Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[Cl:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]2[NH:18][CH:19]=[C:20]([NH2:21])[C:9]=12.[Li+].[OH-]>N1C=CC=CC=1.C1COCC1>[Cl:7][C:8]1[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][N:11]=[C:10]2[NH:18][CH:19]=[C:20]([NH:21][C:4](=[O:5])[CH2:3][O:2][CH3:1])[C:9]=12
Reactant: Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Reactant: COCC(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCC(=O)Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.1 %

Procedure:
2-Methoxyacetyl chloride (0.074 mL, 0.76 mmol) was added to a solution of 4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-amine (120 mg, 0.51 mmol, Example 12, Steps A-G) in pyridine (5 mL) at 0° C. The reaction was stirred at 0° C. for 10 minutes, and the pyridine was removed in vacuo. The residue obtained was dissolved in THF (5 mL), treated with 2N LiOH (3 mL) and stirred for 20 minutes. THF was then removed under reduced pressure, and the aqueous slurry obtained was extracted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated in vacuo to provide N-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide (154 mg, 98% yield) as a solid.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]1=[O:17])(=O)C.C(N(CC)CC)C>CO>[F:23][C:21]1[C:19](=[O:20])[NH:18][C:16](=[O:17])[N:15]([CH:22]=1)[C@@H:6]1[O:7][C@H:8]([CH3:14])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cc(F)c(=O)[nH]c1=O
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Yield: 98 %

Procedure:
2.5 g of 1-(5-deoxy-2,3-di-O-acetyl-β-D-ribofuranosyl)-5-fluorouracil were heated under reflux in 60 ml of methanol in the presence of 0.3 ml of triethylamine until starting material could no longer be detected by thin-layer chromatography. The colourless, clear solution was concentrated under reduced pressure and the white, crystalline material obtained was recrystallised from water. There was obtained pure 5'-deoxy-5-fluorouridine, m.p. 192°-193° C., in 98% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([S:26](Cl)(=[O:28])=[O:27])[S:23][C:22]=2[CH:30]=1>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([S:26]([N:1]3[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]3)(=[O:28])=[O:27])[S:23][C:22]=2[CH:30]=1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Reactant: O=C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In N,N-dimethylformamide (10 ml) was suspended piperidin-4-one (monohydrochloric acid monohydrate, 1.54 g), followed by the addition of diisopropylethylamine (3.48 ml) and 6-chlorobenzo[b]thiophene-2-sulfonyl chloride (2.68 g). The resulting mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was then added to the residue, followed by washing with 1N hydrochloric acid. After extraction, the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (ethyl acetate methylene chloride=3:1), followed by washing with hexane, whereby the title compound (colorless prism crystals, 1.92 g) was obtained.
Reaction SMILES: N1C=CC=CC=1.[O:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1.[ClH:23].[C:24]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([CH2:37][C:38](=[O:40])[NH2:39])=[C:32](O)[CH:31]=[CH:30]2)(=[NH:26])[NH2:25].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.O>[ClH:23].[ClH:23].[O:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([O:20][C:32]3[CH:31]=[CH:30][C:29]4[C:34](=[CH:35][CH:36]=[C:27]([C:24](=[NH:25])[NH2:26])[CH:28]=4)[C:33]=3[CH2:37][C:38](=[O:40])[NH2:39])=[O:19])=[CH:16][CH:15]=2)[CH2:11][CH2:12]1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Reactant: O=C(O)c1ccc(CN2CCOCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3ccc(CN4CCOCC4)cc3)ccc2c1
Reaction time: 2 h
Yield: 67.4 %

Procedure:
15 Milliliters of anhydrous pyridine was added to 612.2 mg of 4-morpholinomethylbenzoic acid, 703.9 mg of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 622.6 mg of DCC and 30.7 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 3 days under cooling with water. Thereafter, the same procedure as in Example 1 was carried out to obtain 440.7 mg of the desired product.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[C:35]2[N:34]=[CH:33][N:32]=[C:23]([NH:24][C@@H:25]3[CH2:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])[C:22]=2[N:21]=[CH:20]1)(=O)C.C[O-].[Mg+2].C[O-]>CO>[O:31]=[C:26]1[C@H:25]([NH:24][C:23]2[C:22]3[N:21]=[CH:20][N:19]([C:35]=3[N:34]=[CH:33][N:32]=2)[C@@H:6]2[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]2[OH:4])[CH2:29][C:28](=[O:30])[NH:27]1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CC(=O)NC4=O)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C1C[C@@H](Nc2ncnc3c2ncn3[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C(=O)N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.2 %

