Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:25][CH2:26][O:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].[I-].[Na+].[ClH:45]>C(O)CCC.C(Cl)Cl>[ClH:45].[ClH:45].[F:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH:11]2[CH2:16][CH2:15][N:14]([CH2:25][CH2:26][O:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: BrCCOc1cccc2ccccc12
Reactant: Fc1ccc(C(Nc2ccc(F)c(F)c2)C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCCCO
Solvent: ClCCl
Product: Fc1ccc(C(Nc2ccc(F)c(F)c2)C2CCN(CCOc3cccc4ccccc34)CC2)cc1
Yield: 53.1 %

Procedure:
A mixture of 4-[[(3,4-difluorophenyl)amino](4-fluorophenyl)methyl]piperidine (5.41 g, 0.0169 mol), 1-(2-bromoethoxy)naphthalene (4.23 g, 0.0169 mol) and sodium bicarbonate (5.53 g, 0.059 mol) in 350 mL of 1-butanol containing sodium iodide (0.2 g) was heated 20 h at reflux. The reaction was concentrated to dryness and partitioned between chloroform and water. The chloroform layer was washed with 5% sodium hydroxide and dried (Na2SO4). Chloroform was removed to give a brown oil. The oil was dissolved in methylene chloride and placed on a silica gel column for flash chromatography. Elution was accomplished using 1% methanol-methylene chloride and 2% methanol-methylene chloride. Fractions of similar purity were combined and solvents removed to give a fluffy grey material. This material was converted to the HCl salt and the salt was recrystallized from methanol-diethyl ether to give a whitish-grey solid. The material was dried 16 h in vacuo at 80° C. This process provided 5.06 g (53.1%) of greyish material, mp 212°-215° C. (dec).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[SH:21].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C1COCC1>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[S:21][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1ccc(C)c(S)c1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C)c(Sc2ccc(C#N)cc2[N+](=O)[O-])c1
Yield: 94.8 %

Procedure:
To a solution of 4-chloro-3-nitrobenzonitrile (5.4 g, 29.67 mmol) in THF (100 mL) was added 2,5-dimethylthiophenol (4.921 g, 35.60 mmol) and K2CO3 (20.45 g, 148.0 mmol). The reaction was monitored with TLC (25% EtOAc in hexanes). After refluxing for 16 hrs, the reaction was complete. The solid was filtered and washed with copious amounts of EtOAc. The filtrate was washed sequentially with saturated NaHCO3, water, saturated NaCl solution, dried over MgSO4, filtered, and evaporated in vacuo. The resulting solid was then sonicated in hexanes and filtered to yield compound 24 as a yellow/white solid (8.00 g, 97.8% HPLC purity, 95% yield). 1H NMR (500 MHz, DMSO-d6): δ8.77 (d, J=2 Hz, 1H), 7.94 (dd, J1=2 Hz, J2=8 Hz, 1H), 7.46 (s, 1H), 7.41 (d, J=8 Hz, 1H), 7.36 (d, J=8 Hz, 1H), 6.76 (d, J=8 Hz, 1H), 2.32 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH:13][C:14]([OH:16])=[O:15])[CH2:10][C@H:9]1[C:17]([N:19]1[CH2:23][CH2:22][S:21][CH2:20]1)=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH2:13][C:14]([OH:16])=[O:15])[CH2:10][C@H:9]1[C:17]([N:19]1[CH2:23][CH2:22][S:21][CH2:20]1)=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(=CC(=O)O)C[C@H]1C(=O)N1CCSC1
Agent: O=[Pt]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(CC(=O)O)C[C@H]1C(=O)N1CCSC1
Yield: 96.8 %

