Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]2[N:12]=[C:13]([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[C:14]([C:15]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[O:24][CH3:25])=[O:16])=[C:8]2[N:7]=1)C=C.CN1C(=O)CC(=O)N(C)C1=O.C(Cl)Cl.CO>C(Cl)Cl.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]2[N:12]=[C:13]([NH:26][C:27](=[O:32])[C:28]([F:30])([F:31])[F:29])[C:14]([C:15]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[O:24][CH3:25])=[O:16])=[C:8]2[N:7]=1
Reactant: C=CCOCc1ccn2nc(NC(=O)C(F)(F)F)c(C(=O)Nc3cnccc3OC)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: CO
Solvent: ClCCl
Product: COc1ccncc1NC(=O)c1c(NC(=O)C(F)(F)F)nn2ccc(CO)nc12
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 84.2 %

Procedure:
5-(Allyloxymethyl)-N-(4-methoxy-3-pyridyl)-2-[(2,2,2-trifluoroacetyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxamide (70 mg, 0.1554 mmol), 1,3-dimethylbarbituric acid (48.53 mg, 0.3108 mmol) and Pd(PPh3)4 (17.96 mg, 0.01554 mmol) were suspended in DCM/MeOH (1.4 mL/0.35 mL) in a pressure tube. The mixture was stirred at 60° C. for ˜2.5 hrs. Further DCM (1.4 mL), MeOH (0.35 mL) and Pd(PPh3)4 (17.96 mg, 0.01554 mmol) were added and the resulting mixture was stirred at 60° C. overnight. The reaction was allowed to cool to RT, the suspended solid was collected by filtration and washed with DCM (2×1 mL) and ether (3×1 mL) to give a purple powder (53.7 mg, 84% Yield) which was used directly into next step without further purification. LC-MS (M+H)+ 411.2; 1H NMR (500 MHz, DMSO-d6) δ 11.66 (s, 1H), 10.34 (s, 1H), 9.45 (s, 1H), 9.37 (d, J=7.1 Hz, 1H), 8.29 (d, J=5.5 Hz, 1H), 7.46 (d, J=7.1 Hz, 1H), 7.23 (d, J=5.6 Hz, 1H), 5.93 (t, J=6.1 Hz, 1H), 4.81 (d, J=6.0 Hz, 2H), 4.06 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[C:3]#[CH:4].[Li]CCCC.[I:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[C:19]=[O:20]>C1COCC1.[Cl-].[Na+].O>[I:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:20])[C:4]#[C:3][CH:2]([CH3:5])[CH3:1]
Reactant: O=C=Nc1ccccc1I
Reactant: C#CC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C#CC(=O)Nc1ccccc1I
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
3-Methyl-but-1-yne (11 g, 0.16 mol) in THF (100 ml) was added n-BuLi (2.5M in hexane) (59 ml, 0.15 mol) at 0° C. The resulting mixture was stirred for 30 minutes. Then a solution of 1-iodo-2-isocyanato-benzene (33 g, 0.14 mol) in THF (100 ml) was dropped into the mixture. After stirring for 2 hours at 0° C., the mixture was treated with brine (100 ml) and extracted with ether (200 ml). The organic layer was dried over sodium sulfate and concentrated to give the crude product 4-methyl-pent-2-ynoic acid (2-iodo-phenyl)-amide (38 g, 90%) as a yellow oil which was used in next step without purification. MS calcd. for C12H12INO 313.1, obsd. (ESI+) [(M+H)+] 314.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([C:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH:9]=2)=[N:6][CH:7]=1.[NH2:16][CH2:17][CH2:18][OH:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([C:8]2[CH2:13][CH2:12][CH:11]([NH:16][CH2:17][CH2:18][OH:19])[CH2:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1C1=CCC(=O)CC1
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Br)cnc1C1=CCC(NCCO)CC1

