Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl>[CH2:1]([O:21][S:36]([C:33]1[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=1)(=[O:38])=[O:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCCCCCO
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of eicosanol (5.0 g, 16.70 mmol) and triethylamine (4 ml) in methylene chloride (80 ml) was added dropwise a solution of 4-chlorobenzene-sulphonyl chloride (3.90 g, 18.50 mmol) in methylene chloride (20 ml) and this solution was stirred for 24 h. The reaction mixture was then diluted with more methylene chloride (100 ml) and washed with water (2×75 ml). The organic layer was dried over MgSO4, filtered and concentrated to give a crude product which was recrystallized from methanol to give n-eicosanyl-4-chlorobenzenesulphonate the product (5.10 g, 65%) m.p. 69°-70° C. max; 3000-2800, 1367, 1184, 1176, 963 cm-1. m/z, 472 (M+). Found C, 66.16%; H 9.75%; S, 6.74% Cl, 7.40% C26H45O3SCl requires C, 66.00%; H, 9.59%; S, 6.78%; Cl, 7.49%. 1Hnmr, 0.855 (t, J-6.6 Hz, 3H); 1.10-1.65 (m); 4.030 (t, J=6.4 Hz, 2H); 7.48-7.53 (m, 2H); 7.80-7.84 (m, 2H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:24])[CH:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:18])[CH3:14].IC>C1(C)C=CC=CC=1.CCCCCC>[CH2:13]([O:15][C:16](=[O:24])[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])([CH3:1])[CH3:18])[CH3:14]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)C(C)N(CC)CC
Agent: [Li]CCCC
Solvent: CI
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)C(C)(C)N(CC)CC
Temperature: -78 °C
Reaction time: 1 h
Yield: 454.5 %

Procedure:
Diisopropyl amine (0.15 moles) was added to a flask and diluted with 50 mL of toluene. The resultant was cooled to −78° C. under nitrogen, and then a hexane solution of n-butyl lithium (0.13 moles) was added thereto, followed by stirring at −78° C. for 1 hour. Further, the mixture was heated to 0° C. and stirred for 1 hour. To this, 2-diethylaminopropionic acid ethyl ester (0.11 moles) was added and the resultant was further stirred for 1 hour, and iodomethane (0.23 moles) was added thereto, and then the temperature was restored to room temperature and the mixture was stirred for 1 hour. The reaction mixture was quenched with ice water, extracted with ethyl acetate and washed with a saturated sodium chloride aqueous solution, and then the organic layer was dried over magnesium sulphate. The solvent was distilled away, and then the residue was purified by column chromatography (hexane/ethyl acetate=4/1) to obtain α-diethylamino isobutyric acid ethyl ester (0.50 moles).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH3:11][C:12]1[CH:21]=[C:20]([CH3:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[CH:23]1[CH2:28][C:27](=[O:29])[C:26]([C:30](=[N:34][O:35][CH2:36][CH3:37])[CH2:31][CH2:32][CH3:33])=[C:25]([OH:38])[CH2:24]1>CC(C)=O>[C:1]([O:29][C:27]1[CH2:28][CH:23]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]([CH3:22])=[CH:21][C:12]=2[CH3:11])[CH2:24][C:25](=[O:38])[C:26]=1[C:30](=[N:34][O:35][CH2:36][CH3:37])[CH2:31][CH2:32][CH3:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCC(=NOCC)C1=C(O)CC(c2c(C)cc(C)c3ccccc23)CC1=O
Agent: [Na]
Solvent: CC(C)=O
Product: CCCC(=NOCC)C1=C(OC(=O)c2ccccc2)CC(c2c(C)cc(C)c3ccccc23)CC1=O
Reaction time: 12 h