Procedure:
A mixture of Example 1C (3.11 g, 0.0090 mol) and platinum oxide (280 mg) in methanol (15 mL) was stirred under an atmosphere of hydrogen at 60 psi pressure for 38 hours at room temperature. Filtration of the catalyst and evaporation of the solvent under reduced pressure provided the desired compound (3.0 g). MS (ESI APCI) m/e 245 (M-Boc+H)+; 1H NMR (400 MHz, DMSO-d6): δ ppm 4.37-4.66 (m, 2 H), 3.65 (m, 2 H), 3.09 (s, 2 H), 2.90 (m, 2 H), 2.34-2.44 (m, 1 H), 2.32 (dd, 1 H), 1.91 (m, 1 H), 1.41 (s, 9 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C1(P(=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: O=Cc1cccc(F)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a solution of 3-fluorobenzaldehyde 3-1 (18.16 g, 146 mmol) in dichloromethane (500 mL) was added ethyl (triphenylphosphoranylidene)acetate (61.2 g; 176 mmol) and the resulting solution was stirred at room temperature for 18 hr. After evaporation of the solvent, the residue was swirled with ether/hexane and filtered. The filtrate was concentrated and then purified on a plug of silica gel eluting with hexane/EtOAc 9:1. Removal of the solvent afforded the title compound 3-2 as an oil (~95% trans) which was used without further purification in the next step. 1H NMR (300 MHz, CDCl3) δ 1.36 (3H, t), 4.28 (2H, q), 6.43 (1H, d), 7.08 (1H, m), 7.2-7.4 (3H, m), 7.64 (1H, d).
Reaction SMILES: ClC(OCC)=O.[C:7]([O:11][C:12]([N:14]1[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:15]1[C:20]([OH:22])=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].C([N:25](CC)CC)C.N>O1CCCC1>[C:7]([O:11][C:12]([N:14]1[CH2:18][CH:17]([OH:19])[CH2:16][CH:15]1[C:20](=[O:22])[NH2:25])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)CC1C(N)=O
Reaction time: 1 h

Procedure:
A solution of 4.98 ml of ethyl chloroformate in 50 ml of anhydrous tetrahydrofuran was added, under cooling at -+° C., to a solution of 11.0 g of 1-(t-butoxycarbonyl)-(2S,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid and 7.25 ml of triethylamine in 160 ml of anhydrous tetrahydrofuran, and the mixture was stirred at the same temperature for one hour. 50 ml of concentrated aqueous ammonia were then added, at the same temperature, and the mixture was allowed to stand while its temperature rose to ambient. The reaction mixture was stirred for one hour, and then concentrated by evaporation under reduced pressure. A saturated aqueous solution of sodium chloride was added to the concentrate, which was then extracted three times with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, to give 7.70 g of (2S,4R)-1-(t-butoxycarbonyl-2-carbamoyl-4-hydroxypyrrolidine.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:23]([NH:25][CH:26]([C:35](=[O:38])[CH2:36]Br)[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16].[F-].[K+].[Cl:41][C:42]1[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[C:43]=1[C:44]([OH:46])=[O:45].CCCCCC.CCOC(C)=O>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:23]([NH:25][CH:26]([C:35](=[O:38])[CH2:36][O:46][C:44](=[O:45])[C:43]1[C:42]([Cl:41])=[CH:50][CH:49]=[CH:48][C:47]=1[Cl:51])[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: CC(C)Cc1c(C(=O)N[C@@H](CC(C)C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CBr)n(C)c2ccccc12
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)Cc1c(C(=O)N[C@@H](CC(C)C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COC(=O)c2c(Cl)cccc2Cl)n(C)c2ccccc12
Yield: 100.7 %

