with decomposition).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]1([OH:12])[CH2:11][NH:10][CH2:9]1.[F:13][C:14]1[C:15]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:16]([CH:20]=[CH:21][C:22]=1[F:23])[C:17](F)=[O:18]>>[F:13][C:14]1[C:15]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:16]([C:17]([N:10]2[CH2:11][C:8]([C@@H:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]3[OH:1])([OH:12])[CH2:9]2)=[O:18])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: OC1CCCCC1C1(O)CNC1
Reactant: O=C(F)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)([C@@H]2CCCC[C@@H]2O)C1

Procedure:
The compounds of examples 25a and 25b were synthesized starting from benzyl 3-hydroxy-3-(2-oxycyclohenyl)azetidine-1-carboxylate prepared according to the procedure given in example 25. The ketone was reduced to give benzyl 3-hydroxy-3-(2-hydroxycyclohexyl)azetidine-1-carboxylate as a mixture of racemic diastereomers which were subjected to hydrogenation to afford 3-(2-hydroxycyclohexyl)azetidin-3-ol. 3-(2-hydroxycyclohexyl)azetidin-3-ol was then carried forward in a coupling step with 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoyl fluoride in the usual manner. The coupled material thus obtained was purified by preparative reverse phase HPLC where fraction 1 was tentatively assigned as (±)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(trans)-2-hydroxycyclohexyl]azetidin-3-ol (Example 25a) and fraction 2 was tentatively assigned as (±)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(cis)-2-hydroxycyclohexyl]azetidin-3-ol.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][C:10]([O:17][CH3:18])=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([CH3:19])=[CH:4][CH:3]=1.[CH2:20]([N:22]([CH2:27][CH3:28])[CH2:23][CH2:24][NH:25][NH2:26])[CH3:21]>>[CH2:20]([N:22]([CH2:27][CH3:28])[CH2:23][CH2:24][N:25]1[C:2]2[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]3[S:7][C:8]4[CH:9]=[C:10]([O:17][CH3:18])[CH:11]=[CH:12][C:13]=4[C:14]([C:15]=23)=[N:26]1)[CH3:21]
Reactant: CCN(CC)CCNN
Reactant: COc1ccc2c(=O)c3c(Cl)ccc(C)c3sc2c1
Product: CCN(CC)CCn1nc2c3c(c(C)ccc31)Sc1cc(OC)ccc1-2

Procedure:
By the condensation of 1-chloro-6-methoxy-4-methyl-9-thioxanthenone with 2-(diethylamino)ethylhydrazine was obtained 2-(2-(diethylamino)ethyl)-8-methoxy-5-methyl-2H(1)benzothiopyrano[4,3,2-cd]indazole. To 0.18g. of this base in acetone (3 ml.) was added 30% aqueous hydrogen peroxide (0.22 ml.). After standing at room temperature for 90 hours the solution was evaporated under reduced pressure. The solid residue gave crystals m.p. 132° - 133° (decomp.) from acetone which consisted of 2-(2-(diethylamino)ethyl)-8-methoxy-5-methyl-2H(1)benzothiopyrano[4,3,2-cd]indazole N-oxide 1.75 hydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[NH4+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([N:28]3[CH2:29][CH2:30][N:25]([CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:26][CH2:27]3)=[N:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2Oc2ccccc21
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Clc1ccc2c(c1)N=C(N1CCN(Cc3ccccc3)CC1)c1ccccc1O2
Temperature: 25 °C
Yield: 95.6 %

