Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(N2C3C=C(F)C(F)=CC=3N=C2C2C(OC)=NC(OC)=CC=2)C(O)=O)CCCCC1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:43]([CH:44]([CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)[C:45](O)=[O:46])[C:42]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:41]=3[N:40]=2)=[CH:35][CH:34]=1.Cl.N[C@H]1CC[C@H](O)CC1.C([O:71][C:72]([C@H:74]1[CH2:79][CH2:78][C@H:77]([NH2:80])[CH2:76][CH2:75]1)=[O:73])C>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:43]([CH:44]([CH:48]3[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]3)[C:45]([NH:80][C@H:77]3[CH2:76][CH2:75][C@H:74]([C:72]([OH:71])=[O:73])[CH2:79][CH2:78]3)=[O:46])[C:42]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:41]=3[N:40]=2)=[CH:35][CH:34]=1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: CCOC(=O)[C@H]1CC[C@H](N)CC1
Agent: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)O)C2CCCCC2)c(OC)n1
Agent: Cl
Agent: N[C@H]1CC[C@H](O)CC1
Product: O=C(N[C@H]1CC[C@H](C(=O)O)CC1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21

Procedure:
The title compound was prepared in analogy to example 8 replacing cyclohexyl-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetic acid with [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid (example 22, intermediate c) and trans-4-amino-cyclohexanol hydrochloride with trans-4-amino-cyclohexanecarboxylic acid ethyl ester ([CAS RN 1678-68-8]), followed by subsequent ester hydrolysis in analogy to example 10. Purification was conducted with chiral preparative HPLC (Chiralpak-AD column) eluting with a gradient of ethanol (+0.5% formic acid)/heptane. MS (ES+): 530 (M+H).
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[C:14]([OH:16])=[O:15].[CH3:17]O>>[CH3:17][O:15][C:14]([CH:6]1[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:5]1)=[O:16]
Reactant: CO
Reactant: O=C(O)C1Cc2ccccc2N1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1Cc2ccccc2N1

Procedure:
Thionyl chloride (12.1 ml, 167.2 mmol) was added dropwise, with stirring and while cooling with ice, to a solution of indoline-2-carboxylic acid (24.8 g, 152.0 mmol) in methanol (500 ml). The reaction mixture was stirred overnight at 40° C. The reaction solution was concentrated and thionyl chloride residues were removed by dragging out with diethyl ether (3 times).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([C:16]#[N:17])=[C:4]([SH:18])[N:3]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[S:24][CH:25]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1C1CCCCC1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1C1CCCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2.00 g (5.42 mmol) of the compound from Example 33A are initially charged in 111 ml of dry DMF, and 1.46 g (5.96 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 1.82 g (21.68 mmol) of sodium bicarbonate are added. The reaction mixture is stirred at RT for 12 h. The mixture is then diluted with 20 ml of water and extracted twice with in each case 100 ml of ethyl acetate. The combined organic phases are washed once with 15 ml of saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate. After removal of the solvent the residue is purified chromatographically on silica gel 60 (mobile phase: gradient cyclohexane/ethyl acetate 50:1→2:1).
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@H:25]3[N:29]([CH3:30])[CH2:28][C@@H:27]([N:31]([CH3:33])[CH3:32])[CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([O:14][C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C@H:25]4[N:29]([CH3:30])[CH2:28][C@@H:27]([N:31]([CH3:33])[CH3:32])[CH2:26]4)=[N:23][N:24]=3)[CH:21]=2)[CH2:6][CH2:5]1
Reactant: CN(C)[C@H]1C[C@@H](c2nnc3ccc(F)cn23)N(C)C1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)[C@H]1C[C@@H](c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)N(C)C1
Reaction time: 0.33 h
Yield: 96.3 %