Procedure:
A slight excess of benzoyl chloride was added to a suspension of the sodium salt of 5-(2,4-dimethylnaphth-1-yl)-2-[1-(ethoxyimino)butyl]-3-hydroxycyclohex-2-en-1-one (0.34 g) in acetone (20 ml) and the mixture was stirred at room temperqature for 12 hr. The mixture was filtered, the filtrate was evaporated and the residue was purified by column chromatography over silica with dichloromethane elution to give 3-benzoyloxy-5-(2,4-dimethylnaphth-1-yl)-2-[1-(ethoxyimino)butyl]cyclohex-2-en-1-one as a pale yellow oil. The product was characterized by proton nuclear magnetic resonance spectroscopy and the spectroscopic data is recorded in Table 4, Example 10.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:21][CH:20]=2)=[C:4]([Cl:17])[CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13].FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][CH:24]=2)=[C:4]([Cl:17])[CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1)c2Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)O)cc1)c2Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a stirred solution of ethyl 8-bromo-7-(4-(tert-butoxycarbonyl)phenoxy)-6-chlorochroman-4-carboxylate (0.26 g, 0.51 mmol) in dichloromethane (5 mL) at ambient temperature was added trifluoroacetic acid (5 mL). The resulting solution was stirred at ambient temperature for 30 minutes. The solution was concentrated and the residual glassy solid was redissolved in ethyl acetate (2 mL). Hexanes (10 mL) were added, and after mixing for a few minutes, the product solidified. The mixture was concentrated to afford 4-(8-bromo-6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid as a light brown powder (0.23 g, 99% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>C1(C)C=CC=CC=1>[ClH:25].[ClH:25].[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][N:15]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=3)[CH2:16][CH2:17]2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(C(CCCN2CCNCC2)c2ccc(F)cc2)cc1
Reactant: Clc1ccc(Cl)nc1
Solvent: Cc1ccccc1
Product: Cl
Product: Fc1ccc(C(CCCN2CCN(c3ccc(Cl)cn3)CC2)c2ccc(F)cc2)cc1

Procedure:
19.8 g (0.06 mole) of 1-[4,4-bis(p-fluorophenyl)butyl]-piperazine and 2.96 g (0.02 mole) of 2,5-dichloropyridine were heated together with 2 ml of toluene at 130° C. (temperature of oil bath) for 20 h.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[C:20]([C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[CH:26][C:27]([S:30][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:28][CH:29]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: CC(C)(C)c1ccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-tert.butyl-thiophenol.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].[C:13]([C:15]([CH3:24])([CH3:23])[C:16]1[CH:17]=[C:18](N)C=C[CH:21]=1)#[N:14].NC1C=[CH:42][C:29]([O:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][CH2:38][CH2:39][CH2:40][OH:41])[N:32]=2)=[CH:28][CH:27]=1>ClCCl>[C:13]([C:15]([CH3:23])([CH3:24])[C:16]1[CH:21]=[C:12]([NH:8][C:1]([NH:3][C:7]2[CH:6]=[CH:42][C:29]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH:37][CH2:38][CH2:39][CH2:40][OH:41])[N:32]=3)=[CH:28][CH:27]=2)=[O:2])[CH:11]=[CH:18][CH:17]=1)#[N:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C#N)c1cccc(N)c1
Reactant: Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Solvent: ClCCl
Product: CC(C)(C#N)c1cccc(NC(=O)Nc2ccc(Oc3ccnc(NCCCO)n3)cc2)c1
Reaction time: 12 h

Procedure:
196 mg (1.21 mmol) 1,1′-Carbonyl-diimidazol (CDI) were given to a solution of 176 mg (1.10 mmol) 3-(cyano-dimethyl-methyl)-phenylamine in 4.0 ml dichloro-methane and stirred for 12 h. A solution of 286 mg (1.10 mmol) 3-[4-(4-Amino-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in 6 ml dichloromethane was added within 30 min. and the mixture stirred for 12 h at r.t. The reaction mixture was evaporated and the residue was purified by chromatography on silica gel (dichloromethane/ethanol 96:4). The obtained material was leached with ether, filtered and dried. Yield 74 mg (15%) of the title compound.
Reaction SMILES: CS(O[CH:6]([C:11]1[CH:20]=[N:19][C:18]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16](=[O:30])[N:15]3[N:31]=[CH:32][N:33]=[C:14]3[C:13]=2[CH:12]=1)[C:7]([F:10])([F:9])[F:8])(=O)=O.CS(Cl)(=O)=[O:36].COC1C=CC(CN2[C:51]3[N:52]=[CH:53][C:54](C(O)C(F)(F)F)=C[C:50]=3C3=NC=NN3C2=O)=CC=1>C(Cl)Cl>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:17]2[C:18]3[N:19]=[CH:20][C:11]([CH:6]([N:52]4[CH2:51][CH2:50][O:36][CH2:54][CH2:53]4)[C:7]([F:9])([F:10])[F:8])=[CH:12][C:13]=3[C:14]3=[N:33][CH:32]=[N:31][N:15]3[C:16]2=[O:30])=[CH:27][CH:26]=1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C(OS(C)(=O)=O)C(F)(F)F)cnc32)cc1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C(O)C(F)(F)F)cnc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C(N4CCOCC4)C(F)(F)F)cnc32)cc1
Reaction time: 2 h

