Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([NH:12][CH2:13][C:14]([OH:16])=O)=[O:11])[CH:8]=[CH:9][C:2]=12.[F:17][CH2:18][CH2:19][NH2:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[F:17][CH2:18][CH2:19][NH:20][C:14]([CH2:13][NH:12][C:10]([C:7]1[CH:8]=[CH:9][C:2]2[C:3]([CH:6]=1)=[N:4][O:5][N:1]=2)=[O:11])=[O:16]
Reactant: NCCF
Reactant: O=C(O)CNC(=O)c1ccc2nonc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNC(=O)c1ccc2nonc2c1)NCCF
Temperature: 5 °C

Procedure:
221 mg (1 mmol) [(benzo[1,2,5]oxadiazole-5-carbonyl)-amino]-acetic acid, 120 mg (1.2 eq.) 2-fluoroethylamine, 162 mg (1.2 eq.) HOBt and 230 mg (1.2 eq.) EDC.HCl are dissolved in 18 mL DMF and cooled to 5° C. 0.7 mL (4 eq.) Hünig's base are added under stirring, the reaction mixture is stirred for an additional 3 hours at room temperature then extracted with water and ethyl acetate. The combined organic phases are washed with brine, dried with sodium sulfate and evaporated to yield the desired product as a beige solid. MS (ES+): 267 (M+1).
Reaction SMILES: [C:1]1([S:7][CH2:8][C@H:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:17][C:16]=2[S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH2:10][C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:32]([O:49][CH2:50][CH2:51][NH:52][CH2:53][CH2:54][O:55][Si:56]([C:69]([CH3:72])([CH3:71])[CH3:70])([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Si:32]([O:49][CH2:50][CH2:51][N:52]([CH2:53][CH2:54][O:55][Si:56]([C:69]([CH3:72])([CH3:71])[CH3:70])([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)[C:11](=[O:12])[CH2:10][C@@H:9]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](=[O:23])(=[O:24])[NH2:22])=[CH:17][C:16]=1[S:25]([C:28]([F:29])([F:31])[F:30])(=[O:27])=[O:26])[CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:45]([CH3:46])([CH3:47])[CH3:48])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)[Si](OCCNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c(S(=O)(=O)C(F)(F)F)c1
Product: CC(C)(C)[Si](OCCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F)(c1ccccc1)c1ccccc1
Yield: 83.1 %

Procedure:
The title product (1.06 g, yield: 83%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 24 utilizing (R)-4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butanoic acid (INTERMEDIATE 8, 600 mg, 1.2 mmol) and bis(2-(tert-butyldiphenylsilyloxy)ethyl)amine (INTERMEDIATE 29, 0.700 g, 1.20 mmol) as starting materials. The title product was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→100% EtOAc/hexanes).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C@@:7]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:11]([C:12](=[O:17])[C@H:13]([O:15][CH3:16])[CH3:14])[N:10]=[C:9]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[S:8]1)=[N+]=[N-].NCCC[C@]1(C2C=CC=CC=2)N(C(=O)[C@@H](OC)C)N=C(C2C=C(F)C=CC=2F)S1.NCCC[C@@]1(C2C=CC=CC=2)N(C(=O)[C@@H](OC)C)N=C(C2C=C(F)C=CC=2F)S1>>[NH2:1][CH2:4][CH2:5][CH2:6][C@@:7]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:11]([C:12](=[O:17])[C@H:13]([O:15][CH3:16])[CH3:14])[N:10]=[C:9]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[S:8]1
Reactant: CO[C@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@]1(CCCN=[N+]=[N-])c1ccccc1
Agent: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1
Agent: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@]1(CCCN)c1ccccc1
Product: CO[C@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@]1(CCCN)c1ccccc1

