Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:23])[CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([O-:16])=O)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[N+:46]([C:49]1[CH:54]=[CH:53][C:52]([C@@H:55]([NH2:57])[CH3:56])=[CH:51][CH:50]=1)([O-:48])=[O:47]>CN(C=O)C>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:23])[CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([NH:57][CH:55]([C:52]2[CH:51]=[CH:50][C:49]([N+:46]([O-:48])=[O:47])=[CH:54][CH:53]=2)[CH3:56])=[O:16])=[CH:9][CH:10]=1)(=[NH:4])[NH2:3]
Reactant: N=C(N)c1ccc(NC(=O)C(C(=O)[O-])c2ccccc2)cc1
Reactant: C[C@H](N)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(NC(=O)C(C(=O)Nc1ccc(C(=N)N)cc1)c1ccccc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
75 mg (0.235 mmol) of the sodium salt from example 2 were dissolved in 2.5 ml DMF. 85 mg (0.265 mmol) TOTU in 2.5 ml DMF were added and stirred for 30 min at rt. Then 34 μl (0.265 mmol) NEM and 53.7 mg (0.265 mmol) of (S)-1-(4-nitrophenyl)-ethylamine in 0.5 ml of DMF was added and the mixture stirred at rt overnight. After filtration, the filtrate was evaporated to dryness and purified by prep. RP-HPLC.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23]C2C=CC=C(Cl)C=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[Cl:55][C:56]1[CH:63]=[CH:62][C:59](C[Zn+])=[CH:58][CH:57]=1>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][C:59]2[CH:62]=[CH:63][C:56]([Cl:55])=[CH:57][CH:58]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(C[Zn+])cc1
Reactant: Clc1cccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Agent: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: [Cl-]
Product: Clc1ccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Yield: 95 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-[(3-chlorophenyl)methyl]pyridazine (Intermediate 48) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and (4-chlorobenzyl)zinc(II) chloride in 95% yield.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12].C(=O)(O)[O-].[K+].S(O[CH:27]([C:41]#[N:42])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:29]=1)(=O)(=O)C>O1CCCC1.CN(C)C=O.CCOCC>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]=[C:2]1[CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([O:13][CH:27]([C:41]#[N:42])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:29]=1)=[O:12]
Reactant: CS(=O)(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C(=O)O)C1=Cc2ccccc2C1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)C1=Cc2ccccc2C1

Procedure:
A mixture of 2-(2-indenyl)-3-methylbutanoic acid (3.4 mmol), potassium bicarbonate (3.4 mmol) in 10 ml of tetrahydrofuran/dimethylformamide (1/1) is stirred for a few minutes and then α-cyano-m-phenoxybenzyl mesylate (3.4 mmol) in 5 ml of tetrahydrofuran/dimethylformamide (1/1) is added. The reaction is worked up by diluting with ether, washing with water and sat. NaCl, drying and evaporating under vacuum to remove solvent to yield α-cyano-m-phenoxybenzyl 2-(2-indenyl)-3-methylbutanoate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]#N)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.C(O)=[O:27]>O=[Pt]=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[O:27])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: O=CO
Reactant: Cc1cc(C#N)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: O=[Pt]=O
Product: Cc1cc(C=O)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 60 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
7-Methyl-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carbonitrile (400.0 mg, 1.16 mmol) and PtO2 (26.0 mg, 0.115 mmol) were added to formic acid (2 mL) and the mixture was heated at 60° C. for three hours. The NMR spectrum showed 40% conversion, so PtO2 (50.0 mg) was added to the mixture and it was allowed to stir at 60° C. overnight. After cooling, the mixture was filtered through Celite® and concentrated. Column chromatography (30% EtOAc/Hexanes) provided the title compound as a white solid (357.5 mg, 88%). 1H NMR (300 MHz, CDCl3): δ 10.08 (s, 1H), 7.71 (s, 2H), 7.35 (d, 3H), 7.19 (d, 3H), 4.80 (s, 2H), 4.32 (s, 2H), 2.83 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][NH:7][C:8]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(=[O:4])=[O:3].[O:23]1[C:27](=O)[CH2:26][NH:25]C1=O.Cl.N>C(Cl)Cl>[CH3:1][S:2]([CH2:5][CH2:6][N:7]1[C:8]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=2[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:25][CH2:26][C:27]1=[O:23])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)CCNc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C1CNC(=O)O1
Agent: Cl
Agent: N
Solvent: ClCCl
Product: CS(=O)(=O)CCN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C

