Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22]([N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32]O)[CH2:27][CH2:26]1)(=[O:24])=[O:23]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:32][CH2:31][N:28]2[CH2:29][CH2:30][N:25]([S:22]([CH3:21])(=[O:23])=[O:24])[CH2:26][CH2:27]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Reactant: CS(=O)(=O)N1CCN(CCO)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2OCCN2CCN(S(C)(=O)=O)CC2)CC1

Procedure:
The title compound was prepared by using Mitsunobu condition from 4-(2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and 2-(4-Methanesulfonyl-piperazin-1-yl)-ethanol.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:9])[CH2:6][CH2:7]1)(=[O:27])=[O:26]
Reactant: O=C(Oc1cccnc1)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCN(C(=O)Oc2cccnc2)CC1
Reaction time: 8 h

Procedure:
To a mixture of pyridin-3-yl 4-hydroxypiperidine-1-carboxylate (330 mg), triethylamine (0.25 mL) and DCM (7 mL) was added slowly dropwise methanesulfonic acid chloride (0.13 mL) at room temperature. After stirring overnight, the reaction liquid was purified directly by silica gel column chromatography (hexane/ethyl acetate=50/50 to 0/100) to obtain pyridin-3-yl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (390 mg) as a colorless solid.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56]O)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56][N:22]2[C:23]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]#[N:33])=[CH:30][CH:31]=3)=[CH:24][N:20]=[CH:21]2)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Cn2cncc2Cc2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To 1-trityl-4-(4-Cyanobenzyl)-imidazole (1.99 g, 4.64 mmol) in CH2Cl2 (9.3 mL), Hunigs base (1.62 mL, 9.28 mmol) and the product from step B (1.0 g 4.64 mmol) at −78° C. was added trifluoromethanesulfonic anhydride (0.78 mL, 4.64 mmol). After 45minutes the reaction was allowed to warm to room temperature. The solvent was evaporated and the residue was dissolved in methanol (50 ml) and heated at reflux for 1 hour, cooled and evaporated to dryness. The residue was partitioned between sat. aq. NaHCO3 solution and CH2Cl2. The organic layer was dried, (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 3% MeOH in CH2Cl2) to afford the title compound.
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[CH2:10](Br)[CH:11]=[CH2:12]>CO>[CH2:12]([N:5]1[CH:4]=[C:3]([F:2])[CH:8]=[N:7][C:6]1=[O:9])[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: O=c1ncc(F)c[nH]1
Agent: [Na]
Solvent: CO
Product: C=CCn1cc(F)cnc1=O
Yield: 48 %

Procedure:
The sodium salt of 5-fluoropyrimid-2-one (0.01 mol) was dissolved in methanol (100 ml) and allyl bromide (0.015 mol) added gradually at room temperature and the reaction allowed to proceed until neutral pH had been reached. The reaction mixture was then concentrated at reduced pressure and the residue extracted with chloroform (100 ml). The chloroform solution was washed with water (2×5 ml) and dried before evaporation; Yield 48%, m.p. 88°-90° C. after recrystallisation from acetone: (Found: C, 55.10; H, 4.80. Calc. for C7H7FN2O: C, 54.56; H, 4.58.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+:11].[Na]>O>[NH2:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5].[Na+:11].[Na+:11]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]
Temperature: 150 °C

Procedure:
A sample of 50 grams of L-aspartic acid was placed in a 1-liter beaker. To this, 50 ml of distilled water were added and magnetically stirred to form a slurry that contained 0.3755 moles of aspartic acid. Next, 75.1 ml of 10 N NaOH (Fisher Scientific) were slowly pipetted into the solution, thereby adding 0.751 moles of sodium (30.04 grams as NaOH). This solution was not lyophilizible, but was dried first at 120° C. for four hours to form a viscous liquid, then at 150° C. for four more hours which on cooling yielded a white, crystalline mass of disodium aspartate.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].C(O[C:12]1[C:13](=[O:20])[C:14](=[O:19])[C:15]=1[O:16][CH2:17][CH3:18])C>CCOCC>[CH2:17]([O:16][C:15]1[C:14](=[O:19])[C:13](=[O:20])[C:12]=1[N:6]1[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]1)[CH3:18]
Reactant: CCN1CCNCC1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCOCC
Product: CCOc1c(N2CCN(CC)CC2)c(=O)c1=O
Yield: 47 %

