Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][P:2]([O-:9])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:10][C:11]([O:13][CH:14]([C:17]#[N:18])[CH:15]=[CH2:16])=[O:12]>>[C:11]([O:13][CH:14]([C:17]#[N:18])[CH2:15][CH2:16][P:2]([CH3:1])(=[O:9])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:12])[CH3:10]
Reactant: C=CC(C#N)OC(C)=O
Reactant: CCCCCOP(C)[O-]
Product: CCCCCOP(C)(=O)CCC(C#N)OC(C)=O
Reaction time: 0.08 h
Yield: 101.1 %

Procedure:
242.0 g of n-pentyl methanephosphonite are heated to 80° C. under nitrogen, and 0.5 g of tert.-butyl perpivalate is added. 63.9 g of acrolein cyanohydrin acetate mixed with 2.5 g of tert.-butyl perpivalate are added dropwise to this solution within 2.25 hours. After reaction is complete, the mixture is stirred for 5 minutes, and 161.5 g of n-pentyl methanephosphonite are distilled out. (Purity: 91.2%, recovery: 93.4%). 142.1 g of n-pentyl (3-acetoxy-3-cyanopropyl)methylphosphinate (purity 94%; yield 97%) remain.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]3[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([CH2:23][CH2:24][CH2:25]OS(C)(=O)=O)[C:15]([C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)=[C:12]32)=[CH:7][C:6]=1[O:36][CH3:37])([CH3:3])[CH3:2].[C:38]([NH2:42])([CH3:41])([CH3:40])[CH3:39].O>CN1CCCC1=O>[C:38]([NH:42][CH2:25][CH2:24][CH2:23][C:16]1[C:15]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)=[C:12]2[C:13]3[C:8](=[CH:7][C:6]([O:36][CH3:37])=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:14]=3)[CH2:9][CH2:10][N:11]2[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:41])([CH3:40])[CH3:39]
Reactant: CCOC(=O)c1c(CCCOS(C)(=O)=O)c(-c2cccs2)c2n1CCc1cc(OC)c(OC(C)C)cc1-2
Reactant: CC(C)(C)N
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1c(CCCNC(C)(C)C)c(-c2cccs2)c2n1CCc1cc(OC)c(OC(C)C)cc1-2
Yield: 87 %

Procedure:
A solution of 30 mg of 6c and 20 mg of tert-butyl amine in 1 ml of N-methylpyrolidone was heated in a microwave oven at 120° C. for 30 min. The reaction mixture was cooled, poured into 5 ml of water and extracted with ethyl acetate. The product was purified by chromatography over silica gel, using a gradient of CH2Cl2/methanol as eluent, to provide 25 mg of 6d;
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][S:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][C:23]([OH:25])=O)[CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl:26]CCl>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][S:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][C:23]([Cl:26])=[O:25])[CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C=Cc1cccc(S(=O)(=O)NCc2ccc3c(c2)OCO3)c1
Reactant: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1cccc(S(=O)(=O)NCc2ccc3c(c2)OCO3)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a suspension of 3-{3-[(benzo[1,3]dioxol-5-ylmethyl)-sulfamoyl]-phenyl}-acrylic acid (0.39 g, 1.08 mmol) in dichloromethane (4 ml) oxalyl chloride (0.28 ml, 3.24 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.41 g, quant.).
Reaction SMILES: [CH3:1][S:2]([C:5]1([C:9]([O:11]C)=[O:10])[CH2:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].O.[OH-].[Li+:15]>O1CCOCC1.O>[CH3:1][S:2]([C:5]1([C:9]([O-:11])=[O:10])[CH2:8][CH2:7][CH2:6]1)(=[O:3])=[O:4].[Li+:15]
Reactant: COC(=O)C1(S(C)(=O)=O)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)C1(C(=O)[O-])CCC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 1-methylsulfonylcyclobutanecarboxlate (0.10 g, 0.52 mmol) in 2 mL of dioxane and 2 mL of water was added lithium hydroxide monohydrate (44 mg, 1.0 mmol). After stirring at 100° C. for 1 h, the reaction mixture was concentrated to dryness, and the residue was azeotroped with toluene to give the crude lithium 1-methylsulfonylcyclobutanecarboxylate, which was used without further purification. Thus, the crude lithium salt was suspended in 2 mL of anhydrous dimethylformamide, and was added N-(2S,3S)-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-amine hydrochloride (0.15 g, 0.52 mmol), tris(pyrrolindinyl)phosphonium hexafluorophosphate (0.41 g, 0.78 mmol) and N-methylmorpholine (0.23 mL, 2.1 mmol). After stirring at room temperature overnight, the reaction mixture was partitioned between water (20 mL) and ether (20 mL). The organic layer was separated, and the aqueous layer was extracted with ether (20 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness, and the residue was purified by flash chromatography on silica gel eluting with 20 to 40% ethyl acetate in hexane to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.57 (m, 1H), 7.49 (s, 1H), 7.43 (m, 2H), 7.10 (d, 2H), 6.92 (d, 2H), 4.38 (m, 1H), 3.35-2.63 (m, 7H), 2.93 (s, 3H), 2.14 (m, 1H), 1.98 (m, 1H), 0.98 (d, 3H). LC-MS: m/e 445 (M+H)+ (3.5 min).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[O:6][C:5]([C:8]2[CH:9]=[C:10]([S:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=3)[CH:11]=[CH:12][CH:13]=2)([CH3:7])[CH2:4][O:3]1.Cl.[NH2:26][OH:27]>>[CH3:1][C:2]1([CH3:24])[O:6][C:5]([C:8]2[CH:9]=[C:10]([S:14][C:15]3[CH:20]=[CH:19][C:18](/[C:21](=[N:26]/[OH:27])/[CH3:22])=[CH:17][CH:16]=3)[CH:11]=[CH:12][CH:13]=2)([CH3:7])[CH2:4][O:3]1
Reactant: CC(=O)c1ccc(Sc2cccc(C3(C)COC(C)(C)O3)c2)cc1
Reactant: NO
Agent: Cl
Product: C/C(=N\O)c1ccc(Sc2cccc(C3(C)COC(C)(C)O3)c2)cc1
Yield: 51 %