Procedure:
To a solution of 0.5 g of 2-(β-methylsulfonylethyl)amino- 5-chlorobenzophenone in 20 ml of dry methylene chloride is added 0.5 g of oxazolidine-2,5-dione. To the mixture is added 20 ml of ethereal hydrogen chloride under cooling. The mixture is stirred at room temperature. After completion of the reaction, the mixture is poured into ice water, basified with aqueous ammonia and extracted with methylene chloride. The extracts are combined and dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure. The residue is added with isopropyl alcohol to form crystals. Recrystallization from acetone gives 1-(β-methylsulfonylethyl)-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one as colorless leaflets, m.p. 218° - 219° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[C:13]3[C:18]4=[C:19]([CH2:21][CH2:22][N:17]4[C:16](=[O:23])[CH2:15][CH2:14]3)[CH:20]=2)=[O:10])[CH2:3][CH2:2]1.[CH2:24]([Cl:33])[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]>>[ClH:33].[O:26]=[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24][N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[C:13]3[C:18]4=[C:19]([CH2:21][CH2:22][N:17]4[C:16](=[O:23])[CH2:15][CH2:14]3)[CH:20]=2)=[O:10])[CH2:5][CH2:6]1
Reactant: O=C(CCl)c1ccccc1
Reactant: O=C(CCC1CCNCC1)c1cc2c3c(c1)CCN3C(=O)CC2
Product: Cl
Product: O=C(CCC1CCN(CC(=O)c2ccccc2)CC1)c1cc2c3c(c1)CCN3C(=O)CC2
Yield: 40.3 %

Procedure:
Using 8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (500 mg) and phenacyl chloride (248 mg) according to the same method as that of Example 81, the title compound (301 mg) was obtained as colorless crystals having a melting point of 114 to 116° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C@H:13]3[CH2:17][CH2:16][O:15][CH2:14]3)[N:11]=[CH:10][C:9]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([N+:23]([O-:25])=[O:24])[CH:3]=1.[N+](C1C=C(B2OC(C)(C)C(C)(C)O2)C=CC=1C1N([C@H]2CCOC2)N=CC=1C(OCC)=O)([O-])=O.I[C:60]1[C:65]([CH3:66])=[CH:64][N:63]=[C:62]([O:67][CH:68]([CH3:70])[CH3:69])[C:61]=1[CH3:71].O>CN(C=O)C>[CH:68]([O:67][C:62]1[C:61]([CH3:71])=[C:60]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:12]([C@H:13]4[CH2:17][CH2:16][O:15][CH2:14]4)[N:11]=[CH:10][C:9]=3[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([N+:23]([O-:25])=[O:24])[CH:3]=2)[C:65]([CH3:66])=[CH:64][N:63]=1)([CH3:70])[CH3:69]
Reactant: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(Br)cc1[N+](=O)[O-]
Reactant: Cc1cnc(OC(C)C)c(C)c1I
Agent: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(-c2c(C)cnc(OC(C)C)c2C)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Ethyl 5-(4-bromo-2-nitrophenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate obtained in Preparation Example 7-(1) (200 mg) was converted to ethyl 5-[2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate by the same method as in Preparation Example 7-(2). A solution of 4-iodo-2-isopropyloxy-3,5-dimethylpyridine obtained in Preparation Example 47 (142 mg) in DMF (0.5 mL), and water (0.5 mL) were added to the reaction mixture, and the mixture was stirred at 110° C. for two hours. The reaction mixture was cooled to room temperature and then partitioned by adding ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 50% to 100%) to give the title compound (138.1 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)#[N:2].C(OC([N:19]1[CH2:24][CH2:23][O:22][C@H:21]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:20]1)=O)(C)(C)C>>[ClH:32].[Cl:32][C:27]1[CH:26]=[C:25]([C@H:21]2[O:22][CH2:23][CH2:24][NH:19][CH2:20]2)[CH:30]=[CH:29][C:28]=1[NH:31][C:9](=[O:11])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N)c(Cl)c2)C1
Product: Cl
Product: N#Cc1ccc(C(=O)Nc2ccc([C@@H]3CNCCO3)cc2Cl)nc1