Procedure:
The titled product (63 mg, 100%, white solid) was prepared as described in Example 82 using N-[(1-methyl-3-isobutyl-indole-2-cabonyl)leucinyl]-3-amino-5-bromo-4-oxo-pentanoic acid, tert-butyl ester (52.9 mg, 0.089 mmol), potassium fluoride (13.0 mg, 0.22 mmol), and 2,6-dichlorobenzoic acid (17.1 mg, 0.089 mmol) in DMF (2.0 ml). TLC (hexane/EtOAc, 50/50): Rf=0.39.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[N:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[N:25]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH:15]([CH2:14][N:13]([C:24]3[N:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[N:25]=3)[CH2:12]2)[CH2:16]1)=[O:8]
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Reactant: Cc1cc(C)nc(Cl)n1
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccccc4-c4ccccc4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-4,6-dimethyl-pyrimidine. MS (ESI) mass calcd. for C25H26N4O, 398.5; m/z found, 399.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][S:15][C:11]=3[CH:10]=2)=[O:7])=[C:4](Cl)[CH:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>O1CCOCC1>[NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][S:15][C:11]=3[CH:10]=2)=[O:7])=[C:4]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:3]=1
Reactant: C1CNCCN1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3ncsc3c2)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: Nc1cc(N2CCNCC2)c(C(=O)Nc2ccc3ncsc3c2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 4-amino-N-benzothiazol-6-yl-2-chloro-5-nitrobenzamide (2 mmol; prepared as in Example 141) in dioxane (5 mL) was charged with piperazine (10 mmol). The contents were heated at reflux for 10 h and the reaction mixture was cooled to RT. The contents were poured onto ice cold water with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 4-amino-N-benzothiazol-6-yl-5-nitro-2-piperazin-1-yl-benzamide as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1.C(OCC)(=O)C>CN(C=O)C.O>[C:10]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([CH2:7][CH2:8][O:9][Si:18]([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19])[N:5]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)c1cc(N)n(CCO)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(N)n(CCO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To 2-(5-amino-3-tert-butyl-pyrazol-1-yl)-ethanol (3.42 g, 0.019 mol), add TBDMSCl (3.38 g, 1.2 equiv.) and imidazole (3.18 g, 2.5 equiv.) in DMF (7 mL) and stir overnight at room temperature under N2. Dilute the reaction with ethyl acetate and water. Wash the organic layer with water then saturated aqueous saturated sodium chloride and then dry over magnesium sulfate, filter, and concentrate in vacuo to give a solid (5.5 g, 99%) which is used without further purification. MS (ES), m/z 298 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:29])[C:18]([C:26]([OH:28])=[O:27])=[CH:19][N:20]2[CH:23]2[CH2:25][CH2:24]2)=[CH:15][C:14]=1[F:30].C(O)(=O)C>CS(C)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:29])[C:18]([C:26]([OH:28])=[O:27])=[CH:19][N:20]2[CH:23]2[CH2:25][CH2:24]2)=[CH:15][C:14]=1[F:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNc1cc2c(cc1F)c(=O)c(C(=O)O)cn2C1CC1
Temperature: 110 °C
Reaction time: 15 h

Procedure:
In a sealed tube N-(tert-butoxycarbonyl)ethylenediamine (5 mL) was added to a solution of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (3 g) in DMSO (6 mL). The reaction mixture was stirred at 110° C. for 15 h. The reaction mixture was allowed to cool at 50° C. and was poured into ice, acetic acid was added to reach pH=5. A precipitate appeared and was separated by filtration and washed with ether to afford a 40:60 mixture of title compounds (4.4 g).
Reaction SMILES: O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[CH2:17]([C:24]1[CH:25]=[CH:26][C:27]2[O:31][C:30](B(O)O)=[CH:29][C:28]=2[CH:35]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CS[C:38]1[N:43]=[CH:42][C:41]([CH:44]=[O:45])=[CH:40][N:39]=1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=C(C([O-])=O)SC=1.[Cu+]>[CH2:17]([C:24]1[CH:25]=[CH:26][C:27]2[O:31][C:30]([C:38]3[N:43]=[CH:42][C:41]([CH:44]=[O:45])=[CH:40][N:39]=3)=[CH:29][C:28]=2[CH:35]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cc2cc(Cc3ccccc3)ccc2o1
Reactant: CSc1ncc(C=O)cn1
Agent: [Cu+]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: O=Cc1cnc(-c2cc3cc(Cc4ccccc4)ccc3o2)nc1
Temperature: 50 °C

Procedure:
A 25 mm tube was charged with trifuran-2-ylphosphine (0.0737 g, 0.317 mmol), Pd2 dba3 (0.0411 g, 0.0397 mmol), 5-benzylbenzofuran-2-ylboronic acid (0.500 g, 1.98 mmol), CuTC (0.492 g, 2.58 mmol), 2-(methylthio)pyrimidine-5-carbaldehyde (0.306 g, 1.98 mmol) under argon. The reactants were diluted in 8 mL THF, sealed, and heated to 50° C. overnight. The mixture was filtered through Celite rinsing with 200 mL EtOAc. The green solution was concentrated and adsorbed onto 5 g silica gel, and purified by ISCO, 0-20% EtOAc/hexanes to give 2-(5-benzylbenzofuran-2-yl)pyrimidine-5-carbaldehyde as a light yellow solid. MS (ESI) m/z: Calculated: 314.1; Observed: 315.1 (M++1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1)[CH3:2].C(O)C.Cl.[N:15]([O-])=[O:16].[Na+]>O>[CH2:1]([C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH3:9])[C:8]=1[N:15]=[O:16])[CH3:2]
Reactant: CCc1cc(C)cc(O)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCc1cc(O)cc(C)c1N=O
Temperature: 0 °C

