Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20](=[O:29])[C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=3)=[CH:10]2)[CH:5]=[CH:4][CH:3]=1.C([Sn](C(C)(C)C)(C(C)(C)C)[C:35]1[O:36][CH:37]=[CH:38][N:39]=1)(C)(C)C.C(#N)C>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[CH3:27])[C:20]([C:11]1[C:12](=[O:19])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:35]3[O:36][CH:37]=[CH:38][N:39]=3)[N:7]=2)[CH:10]=1)=[O:29]
Reactant: CC(C)(C)[Sn](c1ncco1)(C(C)(C)C)C(C)(C)C
Reactant: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(-c4ncco4)n3)c3ccccc3c2=O)cc1C

Procedure:
90 mg (0.2 mmol) of 1-(6-Bromo-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one, 143 mg (0.40 mmol) of 2-tri-t-butylstannyloxazole, 23 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium were dissolved in 2 mL of anhydrous tetrahydrofuran. The resultant mixture was stirred at 75° C. for 18 h. The reaction solution was quenched by pouring into a container having 20 mL of water. The crude product precipitated out of solution and was isolated by filtration. The crude product was purified by flash chromatography to yield 16 mg of 4nn as a colorless solid: LC-MSD, m/z for C27H21N3O3, [M+H]+=436.5, [M+2H]+=437.5; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=2.136 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.35 (d, 6H), 5.62 (s, 2H), 7.06 (d, 1H), 7.19 (d, 1H), 7.35-7.44 (m, 3H), 7.54-7.62 (m, 2H), 7.66 (s, 1H), 7.78 (t, 1H), 7.84 (d, 1H), 8.08 (d, 1H), 8.34 (s, 1H), 8.48 (d, 1H).
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.[C:30]([O:34][C:35]([N:37]1[CH2:44][C@@H:43]([OH:45])[CH2:42][C@H:38]1[C:39](O)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31]>CN(C)C=O>[C:30]([O:34][C:35]([N:37]1[CH2:44][C@H:43]([OH:45])[CH2:42][C@H:38]1[C:39]([NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:40])=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 67.2 %

Procedure:
17.16 g (62.40 mmol) of diphenylphosphoryl azide, 5.70 g (78.08 mmol) of t-butylamine and 10.4 g (104.00 mmol) of triethylamine were added, in that order, to a solution of 12.0 g (51.95 mmol) of (4S)-1-t- butoxycarbonyl-4-hydroxy-L-proline in 100 ml of dimethylformamide, whilst ice-cooling, and the mixture was stirred for 5 hours. At the end of this time, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with a 10% w/v aqueous solution of citric acid, with a 10% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which the mixture was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was recrystallized from ethyl acetate, to give 10.0 g of the title compound as colorless crystals, melting at 192°-193° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[C:11][Si](C)(C)C.[F-].[Cs+]>C(#N)C.O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[CH:11]
Reactant: COC(=O)c1ccccc1C#C[Si](C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CC#N
Product: C#Cc1ccccc1C(=O)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
To a solution of 2-trimethylsilanylethynyl-benzoic acid methyl ester (540 mg, 2.32 mmol) in acetonitrile/water (20 mL/5 mL) is added cesium fluoride (1.41 g, 9.30 mmol). The reaction is stirred at room temperature. After 4 h, the reaction is concentrated and the residue is partitioned between EtOAc (100 mL) and 0.2N HCl (30 mL). The aqueous layer is extracted with EtOAc (100 mL) and the combined organic layers are washed with brine, dried (MgSO4), filtered, and concentrated. The residue is chromatographed eluting with 0 to 5% EtOAc/Hexanes to yield the title compound (358 mg, 96%). GC/MS: 160.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH2:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=2O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:22]([OH:24])[CH3:23]>>[CH2:22]([O:24][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[CH2:12][C:11]1[C:2]([NH2:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:23]
Reactant: COc1cccc(O)c1Cc1cc2ccccc2nc1N
Reactant: CCO
Product: CCOc1cccc(OC)c1Cc1cc2ccccc2nc1N

