Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4](Cl)[C:5](=[O:8])[CH2:6][CH3:7].C1(O)C=CC=CC=1.[C:18]([C:20]1[CH:21]=[C:22]([OH:28])[CH:23]=[C:24]([C:26]#[N:27])[CH:25]=1)#[N:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O.O>[CH3:1][O:2][C:3](=[O:10])[CH:4]([O:28][C:22]1[CH:21]=[C:20]([C:18]#[N:19])[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=1)[C:5](=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)C(Cl)C(=O)OC
Reactant: N#Cc1cc(O)cc(C#N)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Solvent: Oc1ccccc1
Product: CCC(=O)C(Oc1cc(C#N)cc(C#N)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
A solution of 2-chloro-3-oxo-pentanoic acid methyl ester (20 g, 121.5 mmol) in acetone (100 ml) was added to the phenol from Preparation 3 (17.5 g, 121.5 mmol) and caesium carbonate (43.5 g, 133.6 mmol) in acetone (400 ml) under a nitrogen atmosphere. The mixture was stirred at room temperature for 15 minutes and then heated under reflux for 2.5 hours. Water was added and the solvent was evaporated under reduced pressure. The residual aqueous solution was extracted with dichloromethane (3×300 ml) and the combined organic layers were dried over magnesium sulphate and evaporated under reduced pressure. The residual orange oil was pre-adsorbed onto silica gel and then purified by chromatography on silica gel using ethyl acetate in pentane (gradient from 20:80 to 80:20) to give the title compound as a yellow solid (27 g).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([F:11])[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:14]>>[Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([F:11])[C:7]([F:12])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:14]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc(F)c(F)c(Cl)c1Cl
Product: NC(=O)c1cc(F)c(F)c(Cl)c1Cl
Temperature: 0 °C

Procedure:
A solution of 2,3-dichloro-4,5-difluorobenzonitrile (1.0 g) in concentrated sulfuric acid (2.5 ml) was stirred at 90° to 100° C. for 30 minutes and then cooled. The residue was poured into ice water and the resulting precipitate was collected by filtration and recrystallized from benzene to give the title compound (0.51 g) as colorless needles, mp 153°-155° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([O:23][CH2:24][CH3:25])=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[C@@H:36]1[CH2:40][CH2:39][C@H:38]([NH2:41])[CH2:37]1>>[CH2:24]([O:23][C:19]1[C:17]2[O:18][C@@H:13]([CH2:12][NH:41][C@H:38]3[CH2:39][CH2:40][C@@H:36]([C:30]4[C:29]5[C:33](=[CH:34][CH:35]=[C:27]([F:26])[CH:28]=5)[NH:32][CH:31]=4)[CH2:37]3)[CH2:14][O:15][C:16]=2[CH:22]=[CH:21][CH:20]=1)[CH3:25]
Reactant: CCOc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: N[C@H]1CC[C@@H](c2c[nH]c3ccc(F)cc23)C1
Product: CCOc1cccc2c1O[C@@H](CN[C@H]1CC[C@@H](c3c[nH]c4ccc(F)cc34)C1)CO2
Yield: 57.3 %

Procedure:
This compound was prepared in the same manner as for Example 1, using [(2R)-8-ethoxy-2,3-dihydro-benzo[1,4]dioxin-2-yl]methyl 4-methylbenzenesulfonate (0.25 g, 0.68 mmol) and cis-3-(5-fluoro-1H-indol-3-yl)-cyclopentylamine (0.3 g, 1.38 mmol), to afford 0.16 g (64%) of the title compound as its hydrochloride salt: MS (ESI) m/z 411 [M+H]+.
Reaction SMILES: [CH:1]1([C:4](=O)[CH:5]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=O)[C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:33]2)=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH:1]1([C:4]2[S:33][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[N:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)C(NC(=O)c1cccc(C(F)(F)F)c1)C(=O)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1nc(-c2cccc(C(F)(F)F)c2)sc1C1CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a solution (12 mL) of the compound (4.0 g, 12 mmol) obtained in Example 72b in tetrahydrofuran was added 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (4.9 g, 12 mmol), and the mixture was stirred at 80° C. overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=90/10) to give the title compound (3.4 g, 86%) as a colorless solid.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:32](O)=[O:33])[CH2:19][C:20]3[CH:30]=[C:29]([CH3:31])[C:23]4[NH:24][C:25]([O:27][CH3:28])=[N:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1.[CH3:39][C:40]1([CH3:52])[CH2:45][CH2:44][N:43]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:42][CH2:41]1.C(N(CC)CC)C>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:30]=[C:29]([CH3:31])[C:23]4[NH:24][C:25]([O:27][CH3:28])=[N:26][C:22]=4[CH:21]=3)[C:32]([N:49]3[CH2:50][CH2:51][CH:46]([N:43]4[CH2:44][CH2:45][C:40]([CH3:52])([CH3:39])[CH2:41][CH2:42]4)[CH2:47][CH2:48]3)=[O:33])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1
Reactant: COc1nc2cc(C[C@@H](OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C(=O)O)cc(C)c2[nH]1
Reactant: CC1(C)CCN(C2CCNCC2)CC1
Solvent: CCN(CC)CC
Product: COc1nc2cc(C[C@@H](OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C(=O)N3CCC(N4CCC(C)(C)CC4)CC3)cc(C)c2[nH]1