Procedure:
2,2,2-Trifluoro-1-(6-(4-methoxybenzyl)-5-oxo-5,6-dihydropyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-9-yl)ethyl methanesulfonate. Methane sulfonyl chloride (49 μl, 0.63 mmol) was added to a stirred solution of 6-(4-methoxybenzyl)-9-(2,2,2-trifluoro-1-hydroxyethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (Example 87, 127 mg, 0.31 mmol) and TEA (131 μl, 0.94 mmol) in DCM (1.3 mL) and the mixture was stirred for 2 hours. It was diluted with DCM (10 mL), washed with aqueous sodium bicarbonate (5 mL), dried (MgSO4) and concentrated under vacuum to afford the title compound as a brown gum, which was used crude without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[O:8][C:7](=[O:13])[C:6](C(O)=O)=[C:5]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:23](Cl)(=[O:27])[C:24](Cl)=O.C1C[O:32]CC1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[O:8][C:7](=[O:13])[C:6]([CH2:24][C:23]([OH:27])=[O:32])=[C:5]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Cl)c(Cl)cc2oc1=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)Cc1c(-c2ccccc2)c2cc(Cl)c(Cl)cc2oc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution of 6,7-dichloro-2-oxo-4-phenyl-2H-chromene-3-carboxylic acid (0.8 g) in THF (10 ml) was combined with DMF (1 drop) and oxalyl chloride (0.31 ml), and stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, the resultant residue was dissolved in THF (10 ml), and to which a solution of diazomethane prepared from N-methyl-N′-nitro-N-nitrosoguanidine (1.68 g) and potassium hydroxide (3.0 g) in ether (30 ml) was added dropwise. After the effervescence had ceased, the reaction solution was concentrated under reduced pressure. The resultant residue was dissolved in methanol (50 ml), combined with silver oxide, and heated under reflux for 30 minutes. After the insolubles were filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by a column chromatography (packing: silica gel, eluent: ethyl acetate-hexane=1:4). The resultant crude product of methyl (6,7-dichloro-2-oxo-4-phenyl-2H-chromen-3-yl)acetate was dissolved in acetic acid (5 ml) and concentrated hydrochloric acid (2.5 ml), and heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and the resultant residue was dissolved in a solvent mixture of THF (10 ml) and ethyl acetate (50 ml), and then washed with water followed by a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by recrystallization from ethyl acetate to obtain the title compound (0.52 g, yield: 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[K+].I[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1>O.[Cu]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=C(O)Cc1ccc(I)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccc(Sc2ccc(Cl)cc2)cc1

Procedure:
A solution of 6.0 g of 4-chlorothiophenol and 8.0 g of potassium hydroxide in 80 ml of water is heated to 50° C and 0.8 g of copper powder and 10.4 g of 4-iodophenylacetic acid are added. The mixture is heated to reflux and maintained at reflux overnight. The mixture is then cooled and filtered. The filtrate is acidified with concentrated HCl to give a white solid which, on recrystallization from methanol, yields cream colored plates, mp 135°-140° C. A sample is recrystallized frm chloroform-hexane to give white plates, mp 144.5°-148° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]([CH2:23][C@H:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[C:14]([NH:16][C:17]3[S:18][C:19]([F:22])=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:29][NH:30][C:31](=O)[O:32]C1C=CC=CC=1.[OH-].[Na+].O>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([C@H:13]([C:14]([NH:16][C:17]3[S:18][C:19]([F:22])=[CH:20][N:21]=3)=[O:15])[CH2:23][C@H:24]3[CH2:28][CH2:27][N:26]([C:31]([NH:30][CH3:29])=[O:32])[CH2:25]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CNC(=O)Oc1ccccc1
Reactant: O=C(Nc1ncc(F)s1)[C@H](C[C@H]1CCNC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC[C@H](C[C@@H](C(=O)Nc2ncc(F)s2)c2ccc(S(=O)(=O)C3CC3)cc2)C1
Reaction time: 1.5 h
Yield: 74.7 %