Procedure:
To a solution of 4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-one (2.06 g) in dichloromethane (50 ml) was added 2-aminoethanol (0.463 ml) at room temperature with stirring. Then sodium triacetoxyborohydride (1.64 g) was added thereto, and stirred at the same temperature. After completion of the reaction, to the reaction solution was added 10% sodium carbonate aqueous solution, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated. The obtained residue was purified with silica gel column chromatography (chloroform/methanol), and then suspended and washed with a mixed solvent of a small amount of diethyl ether and n-hexane to give 2-[4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-yl]amino ethanol (860 mg) as a light brown solid.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C@H:8]([CH2:23][C:24]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=1[F:32])[CH2:9][C:10](=O)[NH:11][NH:12][C:13]1[N:18]2[N:19]=[CH:20][N:21]=[C:17]2[CH:16]=[CH:15][N:14]=1)(C)(C)C.[C:34](O)(=O)C>>[N:12]1[N:11]=[C:10]([CH2:9][C@H:8]([NH:7][C:6](=[O:5])[CH3:34])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=2[F:32])[N:14]2[CH:15]=[CH:16][C:17]3=[N:21][CH:20]=[N:19][N:18]3[C:13]=12
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NNc1nccc2ncnn12)Cc1cc(F)c(F)cc1F
Reactant: CC(=O)O
Product: CC(=O)N[C@H](Cc1cc(F)c(F)cc1F)Cc1nnc2n1ccc1ncnn12

Procedure:
A solution of 93.1 mg (0.2 mmol) of tert-butyl[(1R)-3-oxo-3-(2-[1,2,4]triazolo[1,5-c]pyrimidin-5-ylhydrazino)-1-(2,4,5-trifluorobenzyl)propyl]carbamate in 10 mL of glacial acetic acid was stirred at reflux under nitrogen for 40 h. The cooled solution was concentrated, and the residue was partitioned between 5 mL of ethyl acetate and 3 mL of saturated sodium carbonate aqueous solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative thin-layer chromatography on silica gel (92.5:7.5 dichloromethane:methanol), giving the title compound as a white solid, mp 233-235° C. LC-MS 390 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98 %

Procedure:
To a solution of (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid di-tert-butyl ester (CAS Reg. No. 170850-75-6) (1 g, 3.48 mmol) in 20 ml of CH2Cl2 was added pyridine (3.9 ml) and p-toluene sulphonyl chloride (0.7 g, 3.67 mmol) and the mixture stirred at room temperature under a nitrogen atmosphere for 72 hours. The solvent was removed under reduced pressure and the residue dissolved in EtOAc (100 ml) and washed with saturated citric acid solution (50 ml) then water (50 ml). The organic phase was dried (magnesium sulphate), filtered and evaporated under reduced pressure. The residue was purified by column chromatography eluting with ethyl acetate:heptane (3:10) to give the title compound (1.5 g, 98%) as a colourless gum.
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].O[CH2:7][C:8]1[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][C:9]=1[N:10]([CH3:12])[CH3:11]>>[ClH:3].[Cl:5][CH2:7][C:8]1[CH:16]=[CH:15][C:14]([CH2:17][Cl:3])=[CH:13][C:9]=1[N:10]([CH3:12])[CH3:11]
Reactant: CN(C)c1cc(CO)ccc1CO
Reactant: O=S(Cl)Cl
Agent: Cl
Product: CN(C)c1cc(CCl)ccc1CCl
Yield: 77 %

Procedure:
Thionyl chloride (35 ml) was added to 2 grams (0.00919 mol) of 2,5-bis(hydroxymethyl)-N,N-dimethylaniline hydrochloride, VIII. The 2,5-bis(hydroxymethyl)-N,N-dimethylaniline hydrochloride (VIII) went into solution immediately, accompanied by evolution of heat and gas. The reaction was stirred for several minutes. The volatiles were removed under reduced pressure to yield 2.38 g of crystalline residue, compound IX. The solid IX was dissolved in a minimum amount of hot acetonitrile; the solution was filtered, and an equivalent amount of ethyl acetate added and the solution cooled. Yield 77%. Elemental analysis: calcd for C10H14Cl3N: C, 47.18; H, 5.54: Cl, 41.78,; N, 5.50. Found: C, 47.04; H, 5.54; N, 5.34
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)[CH2:7][C:8]([OH:10])=[O:9])=[O:5])[CH3:3].O=[C:21]([CH2:25][CH3:26])[C:22]([OH:24])=[O:23].C([BH3-])#N.[Na+]>>[C:22]([CH:21]([NH:1][C@H:2]([C:4]([N:6]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)[CH2:7][C:8]([OH:10])=[O:9])=[O:5])[CH3:3])[CH2:25][CH3:26])([OH:24])=[O:23]
Reactant: C[C@H](N)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reactant: CCC(=O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCC(N[C@@H](C)C(=O)N(CC(=O)O)C1Cc2ccccc2C1)C(=O)O
Yield: 30.1 %