Procedure:
Prepared as previously described in Example 75 using (R)-1-((R)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3 (2H)-yl)-2-methoxypropan-1-one. MS ESI (+) m/z 420 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.52 (m, 1H), 7.44 (d, 2H, J=7 Hz), 7.35 (t, 2H, J=8 Hz), 7.29 (t, 1H, J=7 Hz), 7.13 (m, 2H), 4.68 (q, 1H, J=6 Hz), 3.41 (s, 3H), 3.24 (m, 1H), 2.85 (m, 2H), 2.43 (m, 1H), 1.95 (m, 1H), 1.54 (br, 3H), 1.46 (d, 3H, J=6 Hz). Stereochemistry was assigned by comparison to (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3 (2H)-yl)-2-methoxypropan-1-one and (S)-1-((R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3 (2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=O.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[C:20](=[S:22])[NH2:21]>>[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[C:20]1[S:22][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[C:8]#[N:9])[N:21]=1
Reactant: Cc1ccncc1C(N)=S
Reactant: N#Cc1cccc(C(=O)CBr)c1
Product: Cc1ccncc1-c1nc(-c2cccc(C#N)c2)cs1
Yield: 41.1 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 3-(bromoacetyl)benzonitrile (599 mg) and 4-methylpyridine-3-thiocarboxamide (403 mg), the title compound (302 mg) was obtained as pale-yellow powder crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][N:24]=[CH:23]2.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][N:24]=[CH:23]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2ncncc2c1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc2ncncc2c1
Reaction time: 0.08 h
Yield: 23.9 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (163 mg, 0.723 mmol) in dichloromethane (4 mL) was added pyridine (140 μL, 1.72 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-aminoquinazoline [21] (100 mg, 0.689 mmol) was added. The resulting mixture was stirred for 4 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a pale yellow solid (55 mg, 24%), single spot at Rf 0.56 (ethyl acetate). mp>270° C. (appeared to decompose at about 150° C.), HPLC purity 98% (tR 2.06 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 9.28 (1H, s), 9.25 (1H, s), 7.98 (1H, d, J=4.4 Hz), 7.95 (1H, d, J=5.2 Hz), 7.59-7.53 (3H, m), 7.25-7.20 (1H, m), 2.76 (3H, s). LCMS: 332.11 (M−). FAB-MS (MH+, C15H12ClN3O2S): calcd 334.0417, found 334.0420.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([Br:17])=[CH:12]2)=[O:5].[C:22](OC(=O)C)(=[O:24])[CH3:23].N1C=CC=CC=1>C(Cl)CCl.ClCCl>[C:22]([NH:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([Br:17])=[CH:12]2)=[O:5])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1C(=O)Nc1cccc2cc(Br)cnc12
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)Nc1ccccc1C(=O)Nc1cccc2cc(Br)cnc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.1 %

Procedure:
A mixture of 8-(2-aminobenzoylamino)-3-bromoquinoline (200 mg), acetic anhydride (71.6 mg) and pyridine (139 mg) in ethylene chloride (4 ml) was stirred for 20 hours at ambient temperature. The mixture was diluted with dichloromethane, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was suspended in hot ethanol and allowed to cool to ambient temperature. The resulting precipitates were collected by filtration to give 8-(2-acetamidobenzoylamino)-3-bromoquinoline (200 mg) as yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH3:19][S:20]([CH3:23])(=[O:22])=[O:21]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CS(C)(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)Cc1ccc(Br)cn1
Temperature: -17 °C
Reaction time: 1 h

Procedure:
5-Bromo-2-fluoro-pyridine (2.00 g) dissolved in tetrahydrofuran (20 mL) was added dropwise to a solution of sodium hexamethyldisilazide (2 mol/L in tetrahydrofuran, 28.5 mL) in tetrahydrofuran (20 mL) cooled to ca. −17° C. Dimethylsulfone (4.30 g) was added and stirring continued in the cooling bath for 1 h. The cooling bath was then removed and the solution was stirred at room temperature for one more h. Aqueous NH4Cl solution and brine were added and the resulting mixture was extracted with ethyl acetate. The combined extracts were dried (MgSO4) and the solvent was evaporated. The residue was treated with little ethyl acetate to precipitate the title compound. Yield: 1.73 g (63% of theory); LC (method 3): tR=2.01 min; Mass spectrum (ESI+): m/z=250/252 (Br) [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[CH2:14][S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16])=[O:4].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25]([NH2:31])[N:24]=1.C(Cl)CCC>C(Cl)Cl>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25]([NH:31][C:19]([NH:18][S:15]([CH2:14][C:6]2[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])(=[O:17])=[O:16])=[O:20])[N:24]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CS(=O)(=O)N=C=O
Solvent: ClCCl
Solvent: CCCCCl
Product: COC(=O)c1cccc([N+](=O)[O-])c1CS(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1