Procedure:
A mixture of N6 -[(R)-2,5-dioxo-3-pyrrolidinyl]adenosine 2',3',5'-triacetate (100 mg), magnesium methoxide (24 mg) and methanol (18 ml) was stirred at room temperature for 48 hours. The reaction mixture was then centrifuged (1500 r.p.m.×20 min.) to remove the precipitate formed during the reaction. The supernatant was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography using ethyl acetate-methanol-water (14:2:1) as the eluent. The active fractions were pooled and concentrated under reduced pressure. The residue was dissolved in water and freeze-dried to give N6 -[(R)-2,5-dioxo-3-pyrrolidinyl]adenosine as powders (20.2 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([OH:12])=[C:7]([Cl:13])[CH:6]=1)(=[O:3])[CH3:2].[C:14](OC(=O)CCC)(=O)[CH2:15]CC>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([Cl:13])[C:8]([OH:12])=[C:9]([Cl:11])[CH:10]=1)(=[O:3])[CH2:2][CH2:14][CH3:15]
Reactant: CCCC(=O)OC(=O)CCC
Reactant: CC(=O)Nc1cc(Cl)c(O)c(Cl)c1
Product: CCCC(=O)Nc1cc(Cl)c(O)c(Cl)c1

Procedure:
Using the method described above for the preparation of 4-acetamido-2,6-dichlorophenol (but using butyric anhydride in place of acetic anhydride) there was obtained 4-butyramido-2,-6-dichlorophenol (used as starting material in Example 51) as a solid, m.p. 146°-147°; NMR([CD3 ]2SO): 0.9(3H,t), 1.58(2H,m), 2.25(2H,t), 7.62(2H,s), 9.75(1H,br s) and 9.85(1H,s); m/z 248(M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.C(N(CC)CC)C.[O:33]1[CH2:36][CH:35]([NH2:37])[CH2:34]1>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:37][CH:35]2[CH2:36][O:33][CH2:34]2)=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC1COC1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1cccc([N+](=O)[O-])c1)NC1COC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
THF (30 mL) was added to a mixture of 2-(3-Nitrophenyl)acetic acid (0.8 g, 4.42 mmol), CDI (1.07 g, 8.28 mmol), the mixture was stirred for 2 hrs at 0° C. followed by addition of triethylamine (1.8 ml, 13.25 mmol) and oxetan-3-amine (0.484 g, 6.62 mmol). The reaction mixture was stirred for 12 hrs at room temperature and then concentrated under vacuum. The crude residue was purified by column chromatography using 0-50% ethyl acetate in hexanes as eluent to afford the title product (0.5 g).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[NH:14][CH:13]=[C:12]([CH:15]3[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>CO>[CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[NH:14][CH:13]=[C:12]([CH:15]3[CH2:16][CH2:17][CH:18]([OH:21])[CH2:19][CH2:20]3)[C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ncc2[nH]cc(C3CCC(=O)CC3)c2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCNc1ncc2[nH]cc(C3CCC(O)CC3)c2n1

Procedure:
A solution of N-Butyl-7-(4-((tert-butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)-5-trityl-5H-pyrrolo[3,2-d]pyrim-idin-2-amine (992 mg, 1.54 mmol) in CH2Cl2 (20 mL) was added trifluoroacetic acid (5.0 mL). The reaction mixture was stirred for 4 hours and quenched by a saturated aq. solution of NaHCO3 and diluted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated. The residue was dissolved in MeOH (6.0 mL) and Pd/C (44 mg) was added. The reaction mixture was then stirred under the hydrogen atmosphere for 12 hours and then filtered. The filtrate was concentrated to afford a brown residue. A solution of the residue in CH2Cl2 (10 mL) was added a mixture of PCC (665 Mg, 3.084 mmol) and silica gel (668 mg). After 30 min, the reaction was quenched with water and extracted with EtOAc (3×). The combined organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by ISCO to provide the desired product 4-(2-(butylamino)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)cyclohexanone (MS m/z 287.2 [M+H]+). A solution of 4-(2-(butylamino)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)cyclohexanone in MeOH (10 mL) was added NaBH4 (67 mg, 1.71 mmol) slowly at −40° C. The reaction was quenched with water after 1 h and extracted with EtOAc (3×). The combined organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by ISCO to provide the desired product which was used without further purification. MS m/z 289.2 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[C:9]([O:14][CH2:15][CH2:16][N:17]=[C:18]=[O:19])(=[O:13])[C:10]([CH3:12])=[CH2:11].[N-]=C=O.Cl>O.CN(C)C(=O)C>[C:9]([O:14][CH2:15][CH2:16][NH:17][C:18]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=1)=[O:19])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: Nc1ccc(O)cc1
Agent: Cl
Agent: [N-]=C=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: C=C(C)C(=O)OCCNC(=O)Nc1ccc(O)cc1
Reaction time: 5 h
Yield: 93.3 %