Procedure:
A solution of N-ethylpiperazine (1.529 g) and 3,4-diethoxy-3-cyclobutene-1,2-dione (2.29 g) in ether (40 mL) was stirred at ambient temperature for 16 hours. The precipitated solid was collected by filtration to obtain the title compound (1.5 g) as a white solid. This material was used in Example 2 without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4[CH2:27][CH2:26][CH2:25]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:30])[CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][C:54]([N:56]=[C:57]=[S:58])=[O:55])=[CH:49][CH:48]=1>C(O)C.C1(C)C=CC=CC=1>[F:30][C:4]1[CH:3]=[C:2]([NH:1][C:57]([NH:56][C:54](=[O:55])[CH2:53][C:50]2[CH:51]=[CH:52][C:47]([F:46])=[CH:48][CH:49]=2)=[S:58])[CH:29]=[CH:28][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]3[CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: Nc1ccc(Oc2cc(NC(=O)N3CCN(CCN4CCC4)CC3)ncn2)c(F)c1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCN(CCN4CCC4)CC3)ncn2)c(F)c1
Reaction time: 0.08 h

Procedure:
4-[2-(Azetidin-1-yl)ethyl]piperazine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (31 mg) was dissolved in ethanol (1 ml) under a nitrogen atmosphere, and then (S)-(+)-10-camphorsulfonic acid (47 mg) was added thereto, followed by stirring for 5 min. A 0.25 M solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.448 ml) was added thereto, followed by stirring for 15 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml), water (30 ml), brine (30 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; heptane:ethyl acetate=1:8, ethyl acetate, then ethyl acetate:ethanol=95:5). Fractions containing the target compound were concentrated under reduced pressure to give a residue, which was then purified by LC-MS. Fractions containing the target compound were concentrated to give a residue, which was then partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The organic layer was washed with brine (30 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated to provide the titled compound (0.9 mg) as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[C:8]1[C:14](=O)[C:13]2[N:16]3[C@@:20](OC)([C@H:21](COC(N)=O)[C:12]=2[C:10](=O)[C:9]=1OC)[C@H]1N[C@H]1C3>>[NH:16]1[C:13]2[C:12](=[CH:10][CH:9]=[CH:8][CH:14]=2)[CH2:21][CH2:20]1
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc2c(c1)CCN2

Procedure:
This compound was prepared by the procedure described in Example 1, except that the potassium carbonate was omitted. From 100 mg. of mitomycin A and 69 mg. of indoline was obtained 45 mg. (36% yield) of the desired product having a melting point of 127°-135° C. (decomposition) and providing the following analysis:
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]([CH2:43][CH:44]([CH3:48])[CH2:45][O:46][CH3:47])[C:39](=[O:49])[CH:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]([CH2:43][CH:44]([CH3:48])[CH2:45][O:46][CH3:47])[C:39](=[O:49])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: COCC(C)Cn1ccc(Br)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: COCC(C)Cn1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 4-bromo-1-(3-methoxy-2-methyl-propyl)-1H-pyridin-2-one following a procedure analogous to that described in Example 75 Method 1. Mass spectrum (ESI+): m/z=533 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:25])[C:11]1[CH:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:14]([Cl:22])=[CH:13][C:12]=1[O:23][CH3:24])[CH3:2].S(OC)(O[CH3:30])(=O)=O>>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:25])[C:11]1[CH:16]=[C:15]([N:17]([CH3:30])[S:18]([CH3:21])(=[O:20])=[O:19])[C:14]([Cl:22])=[CH:13][C:12]=1[O:23][CH3:24])[CH3:2]
Reactant: CCN1CCCC1CNC(=O)c1cc(NS(C)(=O)=O)c(Cl)cc1OC
Reactant: COS(=O)(=O)OC
Product: CCN1CCCC1CNC(=O)c1cc(N(C)S(C)(=O)=O)c(Cl)cc1OC

Procedure:
Using N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-chloro-5-methanesulfonamidobenzamide and dimethyl sulfate, the reaction is effected as in Example 5, whereby N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-chloro-5-(N-methylmethanesulfonamido)benzamide is obtained as crystals melting at 140.5° to 142° C.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:29]=[CH:30][C:31]=3[O:32][CH3:33])[C:14]([CH2:16][O:17][C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:21]([O:23][CH3:24])=[O:22])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:52]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl.ClCCl>[C:1]12([C:11]3[CH:12]=[C:13]([CH:29]=[CH:30][C:31]=3[O:32][CH3:33])[C:14]([CH2:16][O:17][C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=3[CH2:28][Br:52])[C:21]([O:23][CH3:24])=[O:22])=[O:15])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(OCC(=O)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(CBr)c(OCC(=O)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)c1
Yield: 34 %

