Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][O:13][C:14]([CH3:23])([C:19]([F:22])([F:21])[F:20])[C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+].CO>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14]([CH3:23])([C:19]([F:20])([F:21])[F:22])[C:15]([OH:17])=[O:16])=[CH:24][CH:25]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(OCc1ccc(-c2ccc(Cl)cc2)cc1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the impure ester fraction from the previous example (fraction A) of (±)-methyl 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionate (15.7 g.), potassium hydroxide (3.0 g.), methanol (300 ml.) and water (30 ml.) is stirred at ambient temperature for 18 hours. The suspension is filtered, and the filtrate is evaporated. The residue is mixed with water, and the mixture is washed with ether. The aqueous phase is acidified with concentrated hydrochloric acid then extracted with ether. The extract is dried with sodium sulphate and evaporated. The residue is crystallised from cyclohexane and from a mixture of toluene and light petroleum (b.p. 60°-80° C.) to give (±)-2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionic acid, m.p. 135°-136° C. (5.7 g.). The above process is repeated with (±)-methyl 2-(4-chloro-1-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate obtained as an oil in Example 16, to give (±)-2-(4-chloro-1-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionic acid, m.p. 120°-121° C. (11.1 g.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11]>>[CH2:14]([O:13][C:9](=[O:12])[CH2:10][CH2:11][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:15]
Reactant: C=CC(=O)OCC
Reactant: Oc1cccc(Br)c1
Product: CCOC(=O)CCOc1cccc(Br)c1

Procedure:
A solution of 3-bromophenol (10.0 g, 57.8 mmole) in 50 mL of ethyl acrylate was treated with 0.9 mL of Triton B. The reaction mixture was heated at reflux for 18 hours. Excess ethyl acrylate was removed by distillation at atmospheric pressure. The resulting residue was diluted with 50 mL toluene and co-evaporated. The remaining product was diluted in 100 mL ether and washed with two 50 mL portions of sodium carbonate solution, 50 mL water and 50 mL saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a pale yellow liquid. The product was purified by flash chromatography (SiO2, 5% ethyl acetate in hexanes) to afford 6.435 g of 3-(3-bromo-phenoxy)-propionic acid ethyl ester as a colorless liquid.
Reaction SMILES: [N:1]1[C:5]2=[CH:6][CH:7]=[C:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:9][C:4]2=[N:3][N:2]=1.[H-].[Na+].[CH3:17][CH2:18][CH2:19]I>CN(C)C=O>[CH2:17]([N:2]1[N:1]=[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:4]2=[N:3]1)[CH2:18][CH3:19]
Reactant: COC(=O)CC1=CC=C2N=NN=C2C1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1nc2ccc(CC(=O)OC)cc2n1
Reaction time: 1 h
Yield: 39.3 %

Procedure:
A solution of methyl 5-benzotriazoleacetate (10 g, 0.0523 mol) in N,N-dimethylformamide was added dropwise to a chilled (ice-bath) suspension of sodium hydride (60% dispersion in oil, 2.3 g, 0.0575 mol) in N,N-dimethylformamide. When the addition was complete, the ice-bath was removed and the mixture stirred for 1 hour. N-Propyl iodide (9.78 g, 0.0575 mol) was added dropwise, and once the addition was complete the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured onto ice/water, and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. The residue was further purified by column chromatography to afford methyl (2-propylbenzotriazol-5-yl)acetate (4.8 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[N:12]1([CH2:18][CH2:19][OH:20])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[NH2:7][C:6]1[CH:8]=[C:2]([N:15]2[CH2:16][CH2:17][N:12]([CH2:18][CH2:19][OH:20])[CH2:13][CH2:14]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1cc(N2CCN(CCO)CC2)ccc1[N+](=O)[O-]
Temperature: 122.5 °C
Reaction time: 24 h
Yield: 77.7 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (5.0 g, 29.0 mmol), 2-piperazin-1-yl-ethanol (11.3 g, 87.0 mmol) and anhydrous potassium carbonate (4.4 g, 31 mmol) in N,N-dimethylacetamide (10 ml) was stirred at 120-125° C. under nitrogen for 1 day. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water (30 ml) and stirred vigorously and cooled at 5° C. overnight. The resulting yellow precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting yellow brown solid was slurried in diethyl ether (30 mL), filtered, washed with additional diethyl ether, dried to afford 2-[4-(3-Amino-4-nitro-phenyl)-piperazin-1-yl]-ethanol (6.0 g, 77%) as a yellow powder.
Reaction SMILES: C([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10](=[O:16])[NH:11][CH2:12][CH:13]([F:15])[F:14])(C)(C)C.ClCCl>Cl.O1CCOCC1>[F:14][CH:13]([F:15])[CH2:12][NH:11][C:10]([CH2:9][CH2:8][NH:7][C:6](=[O:5])[OH:17])=[O:16]
Reactant: CC(C)(C)OC(=O)NCCC(=O)NCC(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)NCCC(=O)NCC(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
[2-(2,2-Difluoro-ethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (2.75 g, 10.9 mmol) was suspended in 4M hydrochloric acid in dioxane (30 ml) and stirred at RT for 18 h. Dichloromethane was added (50 ml) and the solid filtered off and dried in vacuo (2.02 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:32]1[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:34][CH2:33]1)=[O:20])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)c(Cl)cc2nc1OC
Reactant: COc1cccc(N2CCNCC2)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cccc(N2CCN(C(=O)Nc3nc4cc(Cl)c(Cl)cc4nc3OC)CC2)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 65.6 %