Procedure:
To a stirred solution of 8-chloro-10,11-dihydro-dibenz[b,f][1,4]oxazepin-11-one (0.3 g; 1.22 mmol) in dry toluene (10 mL) at room temperature was added 1-benzyl piperazine (1.0 mL; 5.61 mmol; Aldrich) followed by the dropwise addition of TiCI4 (1M in toluene, 1.47 mL; 1.47 mmol). The reaction mixture was refluxed for 2 hours, cooled to room temperature and then poured into an ammonium hydroxide solution (30%, 50 mL). The resulting mixture was extracted with dichloromethane (4×50 mL), and the combined organic phases were then dried (K2CO3) and concentrated. Purification of the product was conducted on silica gel using ethyl acetate:hexane (5:1→4:1) as the eluant to give 0.471 g (95%) of the title compound as a yellow solid; m.p. 50°-52° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10](Br)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH2:12][CH:11]=[CH2:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C=CCBr
Reactant: Cc1cc(C)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1cc(C)cc(C)c1
Reaction time: 18 h
Yield: 100 %

Procedure:
3,5-Dimethylphenol, 12.2 g (100 mmole), 10.8 ml (125 mmole) of allyl bromide, and 16.56 g (120 mmole) of potassium carbonate was dissolved and then refluxed in 50 mlacetone, with stirring, under nitrogen for 18 hours. The reaction was cooled, the insoluble inorganics were filtered off and stripped to give 16.2 g (100%) of subtitled product, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29](Cl)=[O:30])=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29]([N:41]6[CH2:46][CH2:45][O:44][CH2:43][CH2:42]6)=[O:30])=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)Cl)s5)nn34)ccnc2c1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)N6CCOCC6)s5)nn34)ccnc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophene-2-carbonyl chloride (0.260 g, 0.58 mmol) in dichloromethane (5 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.15 ml, 0.86 mmol) and morpholine (0.15 ml, 1.7 mmol). The solution was stirred at room temperature for two hours then was concentrated in vacuo. The brown residue was purified via MPLC chromatography (eluted with 0-5% methanol in dichloromethane) to yield the product as a tan solid. MS m/z=503.0 [M+1]+. Calc'd for C2H22N6O4S: 502.1.
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][C@H:4]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[O:9][CH2:8][CH2:7][N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.C(=O)([O-])O.[Na+]>C1COCC1>[NH2:1][C:2](=[S:36])[CH2:3][C@H:4]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[O:9][CH2:8][CH2:7][N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC(N)=O)C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC(N)=S)C1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 52.6 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(2-amino-2-oxoethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (528 mg, 1.31 mmol) in THF (6 mL) was added Lawesson's reagent (794 mg, 1.96 mmol), and the mixture was stirred at 70° C. for 2.5 hr. To the reaction mixture was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (289 mg).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)[N:3]=1.[H-].[Na+].I[CH3:38].O>CN(C)C=O>[CH3:38][O:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:26][C:27]=3[CH3:28])=[CH:19][CH:20]=2)[N:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (462 mg) in N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 40.0 mg) was added at 0° C., and the solution was stirred at room temperature for 30 minutes. Iodomethane (0.187 ml) was added to the reaction mixture, which was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-methoxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate was obtained (382 mg, yield: 80%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:16]=3[N:12]2[CH2:11][CH:10]1[CH2:26][C:27]([O:29]C)=[O:28].[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:16]=3[N:12]2[CH2:11][CH:10]1[CH2:26][C:27]([OH:29])=[O:28]
Reactant: CCN(CC)c1cccc2nc3n(c12)CC(CC(=O)OC)N3c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CC)c1cccc2nc3n(c12)CC(CC(=O)O)N3c1ccc(Cl)cc1Cl
Yield: 65.3 %

Procedure:
To a solution of methyl [1-(2,4-dichlorophenyl)-5-(diethylamino)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-2-yl]acetate (Example 72; 50.0 mg, 0.112 mmol) in a mixture of tetrahydrofuran (1 mL) and methanol (0.5 mL) was added 1N sodium hydroxide solution (0.224 mL, 0.224 mmol) at room temperature. After the resultant mixture was stirred at room temperature for 1 hr, the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was washed with ethyl acetate to give the title compound as a solid (31.7 mg, 0.0731 mmol, 65%). Analytically pure material was obtained by recrystallization from ethanol/diisopropyl ether.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:20]([O:22]CC)=[O:21])[C:15]([CH2:16][CH2:17][CH2:18][OH:19])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:20]([OH:22])=[O:21])[C:15]([CH2:16][CH2:17][CH2:18][OH:19])=[C:10]3[CH:9]=[CH:8]2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1CCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1CCCO
Temperature: 60 °C
Reaction time: 5 h
Yield: 94.8 %