Procedure:
102 g (749 mmol) of 3-ethyl-5-methylphenol are introduced into 600 ml of ethanol. While stirring vigorously, 600 ml of concentrated hydrochloric acid are added dropwise, keeping the reaction vessel at room temperature by cooling. The reaction mixture is then cooled to 0° C. At this temperature, 77.5 g (1123.5 mmol) of sodium nitrite in 78 ml of deionised water are added dropwise. The resulting mixture is then stirred at 5° C. for 2 hours and subsequently poured into 3 liters of ice-water, when the title compound crystallises out. It is filtered off, washed several times with ice-water and recrystallised from methanol. Yield 88.7 g (71.8% of theory); melting point 138° C. (with decomposition).
Reaction SMILES: O[CH:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][N:4]([CH2:6][CH2:7][C:8]1[CH:12]=[CH:11][N:10]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:9]=1)[CH3:5].CS(O)(=O)=O>FC(F)(F)C(O)=O>[C:16]1([S:13]([N:10]2[C:9]3[CH:2]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:3][N:4]([CH3:5])[CH2:6][CH2:7][C:8]=3[CH:12]=[CH:11]2)(=[O:15])=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(CCc1ccn(S(=O)(=O)c2ccccc2)c1)CC(O)c1ccccc1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCc2ccn(S(=O)(=O)c3ccccc3)c2C(c2ccccc2)C1

Procedure:
A mixture of N-(2-hydroxy-2-phenylethyl)-N-methyl-2-(1-phenylsulphonyl-3-pyrrolyl)ethylamine (5.5 g), trifluoroacetic acid (200 ml) and methanesulphonic acid (2.13 g) was refluxed for 2.5 hours. After evaporating to dryness, water then 0.880 ammonia were added and the product was extracted into dichloromethane. The extracts were washed with water, dried and evaporated to give an oil. The oil was purified by chromatography on silica, eluting with chloroform then increasing amounts of methanol (1-5%) in chloroform to give the title product as a solid, m.p. 115°-116° C. (ethanol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][C:35]=1/[C:36](/[NH:39]O)=[N:37]/[H])[NH:32][CH:31]=[C:30]2[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.C(OCC)(=O)C.C(Cl)CCl>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:37]=[C:36]([C:35]3[CH:34]=[C:33]4[C:29]([C:30]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:31][NH:32]4)=[CH:28][C:27]=3[F:26])[N:39]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: [H]/N=C(\NO)c1cc2[nH]cc(CCC(=O)OCC)c2cc1F
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: On1nnc2ccccc21
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)c(F)cc12
Temperature: 120 °C
Yield: 55.5 %

Procedure:
To a solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (200 mg) in tetrahydrofuran (THF) (10 mL) was added EDC (374 mg) and HOBt (299 mg). The mixture was stirred for half an hour. Ethyl 3-{5-fluoro-6-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D155) (286 mg) was then added and the resulting mixture was stirred further for 1 hour. Finally, TBAF (1019 mg) was added to the solution and the reaction vessel was sealed and heated in macrowave at 120° C. for two hours. After cooling the reaction, the solution was diluted with ethyl acetate (80 mL) and washed with water (2×60 mL). The organic layer was then concentrated under vacuo and the residue was chromatographed on silica gel to give the designed product ethyl 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoate (D157) (250 mg). MS (ES): C25H23FN4O4 requires 462.2; found 463.2 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][N:18]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26]C)=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl.O>CO>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][N:18]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([OH:26])=[O:25])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(F)c(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(F)c(C(=O)O)c1
Temperature: 50 °C
Reaction time: 36 h
Yield: 89.6 %

