Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]([OH:18])=O)[CH:8]=2)[CH:3]=1.S(Cl)(Cl)=O.CN(C)[CH:25]=[O:26]>O1CCCC1>[OH:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]([O:26][CH2:25][CH2:10][CH2:11][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:18])[CH:8]=2)[CH:3]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc2cc(C(=O)O)ccc2cc1O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCOC(=O)c1ccc2cc(O)c(C(=O)O)cc2c1
Temperature: 50 °C

Procedure:
In 10.0 g of tetrahyrofuran, 1.00 g of 2-hydroxy-6-hydroxycarbonyl-3-methoxycarbonylnaphthalene is suspended. To this, 0.94 g of thionyl chloride and a small amount of N,N-dimethylformamide are added, and heated to 50° C. After allowing to proceed the reaction for about 3 hours, the solvent and other volatile are evaporated. To the residue, a solution of 1.27 g of n-decanol dissolved in 10.0 g of tetrahydrofuran is added, and reacted for about 20 hours under reflux. After evaporating the solvent, 15.0 g of N,N-dimethylformamide, 15.0 g of methanol, and 180.0 g of 5% aqueous sodium hydrogencarbonate are added, and reacted for 20 hours at 60° C. After removing insoluble matter, the pH of the reaction mixture is adjusted to pH 2 at 50° C., and the precipitate is recovered by filtration. The product was washed with warm water and methanol, and dried to yield 1.33 g of 2-hydroxy-3-hydroxycarbonyl-6-decyloxycarbonylnaphthalene as a white-yellow powder (melting/decomposing point: 269.2° C. (dec.)).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8](Cl)=[O:9])=[C:6]([N+:11]([O-:13])=[O:12])[C:5]([CH3:14])=[N:4]1)[CH3:2].[OH-].[NH4+:16]>CC(C)=O>[CH2:1]([N:3]1[C:7]([C:8]([NH2:16])=[O:9])=[C:6]([N+:11]([O-:13])=[O:12])[C:5]([CH3:14])=[N:4]1)[CH3:2]
Reactant: [NH4+]
Reactant: CCn1nc(C)c([N+](=O)[O-])c1C(=O)Cl
Agent: [OH-]
Solvent: CC(C)=O
Product: CCn1nc(C)c([N+](=O)[O-])c1C(N)=O
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of 108 g (0.05 mol) of 1-ethyl-3-methyl-4-nitro-pyrazole-5-carbonyl chloride [J. Med. Chem. 16 1346 (1973)] in 100 ml of acetone is added at a fast droprate to 450 ml cold concentrated ammonium hydroxide with stirring. After one hour, the mixture is filtered; the product is washed with water to give 94 g (95%) of 1-ethyl-3-methyl-4-nitropyrazole-5-carboxamide, mp 175°-177° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH:29]1[CH2:31][CH2:30]1>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:28][CH:29]3[CH2:31][CH2:30]3)[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(OCC2CC2)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 90 °C
Yield: 39.7 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (25 mg, 0.095 mmol), potassium carbonate (26 mg, 0.19 mmol) and (bromomethyl)cyclopropane (14 μL, 0.14 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 90° C. for 2 hours. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography of the residue using hexanes/ethyl acetate/dichlrormethane (3.5:0.5:4) followed by trituration with diethyl ether afforded 12 mg (41%) of 3-(2-pyridyl)-5-(3-cyano-5-cylopropylmethoxyphenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.86 (d, 1H), 8.23 (d, 1H), 8.14 (s, 1H), 7.99 (s, 1H), 7.91 (t, 1H), 7.50 (m, 1H), 7.40 (s, 1H), 3.95 (d, 2H), 1.21 (m, 1H), 0.72 (m, 2H), 0.41 (m, 2H).