Procedure:
In analogy to example 79, step a) using 5-cyano-2-pyridinecarboxylic acid (CAS 53234-55-2) instead of 4-cyanopicolinic acid (CAS 640296-19-1) and (+)-(R)-2-(4-Amino-3-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (example 29a) instead of (−)-(S)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester. White solid. MS (ISP): 341.1 ([M+H]+)
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)[F:20])(=O)=O.ClC1C=[N+](F)C=C(Cl)C=1>ClCCl>[F:20][C:10]1[CH:9]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][C:11]=1[OH:14]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[n+]1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Product: Oc1ccc(Oc2ccccc2)cc1F
Yield: 14.3 %

Procedure:
To a 250 ml dichloromethane solution of 4-phenoxyphenol (2 g, 10.7 mmol) was added 3,5-dichloro-1-fluoro-pyridinium triflate (4.14 g, 13.1 mmol). After heating to reflux for 1 hr, the solvent was removed, the crude product was diluted with AcOEt and sat. bicarb. solution. The organic layer was separated, dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel. Elution with 10% methy t-butyl ether/hexanes gave 312 mg of the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1CCCC1.C(O[CH:23]=[C:24]([C:27]#[N:28])[C:25]#[N:26])C.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1.O1CCOCC1>[NH2:26][C:25]1[C:24]([C:27]#[N:28])=[CH:23][C:12]2[CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10][C:11]=2[N:15]=1
Reactant: CCOC=C(C#N)C#N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C1CCNC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: N#Cc1cc2c(nc1N)CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
A solution of 1-benzyl-4-piperidone (26.8 g, 0.14 mole) and pyrrolidine (20 g, 0.28 mole) in toluene (300 ml) is refluxed for 4 hours with distilling off water. The reaction solution is concentrated to dryness under reduced pressure, and to the residue is added anhydrous dioxane (300 ml). To the mixture is added dropwise gradually with stirring a solution of ethoxymethylenemalononitrile (19 g, 0.16 mole) in anhydrous dioxane (40 ml) under ice-cooling. The mixture is warmed to room temperature, and stirred for one hour. To the mixture is added ammonium acetate (22 g, 0.29 mole), and the mixture is stirred at 70° C. overnight, and concentrated to dryness under reduced pressure. To the residue is added isopropanol, and the precipitate crystals are collected by filtration, washed with water, and dried to give 2-amino-6-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carbonitrile (18.3 g, yield; 49%), which is used in the subsequent reaction without purification.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][CH2:12]Br)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1.CCOCC>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][CH2:12][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: BrCCCc1ccc2c(c1)CCC2
Reactant: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: c1cc2c(cc1CCCN1CCCCC1)CCC2

Procedure:
The crude 3-(5-Indanyl)-1-bromopropane (13.0 g, 0.054 M) is dissolved in 200 ml toluene and treated with 50 g of piperidine. The mixture is heated under reflux overnight, then cooled and diluted with ether to precipitate salts. The salts are removed by filtration and the solvent removed from the filtrate in vacuo. The residue is distilled collecting 8.4 g (64%) of desired product boiling at 135°-140° (0.15 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[N:9][N:8]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1.C(=O)([O-])O.[Na+]>C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[N+:9]([O-:34])[N:8]=2)=[CH:24][CH:25]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: [O-][n+]1nc(Nc2ccc(Cl)cc2)c2ccccc2c1Cc1ccncc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.53 g (4.41 mmol) 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine (see Example 4), 1.74 g (about 5.75 mmol) 3-chloroperbenzoic acid (about 57%), and 80 ml acetate is stirred for 1 h at RT. Then 25 ml 1 N aqueous sodium hydrogencarbonate solution is added to the reaction mixture, which is stirred for 10 min, filtered, washed with water, then acetate, and the filter residue purified by means of flash chromatography on silica gel with particle size 0.04-0.06 mm, using an acetate/methanol mixture (19:1). Title compound is obtained after evaporation of the product-containing fractions under vacuum and recrystallization of the filter residue from methanol; m.p. 226-228° C.; ESI-MS: (M+H)+=363.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11](C(O)=O)[C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[C:44]([O:48][C:49]([N:51]1[CH2:56][CH2:55][CH:54]([C:57]2[CH:62]=[CH:61][C:60]([NH2:63])=[CH:59][CH:58]=2)[CH2:53][CH2:52]1)=[O:50])([CH3:47])([CH3:46])[CH3:45].C(N(C(C)C)CC)(C)C.[CH3:73][OH:74]>C(Cl)Cl>[C:44]([O:48][C:49]([N:51]1[CH2:56][CH2:55][CH:54]([C:57]2[CH:62]=[CH:61][C:60]([NH:63][C:73]([C:10]3([C:16]([F:17])([F:18])[F:19])[CH:11]=[CH:12][N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[NH:9]3)=[O:74])=[CH:59][CH:58]=2)[CH2:53][CH2:52]1)=[O:50])([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cn(-c2ccccc2Cl)nc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: CO
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)C3(C(F)(F)F)C=CN(c4ccccc4Cl)N3)cc2)CC1
Reaction time: 0.17 h