Procedure:
Synthesis was performed according to EXAMPLE 3 from 2-[(2-aminoquinolin-3-yl)methyl]-3-methoxyphenol and ethanol.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[NH:15][C:16]([C@@H:18]1[NH:22][C@@H:21]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C@:20]2([C:35]3[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=3)[NH:29][C:28]2=[O:37])[C@H:19]1[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=1[F:45])=[O:17])[C:9]([OH:11])=O)[CH2:2][CH2:3][CH3:4].CC[N:48]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:9](=[O:11])[NH2:48])[CH:12]=[CH:13][C:14]=1[NH:15][C:16]([CH:18]1[NH:22][CH:21]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:20]2([C:35]3[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=3)[NH:29][C:28]2=[O:37])[CH:19]1[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=1[F:45])=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOc1cc(C(N)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Temperature: 80 °C
Yield: 89.5 %

Procedure:
To a solution of rac-3-butoxy-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-benzoic acid (0.1 g, 0.15 mmol) prepared in Example 151 in anhydrous DMF (2 mL) were added EDCI (59 mg, 0.31 mmol), HOBt (41 mg, 0.31 mmol), NH4Cl (81 mg, 1.5 mmol), and triethylamine (31 mg, 0.31 mmol) sequentially. The reaction mixture was heated at 80° C. for 1 h. The mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (25-100% EtOAc in hexanes) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-butoxy-4-carbamoyl-phenyl)-amide as a white solid (88 mg, 89%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=1[OH:6].Cl[C:13]1[CH:14]=[CH:15][C:16]([N+:28]([O-:30])=[O:29])=[C:17]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=1>CN(C)C=O>[OH:11][C:9]1[CH:8]=[CH:7][C:5]([O:6][C:13]2[CH:14]=[CH:15][C:16]([N+:28]([O-:30])=[O:29])=[C:17]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH:18]=2)=[C:4]([CH3:3])[CH:10]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1cc(O)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(O)ccc1Oc1ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.8 %

Procedure:
To a suspension of sodium hydride (55 wt. %, 0.87 g) in N,N-dimethylformamide (20 ml) was added methylhydroquinone (1.24 g). The mixture was stirred at ambient temperature for 15 minutes. To this mixture was added t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2.87 g)in small portions and stirred at 120° C. for 2 hours. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane/ethyl acetate=3/1 as the eluant to afford a mixture (2.20 g) of t-butyl N-[5-(4-hydroxy-2-methylphenoxy)-2-nitrophenyl]-N-methylcarbamate and t-butyl N-[5-(4-hydroxy-3-methylphenoxy)-2-nitrophenyl]-N-methylcarbamate. A mixture of a solution of the above product and palladium on carbon (10%, 0.21 g) was vigorously stirred at ambient temperature under hydrogen atmosphere for 2 hours. At the end of this time the catalyst was removed by filtration and the filtrate was concentrated to give the title compound (1.88 g).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[NH:10][N:9]=[C:8]([C:11]([O-:13])=[O:12])[C:7]=1[CH3:14])[CH3:4]>C(O)C.C1COCC1>[CH2:3]([O:5][C:6]1[NH:10][N:9]=[C:8]([C:11]([OH:13])=[O:12])[C:7]=1[CH3:14])[CH3:4]
Reactant: CCOc1[nH]nc(C(=O)[O-])c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1[nH]nc(C(=O)O)c1C
Yield: 62.6 %