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>O1CCCC1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:31])[O:14][C:11]2[CH:12]=[C:13]3[C:8]([CH2:7][CH2:6][CH2:5][N:4]3[CH2:1][C:2]#[CH:3])=[CH:9][CH:10]=2)=[CH:25][CH:24]=1
Reactant: C#CCN1CCCc2ccc(O)cc21
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCN1CCCc2ccc(OC(=O)Nc3ccc(Cl)cc3)cc21
Temperature: 35 °C

Procedure:
A mixture of 1-(prop-2-ynyl)-1,2,3,4-tetrahydroquinolin-7-ol (400 mg, 2.14 mM) and triethylamine (0.6 mL) in dry tetrahydrofuran (THF; 5 mL) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 4-chlorophenyl isocyanate (411 mg/ml, 3.21 mM) was added at once and then the reaction mixture was further stirred for 32 hours under N2 atmosphere at RT (35° C.). The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chlorophorm-hexane (1:19) to afford 10f as solid. Yield: 520 mg, 71.42%.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([OH:15])=[CH:8]2.[C:16]([O:20][C:21]([NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31]OS(C)(=O)=O)[CH2:26][CH2:25]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O>[C:16]([O:20][C:21](=[O:22])[NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][O:15][C:9]2[CH:10]=[N:11][C:12]3[C:7]([CH:8]=2)=[N:6][C:5]([O:4][CH3:3])=[CH:14][CH:13]=3)[CH2:26][CH2:25]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: COc1ccc2ncc(O)cc2n1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ncc(OCCN3CCC(NC(=O)OC(C)(C)C)CC3)cc2n1
Yield: 30.5 %

Procedure:
Sodium hydride (55% purity, 9 mg, 0.22 mmol, 1.5 eq) is added at room temperature to a stirred solution of 6-methoxy-[1,5]naphthyridin-3-ol (42 mg, 0.22 mmol, 1.0 eq) in N,N-dimethylformamide (5 mL), followed by methanesulfonic acid 2-(4-tert-butoxycarbonylamino-piperidin-1-yl)-ethyl ester (102 mg, 0.22 mmol, 1.0 eq). The reaction mixture is irradiated by microwaves at 110° C. for 10 minutes, then solvent is evaporated, and the residue is extracted with ethyl acetate (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: cyclohexane: ethyl acetate:methanol, 1:1:0 to 0:9:1, v/v/v) to afford {1-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester as an orange solid (27 mg, 29% yield).
Reaction SMILES: [N:1]1([C:7]2[O:12][C:11]([C:13]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:14]=3[S:15][C:16]3[CH:17]=[CH:18][C:19]([CH:27]=[O:28])=[CH:20][C:21]=3[CH2:22]4)=[CH:10][C:9](=[O:29])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C>[OH:28][CH2:27][C:19]1[CH:20]=[C:21]2[C:16]([S:15][C:14]3[C:13]([C:11]4[O:12][C:7]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[CH:8][C:9](=[O:29])[CH:10]=4)=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:17][CH:18]=1
Reactant: O=Cc1ccc2c(c1)Cc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1cc(-c2cccc3c2Sc2ccc(CO)cc2C3)oc(N2CCOCC2)c1
Reaction time: 5 h
Yield: 84 %

Procedure:
To a suspension of 5-(6-Morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthene-2-carbaldehyde (2)(0.392 g, 0.97 mmol) in ethanol (7 mL) at room temperature was added sodium cyanoborohydride (121 mg, 1.93 mmol), followed by the addition of acetic acid (1 mL). After 5 hours, a second addition of acetic acid (1 mL) was made. After a further 12 hours, the excess borohydride was quenched with acetone. After evaporation in vacuo, saturated NaHCO3 was added, followed by extraction into dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The brown coloured solid was dried under vacuum at 50° C. to give the crude title compound (0.332 g, 84%) which was used without any further purification. m/z (LC-MS, ESP), RT=3.09 min, (M++1)=408.3