Procedure:
Ethyl N-(6,7-dichloro-2-methoxyquinoxalin-3-yl)carbamate (28 mg, 0.089 mmol) and 1-(3-methoxy phenyl)piperazine (35 mg, 0.18 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (27 mg, 0.18 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (1:1) mixture and concentration gave 27 mg of the titled compound (yield, 66%). 1H NMR (300 MHz, CDCl3) δ 3.28-3.30 (m, 4H), 3.74-3.76 (m, 4H), 3.81 (s, 3H), 4.19 (s, 3H), 6.47-6.49 (m, 3H), 6.53-6.57 (m, 1H), 7.30 (br s, 1H), 7.85 (s, 1H), 7.92 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][C:5]=1C.Br[CH2:16][CH2:17][O:18][CH2:19][CH2:20]Br.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:11]#[N:12])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:8][CH:9]=1
Reactant: BrCCOCCBr
Reactant: COC(=O)c1ccc(CC#N)cc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2(C#N)CCOCC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methyl 4-(cyanomethyl)-benzoic acid methyl ester (1.92 g, 11.01 mmol) and 1-bromo-2-(2-bromo-ethoxy)-ethane (12.56 mL, 55.04 mmol) were combined in THF (15 mL) and cooled down to 0° C. Potassium bis(trimethylsilyl)-amide (0.5M in toluene, 48.3 mL, 24.21 mmol, 2.2 eq) was added over a period of 15 minutes and then warmed up to room temperature and stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried with MgSO4 and evaporated under vacuum. The crude product was purified by chromatography on silica gel (25% EtOAc/hexanes) to afford 4-(4-cyano-tetrahydro-pyran-4-yl)-benzoic acid methyl ester. To a solution of 4-(4-cyano-tetrahydro-pyran-4-yl)-benzoic acid methyl ester (1.55 g 6.32 mmol) in MeOH (10 mL) was added Et3N (3 mL). H2S was bubbled into the solution. The reaction vessel was stirred at room temperature for 3 days. The reaction mixture was then evaporated and purified by silica gel chromatography (33% EtOAc/hexanes) to afford 4-(4-thiocarbamoyl-tetrahydro-pyran-4-yl)-benzoic acid methyl ester.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH3:7][C:8]1([CH3:22])[NH:13][C:12](=O)[C:11]2[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:10]=2[O:9]1>P(Cl)(Cl)(Cl)=O>[Cl:2][C:12]1[C:11]2[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:10]=2[O:9][C:8]([CH3:22])([CH3:7])[N:13]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC1(C)NC(=O)c2ccc([N+](=O)[O-])cc2O1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)N=C(Cl)c2ccc([N+](=O)[O-])cc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
Phosphorus pentachloride (5.5 g) was added to a solution of 2,2-dimethyl-7-nitro-3,4-dihydro-2H-1,3-benzoxazine-4-one (4 g) in phosphoryl chloride (15 mL) at 0° C., and the mixture was stirred at room temperature for one hour. The mixture was heated to 60° C. and stirred at the same temperature overnight. After cooling to 0° C., the reaction mixture was poured into ice water (300 mL). After stirring for 30 minutes, the mixture was extracted with ethyl acetate (100 mL×2). The combined organic layer was washed with brine (100 mL×2), dried over sodium sulfate and concentrated in vacuo to give the titled compound (2.34 g) as a brown oil, which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]#[C:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)C.C(OC([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][CH2:36][O:37][C:38]3[CH:39]=[C:40]4[C:44](=[CH:45][CH:46]=3)[NH:43][CH:42]=[CH:41]4)[N:33]=2)[CH2:28][CH2:27][CH2:26]1)=O)(C)(C)C>>[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([CH:6]([N:43]2[C:44]3[C:40](=[CH:39][C:38]([O:37][CH2:36][CH2:35][C:32]4[CH:31]=[CH:30][C:29]5[CH2:28][CH2:27][CH2:26][NH:25][C:34]=5[N:33]=4)=[CH:46][CH:45]=3)[CH:41]=[CH:42]2)[CH2:5][C:4]([OH:3])=[O:17])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Reactant: CCOC(=O)C#Cc1cnc2ccccc2c1
Product: O=C(O)CC(c1cnc2ccccc2c1)n1ccc2cc(OCCc3ccc4c(n3)NCCC4)ccc21
Yield: 81 %