Procedure:
Into a 1 liter fask 500 g of N,N-Dimethyl acetamide and 173.5 g (1.6 mole) of p-aminophenol were added. This mixture was placed in cold bath and 234.9 g (1.5 mole) of methacryloyl oxyethyl isocyanate was added over a period of 1 hour. After the addition was complete, stirring was continued for 5 hours at room temperature. The mixture was tested for isocyanate functionality using IR spectroscopy. 30 ml of concentrated HCl was added to the mixture and was stirred for 15 minutes. The mixture was poured into 4.5 liter of water. The deposit was filtered, washed and dried to produce 370 g of 2-(N′-(4-hydroxyphenyl)ureido)ethyl methacrylate.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([Li])CCC.C[O:16][B:17](OC)[O:18]C.Cl>C1COCC1.C(Cl)Cl>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([B:17]([OH:18])[OH:16])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1ccc(B(O)O)cc1
Temperature: -100 °C
Reaction time: 0.08 h
Yield: 59.9 %

Procedure:
A solution of 4-bromobenzonitrile (91 g, 0.50 mole) in THF (1.1 L) was dried in the presence of activated 3 Å molecular sieves at room temp. This solution was filtered and cooled to −100° C. A 1.6 M solution of n-butyllithium in hexanes (355 mL. 0.567 mol) was added to the cold solution over 15 min while maintaining the internal temperature between −105 and −93° C. To the resulting orange reaction mixture was added trimethylborate (81 g, 0.78 mol) over 3 min, briefly increasing the reaction temperature to −72° C. The reaction mixture was recooled to −100° C. over 5 minutes and then was allowed to warm slowly to room temperature over 2.3 h. The reaction mixture was acidified with 4N HCl to pH 2.2, and was diluted with CH2Cl2 (200 mL). The aqueous layer was separated and the organic layer was washed with brine (2×200 mL), dried over anhydrous MgSO4, filtered, and the solvent removed under reduced pressure to a pale yellow solid. This solid was additionally purified by dissolution in 1N NaOH and extraction into CH2Cl2/THF (1:1, 2×200 mL). The aqueous phase was acidified with 4N HCl to pH 2.2 and was extracted into CH2Cl2/THF (1:1, 500 mL). The combined organic extracts were concentrated to a crude solid (64.6 g) that was triturated with diethyl ether (160 mL) and dried under vacuum to afford the intermediate title compound (44.0 g, 59.9%) as a white powder. 1H NMR (d6-acetone, 300 MHz): δ 8.03 (d, 2H, J=8.1), 7.75 (d, 2H, J=8.4), 7.54 (s, 2H).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:9]2[CH2:10][C:11]3[CH:35]=[CH:34][CH:33]=[CH:32][C:12]=3[N:13]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:14][C:8]2=[CH:7][CH:6]=1)=[O:4].[NH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1.O>CS(C)=O>[OH:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][CH2:39][NH:38][C:3]([C:5]2[N:9]3[C:8]([CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[C:19]([CH3:31])[CH:18]=4)=[O:16])[C:12]4[CH:32]=[CH:33][CH:34]=[CH:35][C:11]=4[CH2:10]3)=[CH:7][CH:6]=2)=[O:4])=[CH:42][CH:43]=1
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: NCCc1ccc(O)cc1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCCc4ccc(O)cc4)n3Cc3ccccc32)cc1C
Yield: 94.7 %

Procedure:
The 2,2,2-trichloro-1-[10-(2′-methoxy-2-methyl-biphenyl-4-carbonyl)-10,11-dihydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-3-yl]-ethanone of step D (0.175 g; 0.316 mmol) and tyramine (0.087 g; 0.632 mmol) were stirred in 3 mL of dimethylsulfoxide under a nitrogen atmosphere at 80° C. for 18 hours. The solution was cooled and 15 mL water were added. The resulting solid was filtered and dried to provide the title compound (0.171 g, 94%), m.p. 138-147° C. MS [(+)ESI, m/z]: 572.2 [M+H]+
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[C:14](=[S:15])[CH:13]=[CH:12][O:11][CH:10]=1.[Cl:16][CH:17]([CH3:21])[C:18](Cl)=[O:19]>ClCCl>[Cl:16][CH:17]([CH3:21])[C:18]([O:8][C:9]1[C:14](=[S:15])[CH:13]=[CH:12][O:11][CH:10]=1)=[O:19]
Reactant: CC(Cl)C(=O)Cl
Reactant: Oc1coccc1=S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Cl)C(=O)Oc1coccc1=S
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.2 %