Procedure:
A suspension of sodium hydride (60% dispersion in oil, 548 mg, 14.6 mmol) in dry DMF (10.0 mL) under nitrogen was treated with Intermediate 1 (800 mg, 4.9 mmol) and the mixture was stirred for 20 min. Intermediate 38c (1.28 g, 4.6 mmol) was added and the mixture was stirred at RT for 4 hours then quenched with MeOH. The mixture was further diluted with MeOH and applied to a pre-conditioned (MeOH) SCX-2 cartridge (25 g). The cartridge was eluted with MeOH then 2M NH3 in MeOH. The relevant product containing fractions were combined and concentrated in vacuo to give the title compound as a dark brown oil (1.8 g, 86%). LCMS (Method 3): Rt 0.6, m/z 407 [MH+].
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([Br:34])=[CH:32][CH:33]=3)[C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-:35].[Ca+2].[Cl-]>C(O)(C(F)(F)F)=O>[ClH:35].[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([Br:34])=[CH:32][CH:33]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(Br)nc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: [Cl-]
Agent: [Ca+2]
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(NC(Cc1ccc(Br)nc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
A solution of 1.02 g (1.95 mmol) of (2S)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(6-bromopyridin-3-yl)propanoate in TFA (3.0 mL), protected from the atmosphere by a calcium chloride-filled drying tube was stirred at room temperature for two hours. The reaction mixture was concentrated in vacuo at less than 35° C. and the resulting orange oil was dissolved in 3 mL of dichloromethane to which a solution of 6 mL of 1 M HCl/ether was added. The resulting white solid was filtered and washed with ether to give the title compound as a white powder, 845 mg, 86% yield.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[C:11]([NH:15][S:16]([C:19]1[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:20]=1[C:26]([O:28][CH3:29])=[O:27])(=[O:18])=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C>[C:11]([NH:15][S:16]([C:19]1[CH:24]=[C:23]([NH:25][CH:1]=[O:2])[CH:22]=[CH:21][C:20]=1[C:26]([O:28][CH3:29])=[O:27])(=[O:18])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=CO
Reactant: COC(=O)c1ccc(N)cc1S(=O)(=O)NC(C)(C)C
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC=O)cc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6.5 ml of formic acid are carefully added at 0° C. to 13 ml of acetic anhydride. The mixture is subsequently heated at 50°-60° C. for 2 h. A solution of 16.0 g (0.056 mol) of N-tert-butyl-5-amino-2-methoxycarbonylbenzenesulfonamide in 50 ml of DMF is then added dropwise at 0° C. The cooling bath is removed and the mixture is stirred for a further 4 h at room temperature. The reaction mixture is then shaken up in 800 ml of ethyl acetate and washed with three times 150 ml of water. The organic phase is dried over magnesium sulfate, the solvent is distilled off, and the residue is recrystallized from ethyl acetate/n-heptane. The product is N-tert-butyl-5-formylamino-2-methoxycarbonylbenzenesulfonamide (14.23 g, 82% of theory) which melts at 113°-114° C.
Reaction SMILES: Cl[C:2]([C:13]1[N:14]=[C:15]([CH3:31])[N:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=2)[C:17]=1[CH3:18])=[C:3]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([Cl:12])[CH:7]=1)C=O.CC(C)([O-])C.[K+].O>C1COCC1>[Cl:12][C:8]1[CH:7]=[C:6]([C:3]#[C:2][C:13]2[N:14]=[C:15]([CH3:31])[N:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([C:27]([F:30])([F:28])[F:29])[CH:20]=3)[C:17]=2[CH3:18])[CH:11]=[CH:10][N:9]=1
Reactant: COc1ccc(-n2c(C)nc(C(Cl)=C(C=O)c3ccnc(Cl)c3)c2C)cc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-n2c(C)nc(C#Cc3ccnc(Cl)c3)c2C)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
A solution of 3-Chloro-2-(2-chloro-pyridin-4-yl)-3-[1-(4-methoxy-3-trifluoromethyl-phenyl)-2,5-dimethyl-1H-imidazol-4-yl]-propenal (0.9 g, 1.9 mmol) in 8 mL THF was dropped to a cold (0° C.) suspension of potassium tert-butoxide (0.47 g, 4.2 mmol) in 4 mL THF and water (0.04 mL, 2.1 mmol). The light brown reaction mixture was stirred at 0° C. for 1 hr. The reaction was extracted two times with ethyl acetate, saturated NaHCO3− solution, water and brine. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (n-heptane/ethyl acetate 90:10→0:100) to obtain the desired product as a white solid (0.15 g, 19%), MS: m/e=406.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:21]#N)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[OH-:24].[Na+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[OH2:41]>O1CCOCC1>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)([C:21]([OH:41])=[O:24])[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: [OH-]
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(Cl)c2)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2cccc(Cl)c2)CC1
Temperature: 25 °C
Yield: 75.56 %