Procedure:
(R)-2-(4-(Cyclopropylsulfonyl)phenyl)-N-(5-fluorothiazol-2-yl)-3-((S)-pyrrolidin-3-yl)propanamide (500 mg, 1.05 mmol) was dissolved in tetrahydrofuran (40 mL), and thereafter, phenyl N-methylcarbamate (636 mg, 4.21 mmol) and an aqueous solution of sodium hydroxide (2 M, 2 mL) were added to the above obtained solution under ice-cold condition. The obtained mixture was stirred for 1.5 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated in vacuo. The obtained residue was purified by silica gel chromatography (chloroform/methanol=1%→15%) to obtain the captioned compound (377 mg, 75%) in the form of a white solid.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:12](=[O:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[BrH:15].[NH+]1C=CC=CC=1>C(O)(=O)C>[Br:15][CH2:13][C:12](=[O:14])[C:6](=[N:5][O:4][CH:1]1[CH2:3][CH2:2]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: Br
Reactant: CCOC(=O)C(=NOC1CC1)C(C)=O
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOC1CC1)C(=O)CBr
Temperature: 0 °C

Procedure:
A solution of ethyl 2-cyclopropyloxyimino-3-oxobutyrate (syn isomer)(358 mg) and pyridinium hydrobromide perbromide (633 mg) in acetic acid (2 ml) was heated at 50° C. for 30 minutes. The mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed successively with saturated aqueous solution of sodium bicarbonate and water, dried over magnesium sulfate and concentrated in vacuo to give ethyl 4-bromo-2-cyclopropyloxyimino-3-oxobutyrate (syn isomer)(470 mg). To a solution of the compound obtained above in N,N-dimethylacetamide (2.2 ml) was added thiourea (126 mg) at ambient temperature. The mixture was stirred at the same temperature for an hour. The mixture was pouredd into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was subjected to column chromatography on silica gel using a mixture of chloroform and ethyl acetate (4:1 V/V) as an eluent to give ethyl 2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetate (syn isomer)(l77 mg) as a crystal.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:37](O)=[O:38])=[N:11][C:12]([N:19]([CH3:36])[S:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])(=[O:22])=[O:21])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:74][CH2:75][C:76]1[CH:86]=[CH:85][C:84]([F:87])=[CH:83][C:77]=1[C:78]([O:80][CH2:81][CH3:82])=[O:79]>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:37]([NH:74][CH2:75][C:76]2[CH:86]=[CH:85][C:84]([F:87])=[CH:83][C:77]=2[C:78]([O:80][CH2:81][CH3:82])=[O:79])=[O:38])=[N:11][C:12]([N:19]([CH3:36])[S:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])(=[O:21])=[O:22])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1nc(C(=O)O)c(OCc2ccccc2)c2ncccc12)S(=O)(=O)CCCCCNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc(F)ccc1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(F)ccc1CNC(=O)c1nc(N(C)S(=O)(=O)CCCCCNC(=O)OC(C)(C)C)c2cccnc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71 %

Procedure:
To a solution of 8-(benzyloxy)-5-(5-(tert-butoxycarbonylamino)-N-methylpentylsulfonamido)-1,6-naphthyridine-7-carboxylic acid (Example 2.4; 3.82 mmol) in dichloro methane (38 ml) were added HBTU (4.58 mmol) and DIPEA (15.8 mmol). The mixture was stirred for 5 min at rt. Ethyl 2-(aminomethyl)-5-fluorobenzoate hydrochloride (Example 4; 4.58 mmol) was added portionwise at rt. The mixture was stirred overnight at rt. The product was extracted with CH2Cl2, dried over MgSO4 and concentrated. The crude product was purified by SiO2 column chromatography (AcOEt:Hex, 1:1) to afford the target compound in 71% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15](O)=[O:16])=[CH:12][C:11]=2[CH:18]=1.[BH4-].[Na+]>C(O)(C)(C)C.CO.[Cl-].[Na+].O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([CH2:15][OH:16])=[CH:12][C:11]=2[CH:18]=1
Reactant: O=C(O)c1cc2cc(-c3ccccn3)ccc2o1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CO
Product: OCc1cc2cc(-c3ccccn3)ccc2o1
Temperature: 50 °C
Yield: 61.8 %