Procedure:
Triethylamine (190 mg, 1.9 mmol) was added to a stirred solution of 7 (200 mg, 1.6 mmol) in dichloromethane (10 mL) at 0° C. A solution of 2-chloropropionyl chloride (240 mg, 1.9 mmol) diluted in dichloromethane (1 mL) was added dropwise and the reaction mixture stirred at 0° C. for 10 min. The red solution was evaporated to dryness in vacuo and the resulting residue was purified by rapid silica filtration (dichloromethane) to give 8 as a red oil (270 mg, 79%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:33][C:34]([CH3:39])=[C:35]([CH2:37]Cl)[N:36]=2)=[CH:28][CH:27]=1>O>[C:15]([O:14][C:12]([CH:7]1[CH2:6][C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:37][C:35]3[N:36]=[C:32]([C:29]4[CH:30]=[CH:31][C:26]([Br:25])=[CH:27][CH:28]=4)[O:33][C:34]=3[CH3:39])=[CH:3][CH:4]=2)[O:9][CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCl
Reactant: CC(C)(C)OC(=O)C1COc2cc(O)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1oc(-c2ccc(Br)cc2)nc1COc1ccc2c(c1)OCC(C(=O)OC(C)(C)C)C2
Temperature: 60 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
To a stirred suspension of tert-butyl 7-hydroxychromane-3-carboxylate (1.1 g, 4.4 mmol) and potassium carbonate (1.1 g, 8 mmol), 2-(4-bromophenyl)-4-(chloromethyl)-5-methyl-1,3-oxazole (1.14 g, 4 mmol) was added and the reaction mixture was stirred at 60° C. for overnight. After the completion of the reaction, water (40 ml) was added and the precipitated product was extracted with ethylacetate (60 ml). The organic layer was washed with 50 ml of water twice and dried. The dried solution was evaporated to give the product as brown solid (1.55 g, 77.4%).
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17]CC2C=CC(OC)=CC=2)=[O:16])[CH2:4]1)=O.[CH2:33]([C:40]1[CH:44]=[N:43][N:42]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[N:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:33]([C:40]1[CH:44]=[N:43][N:42]([CH:45]2[CH2:50][CH2:49][N:48]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@H:14]([CH:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)[C:15]([OH:17])=[O:16])[CH2:4]3)[CH2:47][CH2:46]2)[N:41]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: c1ccc(Cc2cnn(C3CCNCC3)n2)cc1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(n3ncc(Cc4ccccc4)n3)CC2)[C@@H](c2ccccc2)C1
Reaction time: 12 h
Yield: 42 %

Procedure:
A Solution of α-(R)-(3-(R)-Formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, para-methoxybenzyl ester (52 mg, 0.12 mmol, (prepared above as Aldehyde 5)), 4-(4-benzyltriazol-2-yl)piperidine (41 mg, 0.17 mmol from Step C) and sodium triacetoxyborohydride, (51 mg 0.24 mmol) in 1 mL of 1,2-dichloroethane was stirred for 12 h. The solvent was removed and the product was purified by preprative HPLC (column: YMC Combiprep ODS-A 20×50 mm, gradient: 5% acetonitrile/water w/0.1% TFA for 1 min then ramp to 100% acetonitrile w/0.1% TFA over 6 min, flow: 20 mL/min). The so isolated material was stirred in 3 mL formic acid for 16 h. After removal of solvent the residue was purified by ion exchange chromatography (3 grams SCX resin, 100% MeOH→2.0M NH3/MeOH) to give 17 mg (42%) of the title compound. 1H NMR (500 MHz, CD3OD). δ1.0-3.6 (m, 29H), 4.05 (s, 2H), 7.15-7.35 (m, 10H), ESI-MS. M/z; (M+H)=542.4 (obs), 542.34 (calc.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.[NH:28]1[CH2:31][CH2:30][C@@H:29]1[C:32]([OH:34])=[O:33]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2)[CH2:5][N:28]1[CH2:31][CH2:30][C@@H:29]1[C:32]([OH:34])=[O:33]
Reactant: O=C(O)[C@H]1CCN1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Product: O=C(O)[C@H]1CCN1Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (106.1 mg, 0.283 mmol) and (R)-azetidine-2-carboxylic acid (86 mg, 0.850 mmol) according to Reference R and the general procedure for reductive amination gave (R)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)azetidine-2-carboxylic acid as a brown solid. MS (ESI) m/z: Calculated: 459.1; Observed: 460.1 (M++1).
Reaction SMILES: [C:1]([NH:4][C@H:5]([CH2:16][OH:17])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].[OH-].[Na+].S(OC)(O[CH3:24])(=O)=O>C(#N)C.CC(C)=O>[CH3:2][C:1]([NH:4][C@@H:5]([C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])[CH2:16][O:17][CH3:24])=[O:3]
Reactant: COS(=O)(=O)OC
Reactant: CC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(C)=O
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Reaction time: 1 h
Yield: 70 %