Procedure:
A solution of methyl 3[(3-(1-adamantyl)-4-methoxybenzoyl)methyloxy]-4-methylbenzoate (2.36 g, 5.26 mmol) and benzoyl peroxide (0.02 g) in carbon tetrachloride (50 ml) was heated to reflux. Benzoyl peroxide (0.03 g) and N-bromosuccinimide (1.05 g, 5.9 mmol) were added. The mixture was heated for four hours at reflux. 50 ml of water and 50 ml of dichloromethane were added. After separation of the phases once settling had taken place, the organic phase was washed twice with 50 ml of water and dried over magnesium sulfate. After concentration on a rotary evaporator at 40° C. under vacuum, the desired product was isolated by flash chromatography (CH2Cl2). Its properties were as follows:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([CH2:14][Cl:15])[C@H:11]2[O:16][C@@](OC)(C)[C@](OC)(C)[O:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([N:8]1[CH2:13][C@H:12]([CH2:14][Cl:15])[C@@H:11]([OH:16])[C@H:10]([OH:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(C)O[C@@H]2[C@@H](CCl)CN(Cc3ccccc3)C[C@H]2O[C@]1(C)OC
Solvent: O=C(O)C(F)(F)F
Product: O[C@@H]1[C@@H](CCl)CN(Cc2ccccc2)C[C@H]1O

Procedure:
To a solution of (2S,3S,4aR,8S,8aR)-6-benzyl-8-(chloromethyl)-2,3-dimethoxy-2,3-dimethyloctahydro-[1,4]dioxino[2,3-c]pyridine (2) (2.2 g, 5.9 mmol) in dicholoromethane (15 mL) was added trifluoroacetic acid (0.35 mol, 26 mL). Reaction mixture was heated at reflux for about 1 hour at which point reaction was judged complete by TLC. Excess solvent and TFA were evaporated in vacuo and the residue was chromatographed using silica gel (2-8% MeOH in CHCl3). Fractions were combined and evaporated to give (1.3 g, 87%) as the title compound. Product was characterized via HPLC/MS (MH+=255) and judged to be >95% pure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]3[C:13]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[OH:23])=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)[C:5]([F:24])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31](I)[CH3:32]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]3[C:13]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[O:23][CH2:31][CH3:32])=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)[C:5]([F:24])=[CH:4][N:3]=1
Reactant: Oc1cnccc1-c1cccc2cc(-c3nc(Cl)ncc3F)sc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cnccc1-c1cccc2cc(-c3nc(Cl)ncc3F)sc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.4 %

Procedure:
Treat a solution of 4-[2-(2-chloro-5-fluoro-pyrimidin-4-yl)-benzo[b]thiophen-7-yl]-pyridin-3-ol (100 mg, 0.28 mmol) and cesium carbonate (100 mg, 0.28 mmol) in dimethylformamide (1 mL) with ethyl iodide (44 mg, 0.28 mmol). Stir the mixture at room temperature for 12 hours. Dilute the mixture with ethyl acetate and wash the solution with three portions of water, one portion of saturated aqueous sodium chloride, dry over sodium sulfate, filter, and concentrate in vacuo. Purify the crude product by column chromatography on 12 g silica gel eluting with a gradient of dichloromethane to ethyl acetate to give the title compound (48 mg, 45%) as a brown solid. MS (ES) m/z 386 [M+1]+.
Reaction SMILES: [CH2:1]([C:7]1[N:8]([CH3:16])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl-].C[Al+]C.[O:21]1[C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C:22]1=[O:28].[Cl-].[NH4+]>C(Cl)Cl.CCCCCC.C(OCC)(=O)C>[CH2:1]([C:7]1[N:8]([CH3:16])[C:9]2[C:14]([C:15]=1[C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C:22]([OH:28])=[O:21])=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc2ccccc2n1C
Reactant: O=C1CCCC(=O)O1
Agent: C[Al+]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCc1c(C(=O)CCCC(=O)O)c2ccccc2n1C
Reaction time: 0.5 h