Procedure:
Using an analogous procedure to that described in Example 68, 4'-[3-(2,2,4-trimethyl-1,3-dioxolan-4-yl)phenylthio]acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-[3-(2,2,4-trimethyl-1,3-dioxolan-4-yl)phenylthio]acetophenone oxime in 51% yield as a gum.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[Cl-].[C:11]1([S:17]([NH:20][CH:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][NH3+:23])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[C:27]([O:26][C:24](=[O:25])[CH:21]([NH:20][S:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])=[O:18])[CH2:22][NH:23][C:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9])([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(O)c1ccc(Br)s1
Reactant: CC(C)(C)OC(=O)C(C[NH3+])NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)C(CNC(=O)c1ccc(Br)s1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.1 %

Procedure:
A mixture of 5-bromothiophene-2-carboxylic acid (3.1 g, 15 mmol), 2-benzenesulfonylamino-2-tert-butoxycarbonyl-ethyl-ammonium chloride (4.58 g, 13.6 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.87 g, 15 mmol), 1-hydroxybenzotriazole (2.01 g, 15 mmol) and 4-methylmorpholine (3 mL, 27.3 mmol) in dry dimethylformamide (DMF, 36 mL) was stirred at room temperature for 16 h. The DMF was removed and the mixture was dissolved in ethyl acetate (400 mL), washed with water (25 mL), saturated NaCl solution (25 mL), 5% KHSO4 (25 mL), saturated NaCl solution (25 mL) and saturated NaHCO3-saturated NaCl mixture (1:1) (25 mL), dried and evaporated. The crude was passed through a column of silica gel with CH2Cl2-acetone (95:5 and 90:10) as eluents yielding 6 g of compound A-1(90% yield).
Reaction SMILES: S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[NH2:10][C:11]1[C:19]([C:20](=[O:23])[NH:21][CH3:22])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O.O>CC(N(C)C)=O>[CH3:22][N:21]1[C:20](=[O:23])[C:19]2[C:11](=[C:12]([C:13]([OH:15])=[O:14])[CH:16]=[CH:17][CH:18]=2)[N:10]=[C:29]1[C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([C:25]([F:24])([F:34])[F:35])[CH:27]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CNC(=O)c1cccc(C(=O)O)c1N
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc2c(C(=O)O)cccc2c1=O
Temperature: 100 °C
Reaction time: 21 h
Yield: 85.9 %

Procedure:
Sodium metabisulfite (3.56 g, 18.7 mmol) was added to a solution of 2-amino-3-(methylcarbamoyl)benzoic acid 31 (2.80 g, 14.4 mmol) and 3-(trifluoromethyl)benzaldehyde 32 (2.51 g, 14.4 mmol) in DMAC (45 mL). The reaction mixture was stirred at 100° C. for 21 h. H2O (150 mL) was added and the resulting precipitate was collected by filtration, rinsed with H2O and dried to give 33 (4.31 g, 84% yield).
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.[N:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH2:26][NH:25][CH2:24][CH2:23]3)=[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:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[C:20]([C:17]5[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=5)[CH:21]=4)[CH2:26]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1cc(-c2ccc3c(c2)CCNC3)ccn1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2cc(-c3ccncc3)ccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][CH:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:11][CH:2]([CH3:1])[CH2:3]1)(=[O:14])[CH3:13]
Reactant: CC1CNc2ccccc2N1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CC(C)Nc2ccccc21