Procedure:
The title compound was synthesized from quinolin-3-yl-propynoic acid ethyl ester and 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in 81% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) δ 8.90 (m, 1H), 8.14 (m, 1.3H), 8.04 (m, 0.7H), 7.79 (m, 2H), 7.58 (m, 1H), 7.30 (d, 1H, J=7.6 Hz), 7.13(m, 2H), 6.93 (m, 1.3H), 6.75 (m, 1.7H), 6.63 (d, 0.7H, J=3.2 Hz), 6.53 (d, 0.3H, J=3.2 Hz), 6.38 (s, 0.7H), 6.32 (s, 0.3H), 4.38 (m, 2H), 4.05 (m, 2H), 3.75 (t, 2H, J=6.4 Hz), 3.19 (t, 2H, J=6.4 Hz), 2.72 (t, 2H, J=6.4 Hz), 1.91 (m, 2H), 1.51 (s, 9H), 1.13 (t, 0.9H, J=7.0 Hz), 1.05 (t, 2.1H, J=7.0 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11]([CH:13]1[CH2:18][CH:17]([CH3:19])[CH2:16][CH2:15][CH:14]1[CH:20]([CH3:22])[CH3:21])=[O:12].[C:23]([Cu])#[N:24]>CN1C(=O)CCC1>[C:23]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11]([CH:13]1[CH2:18][CH:17]([CH3:19])[CH2:16][CH2:15][CH:14]1[CH:20]([CH3:22])[CH3:21])=[O:12])#[N:24]
Reactant: N#C[Cu]
Reactant: CC1CCC(C(C)C)C(C(=O)NCCc2ccccc2Br)C1
Solvent: CN1CCCC1=O
Product: CC1CCC(C(C)C)C(C(=O)NCCc2ccccc2C#N)C1
Reaction time: 0.67 h
Yield: 95.3 %

Procedure:
A 20 mL microwave reaction vessel equipped with a stir bar was charged with 2-isopropyl-5-methyl-cyclohexanecarboxylic acid [2-(2-bromo-phenyl)-ethyl]-amide (1.54 g, 4.2 mmol), CuCN (0.60 g, 6.4 mmol) and NMP (10 mL). The reaction vessel was subjected to microwave at 180° C. for 40 minutes. The reaction mixture was transferred to a round bottom flask and concentrated. The residue to purified by flash chromatography on silica gel (10% ethyl acetate/hexane for elution) to give a colorless solid (1.25 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C([OH:12])C.ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Na+]>O>[NH2:1][C:2]1[N+:7]([O-:12])=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: CCO
Reactant: Nc1cc(Cl)nc(N)n1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(Cl)nc(N)[n+]1[O-]
Temperature: -10 °C
Reaction time: 7 h