Procedure:
tert-Butyl 4-(3-chlorophenyl)-4-cyanopiperidine-1-carboxylate (5.91 g, 18.42 mmol) was dissolved in concentrated HCl (153.5 ml, 1842 mmol). The reaction mixture stirred at reflux over a weekend. The reaction mixture was cooled to room temperature and washed with ether. The aqueous portion was concentrated on a rotary evaporator, and the solids were dried on a high vacuum line. The solids were dissolved in H2O (35 mL), 10% NaOH (29.47 g, 73.69 mmol), and dioxane (30 mL). Solid Boc2O (4.222 g, 19.34 mmol) was added, and reaction mixture stirred at room temperature overnight (14 hours). The reaction mixture was diluted with H2O and washed with ether. The aqueous portion was acidified with solid KHSO4, then extracted with DCM. The combined extracts were dried (Na2SO4), filtered, and concentrated to give 1-(tert-butoxycarbonyl)-4-(3-chlorophenyl)piperidine-4-carboxylic acid (4.73 g, 75.56% yield) as a white powder. HPLC>98%. LC/MS (APCI−) m/z 338 [M−H]−.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[CH2:6][C:5](=[O:9])[CH2:4][O:3]1.[CH2:10](O)[CH3:11]>S(=O)(=O)(O)O>[CH2:10]([O:9][C:5]1[CH2:4][O:3][CH:2]([CH3:1])[C:7](=[O:8])[CH:6]=1)[CH3:11]
Reactant: CC1OCC(=O)CC1=O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC1=CC(=O)C(C)OC1

Procedure:
The product from Example 84C (3.0 g, 23 mmol) was dissolved in ethanol (50 mL), treated with concentrated sulfuric acid (5 drops), heated to reflux for 3 hours and concentrated. The residue was purified by chromatography eluting with 10:1 and then 5:1 and then 2:1 hexane:ethyl acetate to provide the title compound as the faster moving isomer.
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[C:4]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1.[H-].[Na+].Cl[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:24][CH2:23][CH2:22]1>CN(C)C=O>[O:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]([O:1][C:2]2[C:10]3[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=3[CH:5]=[C:4]([C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[CH:3]=2)[CH2:22][CH2:23]1
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cc2n1C
Reactant: ClC1CCOc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)N(C)C)cc2n1C
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 52.1 %