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Cl:17][C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:18]([Cl:17])=[O:20])[CH2:4][CH2:3]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(C(=O)Cl)CC1
Temperature: 0 °C

Procedure:
To solution of methyl piperazine (166 uL, 1.50 mmol) In anhydrous dichloromethane (2 mL), diisopropyl ethyl amine (300 uL, 1.72 mmol) was added. The reaction was cooled to 0° C. under N2. Triphosgene (240 mg, 0.809 mmol) was added and the reaction was allowed to warm to rt. The chloride was used immediately without purification.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[OH2:50]>N1C=CC=CC=1>[C:1]1([S:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[O:50])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O
Reactant: O=C(O)c1ccc(Sc2ccccc2)cc1
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Solvent: c1ccncc1
Product: O=C(O)c1ccc(S(=O)c2ccccc2)cc1
Temperature: 20 °C
Reaction time: 12 h

Procedure:
To a suspension of 4-(phenylthio)benzoic acid (800 mg, 3.5 mmol) in pyridine (5 mL) and water (5 mL) was added N-phenyl-N,N,N-trimethylammonium tribromide (1.4 g, 3.7 mmol). The mixture was stirred at 20° C. for 12 hours. Then the solvent was evaporated in vacuo to give 4-(phenylsulfinyl)benzoic acid which was used directly without further purification. LRMS (M+H)− m/z: calcd 246.04. found 246.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([CH:16]=O)=[N:14][N:13]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[C:10]3=[N:11][CH:12]=2)[CH:2]=1.[F:24][C:25]1[CH:26]=[C:27]([C:31]2[C:32]([NH2:38])=[C:33]([NH2:37])[CH:34]=[N:35][CH:36]=2)[CH:28]=[CH:29][CH:30]=1.[S]>C(O)CCC>[F:24][C:25]1[CH:26]=[C:27]([C:31]2[C:32]3[N:38]=[C:16]([C:15]4[C:9]5[C:10](=[N:11][CH:12]=[C:7]([C:3]6[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=6)[CH:8]=5)[N:13]([CH:18]5[CH2:23][CH2:22][CH2:21][CH2:20][O:19]5)[N:14]=4)[NH:37][C:33]=3[CH:34]=[N:35][CH:36]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1cncc(-c2cccc(F)c2)c1N
Reactant: O=Cc1nn(C2CCCCO2)c2ncc(-c3cccnc3)cc12
Agent: [S]
Solvent: CCCCO
Product: Fc1cccc(-c2cncc3[nH]c(-c4nn(C5CCCCO5)c5ncc(-c6cccnc6)cc45)nc23)c1
Temperature: 25 °C

Procedure:
A solution of 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (CXXXI) (65 mg, 0.21 mmol), 5-(3-fluorophenyl)pyridine-3,4-diamine (LXXV) (45 mg, 0.22 mmol) and sulfur (7 mg, 0.22 mmol) in n-butanol (10 mL) was heated at reflux overnight. The solution was cooled to room temperature, filtered and the solvent was evaporated under reduced pressure to give crude 3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (CXXXII). CXXXII was dissolved in dry DCM (5 mL) before adding triethylsilane (84 μL, 0.52 mmol) and TFA (2.5 mL) The reaction was stirred at room temperature for 2 h under argon. The solvent was evaporated under reduced pressure; the residue was taken up water (10 mL), and basified with 5N NH4OH. The precipitates were filtered, washed by cold water and dried under vacuum at room temperature. The crude product was suspended in DCM (10 mL), sonicated briefly and then heated to boiling for 5 min. The solution was cooled to room temperature and the solids were filtered, washed with DCM and dried under vacuum at room temperature to produce 3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine (3) as a yellow solid (53 mg, 0.13 mmol, 62% yield). 1H NMR (DMSO-d6) δ ppm 7.25-7.34 (m, 1H), 7.54-7.65 (m, 2H), 8.11-8.21 (m, 1H), 8.23-8.30 (m, 1H), 8.37-8.50 (m, 1H), 8.63-8.70 (m, 1H), 8.70-8.80 (m, 1H), 9.02-9.09 (m, 2H), 9.09-9.15 (m, 1H), 13.94 (brs, 1H), 14.59 (s, 1H); ESIMS found for C23H14FN7 m/z 408.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>C(O)C.[Fe]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(CCOc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(CCOc2ccc(N)cc2)cc1