Procedure:
To a solution of 5-pyridin-2yl-benzofuran-2-carboxylic acid (770 mg, 2.9 mmol) in 28 mL t-butanol and 2.5 mL methanol was added NaBH4 (275 mg, 7.2 mmol). The mixture was heated at 50° C. under argon overnight, allowed to cool, poured into brine, extracted with ethyl acetate, washed with brine, dried (MgSO4), and evaporated. Purification by chromatography gave 404 mg of (5-pyridin-2-yl-benzofuran-2-yl)-methanol. MS: (M+H)+=226.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[C:23]1[C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:31][C:30]3[CH:29]=[CH:28][C:27]([C:23]4[NH:24][CH:25]=[CH:26][N:22]=4)=[CH:33][CH:32]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc(-c2ncc[nH]2)cc1
Product: CC(C(=O)Nc1ccc(-c2ncc[nH]2)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
71 mg (0.23 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) (Example 2.2B) and 40 mg (0.25 mmol) of 4-(1H-imidazol-2-yl)aniline (Example 1.2A) were reacted according to General Method 1. Yield: 4 mg (4% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]2([CH3:25])[CH2:12][O:11][S@@:10](=[O:13])[N:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][CH3:24])[CH:7]=1.I([O-])(=O)(=O)=[O:28].[Na+]>C(OCC)(=O)C.C(#N)C.O.[Ru](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C@:8]2([CH3:25])[CH2:12][O:11][S:10](=[O:28])(=[O:13])[N:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][CH3:24])[CH:7]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COc1ccc(CN2[S@](=O)OCC2(C)c2cc(Br)ccc2F)c(OC)c1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: COc1ccc(CN2[C@](C)(c3cc(Br)ccc3F)COS2(=O)=O)c(OC)c1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a mixture of (R)-4-(5-bromo-2-fluoro-phenyl)-3-(2,4-dimethoxy-benzyl)-4-methyl-[1,2,3]oxathiazolidine 2-oxide (15.7 g, 35.3 mmol, Eq: 1.00) and sodium periodate (8.31 g, 38.9 mmol, Eq: 1.1) in ethyl acetate (120 ml), acetonitrile (120 ml) and cold water (192 ml) at 23° C. was added ruthenium(III) chloride (73.3 mg, 353 μmol, Eq: 0.01) and this reaction mixture was stirred vigorously at 23° C. for 30 minutes. Extracted with sat NaHCO3, ethyl acetate, dried the organic layer over Na2SO4, filtered off and evaporated totally. The residue was purified by silica gel column chromatography with heptane/ethyl acetate to give the. The product fractions were collected and totally evaporated, dried in HV to give the (R)-4-(5-bromo-2-fluoro-phenyl)-3-(2,4-dimethoxy-benzyl)-4-methyl-[1,2,3]oxathiazolidine 2,2-dioxide (15.6 g, 33.9 mmol, 95.9% yield) as a white solid. MS (ISN): m/z=458.0 [M−H]− and 460.0 [M+2H]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24]OS(C)(=O)=O)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[N-:35]=[N+:36]=[N-:37].[Na+]>CCOC(C)=O>[N:35]([CH2:24][CH2:23][O:22][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCOS(C)(=O)=O)c2cccc(F)c2)C1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN=[N+]=[N-])c2cccc(F)c2)C1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
(R)-tert-Butyl 3-((R)-(3-fluorophenyl)(2-(methylsulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (13.8 g, 32 mmol) was dissolved into anhydrous DMF (150 mL), solid NaN3 (6.1 g, 96 mmol, 3 eq) was added and the reaction mixture was heated to 80° for overnight. The reaction mixture was cooled to rt and then was added with EtOAc (500 mL), the organic phase was washed with water (3×100 mL) and brine (2×80 mL), dried over Na2SO4 and concentrated in vacuo to give crude (R)-tert-butyl 3-((R)-(2-azidoethoxy)(3-fluorophenyl)methyl)piperidine-1-carboxylate (12 g), which was used in the next step without further purification.