Procedure:
A solution of the sulfonyl isocyanate from Example 6 (approximately 1.2 g) and 0.55 g of 4,6-dimethoxy-2-aminopyrimidine in 5 ml methylene chloride was stirred at room temperature for 4 hours. The reaction mixture was then filtered and the filtrate concentrated in vacuo to give a gummy solid. Trituration with warm n-butyl chloride gave a tan solid which was filtered and washed with ethyl acetate. The yield of 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]methyl-3-nitrobenzoic acid, methyl ester was 1.0 g as a light tan-colored solid, m.p. 177°-181°; IR(nujol): 1730, 1700 cm-1 ; NMR (CDCl3 /DMSO-d6): δ 3.75 (6H, s, OCH3 's), 3.8 (3H, s, CO2CH3), 5.7 (2H, s, --CH2 --), 5.8 (1H, s, heterocyclic ring H), 7.65-8.4 (3H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]([CH3:26])[CH2:14][CH2:15][CH2:16][C:17]1[C:18]([CH3:25])=[C:19]([CH:23]=O)[NH:20][C:21]=1[CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:23][C:19]1[NH:20][C:21]([CH3:22])=[C:17]([CH2:16][CH2:15][CH2:14][N:13]([CH3:12])[CH3:26])[C:18]=1[CH3:25]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C)c1CCCN(C)C
Yield: 71 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one was condensed with 4-(3-dimethylamino-propyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (208 mg, 1.0 mmol) using method B to give 284.9 mg (71%) of 5-bromo-3-[4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydroindol-2-one as a red solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]([CH2:41][CH2:42][NH:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:15][CH2:16][CH2:17][C@H:18]([N:26](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:19]([O:21]C(C)(C)C)=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6]C=C[CH:3]=1.Cl.C(O[CH2:58][CH3:59])C>CCOC(C)=O>[C:2]([C@@:18]([NH2:26])([CH2:17][CH2:16][CH2:15][N:14]([CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:59]=[CH:58][CH:3]=1)=[O:10])[CH2:41][CH2:42][NH:43][C:44]([O:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:45])[C:19]([OH:21])=[O:20])([CH3:7])([CH3:3])[CH3:1]
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)[C@H](CCCN(CCNC(=O)OCc1ccccc1)CCNC(=O)OCc1ccccc1)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@@](N)(CCCN(CCNC(=O)OCc1ccccc1)CCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a solution of tert-butyl (2S)-5-[bis(2-{[(benzyloxy)carbonyl]amino}ethyl)amino]-2-{bis[(tert-butoxy)carbonyl]amino}pentanoate XXII (3.00 g, 4.04 mmol) in EtOAc (20 mL) was added HCl (3.5 M solution in EtOAc, 20 mL). The reaction mixture was stirred for 30 min at room temperature before adding ethyl ether (about 50 mL). The precipitate was filtered and washed with ether to give tert-butyl (2S)-5-[bis(2-{[(benzyloxy)carbonyl]amino}ethyl)amino]-2-aminopentanoic acid as a white crystalline solid (1.82 g, 3.14 mmol, 78% yield).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([O:11][CH2:12][O:13][CH3:14])[CH:7]=[CH:6][C:3]=1C=O.[OH-:15].[Na+].OO>O>[CH3:14][O:13][CH2:12][O:11][C:8]1[C:9]([CH3:10])=[C:2]([OH:1])[C:3]([OH:15])=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: COCOc1ccc(C=O)c(O)c1C
Agent: OO
Agent: [Na+]
Solvent: O
Product: COCOc1ccc(O)c(O)c1C
Temperature: 42.5 °C
Yield: 95.9 %

