Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C(=O)([O-])[O-].[Ca+2].P([O-])([O-])([O-])=O.C([O:26][CH:27]([C:29](=[CH2:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:28])(=O)C>>[OH:26][C@@H:27]([C:29](=[CH2:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:28]
Reactant: C=C(C(=O)OCC)C(C)OC(C)=O
Agent: O=C([O-])[O-]
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Product: C=C(C(=O)OCC)[C@@H](C)O
Temperature: 30 °C
Reaction time: 24 h
Yield: 32.3 %

Procedure:
A loopful of slant culture of Bacillus megaterium No. 1253 was inoculated to a medium (80 ml) containing bouillon 1%, glucose 1% and calcium carbonate 0.2%. The flash was incubated with shaking for 24 hours at 30° C. The resultant seed culture (1.6 ml) was inoculated to the same medium (80 ml) and cultured for 2 days at 30° C. Eighty (80) ml of this cultured broth, 3 ml of 1M phosphate buffer (pH 7.5) and 1 g of ethyl 2-(1-acetoxyethyl)acrylate were poured into a 250 ml wide-mouth flask and incubated for 20 hours at 30° C. with shaking. The whole mixture was extracted twice with 40 ml of ethyl acetate and the combined extract was dried. After removal of the solvent in vacuo, the crude material was applied on a silica gel column and developed with a mixture of n-hexane and ethyl acetate (4:1). The fractions containing the desired compounds were collected and dried in vacuo to give 250 mg of ethyl 2-[(1R)-1-hydroxyethyl]acrylate.
Reaction SMILES: C(N(CC)CC)C.O[CH2:9][C@H:10]([CH3:23])[CH2:11][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13]O.CS(Cl)(=O)=O.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl.CCOC(C)=O>[CH2:29]([N:36]1[CH2:9][C@H:10]([CH3:23])[CH2:11][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: C[C@@H](CO)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
Triethylamine (0.932 mL, 6.69 mmol) was added to a solution of tert-butyl [(1S,3R)-4-hydroxy-1-(hydroxymethyl)-3-methylbutyl]carbamate (0.39 g, 1.7 mmol) in DCM (7.5 mL) at 0° C. Methanesulfonyl chloride (0.388 mL, 5.01 mmol) was then added dropwise to the resulting solution. After stirring at 0° C. for 1 h, the mixture was diluted with DCM (50 mL), washed with saturated aq. NaHCO3 (50 mL), dried over Na2SO4 and concentrated under reduced pressure. Benzylamine (3.65 mL, 33.4 mmol) was added to the resulting residue and mixture was stirred at 70° C. for 18 h, then cooled to room temperature. The reaction mixture was diluted with EtOAc (100 mL), washed with 10% aq. K3PO4 (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-30% EtOAc in hexanes) to give the sub-title compound as a white solid (0.34 g, 67%). LCMS calc. for C18H29N2O2 (M+H)+: m/z=305.2. found 305.2.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][NH2:7].[CH2:8]([O:10][C:11](=[O:25])[CH:12]=[C:13](OCC)[CH2:14][CH:15](OCC)OCC)[CH3:9]>C(O)(=O)C>[CH2:8]([O:10][C:11](=[O:25])[CH2:12][C:13]1[N:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[N:7]=[CH:15][CH:14]=1)[CH3:9]
Reactant: NNc1nccs1
Reactant: CCOC(=O)C=C(CC(OCC)OCC)OCC
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccnn1-c1nccs1

Procedure:
A mixture of thiazol-2-ylhydrazine (2.2 g, 19.1 mmol) and 3,5,5-triethoxy-pent-2-enoic acid ethyl ester (70% purity, 7.1 g, 19.1 mmol) is refluxed in acetic acid overnight. Acetic acid is removed. To the residue is added NaHCO3 (aq.) (40 mL) and ethyl acetate (100 mL). The insoluble material is filtered. The organic layer is dried and solvent removed. The crude is subjected to column separation (hexane/ethyl acetate 3:1) to give (2-thiazol-2-yl-2H-pyrazol-3-yl)-acetic acid ethyl ester as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=1)([CH3:9])[CH3:8])=[O:5])[CH3:2].[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH2:1]([O:3][C:4](=[O:5])[NH:6][C:7]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:31]2[CH2:32][CH2:33][N:28]([C:22]3[C:21]([CH3:20])=[CH:26][C:25]([CH3:27])=[CH:24][N:23]=3)[CH2:29][CH2:30]2)=[O:16])=[CH:18][CH:19]=1)([CH3:8])[CH3:9])[CH3:2]
Reactant: CCOC(=O)NC(C)(C)c1ccc(C(=O)OC)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: CCOC(=O)NC(C)(C)c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cc1
Yield: 82.2 %