Procedure:
To a solution of 2-hexyl-1-methyl-1H-indole in methylene chloride at 0° C. was added dimethyl aluminum chloride solution in hexane. The reaction mixture was stirred for 30 minutes. To this solution dihydro-pyran-2,6-dione was added at 0° C. and the reaction mixture was stirred for 3 hours. The reaction was treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([C:18]3[CH2:19][CH2:20][S:21](=[O:25])(=[O:24])[CH2:22][CH:23]=3)=[C:13]([F:26])[CH:12]=2)[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C(#N)C>[O:25]=[S:21]1(=[O:24])[CH2:20][CH:19]=[C:18]([C:14]2[C:15]([F:17])=[CH:16][C:11]([N:7]3[CH2:6][C@H:5]([CH2:4][NH2:1])[O:9][C:8]3=[O:10])=[CH:12][C:13]=2[F:26])[CH2:23][CH2:22]1
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2cc(F)c(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: NC[C@H]1CN(c2cc(F)c(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(5S)-5-(Azidomethyl)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-1,3-oxazolidin-2-one (WO 01/81350 A1) (7 g, 18.2 mmol) was dissolved in water (15 ml) and acetonitrile (150 ml). Triphenylphosphine (5.73 g, 21.9 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue purified by flash column chromatography on silica gel with 5% methanol in dichloromethane. The fractions containing product were evaporated to near dryness and treated with ethereal HCl to precipitate the hydrochloride salt of the title compound as a white solid (5.03 g, 70%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:8]=[C:7]([SH:9])[NH:6][N:5]=1.Cl[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.O>CN(C)C=O>[NH2:3][C:4]1[N:8]=[C:7]([S:9][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[NH:6][N:5]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: Nc1n[nH]c(S)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Sc2nc(N)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.9 %

Procedure:
To 60% sodium hydride-in-oil (3.89 g) in dimethylformamide (50 ml) was dropwise added a solution (100 ml) of 3-amino-5-mercapto-1H-1,2,4-triazole (10.0 g) in dimethylformamide under ice-cooling. After the dropwise addition, the mixture was stirred at 0° C.-room temperature for 30 minutes and ice-cooled again. A solution (50 ml) of 4-chlorobenzonitrile (13.0 g) in dimethylformamide was dropwise added. The mixture was stirred at 0° C.-room temperature for 30 minutes and at 100°-110° C. for 33 hours. After the reaction, the mixture was cooled to room temperature and added with water, followed by stirring for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The crude product was subjected to silica gel column chromatography (chloroform-methanol) to give 1.86 g of white crystals (yield 9.9%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH2:11]([O:13][C:14](=[O:17])[CH2:15][NH2:16])[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].[F-].[K+]>O.CS(C)=O>[CH2:11]([O:13][C:14](=[O:17])[CH2:15][NH:16][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:12]
Reactant: CCOC(=O)CN
Reactant: N#Cc1cccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CNc1ncccc1C#N
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
2-Chloro-3-cyanopyridine (10.0 g, 72 mmol) was dissolved into anhydrous DMSO (200 ml). Glycine ethyl ester hydrochloride (11 g, 79 mmol) and sodium carbonate (4.5 g, 42 mmol) were added and the mixture was stirred for 10 min under argon. Potassium fluoride (4.2 g, 72 mmol) was added and the mixture was heated to 120° C. for 48 h. The mixture was cooled to room temperature and added to water (400 mL). The crude product was extracted with CH2Cl2 (4×100 mL), dried over MgSO4 and concentrated to an orange solid which was purified by silica gel (CH2Cl2) to give an orange solid (7.5 g, 51%). 1H NMR (300 MHz, CDCl3) δ 8.27 (dd, J=5.0, 2.0 Hz, 1H), 7.69 (dd, J=7.6, 2.0 Hz, 1H), 6.66 (dd, J=7.6, 5.0 Hz, 1H), 5.70 (bs, 1H), 4.21-4.28 (m, 4H), 1.29 (t, J=7.2 Hz, 3H); ESI MS m/z 206 [C10H11N3O2+H]+.
Reaction SMILES: C([O:4][C@H:5]([C:55]1[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=1)[CH2:6][CH2:7][C@@H:8]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C@H:25]4[O:42][C@@H:41]([C:43]([O:45]O)=[O:44])[C@H:36]([O:37]C(=O)C)[C@@H:31]([O:32]C(=O)C)[C@@H:26]4[O:27]C(=O)C)[CH:19]=3)=[CH:14][CH:13]=2)[N:10]([C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=2)[C:9]1=[O:54])(=O)C.O.C(O)(=O)C.CO>CO.C(N(CC)CC)C.ClCCl>[O:24]([C:20]1[CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([C@@H:11]3[C@@H:8]([CH2:7][CH2:6][C@@H:5]([C:55]4[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=4)[OH:4])[C:9](=[O:54])[N:10]3[C:47]3[CH:48]=[CH:49][C:50]([F:53])=[CH:51][CH:52]=3)=[CH:13][CH:14]=2)[CH:23]=[CH:22][CH:21]=1)[C@H:25]1[O:42][C@@H:41]([C:43]([OH:45])=[O:44])[C@H:36]([OH:37])[C@@H:31]([OH:32])[C@@H:26]1[OH:27]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](Oc2cccc(-c3ccc([C@@H]4[C@@H](CC[C@H](OC(C)=O)c5ccc(F)cc5)C(=O)N4c4ccc(F)cc4)cc3)c2)O[C@@H](C(=O)OO)[C@@H]1OC(C)=O
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)[C@@H]1O[C@H](Oc2cccc(-c3ccc([C@@H]4[C@@H](CC[C@H](O)c5ccc(F)cc5)C(=O)N4c4ccc(F)cc4)cc3)c2)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 19 h
Yield: 72.5 %