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
4-[2-(4-Methylphenyl)ethoxy]nitrobenzene (VI) (5.14 g, 0.02 mole) and iron powder (6.7 g, 0.12 mole) were added to 50% aqueous ethanol (50 ml), and a solution of conc. hydrochloric acid (1 ml) in 50% aqueous ethanol (10 ml) was added dropwise thereto over 15 minutes with stirring under reflux. After heating under reflux for an additional 2 hours, the reaction mixture was cooled, neutralized with a dilute aqueous sodium hydroxide solution and extracted with ether. The ether layer was washed with water, dried over anhydrous potassium carbonate, concentrated and distilled to obtain 4.1 g of 4-[2-(4-methylphenyl)ethoxy]aniline (V) (yield, 90.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:25])=[C:7]([CH3:24])[N:8]2[CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[O:22][CH3:23])=[CH:4][C:3]=1[CH3:26].CC1NC2C(C=1C)=CC(C)=C([N+]([O-])=O)C=2.[C:42]1([CH:48]([CH2:52][CH3:53])[C:49](O)=[O:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH3:23][O:22][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:12]=1[CH2:11][N:8]1[C:9]2[C:5](=[CH:4][C:3]([CH3:26])=[C:2]([NH:1][C:49](=[O:50])[CH:48]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:52][CH3:53])[CH:10]=2)[C:6]([CH3:25])=[C:7]1[CH3:24])[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1ccc(Cn2c(C)c(C)c3cc(C)c(N)cc32)c(OC)c1
Reactant: CCC(C(=O)O)c1ccccc1
Agent: Cc1cc2c(C)c(C)[nH]c2cc1[N+](=O)[O-]
Product: CCC(C(=O)Nc1cc2c(cc1C)c(C)c(C)n2Cc1ccc(C(=O)OC)cc1OC)c1ccccc1
Yield: 32 %

Procedure:
Similarly, starting from methyl 4-(6-amino-2,3,5-trimethylindol-1-ylmethyl)-3-methoxybenzoate (itself obtained using the procedures described for A in Example 1 but starting from 2,3,5-trimethyl-6-nitroindole [G]) and 2-phenylbutyric acid, there was obtained methyl 3-methoxy-4-[2,3,5-trimethyl-6-(2-phenylbutanamido)indol-1-ylmethyl]benzoate [Example 83] in 32% yield as a white solid; partial NMR: 0.9 (t,3H,CH2CH3), 1.2 (m,2H, CH2CH3), 3.4 (t,1H,CHPh), 7.3 (s,5H,Ph).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[CH3:31][C:32]1[O:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1[C:35]1[O:36][C:32]([CH3:31])=[CH:33][CH:34]=1)[CH3:2]
Reactant: Cc1ccc(B(O)O)o1
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2ccc(C)o2)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 5-methyl-2-furylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C20H20NO4 (M+H): 338.1382. Found 338.1387
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[S:19](=[O:21])(=[O:20])[N:18](CC[Si](C)(C)C)[C:17](=[O:28])[CH2:16]2)=[C:11]([O:29]CC2C=CC=CC=2)[CH:10]=1.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[OH:29][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[N:15]1[CH2:16][C:17](=[O:28])[NH:18][S:19]1(=[O:21])=[O:20])[CH2:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]1[NH:1][S:43]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:45])=[O:44]
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@@H]3CCCC[C@H]3N)cc2OCc2ccccc2)S1(=O)=O
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=C1CN(c2ccc(C[C@@H]3CCCC[C@H]3NS(=O)(=O)c3ccccc3)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-[4-((1S*,2R*)-2-aminocyclohexylmethyl)-2-benzyloxy-phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and benzenesulfonyl chloride analogous to Example 205, steps B, C and D. MS (M−1)−=478; HPLC retention time=1.10 min. (Method A).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[C:12]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)=[O:13].[C:19](=[O:25])=[N:20]S(Cl)(=O)=O.ClS(NC=O)(=O)=O>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:19]([NH2:20])=[O:25])[C:6](=[O:11])[CH:5]2[C:12]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)=[O:13]