Procedure:
Using methyl 4-(1-ethoxycarbonylamino-1-methylethyl)benzoate (174 mg) described in Preparation Example 70 and 1-(3,5-dimethylpyridin-2-yl)piperazine (138 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (229 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[O:6][C:5]([C:7]([Cl:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(Br)o1

Procedure:
21.0 g of 5-bromo-2-furancarboxylic acid were suspended in 650 ml of toluene and 40 ml of thionyl chloride and the suspension was heated to reflux for 2 hours. The reaction solution was thereafter concentrated, whereby 5-bromo-2-furancarboxylic acid chloride was obtained as the residue.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=1>>[O:32]=[C:30]([CH3:31])[CH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:24][CH:25]=1
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Product: CC(=O)Cc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C using 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 1-(4-hydroxyphenyl)-2-propanone: MS (APCI) m/z 445 (M+1).
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[C:9]([CH2:10]O)=[CH:8][CH:7]=[CH:6][N:5]=1.S(Cl)([Cl:14])=O>>[ClH:14].[Cl:1][CH2:3][C:4]1[C:9]([CH2:10][Cl:14])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccnc1CO
Agent: Cl
Product: ClCc1cccnc1CCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(2-Hydroxymethyl-pyridin-3-yl)-methanol hydrogen chloride (26.79 g, 122 mmol) was added to thionyl chloride (33.8 mL) at 5° C. under an atmosphere of argon. The resulting mixture was allowed to warm to room temperature with stirred over 16 h. The resulting mixture was then evaporated in vacuo to yield 2,3-bis-chloromethyl-pyridine hydrogen chloride as a white solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.O.Cl>CS(C)=O>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:28]5[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: CN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)CC1
Yield: 49.2 %

Procedure:
A suspension of 0.47 g of 1-cyclopropyl-7,8-difluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 0.6 g of 1-methylpiperazine in 7 cm3 of dimethyl sulphoxide is heated at a temperature close to 80° C. for 15 minutes. The reaction mixture is poured into 25 cm3 of water and 9 cm3 of N hydrochloric acid are added. The solid obtained is drained and washed with 3 times 5 cm3 of water. After recrystallizing once from a mixture of 4.5 cm3 of ethanol and 4.5 cm3 of dimethylformamide, 0.29 g of 1-cyclopropyl-7-fluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid melting at 250° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:13]([F:14])=[CH:12][C:11]([C:15]2[CH:16]=[N:17][CH:18]=[N:19][CH:20]=2)=[CH:10][C:7]=1[CH:8]=O)[CH2:2][CH:3]=[CH2:4].[NH2:21][C:22]([NH2:24])=[S:23].Cl[Si](C)(C)C>C(#N)C.CN(C=O)C.CCOC(C)=O>[F:14][C:13]1[C:6]2[O:5][CH2:1][CH2:2][C@@H:3]3[CH2:4][S:23][C:22]([NH2:24])=[N:21][C@@H:8]3[C:7]=2[CH:10]=[C:11]([C:15]2[CH:16]=[N:17][CH:18]=[N:19][CH:20]=2)[CH:12]=1
Reactant: NC(N)=S
Reactant: C=CCCOc1c(F)cc(-c2cncnc2)cc1C=O
Agent: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC#N
Product: NC1=N[C@@H]2c3cc(-c4cncnc4)cc(F)c3OCC[C@@H]2CS1
Reaction time: 1 h
Yield: 0.3 %