Procedure:
The product of step 3 (57.2 mg, 0.068 mmol) was dissolved in 1:1 methanol-triethylamine (2.8 mL). To this solution was added water (4.25 mL). The reaction progress was monitored by TLC (5% acetic acid and 15% methanol in dichloromethane) and was complete after 19 hours. The methanol and triethylamine were evaporated in vacuo, the residue was acidified with 1 N aqueous hydrochloric acid (1.4 mL), extracted with ethyl acetate (20 mL), washed with brine (5 mL), dried over sodium sulfate, filtered, concentrated and purified by chromatography (10 g silica gel, 5% acetic acid and 15% methanol in dichloromethane) to afford 4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl β-L-glucopyranosiduronic acid (32.6 mg, 73%) as an off-white foam; Rf 0.37 (5% acetic acid and 15% methanol in dichloromethane); 1H NMR (300 MHz, CD3OD) δ 7.63 (d, J=7.8 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.33 (m, 7H), 7.06 (m, 5H), 5.03 (m, 1H), 4.63 (t, J=5.1, 5.1 Hz, 2H), 3.94 (m, 3H), 3.13 (m, 1H) 1.91 (m, 4H) ppm; MS [M−H] 660.6.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[C:5]2[O:9][C:8]([F:11])([F:10])[O:7][C:6]=2[CH:12]=1.[C:20](=[O:22])=[O:21].[NH4+].[Cl-].Cl>C(OCC)C>[F:10][C:8]1([F:11])[O:9][C:5]2[C:4]([Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:3][C:2]([C:20]([OH:22])=[O:21])=[CH:12][C:6]=2[O:7]1
Reactant: CC[Si](CC)(CC)c1cc(Br)cc2c1OC(F)(F)O2
Reactant: O=C=O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC[Si](CC)(CC)c1cc(C(=O)O)cc2c1OC(F)(F)O2
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
200 ml of anhydrous diethyl ether were poured to 1.9 g of Mg turnings and 2.0 g of (6-bromo-2,2-difluoro-benzo[1,3]dioxol-4-yl)-triethyl-silane (Eur. J. Org. Chem. 2004, 1, 64) added. The mixture was then stirred at 35° C. for 30 minutes. Then, the heating was shut down and 23.4 g of (6-bromo-2,2-difluoro-benzo[1,3]dioxol-4-yl)-triethyl-silane was added dropwise to the stirred mixture at a rate that ensured gentle boiling. Stirring was continued at 35° C. for 2 h. Then, the mixture was intensely stirred at room temperature under an excess of anhydrous CO2 for 2 h. The reaction mixture was then poured into 300 ml of a saturated aqueous NH4Cl-solution, acidified to pH=3 using aqueous HCl-solution and the organic layer separated. The aqueous layer was then extracted using 200 ml of diethyl ether. The combined organic layer was dried using MgSO4 and evaporated to yield 22.0 g of the title compound that was used without further purification.