Procedure:
To a solution of ethyl 1-(4-fluorobenzyl)-4-(3-hydroxypropyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.41 g, 1.15 mmol) in MeOH (6 mL) was added a solution of sodium hydroxide (92 mg, 2.30 mmol) in 1 mL of water. The resulting mixture was stirred for 5 h at 60° C. The mixture was acidified to pH=6.5 by 1 N HCl and concentrated to afford the title product as brown solid (358 mg, 95% yield). LC-MS (APCl, M+H+): 329.1. HPLC: 96% purity.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:9][CH2:10][CH:11]=[CH2:12])[CH:7]=[CH2:8].CCN(CC)CC>C(OC(=O)C)C>[CH2:6]([N:9]([CH2:10][CH:11]=[CH2:12])[C:3](=[O:4])[CH2:2][Br:1])[CH:7]=[CH2:8]
Reactant: O=C(Br)CBr
Reactant: C=CCNCC=C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
Bromoacetyl bromide (45 g, 0.22 mol) in ethylacetate (25 mL) was added dropwise to a solution of diallyl amine (9.6 g, 0.1 mol), Et3N (15 mL), in ethyl acetate (50 mL) at 0° C. The reaction was then warmed to ambient temperature, and the stirring was continued for about 3 h. The resulting mixture was washed with saturated NaHCO3 solution (3×100 mL) and dried over Na2SO4. The evaporation of the solvent gave 16.2 g of product as a light yellow oil (yield 75%). ESI-MS (m/z): 218 (M+H+). 1H NMR δD (CDCl3): 5.75 (m, 2H, CH), 5.19 (m, 4H, CH2), 3.95 (d, 4H, NCH2), 3.81 (2, 2H, BrCH2).
Reaction SMILES: [OH:1][C@H:2]([CH3:19])[C:3]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:4].[Cl:20][C:21]1[C:26](O)=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O.O1CCCC1>[Cl:20][C:21]1[C:26]([O:1][C@@H:2]([CH3:19])[C:3]([NH:5][CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)=[O:4])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=1
Reactant: C[C@@H](O)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Oc1cc(Cl)cnc1Cl
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](Oc1cc(Cl)cnc1Cl)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a tetrahydrofuran solution (148 ml) of tert-butyl 4-{[(2R)-2-hydroxypropanoyl]amino}piperidine-1-carboxylate (5.13 g), 2,5-dichloropyridin-3-ol (3.40 g) and triphenylphosphine (6.41 g) was added dropwise at room temperature a tetrahydrofuran solution (40 ml) of di-tert-butyl azodicarboxylate (5.63 g) over 10 minutes. The reaction solution was stirred at room temperature for 1 hour, then poured into water, and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 4-({(2S)-2-[(2,5-dichloropyridin-3-yl)oxy]propanoyl}amino)piperidine-1-carboxylate (6.40 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])=[CH:4][C:3]=1[F:19].[CH:20]([Sn](CCCC)(CCCC)CCCC)=[CH2:21]>O1CCOCC1.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>[CH:20]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])=[CH:4][C:3]=1[F:19])=[CH2:21]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of (S)-(−)-N-[[3-[4-iodo-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (5.45 g), vinyltributyltin (5.48 g) and bis(triphenylphosphine)palladium(II) chloride (303 mg) in 1,4-dioxane (72 mL) under N2 is degassed, heated up to reflux, refluxed for seven hours, cooled to ambient temperature and stirred for 12 hours. The mixture is then diluted with ethyl acetate (40 mL) and water (50 mL) and the layers are separated. The aqueous phase is extracted with ethyl acetate (2×30 mL), and the combined organic phase is washed with saline (40 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure and triturated with diethyl ether. The resultant precipitate is filtered to give the title compound, mp 165-166° C.