Procedure:
To a solution of 2-(but-3-enyloxy)-3-fluoro-5-(pyrimidin-5-yl)benzaldehyde from step 4C (662 mg, 2.43 mmol) in acetonitrile (1.62 ml) and DMF (0.810 ml) was added thiourea (185 mg, 2.43 mmol) and chlorotrimethylsilane (0.311 ml, 2.43 mmol). The resulting mixture was brought to reflux and stirred for 1 h. The reaction mixture was then diluted with EtOAc (10 mL), washed with water (3×2 mL), brine (5 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel column chromatography (0-80% EtOAc/hexanes) gave the desired product (3.1 mg, 8.44 μmol, 0.35% yield). 1H NMR (500 MHz, methanol-d4) δ 7.63 (d, J=2.1 Hz, 1H), 7.57 (d, J=2.1 Hz, 2H), 6.03 (s, 1H), 5.99 (d, J=10.4 Hz, 1H), 3.12-3.01 (m, J=6.1, 6.1 Hz, 1H), 2.29-2.16 (m, J=4.6 Hz, 1H), 1.82 (d, J=1.2 Hz, 2H), 1.58 (t, J=12.1 Hz, 1H), 1.35 (dd, J=12.5, 3.1 Hz, 1H), 0.62-0.47 (m, 2H), 0.35-0.18 (m, 1H), −0.07-−0.31 (m, 1H). MS (ESI, M+H)+=331.16
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14](=[O:22])[C:15](=[O:21])[NH:16]2>>[O:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:14]3([OH:22])[C:13]4[C:17](=[CH:18][CH:19]=[CH:20][C:12]=4[Cl:11])[NH:16][C:15]3=[O:21])[C:10]=2[O:9][CH2:8]1
Reactant: Brc1cccc2c1OCO2
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Product: O=C1Nc2cccc(Cl)c2C1(O)c1cccc2c1OCO2
Yield: 43.9 %

Procedure:
With 9.00 g of 4-bromo-1,3-benzodioxol and 1.81 g of 4-chloroisatin as starting materials, 1.33 g of the title compound was obtained by a similar method to Step 21-1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[N:5]2[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=[C:4]2[CH:3]=1.[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1B(O)O>>[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[N:5]2[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=[C:4]2[CH:3]=1
Reactant: N#Cc1ccc(NCCNc2nc(Cl)cc3nc(C(F)(F)F)cn23)nc1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(C(F)(F)F)cn23)nc1

Procedure:
In analogy to the procedure described for Example 7, 11.4 mg (33% of theory) of the product are obtained as a solid starting from 29 mg (0.07 mmol) of 6-[(2-{[7-chloro-2-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5-yl]amino}ethyl)amino]nicotinonitrile (Example 24A) by coupling with 13 mg (0.07 mmol) of (2,4-dichlorophenyl)boronic acid and subsequent purification by preparative HPLC.
Reaction SMILES: [C:1]1([C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:8][CH2:9][C@H:10]([OH:21])[CH2:11][S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:36]I>O1CCCC1>[C:28]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:8][CH2:9][C@H:10]([O:21][CH3:36])[CH2:11][S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccccc1SC[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1SC[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
34.8 g (0.076 mol) of 1-(3-triphenylmethyloxy-2-(S)-hydroxypropylthio)-2-methoxybenzene (XII-1), in solution in 50 ml of distilled tetrahydrofuran, are introduced dropwise into a round-bottomed flask, kept under an inert atmosphere, comprising a suspension of 3.5 g of sodium hydride (0.087 mol) in 30 ml of distilled tetrahydrofuran. The mixture is stirred at ambient temperature for 3 hours and then 5.1 ml (0.082 mol) of methyl iodide are added. After stirring at ambient temperature for 2 hours, the mixture is concentrated under reduced pressure and then the residue is taken up in dichloromethane. The solution obtained is cooled and then diluted with ice-cold water. The phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with water and with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/cyclohexane=70:30) to give 35.8 g (0.076 mol) of the title compound (XIII-1) in the form of an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9](=[O:22])[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([F:21])[F:20])=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:23]([OH:27])[CH2:24][C:25]#[CH:26].[Al]>C(N(CC)CC)C.C(OCC)C.[Cu](I)I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:20][CH:19]([F:21])[O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[O:11])[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:26]#[C:25][CH2:24][CH2:23][OH:27])[CH:3]=2)=[O:22])=[CH:13][CH:14]=1
Reactant: C#CCCO
Reactant: O=C(C(=O)c1ccc(F)c(Br)c1)c1ccc(OC(F)F)cc1
Agent: I[Cu]I
Agent: [Pd]
Agent: [Al]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(C(=O)c1ccc(F)c(C#CCCO)c1)c1ccc(OC(F)F)cc1
Reaction time: 0.07 h
Yield: 82.4 %