Procedure:
By using 1.0 g of L-alanyl-N-(indan-2-yl)glycine, 6.0 g of 2-oxo-butyric acid and 1.0 g of sodium cyanoborohydride in a similar procedure to that of Example 1, there can be obtained 0.4 g of N-(1-carboxypropyl)-L-alanyl-N-(indan-2-yl)glycine as colorless powder.
Reaction SMILES: [O:1]=[C:2]1[C@@H:6]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:5][CH2:4][NH:3]1.Br[CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[Si:19]([O:18][CH2:17][CH2:16][N:3]1[CH2:4][CH2:5][C@H:6]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[C:2]1=[O:1])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Product: CC(C)(C)OC(=O)N[C@H]1CCN(CCO[Si](C)(C)C(C)(C)C)C1=O
Yield: 37 %

Procedure:
(S)-tert-butyl 1-(2-(tert-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidin-3-ylcarbamate was prepared from compound (s)-tert-butyl 2-oxopyrrolidin-3-ylcarbamate (Example 6) and (2-bromoethoxy)(tert-butyl)dimethylsilane according to the general procedure of Example 9. The crude product was purified by column chromatography, eluting with 80% ethyl acetate/hexanes, to provide compound (2b) in 37% yield.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:3]1[CH:21]([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].[Br:30][CH2:31][CH2:32][CH2:33]Br.O>CN(C)C=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:33][CH2:32][CH2:31][Br:30])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:3]1[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)c1c(S(=O)(=O)c2ccc(O)cc2)c2ccccc2n1C
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1c(S(=O)(=O)c2ccc(OCCCBr)cc2)c2ccccc2n1C
Temperature: 100 °C
Yield: 70.5 %

Procedure:
To a solution of 2.8 g (0.0085 mol) of 1-methyl-2-isopropyl-3-(4-hydroxy-benzenesulphonyl)indole in 100 ml of N,N-dimethyl formamide were added 14 g of anhydrous and crushed potassium carbonate. After that 6.8 g (0.037 mol) of 1,3-dibromopropane were added and the medium was heated at 100° C. for 0.5 hour. The mixture was poured into water, extracted with ethyl ether and the ethereal fraction was washed with water, dried on anhydrous sodium sulphate, filtered and evaporated to obtain 2.7 g of 1-methyl-3-[4-(3-bromo-propoxy)benzenesulphonyl]-2-isopropyl-indole (yield: 69%). This crude bromopropoxy derivative was dissolved in 60 ml of dimethylsulphoxide and 2.2 g (0.03 mol) of tert-butylamine were added. The medium was then stirred at room-temperature for 48 hours, poured into water and extracted with ethyl ether. The ethereal solution was then washed with water, dried on anhydrous sodium sulphate, filtered and evaporated. The crude product so obtained (2.3 g) was then purified by chromatography on a silica column (solvent:methanol).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:21]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])[CH2:22][Br:23])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[CH:11]([C:16]([OH:18])=[O:17])[CH:12](O)[CH2:13][S:14][C@H:9]12)=[O:6].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>C(C(C)=O)C(C)C>[CH3:1][O:2][N:3]=[C:4]([C:21]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])[CH2:22][Br:23])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[C:11]([C:16]([OH:18])=[O:17])=[CH:12][CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CCOC(CBr)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)CC(C)C
Product: CCOC(CBr)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Yield: 69.7 %

Procedure:
7-(2-Methoxyimino-3,3-diethoxy-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 5 g), acetic anhydride (4.55 ml), sodium acetate (1.45 g), and methyl isobutyl ketone (50 ml) were treated in a similar manner to that of Example 43 to give 7-(2-methoxyimino-3,3-diethoxy-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 3.36 g).
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH3:19])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])[CH3:19])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCCC[C@@H](O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 4 (294 mg, 1.16 mmol) and 1-bromohexadecane (1.42 g, 4.64 mmol), alcohol 42 was obtained as a colorless oil (283 mg, 51% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C(OC(O)C)C>N1C=CC=CC=1>[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[CH:21][CH:20]=1
Reactant: Nc1ccc(F)cc1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: CCOC(C)O
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)cc3)c2cc1OC
Yield: 90.8 %