Procedure:
To a stirred suspension of 4-hydroxy-N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide (50 mg, 0.21 mmol, WO 2004054984) in N,N-dimethylformamide (2 mL) was added sodium hydride (60% dispersion in mineral oil, 11 mg, 0.27 mmol) at room temperature. After stirring for 20 minutes, a solution of 4-chlorochromane (71 mg, 0.42 mmol, WO 2000078751) in N,N-dimethylformamide (1 mL) was added at room temperature. The reaction mixture was warmed to 70° C., and stirred for 6 hours at the same temperature. The reaction mixture was quenched with sodium hydrogencarbonate aqueous solution, and extracted with ethyl acetate (20 mL×2). The combined extracts were washed with water and brine, dried over magnesium sulfate, and concentrated in vacuum. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol=10:1 as an eluent) to afford the title compound as a white solid (40 mg, 52%):
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[C:7]([CH3:35])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][NH:17][C:18]2[N:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)=[CH:20][N:19]=2)[N:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].CI.[CH3:39]C(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:36])[C:7]([CH3:8])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][N:17]([CH3:39])[C:18]2[N:19]=[CH:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]([F:32])([F:34])[F:33])=[CH:28][CH:29]=3)=[CH:22][N:23]=2)[N:14]=1)[CH3:35])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ncc(-c3ccc(OC(F)(F)F)cc3)cn2)cs1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(-c2ccc(OC(F)(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
2-Methyl-2-({4-[2-({5-[4-(trifluoromethoxy)phenyl]pyrimidin-2-yl}amino)ethyl]-1,3-thiazol-2-yl}thio)propionic acid tert-butyl ester (620 mg) synthesized in Example 162-2 and methyl iodide (325 mg) were dissolved in N,N-dimethylformamide (6.0 mL), potassium tertiary butoxide (154 mg) was added, and the mixture was stirred at room temperature for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1) to give the title compound (215 mg) as a colorless oil.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:14]=[C:15]1[O:18][C:17](=[O:19])[CH2:16]1>ClCCCl>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:17](=[O:19])[CH2:16][C:15](=[O:18])[CH3:14])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C=C1CC(=O)O1
Reactant: Nc1ccc(Cn2ccnc2)cc1
Solvent: ClCCCl
Product: CC(=O)CC(=O)Nc1ccc(Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To a stirred solution of 10 parts of 4-[(1H-imidazol-l-yl)methyl]benzenamine in 180 parts of 1,2-dichloroethane were added dropwise 3.9 parts of 4-methylene-2-oxetanone. After stirring for 1/2 hour at room temperature, the precipitate was filtered off, washed with 1,2-dichloroethane and dried, yielding 9.8 parts (74.8%) of N-[4-(1H-imidazol-1-ylmethyl)phenyl]-3-oxobutanamide; mp. 175° C. (interm. 57).
Reaction SMILES: [CH3:1][CH:2]([CH3:37])[C:3]([O:5][C@@H:6]1[C@H:10]([O:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[C@@H:9]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[O:8][CH:7]1[N:22]1[CH:30]=[N:29][C:28]2[C:23]1=[N:24][CH:25]=[N:26][C:27]=2[NH:31][C@@H:32]1[CH2:36][CH2:35][O:34][CH2:33]1)=[O:4].[CH:38]1(C(O)=O)[CH2:42]C[CH2:40][CH2:39]1.C(OC(=O)C(C)C)(=O)C(C)C>>[CH3:1][CH:2]([CH3:37])[C:3]([O:5][C@@H:6]1[C@H:10]([O:11][C:12](=[O:16])[CH:13]([CH3:14])[CH3:15])[C@@H:9]([CH2:17][O:18][C:19]([CH:20]2[CH2:40][CH2:39][CH2:38][CH2:42]2)=[O:21])[O:8][CH:7]1[N:22]1[CH:30]=[N:29][C:28]2[C:23]1=[N:24][CH:25]=[N:26][C:27]=2[NH:31][C@@H:32]1[CH2:36][CH2:35][O:34][CH2:33]1)=[O:4]
Reactant: O=C(O)C1CCCC1
Reactant: CC(=O)OC[C@H]1OC(n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@H](OC(=O)C(C)C)[C@@H]1OC(=O)C(C)C
Agent: CC(C)C(=O)OC(=O)C(C)C
Product: CC(C)C(=O)O[C@@H]1[C@@H](COC(=O)C2CCCC2)OC(n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@@H]1OC(=O)C(C)C

Procedure:
Compound 17 was prepared in the manner of compound 15 utilizing cyclopentanecarboxylic acid under conditions B for introduction of the ester group at the 5′ hydroxyl group, and isobutyric anhydride under conditions A for the introduction of the 2′ and 3′ hydroxyl groups: 1H NMR(CDCl3) δ1.05-1.23 (m, 12H), 1.52-2.05 (m, 8H), 2.26-2.38 (m,1H), 2.49-2.63(m,2H), 2.71-2.79 (m, 1H), 3.75-3.87(m,2H), 3.94-4.06(m,2H), 4.34-4.45 (m, 3H), 4.78-4.86(m, 1H), 5.58 (dd, 1H), 5.81 (dd, 1H), 6.17 (d, 1H), 6.95 (br s, 1H), 7.97 (s,1H), 8.37(s,1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1.[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].C(N(CC)CC)C>C1COCC1>[S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)([O:7][CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:10])=[O:9]
Reactant: OCC1CCOC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCC2CCOC2)cc1
Yield: 91.2 %

Procedure:
A mixture comprising 50 g of (tetrahydro-3-furanyl)methanol, 95 g of tosyl chloride, 52 g of triethylamine and 450 ml of THF was refluxed for 8 hours. After separation of insolubles by filtration, the reaction fluid was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/7) to obtain 114.5 g of (tetrahydro-3-furanyl)methyl tosylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2>CCOCC.[BH4-].[Zn+2].[BH4-]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2
Reactant: Fc1ccc2[nH]ccc2c1
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Product: Fc1ccc2c(c1)CCN2
Reaction time: 48 h
Yield: 102.1 %