Reactant: O=C1Nc2ccc(Cl)nc2C1C(=O)c1ccco1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=CNS(=O)(=O)Cl
Solvent: CC#N
Product: NC(=O)N1C(=O)C(C(=O)c2ccco2)c2nc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared from 5-chloro-3-(2-furoyl)-4-azaoxindole (Example 23) according to the procedure of Example 2C, using 5-chloro-3-(2-furoyl)-4-azaoxindole (200 mg, 0.76 mmol), N-chlorosulfonyl isocyanate (0.10 mL, 1.1 mmol) and acetonitrile (8 mL). Hydrolysis of the N-chlorosulfonyl carboxamide was achieved by quenching the above reaction with water and allowing the mixture to stir at room temperature overnight. The product was collected by filtration and recrystallized from DMSO. Yield: 75 mg (32%).
Reaction SMILES: [CH:1]1([C:4]2[C:9]([CH2:10]O)=[CH:8][CH:7]=[C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:5]=2)[CH2:3][CH2:2]1.O=S(Cl)[Cl:24]>C(Cl)Cl>[Cl:24][CH2:10][C:9]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: OCc1ccc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2ccc(CCl)c(C3CC3)n2)cc1

Procedure:
0.127 g (0.433 mmol) of the above prepared [2-cyclopropyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol was dissolved in 2.0 ml of CH2Cl2 and treated at 0° C. with 0.063 ml (2 eq.) of SOCl2. The reaction mixture was kept at 0° C. for 5 Min. and at RT for 60 Min. Pouring onto crashed ice/NaHCO3, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents afforded 0.137 g of pure title compound as off-white solid.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH:14]2[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]2)[CH2:10]1)C1C=CC=CC=1.C=O.C([BH3-])#N.[Na+]>O>[CH3:1][NH:8][CH:9]1[CH:14]2[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]2)[CH2:10]1
Reactant: c1ccc(CNC2CN3CCC2CC3)cc1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: CNC1CN2CCC1CC2
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 73.7 g of 3-benzylamino quinuclidine in water (≃300 to 400 ml) are added, while cooling to 5° C., 51 ml of a 40% aqueous formaldehyde solution. Then after the addition, the mixture is left for 30 minutes at 5° C., then 32 g of sodium cyanoborohydride are added within 1 to 2 hours. Then it is left at room temperature for 12 hours, extracted with ethyl acetate, the mixture obtained is dried on sodium (or magnesium) sulfate, filtered, the filtrate is evaporated and the residue is distilled (Boiling point [0.04 mm/Hg]=125° C.). Thus the expected product is obtained practically quantitatively.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:3]=1[CH:24]([CH2:29][CH2:30][CH3:31])[C:25]([O:27]C)=[O:26].[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)[C:3]=1[CH:24]([CH2:29][CH2:30][CH3:31])[C:25]([OH:27])=[O:26]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C(F)(F)F)cc1)CCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(C(F)(F)F)cc1)CCC3
Temperature: 25 °C
Yield: 46.4 %

Procedure:
To a solution of methyl [2-methyl-4-(4-trifluoromethylphenyl)-6,7-dihydro-5H-cyclo penta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate (0.087 g; 0.194 mmol) in methanol (4 mL) and ethanol (2 mL) was added a 5% sodium hydroxide solution (5.2 mL; 6.500 mmol). The reaction mixture was heated under reflux for 5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water, acidified with 1N HCl (pH˜2) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.039 g (46%) of the title compound as a white powder.