Procedure:
To 1-(2-chloro-phenyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid described above (320 mg, 1.10 mmol) in methylene chloride (10 mL) was added bromotrispyrrolidinophosphonium hexafluorophosphate (770 mg, 1.65 mmol). The reaction was stirred for 10 minutes and then 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (320 mg, 1.10 mmol) followed by diisopropylethylamine (0.60 mL, 3.30 mmol) were added. The reaction was stirred at room temperature overnight. The crude mixture was diluted in methanol (100 mL), loaded onto silica gel and purified using Isco chromatography (eluting with ethyl acetate and hexanes) to give 4-(4-{[1-(2-chloro-phenyl)-3-trifluoromethyl-1H-pyrazole-carbonyl]-amino}-phenyl)-piperidine-1-carboxylic acid tert-butyl ester. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11]([O:16]CC)(=S)[C:12]([NH2:14])=O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[NH:9][C:11](=[O:16])[C:12]([NH2:14])=[N:10]2
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CCOC(=S)C(N)=O
Solvent: CCO
Product: Nc1nc2cc(Cl)c(Cl)cc2[nH]c1=O
Temperature: 25 °C
Yield: 20 %

Procedure:
An adaptation of the method of Burrell et al., J. Chem. Soc. Perkin I. 2707 (1973), was used. A mixture of 4,5-dichloro-1,2-phenylenediamine (354 mg, 2.00 mmol; Aldrich Co.) and ethyl thiooxamate (333 mg, 2.50 mmol; Aldrich Co.) in 5 mL of ethanol was heated to reflux. The resulting brown solution was stirred under reflux for 10 h. The resulting brown suspension was cooled down to 25° C. A brown precipitate appeared. The mixture was vacuum filtered and the brown solid was washed with EtOH (5×2 mL) and dried in vacuum at 60° C. overnight to yield 92 mg (20%) of 6,7-dichloro-3-aminoquinoxalin-2(1H)-one: mp dec.>350° C. 1H NMR (300 MHz, DMSO-d6) δ 12.261 (br s, 1H, NH), 7.421 (s, 1H, H-5), 7.252 (s, 1H, H-8). Mass: calcd. for C8H5Cl2N3O (M+) M/z 228.9810, found 228.9820.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][C:18]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=4)=[CH:19][C:14]=3[CH:13]=[C:12]([C:30]([O:32]C)=[O:31])[CH2:11][CH2:10]2)[CH:5]=[N:4]1)[CH3:2].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][C:18]([C:20]4[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=4)=[CH:19][C:14]=3[CH:13]=[C:12]([C:30]([OH:32])=[O:31])[CH2:11][CH2:10]2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cnn(CC)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cnn(CC)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.1 %

Procedure:
To a solution of methyl 1-[(1-ethylpyrazol-4-yl)methyl]-7-(4-propoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (370 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 1 day. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to neutral, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give 1-[(1-ethylpyrazol-4-yl)methyl]-7-(4-propoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (330 mg) as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:16]=[C:17]([C:25]([OH:27])=[O:26])[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO.CCOCC>[OH:14][C:11]1([C:15]2[CH:16]=[C:17]([C:25]([O:27][CH3:28])=[O:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(C(=O)O)c3ccccc3c2)CC1
Solvent: CCOCC
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc2ccccc12