Procedure:
A solution of 6.8 grams (0.05 moles) of 5-fluoro-1H-indole in 50 ml of ether was cooled to 0° C. under nitrogen. 507 ml of a 0.15M solution of zinc borohydride in ether was added dropwise. The reaction was allowed to stir for 48 hours. The reaction was quenched with dilute hydrochloric acid. The pH was adjusted to 8.0 with dilute sodium hydroxide. The ether layer was separated, dried and evaporated to give 7 grams of the titled compound.
Reaction SMILES: [CH:1]1([CH2:4][C@H:5]([NH:10]C(=O)OC(C)(C)C)[C:6]([OH:9])([CH3:8])[CH3:7])[CH2:3][CH2:2]1.Cl>C(OCC)(=O)C.O>[NH2:10][C@@H:5]([CH2:4][CH:1]1[CH2:3][CH2:2]1)[C:6]([CH3:8])([OH:9])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CC1)C(C)(C)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(O)[C@@H](N)CC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A solution of (S)-tert-butyl 1-cyclopropyl-3-hydroxy-3-methylbutan-2-ylcarbamate (0.8 g, 3 mmol) in ethyl acetate was saturated with hydrochloride (10 mL) and stirred for 1 h at room temperature. After diluting with water (20 mL), the layers were separated and the water phase was washed with ethyl acetate (20 mL). Then it was adjusted with 1 N NaOH to pH=8˜9 and extracted with methylene chloride (3×20 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound as yellow oil (0.3 g, 64%); MS (EI): m/e=144.2 [M+Na]+.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11]O)[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[ClH:13]>C(O)=O.O>[Cl:13][CH2:11][C@H:9]([OH:10])[C@H:7]1[O:8][C:2](=[O:1])[C:3]([OH:4])=[C:5]1[OH:6]
Reactant: Cl
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: O
Solvent: O=CO
Product: O=C1O[C@H]([C@@H](O)CCl)C(O)=C1O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
360 g of L-ascorbic acid in 1000 ml of formic acid are treated in a pressure vessel at 50° C with 145 g of hydrogen chloride gas in such a manner that the dosage velocity amounts to about 6.6 g per hour and the pressure amounts to about 0.4 to 0.6 atmospheres. Subsequently, the black mass obtained is evaporated at 60° C to a thick, pitch-like paste. This paste is stirred with about 2 liters of water at 60° C for 30 minutes. Subsequently, the water is evaporated off at 60° C under reduced pressure. The solid residue obtained is again dissolved in 2 liters of water, stirred at 60° C for 30 minutes and evaporated to dryness under reduced pressure at this temperature. This procedure is repeated once again. The residue is dissolved in 1.4 liters of water and extracted at room temperature 6 times with 1 liter of ethyl acetate each time. The combined ethyl acetate extracts are stirred with 20 g of active carbon for 15 minutes and subsequently filtered. The filtrate is freed from entrained water, dried over about 200 g of sodium sulfate, filtered and evaporated under reduced pressure at 40° C. The residue is dissolved in 600 ml of nitromethane at 80° C and filtered. The filter residue is back-washed with 100 ml of hot nitromethane (80° C). The combined nitromethane solutions are cooled to room temperature and the crystals obtained are filtered off. The crystals are dissolved at 80° C in 600 ml of nitromethane, treated with 5 g of active carbon and, after stirring for about 15 minutes at 80° C, filtered. The filter residue is washed with 100 ml of hot nitromethane (80° C). The combined nitromethane solutions are left to stand overnight at room temperature. The crystals obtained are filtered off and dissolved in 600 ml of nitromethane at about 70° C, treated with 5 g of active carbon and, after stirring for 15 minutes, filtered. The filter residue is washed with 100 ml of hot nitromethane (60° C). The combined nitromethane solutions are left to stand overnight at room temperature. The white crystals obtained are filtered off, dispersed in 100 mls of nitromethane and subsequently filtered. The thus-purified crystals are dried at 60° C under reduced pressure and further dried at 60° C for 48 hours under strongly reduced pressure (about 0.3 mmHg). There is obtained 6-chloro-6-deoxy-L-ascorbic acid of melting point 144° C.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].P(Br)(Br)[Br:15]>N1C=CC=CC=1>[Br-:15].[Br-:15].[CH2:11]([OH:12])[CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13]
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: OCCOCCOCCOCCO
Product: [Br-]
Temperature: 25 °C

Procedure:
300 g. of tetraethylene glycol and 100 g. of anhydrous pyridine are slowly added to 727 g. of phosphorus tribromide, while agitating and cooling the mixture. After cooling to room temperature, the mixture is poured on to ice and the organic phase is decanted, washed with water and dilute hydrochloric acid and dried over sodium sulphate. After distillation under vacuum (123° C.-125° C. and 0.4 mm. Hg) the title comound is obtained.