Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=N[CH:3]=1.[NH2:10][C:11]1[C:19]([CH3:20])=[CH:18][C:17]([O:21][CH3:22])=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14].[CH3:23]N(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O.CN(C=O)C>[C:1]([NH:10][C:11]1[C:19]([CH3:20])=[CH:18][C:17]([O:21][CH3:22])=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14])(=[O:9])[C:2]1[CH:3]=[CH:23][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccnc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COc1cc(C)c(N)c(C(N)=O)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C)c(NC(=O)c2ccccc2)c(C(N)=O)c1
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A 50 mL round-bottom flask was charged with nicotinic acid (41 mg, 0.33 mmol, 1.0 eq.), 2-amino-5-methoxy-3-methylbenzamide (60 mg, 0.33 mmol, 1.0 eq.) and HBTU (190 mg, 0.50 mmol, 1.5 eq), which were suspended in 4 mL, of DMF. DIPEA (86 mg, 0.66 mmol, 2.0 eq.) was added dropwise at room temperature and the reaction mixture was stirred overnight. The reaction mixture was added to water (10 mL) dropwise with stirring. The mixture was extracted with ethyl acetate. The ethyl acetate was evaporated and 55 mg of the orange solid (58.5% yield) was obtained. LCMS m/z=286.1 (M+1) (Method B) (retention time=1.24 min).
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15]Br.O>CO>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15][O:11][C:10]1[C:5]([NH2:4])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: Nc1ncccc1O
Reactant: Fc1cccc(F)c1CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ncccc1OCc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
At RT, 51 g of sodium methoxide (953 mmol, 1.05 equivalents) were initially charged in 1000 ml of methanol, 100 g of 2-amino-3-hydroxypyridine (908 mmol, 1 equivalent) were added and the mixture was stirred at RT for another 15 min. The reaction mixture was concentrated under reduced pressure, the residue was taken up in 2500 ml of DMSO and 197 g of 2,6-difluorobenzyl bromide (953 mmol, 1.05 equivalents) were added. After 4 h at RT, the reaction mixture was poured into 20 l of water and stirred for 15 min, the solid was filtered off, washed with 1 l of water, 100 ml of isopropanol and 500 ml of petroleum ether and dried under high vacuum. This gave 171 g of the title compound (78% of theory).
Reaction SMILES: CO.C(OC(=O)[C:7](=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:8]([O:10]CC)=[O:9])C.[C-:22]#[N:23].[K+]>O>[C:22]([CH:13]([C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[CH2:7][C:8]([OH:10])=[O:9])#[N:23]
Reactant: [C-]#N
Reactant: CCOC(=O)C(=Cc1ccc(O)cc1)C(=O)OCC
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#CC(CC(=O)O)c1ccc(O)cc1
Temperature: 70 °C
Yield: 72.3 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged with methanol (6 mL) and water (1 mL). To the stirred solvent was added 2-(4-hydroxy-benzylidene)-malonic acid diethyl ester (1 g, 3.8 mmol), followed by potassium cyanide (0.492 g, 7.6 mmol). The RM was heated at 70° C. for 2 h. The RM was concentrated, diluted with saturated NaHCO3 solution (50 mL) and washed with ethyl acetate (50 mL×2). The aqueous layer was acidified to pH 3 with 1N hydrochloric acid and extracted with ethyl acetate (50 mL×2). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as brown liquid. (0.6 g, yield: 72.3%); MS (ESI, 120 eV): m/z=190.0 (M−H)+; 1H NMR (300 MHz, DMSO-d6): δ 12.69 (s, 1H), 9.58 (s, 1H), 7.22-7.24 (d, 2H), 6.75-6.78 (d, 2H), 4.28-4.40 (m, 1H), 2.77-3.12 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16])=[CH:4][C:3]=1[S:23]([NH:26][CH2:27][O:28][C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])(=[O:25])=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:45][Cl:46]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16])=[CH:4][C:3]=1[S:23]([NH:26][CH2:27][O:28][C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:45][Cl:46])=[O:35])(=[O:25])=[O:24]