Procedure:
Into a 2.0 L, 4-Necked, RB flask equipped with two addition funnels, thermometer socket and a pH meter was charged 800 mL of DM water. The contents were kept under nitrogen atmosphere. 2-Hydroxy-4-(methoxymethoxy)-3-methylbenzaldehyde (100 g) was added to the reaction mass under stirring. Aqueous sodium hydroxide (0.5 mL, dissolve 24.6 g of sodium hydroxide in 82.0 mL of DM Water) was added to the reaction mass to get a pH of 7.0-8.0. Reaction mass was heated to 40-45° C. Simultaneous addition of aqueous sodium hydroxide and hydrogen peroxide to, the reaction was started using two addition funnels. During the addition pH of the reaction mass was maintained at 7.8-8.4 and the temperature at 40-45° C. After the completion of addition, maintained the reaction mass at 40-45° C. for 4.0 h. The reaction mass was cooled to 25-30° C. and extracted with 3×500 mL of ethyl acetate. Combined organic layer was washed with 500 mL of saturated NaCl solution, treated with 20 g of activated carbon, dried with sodium sulphate, and distilled of solvent under vacuum to get 90 g of crude 4-(methoxymethoxy)-3-methylbenzene-1,2-diol as thick syrup. HPLC purity of sample is about 85%. The material is directly used in next stage. A small sample is purified by column chromatography for characterization purpose. M.R.: 60.5-61.5° C. IR (neat): 3487, 3200, 2969, 2942, 1630, 1621, 1488, 1443, 1405, 1378, 1307, 1290, 1242, 1150, 1086, 1042, 1007, 987, 904, 881, 806, 735, 660, 606 cm−1. 1H-NMR (CDCl3, 400 MHz): δ 8.79 (s, 1H, exchangeable with D2O, OH), 8.19 (s, 1H, exchangeable with D2O, OH), 6.51 (d, J=8.4 Hz, 1H, Ar. H), 6.34 (d, J=8.8 Hz, 1H, Ar. H), 5.02 (s, 2H, OCH2O), 3.36 (s, 3H, OMe), 2.01 (s, 3H, ArCH3). 13C-NMR (CDCl3, 100 MHz): δ 148.45 (C-4), 143.92 (C-2), 139.95 (C-1), 114.64 (C-3), 111.77 (C-6), 105.60 (C-5), 95.16 (OCH2O), 55.49 (OMe), 9.17 (ArCH3). Mass (EI-MS): 184.46 (M), 183.3 (M−1)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:11][C:12]2[CH:13]=[C:14]([CH:17]=[C:18]([Cl:20])[CH:19]=2)[C:15]#[N:16])[C:6]([CH2:9][CH3:10])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[C:25]([CH3:31])[NH:26][C:27]=1[C:28](O)=[O:29].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:22][C:23]1[N:24]=[C:25]([CH3:31])[NH:26][C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[C:5]([O:11][C:12]2[CH:13]=[C:14]([C:15]#[N:16])[CH:17]=[C:18]([Cl:20])[CH:19]=2)[C:4]=1[F:21])=[O:29]
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Reactant: CCc1ccc(CN)c(F)c1Oc1cc(Cl)cc(C#N)c1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCc1ccc(CNC(=O)c2[nH]c(C)nc2Cl)c(F)c1Oc1cc(Cl)cc(C#N)c1
Yield: 47.3 %

Procedure:
A solution of 3-{[3-(aminomethyl)-6-ethyl-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.075 g, 0.246 mmol), 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (0.040 g, 0.246 mmol), EDC (0.047 g, 0.246 mmol) and HOBT (0.038 g, 0.246 mmol) in DMF (4 ml) was stirred at RT under an atmosphere of nitrogen for 1 h then ethyl acetate (100 mL) and saturated aqueous NaHCO3 solution (100 mL) were added. The organic layer was separated, washed with saturated aqueous NaHCO3 solution (100 mL), water (100 mL), dried over MgSO4, filtered and concentrated. The material was purified by Reverse Phase HPLC (MeCN/water+0.1% TFA). The desired product was washed with saturated NaHCO3 solution and extraced with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution (50 mL), water (50 mL), dried over MgSO4, filtered and concentrated to give the title compound (0.052 g, 47%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.06 (br. s., 1H), 7.29 (s, 1H), 7.20 (d, 1H), 7.03-7.12 (m, 3H), 6.97 (s, 1H), 4.67 (d, 2H), 2.53 (q, 2H), 2.37 (s, 3H), 1.13 (t, 3H). LCMS m/z 447.05 (M+H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH-:29].[Na+].O>CO.O1CCCC1>[NH2:2][C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[S:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:5][CH:4]=1)=[O:29]
Reactant: [OH-]
Reactant: N#Cc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cn1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cn1
Temperature: 60 °C
Reaction time: 48 h
Yield: 12.3 %