Procedure:
In a 0.5-2 ml Biotage conical microwave vial equipped with magnetic spin vane was dissolved 1-(3-Bromo-4-fluoro-phenyl)-2-(4-difluoromethoxy-phenyl)-ethane-1,2-dione (100 mg, 0.268 mmol) in triethylamine (1.25 mL). Copper iodide (10 mg, 0.052 mmol) and Tetrakis(triphenylphosphine) palladium (20 mg, 0.017 mmol) were added. Lastly But-3-yn-1-ol (100 mg, 1.04 mmol) was added, the vial was covered with a teflon septa, an aluminum cap was crimped in place, and the assembly was set on a Biotage Emrys microwave instrument to irradiate at 80° C. for one hour. The crude reaction was diluted with diethylether (60 mL), washed with saturated ammonium chloride (2×30 mL) and purified via column chromatography on a Yamazen W-Prep 2XY using a two-step automatic gradient elution: 100% hexanes (4 min) to 18% EtOAc (12 min), hold 4 min then to 80% EtOAc (16 min) hold 15 minutes. The resultant oil was placed under high vacuum overnight to afford 80 mgs of beige solid (82%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:6]#[N:7].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[O:17]1[CH2:18][CH2:19][N:14]([CH2:2][C:3]2[CH:4]=[C:5]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=2)[C:6]#[N:7])[CH2:15][CH2:16]1
Reactant: N#Cc1cc(CBr)cc([N+](=O)[O-])c1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(CN2CCOCC2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To a stirred solution of 3-(bromomethyl)-5-nitrobenzonitrile (1.50 g, 6.22 mmol) and morpholine (0.65 g, 7.46 mmol) in CH2Cl2 (15 mL) was added triethylamine (1.88 g, 18.66 mmol) dropwise at 0° C. The mixture was stirred at room temperature overnight and then evaporated to dryness under reduced pressure. The residue was diluted with water (15 mL) and extracted with EtOAc (3×50 mL). The EtOAc solution was dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 3-(morpholinomethyl)-5-nitrobenzonitrile (0.87 g, 85%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.45 (br s, 1 H), 8.41 (br s, 1H), 8.01 (br s, 1H), 3.74 (br t, 4H, J=4.4 Hz), 3.64 (s, 2H), 2.48 (br t, 4H, J=4.4 Hz).
Reaction SMILES: [OH:1][CH:2]([C:7]1[C:8]([I:18])=[C:9]2[CH:16]=[CH:15][N:14]([CH3:17])[C:10]2=[N:11][C:12]=1[CH3:13])[C:3]([O:5][CH3:6])=[O:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C(OCC)(=O)C>ClCCl>[I:18][C:8]1[C:7]([C:2](=[O:1])[C:3]([O:5][CH3:6])=[O:4])=[C:12]([CH3:13])[N:11]=[C:10]2[N:14]([CH3:17])[CH:15]=[CH:16][C:9]=12
Reactant: COC(=O)C(O)c1c(C)nc2c(ccn2C)c1I
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C(=O)c1c(C)nc2c(ccn2C)c1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
An 0° C. solution of methyl 2-hydroxy-2-(4-iodo-1,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (12.0 g, 33.3 mmol) in dichloromethane (DCM) (120 mL) was treated with Dess-Martin periodinane (19.84 g, 46.8 mmol) in one portion and warmed to ambient temperature. After 18 h, sat. aq. Na2S2O3 was added and the reaction mixture was stirred for 20 min. Ethyl acetate was added and the layers partitioned. The organic phase was washed with sat. aq. NaHCO3, brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by ISCO (0-30% EtOAc-hexanes) to afford methyl 2-(4-iodo-1,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-oxoacetate (9.6 g, 26.8 mmol, 74.5% yield) as light yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.58 (s, 3H) 3.86 (s, 3H) 3.93 (s, 3H) 6.35 (d, J=3.52 Hz, 1H) 7.22 (d, 1H). LC/MS (m/z) ES+=359.9 (M+1)+
Reaction SMILES: [NH2:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([O:21]C)[CH:14]=2)[C:3]1=[O:23].Cl.[NH+]1C=CC=CC=1>C(O)CCC>[NH2:1][N:2]1[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([OH:21])[CH:14]=2)[C:3]1=[O:23]
Reactant: COc1cc(-n2c(=O)cc(C(F)(F)F)n(N)c2=O)ccc1C#N
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CCCCO
Product: N#Cc1ccc(-n2c(=O)cc(C(F)(F)F)n(N)c2=O)cc1O
Yield: 20.9 %

Procedure:
1-Amino-3-[4-cyano-3-methoxyphenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (2.0 g) and pyridinium hydrochloride (2.1 g) were stirred for 2 hours at 200-210° C. After cooling, the reaction mixture was dissolved in 100 ml of n-butanol, whereupon the solution was washed three times using in each case 30 ml of water. The organic phase was dried over sodium sulfate and subsequently freed from solvent. After crystallization using 10 ml of diisopropyl ether and chromatographic purification of the crude product (eluent: dichloromethane/ethyl acetate=9:1 to 1:1), 0.4 g of the desired product was obtained. M.p.: >230° C.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:14]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][CH2:23][CH2:24]Br)=[C:19]([CH2:28][CH2:29][CH3:30])[C:18]=1[OH:31])(=[O:16])[CH3:15].[OH-].[K+].Cl>C(O)C>[C:14]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][CH2:23][CH2:24][S:1][C:2]2[NH:3][C:4]3[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[C:19]([CH2:28][CH2:29][CH3:30])[C:18]=1[OH:31])(=[O:16])[CH3:15]
Reactant: O=C(O)c1ccc2nc(S)[nH]c2c1
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1c(OCCCSc2nc3ccc(C(=O)O)cc3[nH]2)ccc(C(C)=O)c1O
Temperature: 0 °C
Yield: 110.3 %