Reactant: O=C(O)CCCCC(=O)OCNS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl
Reactant: ClCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: O=C(CCCCC(=O)OCNS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl)OCCl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The 6-(2-chloro-4-[(2-furanylmethyl)amino]-5-(2,2,2-trichloroethoxycarbonyl)phenylsulfonamidomethoxy)(6-oxo)hexanoic acid (0.060 mole) is dispersed with stirring in a methanol-water mixture (100 mL), and an aqueous solution of cesium carbonate (2 molar) is added dropwise until the solution pH is 6.6. The volatiles are removed by spin evaporation in vacuo. The resulting cesium salt is dried by addition of toluene and removal of the volatiles under reduced pressure. This is repeated several times. The dry cesium salt is dissolved in dimethylformamide (100 mL), and bromochloromethane (Aldrich) (0.060 mole) is slowly added to the solution. The reaction is stirred at ambient temperature in the dark for 12 hours. The mixture is filtered to remove cesium bromide, and the volatiles are removed by spin evaporation in vacuo. The reaction mixture is diluted with dichloromethane (200 mL) and extracted with sodium bicarbonate solution, washed with water, and then with a saturated sodium chloride solution. The organic layer may be dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give chloromethyl 6-(2-chloro-4-[(2-furanylmethyl)amino]-5-(2,2,2-trichloroethoxycarbonyl)phenylsulfonamidomethoxy)(6-oxo)hexanoate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=[O:15])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:24])=O>ClCCl.CN(C)C=O>[Cl:24][C:14]([C:13]1[CH:12]=[C:11]([CH:19]=[CH:18][CH:17]=1)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:20])=[O:15]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Cl)c1
Temperature: 0 °C

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid 1.1c (3.00 g, 10.14 mmol, 1.00 equiv) in dichloromethane (50 mL). This was followed by the addition of oxalyl dichloride (4.50 g, 35.43 mmol, 3.00 equiv) dropwise with stirring at 0° C. To this was added N,N-dimethylformamide (one drop). The resulting solution was stirred for 1.5 h at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 3.18 g (99%) of tert-butyl 3-(3-(chlorocarbonyl)benzylthio)propanoate as red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:17](=[N:20][O:21][CH2:22][CH:23](O)[CH3:24])([CH3:19])[CH3:18].[Na]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([O:16][CH:23]([CH3:24])[CH2:22][O:21][N:20]=[C:17]([CH3:19])[CH3:18])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C([O-])COc1ccc(Cl)c2cccnc12
Reactant: CC(C)=NOCC(C)O
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)=NOCC(C)OC(=O)COc1ccc(Cl)c2cccnc12
Temperature: 50 °C
Yield: 51.3 %

Procedure:
4.75 g (0.02 mol) of 5-chloroquinolin-8-oxyacetate are suspended in 50 ml of tetrahydrofuran, 3.2 g (0.02 mol) of N,N'-carbonyldiimidazole are added and the suspension is heated to 50° C. until the evolution of gas has ended. A solution of 2.62 g (0.02 mol) of 1-isopropylideneaminooxy-2-propanol and 50 mg of sodium in 10 ml of tetrahydrofuran (THF) is added dropwise to this suspension and the mixture is heated under reflux. After the reaction, the THF is stripped off under reduced pressure, the residue is taken up in ethyl acetate and the solution is washed with 5% strength NaOH and NaCl solution. The organic phase is dried over MgSO4 and concentrated and the residue is recrystallized from heptane. 3.6 g (45.6% of theory) of 1-isopropylideneaminooxy-2-propyl 5-chloroquinolin-8-oxyacetate of melting point 102° C. are obtained.