Procedure:
Prepared analogously to Example 7i from 90 mg (0.16 mmol) (R)-1-carboxy-2-(2-methoxy-7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 55 mg (0.20 mmol) 4,4-dimethyl-[1,4′]bipiperidinyl (used as the bis-hydrochloride salt), using 100 μL (0.72 mmol) triethylamine.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20](S(C2C=CC(C)=CC=2)(=O)=O)[C:21]2[C:26]([C:27]=1[F:28])=[CH:25][CH:24]=[CH:23][CH:22]=2)=O.[OH-].[Na+]>CS(O)(=O)=O>[NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[CH2:17][C:19]1[NH:20][C:21]2[C:26]([C:27]=1[F:28])=[CH:25][CH:24]=[CH:23][CH:22]=2
Reactant: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)c(F)c3ccccc32)cc1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2cc(-n3ncc(Cc4[nH]c5ccccc5c4F)c3N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
[5-Amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[3-fluoro-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone (25.0 mg, 0.041 mmol) was dissolved in methane sulfonic acid (0.25 ml), and stirred at room temperature for one hour. The pH of the reaction mixture was adjusted to 6 using an aqueous solution of 1 M sodium hydroxide. After extraction with ethyl acetate, the extract was dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=60/1 to 40/1) to give [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(3-fluoro-1H-indol-2-yl)-methan one was obtained as a pale yellow solid (8.7 g, with a yield of 55%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[H-].[Na+].[CH2:20]([Si:22](Cl)([CH2:25][CH3:26])[CH2:23][CH3:24])[CH3:21].CCOCC>C1COCC1>[F:1][C:2]1[C:3]([NH:17][Si:22]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:20][CH3:21])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Reactant: CC[Si](Cl)(CC)CC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)Nc1nc(OCc2ccc(F)cc2)ncc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
To a magnetically stirred mixture of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.25 g, 1.05 mmol) in dry THF (5 mL) at 0° C. was added NaH (0.042 g of 60 wt. % suspension in mineral oil, 1.05 mmol). When bubbling ceased, triethylsilyl chloride (0.158 g, 1.05 mmol) was added dropwise (neat) via syringe. After stirring overnight at ambient temperature, the reaction mixture was poured into ether and washed with a mixture of aqueous saturated sodium bicarbonate and brine solution. The organic layer was separated, dried over Na2SO4, filtered, and evaporated to give a white solid. This crude material was purified on silica by column chromatography (EtOAc/hexanes gradient) to give 0.121 g (33%) of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]-triethylsilanylamine as a clear yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J=2.5 Hz, 1H), 7.39 (m, 2H), 7.03 (t, J=8.6 Hz, 2H), 5.27 (s, 2H), 4.53 (s, 1H), 0.99 (m, 9H), 0.83 (m, 6H); HPLC-MS (ESI) m/z 352 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.[Li][CH2:12]CCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[CH2:12]
Reactant: [Li]CCCC
Reactant: Cc1ccc(C=O)cc1I
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(C)c(I)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
This aldehyde (1 mmol)was added to a premixed solution of 1.5 mmol of methyl triphenylphosphonium bromide and 1.2 mmol of n-BuLi in 5 mL of THF at 0° C. and this mixture was stirred for 3-6 h at rt and then processed by extraction and chromatography to give 3-iodo-4-methylstyrene.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=O)[CH2:5][CH:4]=[CH:3][CH2:2]1.O.NN.[OH-].[K+].O>C(O)CO>[CH:1]1([CH2:6][C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:2][CH:3]=[CH:4][CH2:5]1
Reactant: COc1ncccc1C(=O)C1CC=CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COc1ncccc1CC1CC=CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.9 %