Procedure:
2 M solution of sodium hydroxide (98 ml, 197 mmol) was added to a solution of 5-ethoxy-4-methyl-1H-pyrazole-3-carboxylate (7.8 g, 39.4 mmol) in ethanol (70 ml) and THF (30 ml). The reaction mixture was refluxed for 3 h and then the solvents were evaporated and water (200 ml) was added to the residue. It was acidified to pH 1 with conc. HCl and extracted three times with EtOAc. The precipitate formed in the extraction was filtered and washed with EtOAc and the filtrate evaporated to dryness affording 4.2 g (62%) of the title compound. LC-MS: [M+1]=171.17.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([NH:14][CH3:15])[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19].[CH2:20]([NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[CH3:21]>C(#N)C>[CH2:20]([NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][N:26]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:19])[C:6]([C:16]([OH:18])=[O:17])=[CH:7][N:8]3[NH:14][CH3:15])=[CH:3][C:2]=2[F:1])[CH2:25]1)[CH3:21]
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: CCNCC1CCNC1
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(NC)c3c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To 0.75 g (2.75 mmol) of the 6,7,8-trifluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid in 15 ml of acetonitrile was added 0.44 g (1.05 equivalent) of 1,8-diazobicyclo[5.4.0]undec-7-ene, and 0.352 g (1.0 equivalent) of N-ethyl-3-pyrrolidinemethanamine. The mixture was refluxed for one hour and then stirred at room temperature overnight. The solids were filtered to give 0.68 g of 7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid, mp 222°-224° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:2][C:3]2[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:15][CH:14]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cccnc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1COc1ccc(F)cc1
Reaction time: 3 h
Yield: 62.7 %

Procedure:
2-Bromomethyl-3-nitropyridine (100 mg, 0.456 mmol) prepared in Step 2 was added at room temperature to a solution of 4-fluorophenol (56 mg, 0.502 mmol) and potassium carbonate (189 mg, 1.37 mmol) in N,N-dimethylformamide (3 ml) and then stirred for 3 hours. The reaction mixture was diluted with ethyl acetate (10 ml), washed with a saturated sodium bicarbonate solution, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (dichloromethane/n-hexane=2/1, v/v) to give 71 mg of the titled compound as yellow solid.
Reaction SMILES: F[C:2]1[C:9]([I:10])=[CH:8][CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]#[N:5].[SH:15][CH2:16][C:17]([NH2:19])=[O:18].C[O-].[Na+]>CO>[NH2:5][C:4]1[C:3]2[C:6]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:8]=[C:9]([I:10])[C:2]=2[S:15][C:16]=1[C:17]([NH2:19])=[O:18]
Reactant: N#Cc1c(C(F)(F)F)ccc(I)c1F
Reactant: NC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1sc2c(I)ccc(C(F)(F)F)c2c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.1 %

Procedure:
To the above benzonitrile intermediate (140 mg, 0.444 mmol) in 4 mL of MeOH was added 2-mercaptoacetamide (100 mg/mL in MeOH-ammonia solution) (0.49 mL, 0.533 mmol) and 0.5M sodium methoxide in MeOH (1.78 mL, 0.89 mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was concentrated and purified by silica gel chromatography eluting with 2-5% MeOH/CH2Cl2. The product fractions were collected and concentrated to afford 79 mg (46%) of 3-amino-7-iodo-4-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid amide as a yellow crystalline solid.
Reaction SMILES: C(C1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20](O)=[CH:19][N:18]=2)=CC=1)=CCCCCCCCC.N1C=CC=[CH:26][CH:25]=1>ClCCl>[N:22]1([C:21]2[CH:20]=[CH:19][N:18]=[CH:26][CH:25]=2)[CH2:16][CH2:15][CH2:14][CH2:17]1
Reactant: c1ccncc1
Reactant: CCCCCCCCC=Cc1ccc(-c2ncc(O)cn2)cc1
Solvent: ClCCl
Product: c1cc(N2CCCC2)ccn1

Procedure:
A reactor was charged with 1.0g (2.67 mmol) of the 2-{4-(1-decenyl)-phenyl}-5-hydroxypyrimidine obtained above, 2 ml of pyridine, 0.01 g of 4-pyrrolidinopyridine and 20 ml of dichloromethane. While cooling the mixture to a temperature not higher than 0° C. in an atmosphere of nitrogen gas, 1.13 g (4 mmol) of trifluoromethanesulfonic acid anhydride was dropwise added and stirred for two hours. After extraction with water, the organic layer was washed successively with 1 N-hydrochloric acid and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent, purification of the residue by silica gel column chromatography gave 1.06 g (yield 90%) of 2-{4-(1-decenyl)-phenyl}-5-trifluoromethylsulfonyloxypyrimidine.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[CH:8]1(C=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Cl>N1C=CC=CC=1.N1CCCCC1>[CH:8]1([CH:1]=[CH:2][C:3]([OH:5])=[O:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(O)CC(=O)O
Reactant: O=CC1CCCCC1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=CC1CCCCC1
Yield: 107.4 %