Reaction SMILES: [C:1]([O:4][C@@H](C(N)(C)[C@H](O)C)C)(=[O:3])[CH3:2].[CH3:13][C@:14]([N+:20]([O-])=O)([C@@H:17]([OH:19])[CH3:18])[CH2:15][OH:16]>>[C:1]([OH:4])(=[O:3])[CH3:2].[NH2:20][C@@:14]([CH3:13])([C@@H:17]([OH:19])[CH3:18])[CH2:15][OH:16]
Reactant: CC(=O)O[C@H](C)C(C)(N)[C@@H](C)O
Reactant: C[C@H](O)[C@@](C)(CO)[N+](=O)[O-]
Product: CC(=O)O
Product: C[C@H](O)[C@](C)(N)CO
Yield: 93 %

Procedure:
Using the procedure described for 5D (+-)(2R*,3S*)-2-methyl-2-nitro-1,3-butanediol (6A) gave (+-)(2R*,3S*)-2-amino-2-methyl-1,3-butanediol acetate (93%) mp 163°-165° (C,H,N).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.N1CCCCC1.[F:23][C:24]([F:29])([F:28])[C:25]([CH3:27])=[O:26]>C1COCC1>[F:23][C:24]([F:29])([F:28])[C:25](=[O:26])[CH:27]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)C(F)(F)F
Reactant: O=CC=CC=Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(C=CC=CC=Cc1ccccc1)C(F)(F)F

Procedure:
1,1,1-Trifluoro-8-phenyl-3,5,7-octatrien-2-one is prepared as outlined in Scheme IIIA. 1,1,1-Trifluoro-8-phenyl-3,5,7-octatrien-2-one is prepared by reacting 5-phenyl-2,4-pentadienal in THF with an equal amount of acetic acid and piperidine followed by addition of 1,1,1-trifluoroacetone at room temperature under nitrogen.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]2[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]=1)=[O:6].[N:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[N:49]1[CH2:54][CH2:53][CH:52]([NH:55][C:56](N2C=CN=C2)=[O:57])[CH2:51][CH2:50]1>C1(C)C=CC=CC=1.CC(O)C.ClCCl>[N:49]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][N:43]=2)[CH2:54][CH2:53][CH:52]([NH:55][C:56](=[O:57])[NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:8]=2)=[O:6])[CH2:51][CH2:50]1
Reactant: O=C(NC1CCN(c2ccccn2)CC1)n1ccnc1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: ClCCl
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
9-((1R,2S,3R,4S)-2,3-Dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (2-amino-ethyl)-amide (25 mg, 0.044 mmol) is dissolved in toluene (2 ml) and iPrOH (1 ml). N-[1-(2-Pyridinyl)-4-piperidinyl]-1H-imidazole-1-carboxamide (prepared using the procedure described in international patent application WO 01/94368) (12 mg, 0.044 mmol) is added as a solution in dichloromethane. The reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 24 hours. The solvent is removed in vacuo. The title compound is obtained by flash column chromatography (Isolute™ C18, 0-100% acetonitrile in water). MS (ES+) m/e 388.7(MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19].[I-].[CH3:22][N:23]1[C:31]2[C:26](=[C:27]([CH3:32])[CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:33][N+](C)(C)C)=[CH:24]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:33][C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[N:23]([CH3:22])[CH:24]=2)[C:11]1=[O:19]
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Reactant: COC(=O)c1ccccc1-n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1-n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Temperature: 60 °C
Yield: 85.5 %

Procedure:
To a solution of 2-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-benzoic acid methyl ester (30 mg, 0.11 mmol) in DMF (1.0 mL) are added (1,4-Dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium iodide (46 mg, 0.13 mmol) and K2CO3 (31 mg, 0.22 mmol) at room temperature. The solution is heated to 60° C. for 16 hr and it is cooled down to room temperature for another 48 hr. Then 30 mL of water is added. The mixture is extracted with EtOAc (3×30 mL) and the combined organic layers are washed with water (3×100 mL), dried with Na2SO4 and concentrated to give crude product. Purification by preparative TLC affords 40 mg (86%) of 2-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-benzoic acid methyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:30])/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)[CH:18]=3)=[CH:9][CH:8]=2)[CH:2]=1.ClC1C=CC=C(C(OO)=[O:39])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[O-:39][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:30])/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=4)[CH:18]=3)=[CH:11][CH:12]=2)[CH:2]=1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(-c4cccnc4)cc3)c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(-c4ccc[n+]([O-])c4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.9 %