Procedure:
Cyclopent-3-enyl-(2-methoxy-pyridin-3-yl)-methanone (10.0 g, 49.3 mmol), hydrazine hydrate (6.33 g, 198 mmol) and pulverized potassium hydroxide (85% KOH) (16.8 g, 300 mmol) were warmed in ethylene glycol (100 mL) until solution occurred at 100° C. then to 180° C. for 18 h. The mixture was cooled to room temperature and treated with water (100 mL) then extracted with 50% EtOAc/hexanes (3×80 mL). The organic layer was washed with saturated aqueous NaCl solution, dried over Na2SO4 and concentrated to an oil. Purification by chromatography on silica gel eluting with 10% EtOAc/hexanes provided the desired product as an oil 4.75 g (51%). (TLC 10% Et2O/hexanes Rf 0.80); 1H NMR (400 MHz, CDCl3) δ 8.01 (dd, J=5.0, 1.7 Hz, 1H), 7.37 (dd, J=7.2, 1.5 Hz, 1H), 6.81 (dd, J=7.2, 5.0 Hz, 1H), 5.66 (s, 2H), 3.95 (s, 3H), 2.61 (m, 3H), 2.40 (m, 2H), 2.03 (m, 2H); GCMS m/z 189 (M)+. 3-Cyclopent-3-enyl-1H-pyrazolo[3,4-b]pyridine was also isolated 4.45 g (49%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[N+:24]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.C(Cl)Cl.[Pt](=O)=O>[NH2:24][C:10]1[CH:11]=[C:12]([O:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C(Oc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)c1ccccc1
Agent: O=[Pt]=O
Solvent: ClCCl
Solvent: CO
Product: Nc1cc(OC(=O)c2ccccc2)ccc1OCc1ccccc1
Yield: 79.3 %

Procedure:
A Parr hydrogenator was charged with platinum (IV) oxide (PtO2) (0.3 g) and a solution of benzoic acid 4-benzyloxy-3-nitro-phenyl ester(5.23 g, 15 mmol) (which was obtained in Example 15) in methanol (80 mL) and CH2Cl2 (40 mL). This mixture was then hydrogenated at 5 psi of hydrogen at 0˜10° C. for 2 hours. The reaction mixture was filtered through a short pad of celite and concentrated. Recrystallization from CH2Cl2/hexanes gave the title compound as a white solid (3.80 g, 79%); 1H NMR (300 MHz, CDCl3) δ 5.09(s, 2 H), 6.57(dd, J=10.1, 2.7 Hz, 1 H), 7.10(d, J=2.7 Hz, 1 H), 7.30–7.50(m, 8 H), 7.55–7.65(m, 1 H), 8.15–8.25(m, 2 H); MS (ES) m/z: 320.0 (MH+, 100%); HRMS Calcd. for C20H18NO3(MH+): 320.1281. Found: 320.1278.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[Se:10][C:6]=2[N:5]=[CH:4][N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19]>C(O)(C)C>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[C:7]3[C:8]4[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=4[Se:10][C:6]=3[N:5]=[CH:4][N:3]=2)[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: Clc1ncnc2[se]c3c(c12)CCCC3
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CC(C)O
Product: Fc1ccc(Nc2ncnc3[se]c4c(c23)CCCC4)cc1Cl
Yield: 88 %

Procedure:
To a solution of step b compound (300 mg, 1.10 mmol) in isopropyl alcohol (10 mL) was added 3-chloro-4-fluoroaniline (640 mg, 4.4 mmol) at rt and the mixture was refluxed for 7 h. The mixture was allowed to rt and the contents were poured into ice cold water. The solution was extracted with chloroform (3×100 mL) and the combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-ethyl acetate (95:5) as eluents to give the product (370 mg, 88%). The crude product was further recrystallized from chloroform-hexane to give the pure product as a pale pink color solid, mp 146-148° C. IR (neat) νmax 3458, 2931, 1605, 1564, 1254, 1195, 1121, 1041, 965 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 8.36 (1H, s), 8.20 (1H, s), 7.89 (1H, dd, J=6.8, 2.8 Hz), 7.58-7.62 (1H, m), 7.39 (1H, t, J=9.0 Hz), 3.10 (2H, br s), 2.91 (2H, br s), 1.84 (4H, br s); LC-MS (negative ion mode): m/z 380, 382 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].[C:22](=O)([O-])[O-].[K+].[K+].CI>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:22])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Temperature: 0 °C