Procedure:
(R)-2-Acetamido-N-benzyl-3-hydroxypropionamide (25 g, 0.1059 mole) was suspended in 125 ml of acetonitrile at room temperature. To this was added aqueous sodium hydroxide solution (6.3 g in 15 ml, 0.158 mol) drop wise, followed by dimethyl sulfate (26.7 g, 0.211 mole) drop wise. The reaction mixture was stirred for one hour and concentrated under reduced pressure. The resulting residue was dissolved in 200 ml dichloromethane and the solution washed with water (100 ml×3). The organic layer was treated with 1 g charcoal and stirred for one hour. It was filtered and the filtrate was concentrated under reduced pressure. The solid residue obtained was dissolved in acetone and precipitated by adding diisopropyl ether to obtain Lacosamide. (18.5 g, Yield: 70%; chiral HPLC: 99.8% and chemical HPLC: 99.7%)
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20](F)[C:17]=1[C:18]#[N:19].[C:25]([O:29][CH3:30])(=[O:28])[CH2:26][SH:27].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[NH2:19][C:18]1[C:17]2[C:16]([O:15][CH2:14][CH2:13][CH2:12][N:3]3[C:2](=[O:1])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[C:4]3=[O:11])=[CH:23][CH:22]=[CH:21][C:20]=2[S:27][C:26]=1[C:25]([O:29][CH3:30])=[O:28]
Reactant: N#Cc1c(F)cccc1OCCCN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1sc2cccc(OCCCN3C(=O)c4ccccc4C3=O)c2c1N

Procedure:
A mixture of EXAMPLE 14A (0.5 g, 1.54 mmol), methyl thioglycolate (217 μL, 2.31 mmol), and sodium carbonate (653 mg, 6.16 mmol), was heated in methanol (7.7 mL) at 70° C. for 21 hours. The mixture was cooled, diluted with water, and the precipitate filtered and dried. The crude product was purified by flash chromatography on silica gel using a gradient of 0-2% methanol in dichloromethane to provide the title compound as an 85% pure mixture with unreacted EXAMPLE 14A. 1H NMR (DMSO-d6) δ 7.79-7.88 (m, 5H), 7.33-7.44 (m, 2H), 6.97 (s, 1H), 6.86 (dd, J=7.8, 1.0 Hz, 1H), 4.23 (t, J=5.8 Hz, 2H), 3.80 (t, J=6.8 Hz, 2H), 3.77 (s, 3H), 2.17 (quin, J=6.1 Hz, 2H).
Reaction SMILES: [CH3:1][CH:2]1[C:6]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C:5](=[CH2:13])[C:4](=[O:14])[CH2:3]1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:3][C:4](=[O:14])[C@@:5]2([O:23][CH2:13]2)[C:6]21[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2
Reactant: C=C1C(=O)CC(C)C12CCCCCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@H]1CC(=O)[C@]2(CO2)C12CCCCCC2
Yield: 17.6 %

Procedure:
Following the same general procedure of Example 3, 4-methyl-1-methylenespiro[4.6]undecan-2-one (5.29 g, 27.5 mmol) was reacted with 70% 3-chloroperbenzoic acid (13.6 g, 55.0 mmol) in CH2Cl2 (75 mL+150 mL) at room temp. for 4 d, with additional portions of 70% 3-chloroperbenzoic acid (7.00 g, 28.4 mmol) being added after every day. Work-up with aq. 20% NaHSO3 (250 mL) and purification by silica-gel FC (pentane/Et2O, 9:1, Rf=0.19) provided (3R*,11S*)-11-methyl-1-oxadispiro[2.0.6.3]tridecan-13-one (1.01 g, 18%), besides the (3R*,11R*)-diastereomer (Rf=0.14, 820 mg, 14%).