Procedure:
A mixture of 0.5 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.44 g of 4-fluoroaniline, 0.16 ml of pyridine, and 6 ml of ethoxyethanol was stirred, under nitrogen, at reflux temperature for 4 h. The mixture was cooled and partitioned with dichloromethane and aqueous sodium bicarbonate. The organic layer was washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate to give 0.59 g of 4-[(4-fluorophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile as a solid, mp 282-285° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([O:6][C:7]([C:9]1[C:18]([Cl:19])=[CH:17][C:16]2[C:11](=[C:12]([CH:20]=O)[CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:8])[CH3:5].C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1.CO>[CH2:4]([O:6][C:7]([C:9]1[C:18]([Cl:19])=[CH:17][C:16]2[C:11](=[C:12]([CH2:20][N:2]([CH3:3])[CH3:1])[CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:8])[CH3:5]
Reactant: CNC
Reactant: CCOC(=O)c1cc2c(C=O)cccc2cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1cc2c(CN(C)C)cccc2cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.3 %

Procedure:
A solution of dimethylamine (5.6 M in EtOH, 0.36 ml, 2.0 mmol, 1.5 equiv) was added to a solution of 3-chloro-8-formyl-naphthalene-2-carboxylic acid ethyl ester (350 mg, 1.33 mmol) in THF (6.5 ml). After stirring at room temperature for 16 hours, a solution of sodium cyanoborohydride (101 mg, 1.6 mmol, 1.2 equiv) in MeOH (3.0 ml) and acetic acid (0.38 ml, 6.7 mmol, 5.0 equiv) were added, and the reaction mixture was stirred at room temperature for 3 hours. After dilution with water (75 ml), the mixture was extracted with CH2Cl2 (total of 400 ml). The combined organic layers were washed with concentrated aqueous NaHCO3 solution, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (gradient of hexane/EtOAc 100:0 to 1:2) to afford the title compound (133 mg, 34%) as a mixture of regioisomers, which could be separated for analytical purposes. 3-Chloro-8-dimethylaminomethyl-naphthalene-2-carboxylic acid ethyl ester 1H NMR (400 MHz, CDCl3): δ=8.72 (s, 1H), 8.08 (s, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.61-7.55 (m, 2H), 4.42 (q, J=7.1 Hz, 2H), 3.97 (br s, 2H), 2.33 (s, 6H), 1.40 (t, J=7.1 Hz, 3H). MS (ES+): 292 (M+H)+. 3-Chloro-5-dimethylaminomethyl-naphthalene-2-carboxylic acid ethyl ester: 1H NMR (400 MHz, CDCl3): δ=8.39 (s, 1H), 8.35 (s, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.57-7.50 (m, 2H), 4.41 (q, J=7.1 Hz, 2H), 3.81 (s, 2H), 2.24 (s, 6H), 1.40 (t, J=7.1 Hz, 3H). MS (ES+): 292 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[C:27]5[CH:28]=[CH:29][S:30][C:26]=5[CH:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)=O)=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:13][CH2:14][N:16]3[CH2:21][CH2:20][N:19]([C:22]4[C:27]5[CH:28]=[CH:29][S:30][C:26]=5[CH:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cc1cc(=O)[nH]c2cc(F)ccc12)N1CCN(c2nccc3sccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1cc(CCN2CCN(c3nccc4sccc34)CC2)c2ccc(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
107.7 kg (1 eq.) of intermediate 7-fluoro-4-[2-[4-(thieno[3,2-c]pyridin-4-yl)piperazin-1-yl]-2-oxoethyl]quinolin-2(1H)-one (I), followed by 3231 of THF, are introduced, in thirty minutes at 10° C., into a suspension of 22.2 kg (2.3 eq.) of lithium aluminium hydride in 580 l of tetrahydrofuran, in a reactor. The mixture is stirred for three hours at ambient temperature and then, after verification that the reaction is complete, the mixture is cooled and 21.5 l of water, 21.5 l of 4N sodium hydroxide and 180 l of water are added successively without the temperature exceeding 15° C. The mixture is stirred for one hour and the inorganic salts are filtered off. The mixture is concentrated to three volumes of THF and run into 1400 l of water. The mixture is filtered and a paste is re-formed in 1000 l of a water/THF mixture: 3/7. The product is dried under vacuum at 50° C. Compound (V) is obtained.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH2:13]([O:16][C:17]([N:19]1[C@H:23]([CH:24]([OH:33])[C:25]2[N:26]3[CH:32]=[N:31][CH:30]=[C:27]3[S:28][CH:29]=2)[CH2:22][C@@H:21]([OH:34])[CH2:20]1)=[O:18])[CH:14]=[CH2:15].C(=O)([O-])O.[Na+]>C1COCC1>[CH2:13]([O:16][C:17]([N:19]1[C@H:23]([CH:24]([C:25]2[N:26]3[CH:32]=[N:31][CH:30]=[C:27]3[S:28][CH:29]=2)[OH:33])[CH2:22][C@@H:21]([O:34][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:20]1)=[O:18])[CH:14]=[CH2:15]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(O)c1csc2cncn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(O)c1csc2cncn12
Reaction time: 0.67 h