Procedure:
A suspension of 15 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester in 150 ml. of dimethylsulfoxide is treated under an atmosphere of argon at 15°-20° C. with 13.8 g. of finely ground dry potassium carbonate and 14 ml. of methyl iodide, the mixture is stirred intensively at room temperature for 1 hour and then poured on to 750 ml. of ice-water. After the addition of 35 g. of sodium chloride, the precipitated product is removed by filtration, washed with water and dissolved in methylene chloride. The organic phase is dried over sodium sulfate and evaporated. The residue crystallizes upon trituration with hexane. Recrystallization from ethanol yields 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid ethyl ester in the form of almost colorless crystals having a melting point of 94°-96° C.
Reaction SMILES: Cl[Sn]Cl.O.[F:5][C:6]1[CH:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][C:25]=3[NH:26][S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[CH:17][CH:16]=2)[CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1.C([O-])(O)=O.[Na+]>CCO>[NH2:12][C:10]1[CH:11]=[C:6]([F:5])[CH:7]=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[S:22][CH:23]=[CH:24][C:25]=3[NH:26][S:27]([CH:30]([CH3:31])[CH3:32])(=[O:28])=[O:29])=[CH:19][CH:20]=2)[CH:9]=1
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2cc(F)cc([N+](=O)[O-])c2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2cc(N)cc(F)c2)cc1

Procedure:
Add SnCl2.2 H2O (8.5 mmol) to a solution of propane-2-sulfonic acid [2-(3′-fluoro-5′-nitro-biphenyl-4-yl)-thiophen-3-yl]-amide (1.2 mmol) in EtOH (40 mL). Heat the reaction at 70° C. for 30 min and then at room temperature overnight. Add a saturated solution of NaHCO3 (pH=11-12) and extract with EtOAc (2×50 mL). Dry over NaSO4, filter and evaporate to dryness to provide the title compound. MS (ES−): 389 (M−1).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][CH:7]2[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:2]2([CH3:16])[CH3:1])=[CH:21][CH:20]=1
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CNC2CCN(C(=O)OC(C)(C)C)CC2(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
tert-Butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (3.3 g, 14.53 mmol, 1 eq) and 4-methoxybenzylamine (3.98 g, 29.07 mmol, 2 eq) were dissolved in dichloromethane (40 ml), and stirring was carried out for 2 h at RT. The reaction mixture was cooled to 0° C., and Na(OAc)3BH (9.24 g, 43.61 mmol, 3 eq) was added in portions. Then stirring was carried out for 16 h at RT. The reaction mixture was diluted with dichloromethane (150 ml), washed with water and sat. NaCl solution (in each case 100 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (Alox neutral, 10% ethyl acetate in hexane) (colourless oil). Yield: 38% (1.948 g, 5.59 mmol).
Reaction SMILES: [S:1]([O:5][C:6]1[CH:23]=[CH:22][C:21]2[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](C(=O)NCCCCCCC)=[CH:14][CH2:13]4)[CH2:10][CH2:9][C:8]=2[CH:7]=1)(=[O:4])(=[O:3])[NH2:2].OC1C=CC2[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)[C@@H]([NH:53][C:54](=[O:62])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])CC4)CCC=2C=1>>[S:1]([O:5][C:6]1[CH:23]=[CH:22][C:21]2[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C@@H:15]([NH:53][C:54](=[O:62])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]=2[CH:7]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: CCCCCCCC(=O)N[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Reactant: CCCCCCCNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Product: CCCCCCCC(=O)N[C@H]1CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Yield: 50 %