Procedure:
3.34 g (32.1 mmol) of malonic acid are dissolved in pyridine (10 ml), after the weakly exothermic reaction has subsided 3.0 g (26.7 mmol) of cyclohexanecarbaldehyde and 0.23 g (2.7 mmol) of piperidine are added, and the reaction mixture is heated to reflux for 4 h. The cooled reaction solution is added to a mixture of ice and concentrated hydrochloric acid, the aqueous phase is extracted three times with diethyl ether, the combined organic phases are dried over sodium sulfate, filtered, and the solvent is removed in vacuo. 4.42 g of product are obtained, which is reacted further without purification.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.C1C(=O)N([Cl:17])C(=O)C1>CC#N>[Cl:17][C:7]1[C:3]([C:2]([F:9])([F:8])[F:1])=[N:4][NH:5][CH:6]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: FC(F)(F)c1n[nH]cc1Cl
Temperature: 80 °C
Yield: 76.8 %

Procedure:
A mixture of 3-(trifluoromethyl)pyrazole (1.58 g, 11.6 mmol) and NCS (1.55 g, 11.6 mmol) in CH3CN (20 mL) was heated at 80° C. for 3 hrs. It was then cooled to rt, evaporated in vacuo, and purified by flash chromatography (SiO2) with a gradient elution of 0 to 15% EtOAc/CH2Cl2 to afford 4-chloro-3-(trifluoromethyl)pyrazole (1.52 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].[Cl:13]N1C(=O)CCC1=O>>[Cl:13][C:5]1[C:6]([C:9]([F:10])([F:11])[F:12])=[CH:7][CH:8]=[C:2]([Cl:1])[C:3]=1[NH2:4]
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Product: Nc1c(Cl)ccc(C(F)(F)F)c1Cl

Procedure:
This material was prepared by chlorination of 2-chloro-5-trifluoromethylaniline with N-chlorosuccinimide followed by chromatographic purification. The product was isolated as a yellow oil which was characterized by IR and 1H NMR spectroscopy and combustion analysis.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:35]([O:37]CC)=[O:36])=[C:21]([CH2:23][N:24]3[C:32](=[O:33])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]3=[O:34])[N:22]=2)[CH2:14][CH2:13]1)=[O:10].[Li+].[OH-:41]>C1COCC1.O>[C:32]([C:31]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:25]([NH:24][CH2:23][C:21]1[N:22]=[C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[CH2:13][CH2:14]2)[S:19][C:20]=1[C:35]([OH:37])=[O:36])=[O:34])([OH:41])=[O:33]
Reactant: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1CN1C(=O)c2ccccc2C1=O
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1[nH]c(C(=O)NC2CCN(c3nc(CNC(=O)c4ccccc4C(=O)O)c(C(=O)O)s3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1,3-thiazole-5-carboxylate (Example 277; 194 mg, 0.32 mmol) in anhydrous THF (2 ml) was added 2 N LiOH (0.82 ml). The mixture was stirred at room temperature for 4 h. The mixture was acidified to pH 3 and the precipitate that formed was diluted with water and extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to give the title compound (160 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:16][C:15]3=[CH:17][NH:18][C:13]4[C:14]3=[C:9]([CH:10]=[CH:11][N:12]=4)[C:8]2=[O:19])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:27]([CH2:29][C:30](ON1C(=O)CCC1=O)=[O:31])#[N:28]>CCO>[O:31]=[C:30]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH2:16][C:15]3=[CH:17][NH:18][C:13]4[C:14]3=[C:9]([CH:10]=[CH:11][N:12]=4)[C:8]2=[O:19])[CH2:5][CH2:6]1)[CH2:29][C:27]#[N:28]
Reactant: O=C1c2ccnc3[nH]cc(c23)CN1C1CCNCC1
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#CCC(=O)N1CCC(N2Cc3c[nH]c4nccc(c34)C2=O)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 23.3 %