Reaction SMILES: C([O:14][C:15](=[O:76])[C@@H:16]([O:41]/[N:42]=[C:43](/[C:63]1[N:64]=[C:65]([NH:68]C(OC(C)(C)C)=O)[S:66][CH:67]=1)\[C:44]([NH:46][C@H:47]1[C@@H:50]([CH2:51][N:52]2[CH2:56][CH2:55][O:54][C:53]2=[O:57])[N:49]([S:58]([OH:61])(=[O:60])=[O:59])[C:48]1=[O:62])=[O:45])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[NH:40])[NH:26][CH:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]2)=[CH:21][CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:68][C:65]1[S:66][CH:67]=[C:63](/[C:43](=[N:42]/[O:41][C@@H:16]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25](=[NH:40])[NH:26][CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=2)[C:15]([OH:76])=[O:14])/[C:44](=[O:45])[NH:46][C@H:47]2[C@@H:50]([CH2:51][N:52]3[CH2:56][CH2:55][O:54][C:53]3=[O:57])[N:49]([S:58]([OH:61])(=[O:59])=[O:60])[C:48]2=[O:62])[N:64]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/O[C@@H](COc2ccc(C(=N)NC3CCN(C(=O)OC(C)(C)C)CC3)cc2)C(=O)OC(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CN2CCOC2=O)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(NC1CCNCC1)c1ccc(OC[C@H](O/N=C(\C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CN2CCOC2=O)c2csc(N)n2)C(=O)O)cc1
Yield: 29.7 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (3S,4R)-3-((Z)-2-((((S)-1-(benzhydryloxy)-3-(4-(N-(1-(tert-butoxycarbonyl)piperidin-4-yl)carbamimidoyl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-oxo-4-((2-oxooxazolidin-3-yl)methyl)azetidine-1-sulfonic acid (117 mg, 0.107 mmol), DCM (5.3 mL) and TFA (0.413 mL, 5.37 mmol). The crude residue was purified by reverse phase prep HPLC (Xselect CSH, 30×100 mm, 5 μM, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (23 mg, 28%) as a white powder. LC/MS: Rt=0.42 min, m/z=724.5 (M+1) Method 2m_acidic_polar; 1H NMR (500 MHz, DMSO-d6) δ 9.53 (d, J=7.57 Hz, 1H), 9.43-9.36 (m, 2H), 9.01 (br s, 1H), 8.53-8.36 (m, 2H), 7.72 (d, J=8.5 Hz, 3H), 7.26 (br s, 2H), 7.15 (d, J=8.8 Hz, 2H), 6.82 (s, 1H), 5.19 (dd, J=8.7, 5.8 Hz, 1H), 5.02 (t, J=3.8 Hz, 1H), 4.51-4.42 (m, 2H), 4.12-3.96 (m, 3H), 3.90-3.81 (m, 1H), 3.73 (d, J=7.3 Hz, 1H), 3.69-3.62 (m, 1H), 3.58-3.53 (m, 1H), 3.20-3.16 (m, 1H), 2.98-2.85 (m, 1H) 2.13-2.04 (m, 1H), 1.85-1.72 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[C:10](Cl)(=[O:12])[CH3:11].O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[N:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC(=O)Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(Cl)cc(Cl)n1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A solution of 4,6-dichloro-pyrimidin-2-ylamine (5 g, 30 mmol) and acetyl chloride (4.7 g, 60 mmol) in acetic acid (200 mL) was stirred at 80° C. under nitrogen overnight. The solution was cooled to RT and water (150 mL) was added. The mixture was extracted with ethyl acetate (3×150 mL), and the combined organics were washed with brine, dried over sodium sulfate and concentrated to give N-(4,6-dichloro-pyrimidin-2-yl)-acetamide (5.0 g, 79% yield).