Procedure:
To a solution of N-(6-cyanopyridin-3-yl)-4-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine-1-carboxamide (100 mg, 0.255 mmol) in methanol/tetrahydrofuran (1:4) (15 ml) was added a 1N aqueous sodium hydroxide solution (2.56 ml, 2.55 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 days. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 12.8 mg (12.2%) of the desired product as a solid.
Reaction SMILES: C([N:3](CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH2:19][CH2:20][C:21]2[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=2)[O:24][CH2:25][CH2:26][CH2:27][C:28](O)=[O:29])(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(OC(Cl)=O)C.Cl.C(N(CC)CC)C.N>C1COCC1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH2:19][CH2:20][C:21]2[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=2)[O:24][CH2:25][CH2:26][CH2:27][C:28]([NH2:3])=[O:29])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=C(O)CCCOc1cccc(CCNS(=O)(=O)c2ccc(Cl)cc2)c1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)CCCOc1cccc(CCNS(=O)(=O)c2ccc(Cl)cc2)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution cooled to -10° C. of 100 ml abs. THF, 4.32 g (43 mmol)triethylamine and 14.4 g (36 mmol) 4-[3-[2-(4-chlorophenylsulphonylamino)-ethyl]-phenoxy]butyric acid one slowly adds dropwise a mixture of 4.02 g (37 mmol) chloroformic acid ethylester and 30 ml abs. THF. One allows to come to room temperature, stirs a further 30 min and filters off with suction the precipitated triethylaminehydrochloride. The filtrate is then gassed with ammonia with ice cooling. It is then stirred for 6 hrs. at room temperature, evaporated and mixed with 2N HCl. One adds ethyl acetate thereto, mixes up very vigorously and separates the phases. The ethyl acetate phase is shaken out twice with bicarbonate solution and twice with water, then dried with Na2SO4 and evaporated. After recrystallisation from ethyl acetate, one obtains colourless crystals. Yield: 12.8 g (89% of theory); m.p. 110°-112° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C(=O)([O-])[O-].[K+].[K+].[C:19](#N)[CH3:20]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][CH3:20])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: CC#N
Reactant: Oc1ccc(Br)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccc(Br)c(C(F)(F)F)c1

Procedure:
A stirred suspension of 4-bromo-3-trifluoromethyl-phenol (117.6 g, 0.49 mol) iodoethane (77.6 g, 0.49 mol) and potassium carbonate (101.2 g, 0.73 mol) in acetonitrile (600 ml) was heated to reflux for 2.5 hours. The mixture was concentrated under reduced pressure before partitioning between dichloromethane (1 litre) and water (1 litre). The organic phase was collected and dried over magnesium sulfate before concentration under reduced pressure to afford 4-bromo-1-ethoxy-3-trifluoromethyl-benzene (126.97 g). 1H NMR (CDCl3): δ 7.66 (s, 1H) 7.56 (d, 1H) 6.86 (s, 1H) 4.09 (q, 2H) 1.44 (t, 3H).
Reaction SMILES: O.NN.[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=1[F:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[Ni].CO>[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=1[F:21])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccc(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.91 ml of hydrazine monohydrate and about 1 g of developed Raney nickel catalyst were added to a methanol (60 ml) solution of 4.94 g of 4-benzyloxy-3-fluoronitrobenzene, and the reaction liquid was stirred at room temperature for 2 hours. The catalyst was removed through filtration through Celite, and the solvent was evaporated away under reduced pressure to obtain the entitled compound as a yellow oily substance.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[CH:15][N:16]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]4=[O:31])=[N:22][CH:23]=3)[C:10]=2[CH:9]1[C:32]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=1)=O)(C)(C)C>CCOC(C)=O>[Cl:30][C:28]1[CH:27]=[CH:26][C:25](=[O:31])[N:24]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][N:16]3[C:10]4[CH:9]([C:32]5[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=5)[NH:8][CH2:13][CH2:12][C:11]=4[N:14]=[CH:15]3)=[CH:23][N:22]=2)[CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ncn(Cc3ccc(-n4cc(Cl)ccc4=O)nc3)c2C1c1ccc(C#N)cc1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C2NCCc3ncn(Cc4ccc(-n5cc(Cl)ccc5=O)nc4)c32)cc1
Temperature: 0 °C

Procedure:
3-(5-Chloro-2-oxo-2H-[1,2']bipyridinyl-5'-ylmethyl)-4-(4-cyano-phenyl)-3,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (0.27 g, 0.50 mmol) was dissolved in EtOAc, cooled to 0° C., degassed with Ar, and saturated with anh. HCl gas. The solution was concentated in vacuo and the diastereomers separated using a Chiralcel OD column (25 cm×2 cm, 10/90-0/100 Hexane/EtOH with 0.1% DEA, flow 5.0 mL/min) followed by enantiomer seperation using a Delta Pak C18 column (0-100% H2O (0.1% NH4HCO3)/CH3CN) to give the title compound. 1H NMR (CDCl3); δ 8.01-7.96 (m, 3H), 7.60 (d, 2H, J=8 Hz), 7.54 (s, 1H), 7.37-7.30 (m, 2H), 7.27-7.21 (m, 3H), 6.61 (d, 1H, J=10 Hz), 4.85 (d, 1H, J=16 Hz), 4.79 (s, 1H), 4.45 (s, 1H, J=16 Hz), 3.05-3.01 (m, 2H), 2.80-2.77 (m, 2H).