Procedure:
To a solution of methyl 5-[{4-[(4-butylphenyl)ethynyl]benzyl}(hexyl)amino]-2-fluoro-benzoate (454 mg, 0.91 mmol) in MeOH (40 mL) was added an aqueous solution of NaOH (2.7 mL, 1N). The reaction mixture was stirred at 50° C. for 36 hrs. Then an aqueous solution of HCl (5 mL, 1N) was added and the reaction mixture was poured into water (100 mL) and extracted with Et2O (200 mL+2×100 mL). The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure to give 396 mg (90%) of the title compound as a beige powder. HPLC, Rt: 5.8 min (purity: 99.1%). LC/MS, M+(ESI): 486.1, M−(ESI): 484.0. 1H NMR (CDCl3) δ: 7.48 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.29 (dd, J=5.6, 3.3 Hz, 1H), 7.17 (m, 4H), 6.97 (dd, J=10.2, 9.0 Hz, 1H), 6.78 (ddd, J=9.0, 3.4, 3.3 Hz, 1H), 4.52 (s, 2H), 3.39 (t, J=7.6 Hz, 2H), 2.62 (t, J=7.6 Hz, 2H), 1.61 (m, 4H), 1.42-1.25 (m, 8H), 0.94 (t, J=7.3 Hz, 3H), 0.90 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[N:3]1[C:12]2[C:7](=[CH:8][C:9](I)=[CH:10][CH:11]=2)[C:6](=[O:14])[C:5]([C:15]([O:17]CCCC)=O)=[CH:4]1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:15]([C:5]2[C:6](=[O:14])[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:4]#[C:5][CH2:6][OH:14])[CH:8]=3)[N:3]([N:2]([CH3:1])[CH3:22])[CH:4]=2)=[O:17])=[CH:26][CH:25]=1
Reactant: CCCCOC(=O)c1cn(N(C)C)c2ccc(I)cc2c1=O
Reactant: NCc1ccc(Cl)cc1
Product: CN(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Butyl 1-(dimethylamino)-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate (0.50 g) from Preparation No. 58 and 4-chlorobenzylamine (0.29 mL) are heated to 170° C. for 7 hours. The reaction is cooled to rt, and the crude solid is recrystallized in acetic acid yielding 0.54 g of the amide. The resulting amide (0.25 g), copper (I) iodide (30 mg), and bis(triphenylphosphine)palladium (II) chloride (18 mg) are suspended in diethylamine (8 mL). Propargyl alcohol (36 μL) is added and the mixture is allowed to stir at room temperature for 16 h. The mixture is diluted with ethanol and then concentrated in vacuo. The crude solid is triturated with dichloromethane and purified by column chromatography (2% MeOH/CH2Cl2), affording 9 mg of the title compound as a beige solid.
Reaction SMILES: Cl.[Br:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:13]([O-])=O)[CH:6]=[N:5][CH:4]=1.O.O.Cl[Sn]Cl>C(O)C>[NH2:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[C:3]([Br:2])=[CH:4][N:5]=[CH:6]2
Reactant: O=[N+]([O-])c1cccc2cncc(Br)c12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cccc2cncc(Br)c12
Reaction time: 3 h

Procedure:
100 ml of concentrated hydrochloric acid are added to a suspension of 16 g of the compound obtained in Step 1 in 55 ml of ethanol. The mixture is cooled with ice and stirred whilst a solution of 62.6 g of SnCl2.2H2O in 100 ml of ethanol is being introduced and then for a further 3 hours. After removal of the solvent by evaporation, the residue is diluted with 140 ml of ice-cold water and rendered basic with 2N sodium hydroxide solution. The resulting aqueous phase is extracted 3 times with 350 ml of methylene chloride each time. The combined organic phases are dried over MgSO4 and evaporated. The residue is purified by flash chromatography (CH2Cl2/MeOH: 98/2) to yield the expected product.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].CC(C)([O-])C.[K+].F[C:11]1[C:12]2[C:16]([CH:17]=[CH:18][CH:19]=1)=[N:15][N:14]([CH3:20])[C:13]=2[S:21]([NH2:24])(=[O:23])=[O:22]>CS(C)=O>[CH2:1]([S:3][C:11]1[C:12]2[C:16]([CH:17]=[CH:18][CH:19]=1)=[N:15][N:14]([CH3:20])[C:13]=2[S:21]([NH2:24])(=[O:23])=[O:22])[CH3:2]
Reactant: Cn1nc2cccc(F)c2c1S(N)(=O)=O
Reactant: CCS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCSc1cccc2nn(C)c(S(N)(=O)=O)c12
Temperature: 120 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
4.8 g (77 mmol) of ethanethiol was added to a solution containing 8.6 g (77 mmol) of potassium t-butoxide in DMSO (70 ml), under cooling with ice, and 8 g (35 mmol) of 4-fluoro-2-methyl-2H-indazole-3-sulfonamide was further added thereto. This mixture was stirred at 120° C. for 2 hours. After confirming the disappearance of the starting material by TLC, treatment was conducted in the same manner as in Preparation Example 6 to obtain 6.8 g (yield: 72.5%) of the desired product. Melting: 145°-147° C.