Procedure:
Triethylamine (0.165 ml) and 0.080 ml of methanesulfonyl chloride are successively added to 313 mg of crude (3R,5S)-1-allyloxycarbonyl-3-hydroxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-3-yl)methyl]pyrrolidine (stereoisomer B) in 8.5 ml of THF in an argon atmosphere at −14° C., and the mixture is stirred in this state for 40 min. Further, 0.008 ml of methanesulfonyl chloride is added thereto, and the mixture is stirred for 20 min. A 5% aqueous sodium hydrogencarbonate solution (20 ml) is added thereto, and the mixture is extracted wit 50 ml of ethyl acetate. The organic layer is dried over magnesium sulfate and filtered. The solvent is removed by evaporation under reduced pressure to give 355 mg of crude (3R,5S)-1-allyloxycarbonyl-5-[1-hydroxy-(imidazo[5,1-b]thiazol-3-yl)methyl]-3-methanesulfonyloxypyrrolidine (stereoisomer B) as a slight yellow amorphous material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)#[N:14]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:24]3[CH2:23][CH2:22][N:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[C:13]#[N:14])[CH2:26][CH2:25]3)[N:10]=2)[CH:7]=1
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Product: N#Cc1ccccc1N1CCN(Cc2cn3cc(Cl)ccc3n2)CC1

Procedure:
Following the general procedure of Example 11 and making noncritical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4. Step 1; 0.3373 g) and 1-(2-cyanophenyl)piperazine (Emka-Chemie; 0.347 g) give, after crystallization from dichloromethane/ethyl acetate, 0.309 g of the title compound; mp 167-169° C.; MS m/z 351, 353; IR (mineral oil) 1326, 1448, 809, 1484, 1073 cm-1 ; 1H NMR (CDCl3) δ2.79, 3.27, 3.79, 6.99, 7.12, 7.52, 8.14.
Reaction SMILES: C[O:2][C:3]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[N:28][N:27]=[N:26]2)=[CH:21][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:6].B(Br)(Br)Br.CO.ClCCl.C1(C)C=CC=CC=1.CO>ClCCl>[OH:2][C:3]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[N:28][N:27]=[N:26]2)=[CH:21][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCO)(c2ccccc2)C1
Agent: BrB(Br)Br
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: O=C(c1cc(-n2cnnn2)ccc1O)N1CCC(CCO)(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Combine 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) (2.0 g, 5.1 mmol) and anhydrous dichloromethane (100 mL). Cool in an ice bath. Add a solution of boron tribromide (17.8 mL, 1 M, 17.8 mmol) and stir. After 2 hours, pour the reaction mixture into ice-water and stir vigorously. After 18 hours, separate the layers and extract the organic layer with water. Saturate the aqueous layer with sodium chloride and extract with dichloromethane. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia to give a residue. Combine the residue and toluene/methanol. Evaporate invacao to give a residue, dissolve in dichloromethane, filter, evaporate, combine with dichloromethane, again evaporate to remove residual toluene to give the title compound: mp; 86-96° C. Rf=0.37 (silica gel, 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH2:11][CH:12]1[CH2:16][O:15][C:14](=[S:17])[NH:13]1.C(N(CC)CC)C>C1COCC1>[S:17]=[C:14]1[NH:13][CH:12]([CH2:11][O:10][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][O:15]1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCC1COC(=S)N1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCC1COC(=S)N1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.2 %

Procedure:
A solution of benzoyl chloride (14.6 mL, 126.1 mmol) in dry THF (50 mL) was added to a solution of 4-hydroxymethyl-1,3-oxazolidine-2-thione (14.0 g, 105.1 mmol) in dry THF (250 mL) and triethylamine (17.5 mL, 126.1 mmol) at 0° C. After 12 hours of stirring at room temperature, triethylamine hydrochloride was filtered off, and the solvent was distilled out in vacuo. The residue was purified by silica gel column chromatography eluted with ethyl acetate/acetone (1/1=v/v), followed by recrystallization from a mixed solvent [n-hexane/ethyl acetate (3/1=v/v)] to afford benzoic acid 2-thioxo-oxazolidin-4-ylmethyl ester as a colorless solid (20.5 g, 82%).