Procedure:
75 g. of 2,4-diamino-6-chloropyrimidine are dissolved in 1500 ml. of ethanol at 35° C. The solution is cooled to -10° C. and a solution of 100 g. of 3-chloro-perbenzoic acid in 500 ml. of ethanol is slowly added dropwise in the course of 1 hour. The suspension is subsequently stirred at -10° C. for 7 hours and left to stand at 5° C. overnight. The suspension is neutralized with 24 g. of sodium hydroxide in 100 ml. of water. The solid material is filtered off and recrystallized from ethanol, there being obtained pure 2,4-diamino-6-chloropyrimidine-3-oxide.
Reaction SMILES: Br.[OH:2][C:3]1[C:19]([OH:20])=[CH:18][C:6]2[CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[OH-].[Na+].[C:23](Cl)([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>CN(C)C=O>[OH:2][C:3]1[C:19]([OH:20])=[CH:18][C:6]2[CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][N:9]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Oc1cc2c(cc1O)C(c1ccccc1)CNCC2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCc2cc(O)c(O)cc2C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7.10 g. (18.6 mole) of 7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide in 120 ml. of aqueous dimethyl-formamide at 0° under an argon atmosphere is basified to pH 10.0 with 10% sodium hydroxide solution. To this cold mixture is added 13.0 g. (76 mole) of carbobenzyloxy chloride in small portions over 15 minutes with concomitant addition of 10% alkali so as to maintain a pH of 10 to 10.5. The reaction is allowed to warm to room temperature after stirring at 0° for 11/2 hours. The mixture is diluted with saturated salt and extracted with three portions of ethyl acetate. The combined organic extract is backwashed twice with saturated salt. The dried extract is concentrated in vacuo and heated at 75°/0.1 mm Hg to remove any benzyl alcohol to yield 7,8-dihydroxy-N-carbobenzyloxy-1-phenyl-2,3,4,5-tetrahydro-1-H-3-benzazepine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26](C)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([NH2:30])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N
Reactant: CC(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O
Product: CC(C)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(4-fluorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 376) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.024 g, 6%). mp 132-136° C. 1H NMR (300 MHz, DMSO d6) δ 0.79 (d, J=6 Hz, 6H), 1.83 (m, 1H), 4.19 (d, J=6 Hz, 2H), 7.36 (m, 2H), 7.50 (m, 2H), 7.66 (m, 2H), 7.84 (m, 2H), 7.95 (m, 2H), 8.18 (s, 1H). MS (DCI/NH3) m/z 418 (M+H)+, 435 (M+NH4)+. Anal. calc. for C20H20FN3O4S: C, 57.54; H, 4.83; N, 10.07. Found C, 57.26; H, 5.00; N, 9.78.
Reaction SMILES: [C:1]1([C@@H:7]([CH3:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[C:13]1([CH3:22])[C:14]([C:19](Cl)=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=1>ClCCl>[CH3:22][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([NH:9][CH2:8][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:10])=[O:20]
Reactant: C[C@@H](CN)c1ccccc1
Reactant: Cc1ccccc1C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccccc1C(=O)NC[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (R)-2-phenylpropyl amine (1.24 g; 9.17 mmol), 1N NaOH (20 mL), and dichloromethane (20 mL) is treated with o-toluoyl chloride (1.42 g; 9.17 mmol) added dropwise; the mixture is then stirred at room temperature for 1 hour. The phases are separated and the aqueous layer extracted with dichloromethane (2×70 ml). The combined extracts are washed with water (1×30 mL) and brine (1×30 mL), dried over magnesium sulfate, and evaporated to give the product as a white solid.
Reaction SMILES: [C:1]1([C:11]#[C:12][CH2:13][CH2:14][CH2:15][OH:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C>[C:1]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OCCCC#Cc1cccc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: OCCCCCc1cccc2ccccc12
Yield: 93.3 %