Procedure:
To a solution of 1.3 g (3.5 mmol) of the above 3-[1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl]-1-naphthoic acid in 10 mL of methanol and 10 mL of ether was added 2.0 mL (4.0 mmol) of a 2.0 M solution of (trimethylsilyl)diazomethane in ether. Glacial acetic acid was the added dropwise until gas evolution ceased and then the reaction was concentrated in vacuo to yield the crude title compound as a yellow oil. LC/MS 408.1 (M+23).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH:11]=3)[C:5]=2[N:6]=1.[C:22]1([CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH2:30]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:29][CH2:30][S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:11]=4)[C:5]=3[N:6]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ICCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1ccc2c(c1)CCc1sc(S)nc1-2
Product: O=C(O)COc1ccc2c(c1)CCc1sc(SCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 54 %

Procedure:
Using ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-7-yl)oxy]acetate and 3,3-diphenylpropyl iodide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 54%.
Reaction SMILES: BrC1C2C(Cl)=NC=NC=2[N:4](C(C)C)C=1.CON(C)C(C1C=C(Cl)C=CN=1)=O.[NH2:28][C:29]1[C:30]2[C:37]([C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[C:42](N)[N:41]=3)=[O:39])=[CH:36][N:35]([CH:47]([CH3:49])[CH3:48])[C:31]=2[N:32]=[CH:33][N:34]=1>>[NH2:28][C:29]1[C:30]2[C:37]([C:38]([C:40]3[CH:45]=[C:44]([NH2:4])[CH:43]=[CH:42][N:41]=3)=[O:39])=[CH:36][N:35]([CH:47]([CH3:49])[CH3:48])[C:31]=2[N:32]=[CH:33][N:34]=1
Reactant: CC(C)n1cc(Br)c2c(Cl)ncnc21
Reactant: CC(C)n1cc(C(=O)c2cccc(N)n2)c2c(N)ncnc21
Agent: CON(C)C(=O)c1cc(Cl)ccn1
Product: CC(C)n1cc(C(=O)c2cc(N)ccn2)c2c(N)ncnc21

Procedure:
The title compound was prepared from 5-Bromo4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (6.5 g, 23.7 mmol) and 4-Chloro-pyridine-2-carboxylic acid methoxy-methyl-amide (5.7 g, 28.5 mmol) by procedures analogous to those described for the preparation (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(6-amino-pyridin-2-yl)-methanone. MS:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16][C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:9][CH2:8]2)[CH:2]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:40]=[C:39]([CH3:41])[C:38]([S:42]([N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH:46]2[CH2:51][CH2:52][CH2:53][S:54](Cl)(=[O:56])=[O:55])(=[O:44])=[O:43])=[C:37]([CH3:58])[CH:36]=1>C(Cl)Cl>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH3:58])[C:38]([S:42]([N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH:46]2[CH2:51][CH2:52][CH2:53][S:54]([N:13]2[CH2:12][CH2:11][C:10]3([CH2:9][CH2:8][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)([O:18][CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)[CH2:15][CH2:14]2)(=[O:55])=[O:56])(=[O:44])=[O:43])=[C:39]([CH3:41])[CH:40]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCS(=O)(=O)Cl)c(C)c1
Reactant: c1cncc(C2(OCCN3CCCC3)CCC3(CCNCC3)CC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCS(=O)(=O)N2CCC3(CC2)CCC(OCCN2CCCC2)(c2cccnc2)CC3)c(C)c1
Reaction time: 1 h
Yield: 47 %

Procedure:
9-(Pyridin-3-yl)-9-(2-(pyrrolidin-1-yl)ethoxy)-3-azaspiro[5.5]undecane (0.26 mmol, 1 eq) was dissolved in methylene chloride (3 ml) at 0° C., triethylamine (1.04 mmol, 4 eq) was added, and 3-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)propane-1-sulfonyl chloride (0.26 mmol, 1 eq), dissolved in methylene chloride (2 ml) was added to the mixture. After 1 h at room temperature, the mixture was diluted with methylene chloride (20 ml). The organic phase was washed with water (10 ml) and saturated sodium chloride solution (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (1-5% methanol in methylene chloride). Yield: 47%. MS, Rt=3.6 min, m/z=731.5 [MH]+.