Procedure:
4-(Piperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one (34 mg, 0.133 mmol) and triethylamine (0.055 mL, 0.398 mmol) were dissolved in EtOH (4 mL) and cooled to 0° C. and allowed to stir for 10 min. Then 2,5-dioxopyrrolidin-1-yl 2-cyanoacetate (29 mg, 0.159 mmol) dissolved in EtOH (1 mL) was added dropwise and the mixture was allowed to stir for 30 min at 0° C. The solution was concentrated in vacuo and purified via preparative HPLC eluting with 10% to 40% B in A and gave 10 mg of the title compound as its TFA salt. 1H NMR (400 MHz, CD3OD) δ 7.60 (m, 1H), 7.43 (m, 1H), 4.98 (s, 2H), 4.84-4.88 (m, 1H), 4.68-4.72 (m, 1H), 3.89-3.95 (m, 3H), 3.33 (m, 1H), 2.80-2.88 (m, 1H), 1.86-2.05 (m, 4H). [M+H] found 324.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[O:14]1[C:22]2[CH2:21][CH2:20][NH:19][CH2:18][C:17]=2[CH:16]=[CH:15]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[O:14][CH:15]=[CH:16][C:17]=4[CH2:18]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: c1cc2c(o1)CCNC2
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2occc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4,5,6,7-tetrahydro-furo[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[C:4]([CH2:8][O:9][CH3:10])[S:5][C:6]=1[CH3:7].[CH2:12]([O:14]CC)C.C([Li])CCC>CN(C)C=O>[CH3:7][C:6]1[S:5][C:4]([CH2:8][O:9][CH3:10])=[C:3]([CH3:11])[C:2]=1[CH:12]=[O:14]
Reactant: COCc1sc(C)c(Br)c1C
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: COCc1sc(C)c(C=O)c1C
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
15.5 G. of 4-bromo-3,5-dimethyl-2-methoxymethylthiophene was dissolved in 200 ml. of anhydrous ethyl ether under argon. The resulting solution was cooled to -70° C. and 22 ml. of a 2.4 M solution of n-butyl lithium was slowly added. The reaction mixture was warmed to -30° C. for 10 minutes and then cooled to -70° C. 7.3 G. of dimethylformamide was slowly added and the reaction was warmed to room temperature for 14 hours. The resulting reaction mixture was poured into ice water, stirred for 15 minutes and extracted with ethyl ether. The combined ether extracts were washed with a solution of 5% sodium carbonate, a saturated solution of sodium chloride, dried over sodium sulfate, filtered and evaporated to yield 2,4-dimethyl-5-methoxymethylthiophene-3-carboxaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:48]([N+:52]1[N:56]=[C:55]([CH3:57])[S:54][C:53]=1[CH3:58])[CH2:49][CH2:50][CH3:51]>>[CH2:48]([N:52]1[N:56]=[C:55]([CH3:57])[S:54]/[C:53]/1=[CH:58]\[C:6]([C:5]1[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:8])[CH2:49][CH2:50][CH3:51]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: COc1cc(OC)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3,5-dimethoxybenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.87-0.97 (m, 3 H) 1.28-1.37 (m, 2 H) 1.71-1.80 (m, 2 H) 2.46-2.48 (m, 3 H) 3.77-3.83 (m, 6 H) 4.23 (t, 2 H) 6.60-6.68 (m, 2 H) 7.10-7.14 (m, 2 H); MS (ESI) m/z 335 (M+H)+.
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([NH:19]C(OCC)=O)[CH2:15][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[C:1]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([NH2:19])[CH2:15][CH2:14]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)NN1CCN(CCCCC(=O)c2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NN1CCN(CCCCC(=O)c2ccccc2)CC1
Yield: 114.8 %

Procedure:
30.0 g of 4-(4-benzoylbutyl)-1-(ethoxycarbonylamino)piperazine was dissolved in 250 ml of ethanol, and a solution of 50.5 g of potassium hydroxide in 50 ml of water was added. The mixture was heated under reflux for 3 hours. Ethanol was evaporated, and water was added. Extraction with chloroform gave 27.0 g of the title compound. The hydrochloride of this product had a melting point of 213° to 215° C. (decomp.).