Procedure:
A mixture of 3.5 grams (0.017 mole) of 5-(naphth-1-yl)-4-pentyn-1-ol and 0.5 gram (catalyst) of 10% palladium on carbon in 30 mL of ethanol was shaken in a Parr hydrogenator until the theoretical amount of hydrogen gas was taken up. The reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure, yielding 3.4 grams of 5-(naphth-1-yl)pentanol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[NH2:17])=[CH:4][CH:3]=1.Cl[C:20]([C:22]1[S:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[C:23]=1[Cl:31])=[O:21]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:20]([C:22]2[S:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[C:23]=2[Cl:31])=[O:21])=[CH:6][CH:7]=1
Reactant: Cc1ccc(N)c(C(=O)Nc2ccc(Cl)cc2)c1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2sc3ccccc3c2Cl)c(C(=O)Nc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
To a solution of N-(4-chlorophenyl)-2-amino-5-methylbenzamide (0.11 g, 0.42 mmol) in pyridine (5 mL) at 0° C. was added 2-chlorocarbonyl-3-chlorobenzo[b]thiophene (0.15 g, 0.64 mmol), and the mixture allowed to warm to ambient temperature with stirring. After 16 hours, the mixture was poured onto water (5 mL) and the resulting white solid collected by filtration and dried in vacuo. Recrystallization from acetonitrile afforded 0.095 g (50% yield) of N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide, as a white crystalline solid; NMR (DMSO-d6 /TFA) 11.4 (s, 1), 10.7 (s, 1), 8.2 (d, 1), 7.4-8.2 (m, 10), 2.4 (s, 3) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH:12]2[CH:16]=[CH:15][NH:14][N:13]2[CH3:17])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]2[CH:16]=[CH:15][NH:14][N:13]2[CH3:17])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C2C=CNN2C)cc1Cl
Agent: [Na+]
Agent: [OH-]
Product: CN1NC=CC1c1ccc(C(=O)O)c(Cl)c1

Procedure:
The title compound was prepared in the same manner as described in Example 70, employing 2-chloro-4-(2-methyl-1H-pyrazol-3yl)-benzoic acid, methyl ester (0.464 g) and 2.5N sodium hydroxide (1.04 ml). 1H NMR (300 MHz), (DMSO-d6) δ: 3.89 (s, 3H), 6.56 (d, 1H), 7.49 (d, 1H), 7.59-7.90 (m, 3H)
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9]2=[O:18])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:25][N:26]([CH3:36])[C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>O1CCOCC1.O>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[C:8]2=[CH:7][C:5]1[O:6][C:2]([C:30]2[CH:31]=[N:32][C:27]([N:26]([CH3:36])[CH3:25])=[CH:28][CH:29]=2)=[CH:3][CH:4]=1
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(Br)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CN(C)c1ccc(-c2ccc(C=C3C(=O)Nc4ccc(Cl)cc43)o2)cn1
Temperature: 120 °C

Procedure:
To 3-((5-bromofuran-2-yl)methylene)-5-chloroindolin-2-one (50 mg, 0.155 mmol) in dioxane/water (5% water) was added Cs2CO3 (152 mg, 0.466 mmol) and 6-(dimethylamino)pyridin-3-ylboronic acid (34 mg, 0.186 mmol). The mixture was degassed with nitrogen for 5 minutes then heated in microwave for 20 minutes at 120° C. The solution was diluted with water and the solid formed was isolated by filtration. The solid was purified by HPLC to yield 5-chloro-3-((5-(6-(dimethylamino)pyridin-3-yl)furan-2-yl)methylene)indolin-2-one. LCMS (M+1=366).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:17])[C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>C(Cl)Cl>[Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:17][C:28]([CH:25]3[CH2:27][CH2:26]3)=[O:29])[C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nn2cccc(Br)c2c1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1nn2cccc(Br)c2c1-c1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Bromo-3-phenyl-pyrazolo[1,5-a]pyridin-2-ylamine (0.295 g 1 eq) was dissolved in DCM (3 mL) at 5° C. and Et3N (356 μL) was added followed by the cyclopropane carbonyl chloride (234 μL). The reaction mixture was then allowed to warm to room temperature. The solvent was removed in vacuo the residue was treated with 7 M methanolic ammonia solution (5 mL) and stirred at room temp for 1 h to hydrolyse any bis-acylated product. The solvent was removed in vacuo and the residue was re-dissolved in DCM and washed with water and brine. The organics were passed through a hydrophobic frit and concentrated in vacuo. Purification by preparative HPLC