Procedure:
To a solution of (E)-N[4—(3-pyridyl)phenyl]-3—(4-methylphenyl)cinnamamide (250 mg) in tetrahydrofuran (20 ml) was added 3-chloroperbenzoic acid (70%, 0.24 g) at 0° C., and the mixture was stirred at room temperature for 18 hours. To theireaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes and extracted with dichloromethane. The organic layer was washediwith saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was recrystallized from ethanol-tetrahydrofuran-acetone to give (E)-N-[4—(1-oxidopyridin-3-yl)phenyl]-3—(4-methylphenyl)cinnamamide (Compound 193) (208 mg) as pale yellow crystals. 1H-NMR (200 MHz, DMSO-d6) δ 2.38 (3H, s), 6.95 (1H, d, J=15.7 Hz), 7.31 (2H, d, J=8.1 Hz), 7.45-7.57 (2H, m), 7.59-7.94 (12H, m), 8.19 (1H, d, J=6.5 Hz), 8.58 (1H, s). IR (KBr) 3423, 1672, 1597, 1531, 1477, 1340, 1201, 901, 835, 793 cm−1;
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([Cl:12])[CH:10]=2)[C:5](=[O:14])[C:4]([C:15]([OH:17])=[O:16])=[CH:3]1.O.O.O.O.O.O.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[ClH:12].[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:10]=2)[C:5](=[O:14])[C:4]([C:15]([OH:17])=[O:16])=[CH:3]1
Reactant: C1CNCCN1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: O
Product: Cl
Product: Cn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Yield: 39.9 %

Procedure:
A mixture of 1-methyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 0.85 g (3.3 millimole) and piperazine hexahydrate 10 g (50 millimole) was heated in a sealed tube at 125°-135° C. (inner temperature) for 22 hours. After cooling, the reaction mixture was evaporated under vacuum. The residue was acidified with acetic acid and the insoluble matters were removed by filtration. The filtrate was neutralized with an aqueous solution of caustic soda. The precipitated crystals were collected by filtration, washed with water and dried. The crystals were dissolved in hot diluted hydrochloric acid, reprecipitated with the addition of ethanol, collected by filtration and dried. Recrystallizing the crystals from a mixed solution of water and ethanol, 0.45 g (40%) of 1-methyl-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride was obtained. Colorless powders.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:36])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:22]1)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[NH2:8][C@@H:9]([CH3:36])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:22]1)=[O:11]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@H](N)C(=O)Nc1ccc(F)cc1N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
To an ice-cooled solution of 2,2-dimethylpropionic acid 2-{(R)-3-[2-((S)-2-tert-butoxycarbonylaminopropionylamino)-5-fluorophenylamino]-piperidin-1-yl}ethyl ester (0.74 mmol) in DCM (20 mL) was added TFA (5 mL) and the mixture stirred at RT for 1.5 h. Toluene was added and volatiles were removed in vacuo. The resulting residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording the title compound as a purple oil (0.255 g, 84% over 2 steps). LCMS (Method J): RT 1.65 min [M+H]+ 409.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][C:17]#[CH:18])[C:12]([Br:19])=[CH:11][N:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29].O>C1COCC1>[CH2:31]([O:30][C:28](=[O:29])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][C:17]#[CH:18])[C:12]([Br:19])=[CH:11][N:10]=2)=[CH:4][CH:3]=1)[CH2:32][CH2:33][CH3:34]
Reactant: C#CCNc1nc(Nc2ccc(N)cc2)ncc1Br
Reactant: CCCCOC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C#CCNc1nc(Nc2ccc(NC(=O)OCCCC)cc2)ncc1Br

Procedure:
N2-(4-Amino-phenyl)-5-bromo-N4-prop-2-ynyl-pyrimidine-2,4-diamine (0.31 mmol, prepared in analogy to procedure 21) was dissolved in THF (20 ml), triethyl amine (0.33 mmole) and butyl chloroformate (0.33 mmole) were added at room temperature and the reaction was stirred at this temperature until the starting material disappeared (TLC, 3 h). The reaction was poured into water and [4-(5-Bromo-4-prop-2-ynylamino-pyrimidin-2-ylamino)-phenyl]-carbamic acid butyl ester was isolated by filtration. Yield: 91 mg (70%). ESI-MS: 419.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:35])[N:27]3[C:30]([O:32][CH2:33]Cl)=[O:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.[C:36]([O-:39])(=[O:38])[CH3:37].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:35])[N:27]3[C:30]([O:32][CH2:33][O:38][C:36](=[O:39])[CH3:37])=[O:31])=[CH:22][CH:21]=2)[CH2:13][CH2:14]1
Reactant: CC(=O)[O-]
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1C(=O)OCCl
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCOC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of chloromethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (1.20 g, 2.22 mmol) in dimethyl formamide (20 mL) was added cesium acetate (639 mg, 3.33 mmol). The reaction was then stirred at ambient temperature overnight. The reaction was diluted with ethyl acetate (50 mL) and quenched with water/brine (1:1, 50 mL). The reaction was extracted with ethyl acetate (3×50 mL). The combined organics were washed with water (50 mL) then brine (50 mL) and dried (MgSO4) and concentrated. The crude product was purified by column chromatography on silica eluting with 0-10% tetrahydrofuran/dichloromethane with 1% Et3N to give the product which required further purification. The product was purified by column chromatography on silica eluting with 0.5% Et3N/ethyl acetate to give acetoxymethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate, Compound-87 (243 mg, 19% over 2 steps).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH3:12][C@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14]1.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:12][C@@H:13]1[NH:14][CH2:15][CH2:16][N:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH2:18]1
Reactant: C[C@H]1CNCCN1
Reactant: FC(F)(F)c1ccc(Br)nc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@H]1CN(c2ccc(C(F)(F)F)cn2)CCN1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
2-Bromo-5-trifluoromethyl-pyridine (1.06 g, 4.69 mmol), (S)-2-methylpiperazine (1.03 g, 10.28 mmol) and triethylamine (1.5 mL, 10.76 mmol) were stirred in toluene (10 mL) at 110° C. for 26 h. The reaction was cooled to room temperature, diluted with ethyl acetate (150 mL) and washed with water and brine. The organic layer was dried (MgSO4), filtered and concentrated. The crude mixture was purified by automated silica gel flash column chromatography (gradient eluent 0-20% MeOH/dichloromethane) to afford 3-(S)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine (926 mg, 81%) as a yellow solid. 1H NMR (400 MHz, CDCl3) 8.38 (s, 1H), 7.62 (dd, 1H), 7.63 (d, 1H), 4.29-4.20 (m, 2H), 3.16-3.12 (m, 1H), 3.02-2.85 (m, 3H), 2.64-2.52 (m, 2H), 1.18 (d, 3H).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[NH:9]1[C:17]2[C:12](=[CH:13][C:14](/[CH:18]=[C:19]3/[C:20](=[O:28])[NH:21][C:22]4[C:27]/3=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:15][CH:16]=2)[CH:11]=[N:10]1>CN(C=O)C>[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([C@H:18]3[C@@:19]4([C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[NH:21][C:20]4=[O:28])[CH2:2]3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1
Reactant: C[S+](C)(C)=O
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
To a solution of trimethylsulfoxonium iodide (33 mg, 0.15 mmol) in anhydrous DMF (1 mL) was added sodium hydride (60% dispersion in oil) (16 mg, 0.4 mmol) at 0° C. The mixture was stirred for 15 min after which time (E)-3-((1H-indazol-5-yl)methylene)indolin-2-one (26 mg, 0.1 mmol) was added. The solution was stirred overnight at rt. The reaction was quenched with sat. NH4Cl solution (2 mL), extracted with EtOAc (50 mL), dried over MgSO4 and concentrated to dryness. The title was compound isolated by preparative HPLC) as a white solid (5 mg, 18%). 1H NMR (400 MHz, d6-DMSO) δ 13.03 (s, 1H), 10.58 (d, 1H, J=8.3 Hz), 8.02 (s, 1H), 7.74 (s, 1H), 7.40 (d, 1H, J=8.9 Hz), 7.11 (d, 1H, J=8.6 Hz), 6.98 (t, 1H, J=7.7 Hz), 6.83 (d, 1H, J=7.6 Hz), 6.50 (t, 1H, J=7.3 Hz), 5.94 (d, 1H, 7.5 Hz), 3.17-3.13 (m, 1H), 2.27-2.23 (m, 1H), 1.98-1.95 (m, 1H); MS ESI 276.1 [M+H]+, calcd for [C17H13N30+H]+ 276.3.