Procedure:
A mixture of 2-mercaptobenzimidazole-5-carboxylic acid (3.25 g), 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylbromide (2.00 g) and potassium hydroxide (1.27 g) in ethanol (30 ml) was refluxed for 4 hours. Then, the reacting mixture was poured into ice-water, made acidic with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then evaporated. The resulting residue was purified by silica gel column chromatography, eluting with dichloromethane-ethyl acetate-methanol (10:2:1), and recrystallized from n-hexane-ethyl acetate to give the title compounds (3.00 g, 67.1%) as pale yellow crystals, mp 106-108 ° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.FC(F)(F)S(O)(=O)=O.[C:18]([N:23]1[CH2:27][CH2:26][O:25][C:24]1=[O:28])(=[O:22])/[CH:19]=[CH:20]/[CH3:21].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:20]([CH3:21])[CH2:19][C:18]([N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])=[O:22])=[CH:5][CH:4]=1
Reactant: C/C=C/C(=O)N1CCOC1=O
Reactant: COc1ccc(N)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: COc1ccc(NC(C)CC(=O)N2CCOC2=O)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.6 %

Procedure:
A solution of anisidine (55.4 mg, 0.45 mmol) in toluene (1.5 ml) was cooled to 0° C., and trifluoromethanesulfonic acid (40 μL, 0.45 mmol) was added dropwise. The mixture was stirred for 10 minutes, and to this solution were added Pd((R)-binap)(OH2)2(OTf)2 (8 mg, 0.00752 mmol) and 3-crotonoyl-1,3-oxazolidin-2-one (47 mg, 0.3 mmol). The ice-cooling bath was removed and the mixture was reacted at room temperature for 20 hours. A saturated aqueous solution of ammonium chloride was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was concentrated and purified by a silica gel column chromatography (hexane:ethyl acetate=4:1) to give the objective 3-[3-(4-methoxyphenylamino)butyryl]-1,3-oxazolidin-2-one (66.5 mg, 96% yield). The enantiomeric excess was determined by a liquid chromatography with an optical isomer separating column (column: AD-H) to be 94% e.e.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH:20]([CH3:25])[CH2:19]1.Cl>C1COCC1>[CH:9]([O:8][C:4]1[CH:3]=[C:2]([C:20]2([CH3:25])[CH:21]([OH:24])[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19]2)[CH:7]=[CH:6][CH:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1cccc(Br)c1
Reactant: CC1CN(C)CCC1=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Oc1cccc(C2(C)CN(C)CCC2O)c1
Temperature: -70 °C
Reaction time: 2 h
Yield: 662.3 %

Procedure:
The 3-bromo-i-propoxybenzene (200 g, 0.08703 mol) was combined with THF (540 ml) under nitrogen and cooled to about -75° C. n-Butyl lithium (565 ml, 0.8306 mol) was added dropwise while maintaining the mixture at less than -70° C. After 2 hours 1,3-Dimethyl-4-piperidone (106.7 g, 0.8389 mol) was added while maintaining the temperature of the mixture between -80° C. and -70° C. After stirring 2 hours at -70° C., the reaction mixture was then added to 6N HCl (280 ml) while maintaining the temperature at 20°-25° C. The pH was adjusted to 1 with 12 N HCl. The aqueous layer containing product was separated and heptane (320 ml) was added along with 50% NaOH (48 ml, pH=13-14) and the resulting mixture allowed to stand overnight. The mixture was heated to 45°-50° C. and the upper layer was separated. The remaining aqueous layer was extracted with heptane (320 ml) at 45°-50° C. The combined organic fractions were washed with de-ionized water (120 ml) at 45°-50° C. The resulting organic layer was vacuum distilled at a pot temperature of about 55° C. at 100 mmHg. Crystallization from heptane and drying provided 151.8 g of 3-(3-i-propoxyphenyl)-1,3-dimethyl-4-hydroxypiperidine. Melting point 75.0°- 76.0° C.