Procedure:
Sulfamates 11a (50%) were prepared by using the procedure outlined in Example 1 for the synthesis of sulfamate (5a), but using compound 10a instead of compound 4a.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:37])[C:10]=1[CH2:11][S:12][C:13]1[N:14]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:15]([C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[CH:22]=2)([CH3:20])[CH3:19])=[CH:16][N:17]=1)[C:5](O)=[O:6].[NH2:38][C@@H:39]([CH2:47][CH2:48][CH2:49][NH:50][C:51]([NH2:53])=[NH:52])[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:37])[C:10]=1[CH2:11][S:12][C:13]1[N:14]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[C:15]([C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[CH:22]=2)([CH3:19])[CH3:20])=[CH:16][N:17]=1)[C:5]([NH:38][C@@H:39]([CH2:47][CH2:48][CH2:49][NH:50][C:51]([NH2:53])=[NH:52])[C:40]([O:42][C:43]([CH3:46])([CH3:44])[CH3:45])=[O:41])=[O:6]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCCNC(=N)N
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)O)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)N[C@@H](CCCNC(=N)N)C(=O)OC(C)(C)C)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of 3-chloro-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-5-fluorobenzoic acid (0.96 g, 1.70 mmol) and (S)-tert-butyl 2-amino-5-guanidinopentanoate (0.54 g, 1.79 mmol) in DMF (4 mL) at 0° C. was added HATU (0.69 g, 1.79 mmol) and DIPEA (0.82 mL, 5.27 mmol). The reaction was stirred at room temperature for 1 h, quenched with satd NaHCO3 and diluted with EtOAc. The mixture was washed with water (10 mL), brine (10 mL) and dried with Na2SO4. The residue was purified by column chromatography (silica, MeOH/DCM) to afford (S)-tert-butyl 2-(3-chloro-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-5-fluorobenzamido)-5-guanidinopentanoate (1.2 g) as a white solid. The solids were dissolved in 4N HCl in dioxane (8 mL) and stirred for 3 h. The reaction was concentrated and purified by chromatography (silica, MeOH/DCM) to yield the title compound (380 mg) as a white solid. 1H-NMR (DMSO-d6, 400 MHz) δ 8.84 (d, J=7.6 Hz, 1H), 7.81 (s, 1H), 7.64-7.61 (m, 1H), 7.46-7.43 (m, 1H), 7.21 (d, J=8.30 Hz, 1H), 7.18 (s, 1H), 7.01-6.93 (m, 2H), 6.61-6.57 (m, 1H), 6.54-6.49 (m, 3H), 4.37-4.31 (m, 1H), 4.07 (s, 2H), 3.68 (s, 3H), 3.15-3.11 (m, 2H), 1.88-1.70 (m, 2H), 1.61-1.54 (m, 2H), 1.47-1.46 (m, 6H), 1.42 (s, 9H); MS (EI) m/z 719 [MH]+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][N:4]=[C:5]([NH2:16])[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][C:14]#[N:15])[N:8]=1>[Ni].N>[F:18][C:2]([F:1])([F:17])[CH2:3][N:4]=[C:5]([NH2:16])[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][NH2:15])[N:8]=1
Reactant: N#CCCn1ccc(NC(N)=NCC(F)(F)F)n1
Agent: [Ni]
Agent: N
Product: NCCCn1ccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-[2-(2,2,2-trifluoroethyl)guanidino]-1-(2-cyanoethyl)pyrazole (0.32 g.), saturated ethanolic ammonia (10 ml.) and Raney nickel (0.2 g.) was stirred vigorously under an atmosphere of hydrogen at room temperature and atmospheric pressure for 3 hours. The mixture was filtered and the filtrate evaporated to dryness to give 3-[2-(2,2,2-trifluoroethyl)guanidino]-1-(3-aminopropyl)pyrazole which was used without further purification.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[S:6][C:7]([CH:15]([CH3:17])[CH3:16])=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:9]=1)C>Cl.CC(C)=O>[CH:4]([C:5]1[S:6][C:7]([CH:15]([CH3:16])[CH3:17])=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:9]=1)=[O:3]
Reactant: CCOC(=O)c1nc(C(OCC)OCC)sc1C(C)C
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)c1nc(C=O)sc1C(C)C
Yield: 99.9 %

Procedure:
A solution of ethyl 2-[bis(ethyloxy)methyl]-5-(1-methylethyl)-1,3-thiazole-4-carboxylate (430 mg) in a mixture of 10% 1M hydrochloric acid solution in acetone (50 ml) was heated at reflux for 1 h. The mixture was concentrated in vacuo, taken up in DCM (20 ml), washed with saturated sodium bicarbonate solution (10 ml), separated by hydrophobic frit and evaporated to give the title compound as a yellow oil (324 mg).