Procedure:
Using the method of Example 15, 3-methyl-1,2,3,4-tetrahydroquinoxaline is reacted with acetic anhydride to provide 1-acetyl-3-methyl-1,2,3,4-tetrahydroquinoxaline.
Reaction SMILES: [CH2:1]([N:9]1[C:18]2[C:13](=[C:14]([CH3:33])[C:15]([CH2:27][C:28]([O:30]CC)=[O:29])=[C:16]([CH3:26])[C:17]=2[NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:12][CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+]>C(O)C.O>[CH2:1]([N:9]1[C:18]2[C:13](=[C:14]([CH3:33])[C:15]([CH2:27][C:28]([OH:30])=[O:29])=[C:16]([CH3:26])[C:17]=2[NH:19][C:20](=[O:25])[C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:12][CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN1CCCc2c(C)c(CC(=O)OCC)c(C)c(NC(=O)C(C)(C)C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCN1CCCc2c(C)c(CC(=O)O)c(C)c(NC(=O)C(C)(C)C)c21
Temperature: 50 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
N-(1-Octyl-6-ethoxycarbonylmethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide (230 mg) was dissolved in ethanol (5 ml), and a solution of NaOH (100 mg) in water (2 ml) was added, which was followed by stirring at 50° C. for 1 hr. The solvent of the reaction mixture was evaporated under reduced pressure. The residue was dissolved in water (50 ml) and washed with ethyl acetate (20 ml). The aqueous layer was adjusted to pH 1-2 with 2N sulfuric acid and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 130 mg of powdery title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:18]1([CH2:21][C@@H:22]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[NH2:23])[CH2:20][CH2:19]1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([NH:23][C@H:22]([C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[CH2:21][CH:18]1[CH2:20][CH2:19]1)=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@@H](CC1CC1)C(=O)OCc1ccccc1
Agent: Cl
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC1CC1)C(=O)OCc1ccccc1

Procedure:
N-(tert-Butoxycarbonyl)-D-leucine (540 mg, 2.32 mmol) and benzyl 3-cyclopropyl-L-alaninate hydrochloride (Example 3A, 490 mg, 1.93 mmol) are reacted by general procedure 6. The crude product is purified by preparative HPLC, (method 16), resulting in a quantitive yield of the product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:20](=[O:21])[CH2:19][CH2:18][Cl:17])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCCl
Reactant: CC(C)(C)c1ccc(N2CCNCC2)cc1
Product: CC(C)(C)c1ccc(N2CCN(C(=O)CCCl)CC2)cc1

Procedure:
A target compound (1.59 g, 5.148 mmol, 76.4%) was yielded as liquid in the same manner as Reference Example 13 by reacting 1-(4-t-butylphenyl)piperazine (1.47 g, 6.732 mmol) with 3-chloropropionyl chloride (647.5 mg, 6.732 mmol) and purifying by separation through column chromatography (EtOAc:hexane:CH2Cl2, 1:1:5).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]([CH3:18])[CH2:12]2)([OH:8])[C:4]([F:7])([F:6])[F:5].C1CCN2C(=NCCC2)CC1.[Si:32](Cl)([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34]>CN(C=O)C>[CH3:18][CH:13]1[CH2:12][C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:3]([O:8][Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34])([C:2]([F:1])([F:19])[F:20])[C:4]([F:7])([F:6])[F:5])[CH:10]=2)[NH:14]1
Reactant: CC1Cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2N1
Reactant: CC[Si](Cl)(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC[Si](CC)(CC)OC(c1ccc2c(c1)CC(C)N2)(C(F)(F)F)C(F)(F)F
Reaction time: 10 h
Yield: 99.4 %

Procedure:
To a solution of 5.9 g (19.7 mmol) of 1,1,1,3,3,3-hexafluoro-2-(2-methyl-2,3-dihydro-1H-indol-5-yl)-propan-2-ol in DMF were added 2.94 mL (19.7 mmol) of DBU and after 30 min 3.3 mL (19.7 mmol) of TESCl. After 10 hrs, additional 0.44 mL (3.0 mmol) of DBU and 1.65 mL (9.85 mmol) of TESCl were added and stirring was continued for 2 hrs. The solvent and excess TESCl were evaporated i.v. and the residue was distributed between Et2O and a saturated aqueous solution of NH4Cl. The combined organic phases were dried over Na2SO4 and evaporated to yield 8.1 g (99%) of 2-methyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-2,3-dihydro-1H-indole, red liquid, MS: 414 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]([C:11]1[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[N:13][NH:14][CH:15]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23][O:24][CH2:25]Cl>CN(C)C=O>[C:3]([C:11]1[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[N:13][N:14]([CH2:23][O:24][CH3:25])[CH:15]=1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COCCl
Reactant: O=C(c1ccccc1)c1c[nH]nc1-c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCn1cc(C(=O)c2ccccc2)c(-c2cccc(Cl)c2)n1
Temperature: 0 °C

Procedure:
To 55% sodium hydride (1.9 g) was added N,N-dimethylformamide (3 ml) and stirred while cooled with ice. To this was then added dropwise a solution of 4-benzoyl-3-(3-chlorophenyl)pyrazole (1.24 g) in N,N-dimethylformamide. The reaction mixture was stirred for 20 minutes at room temperature after the vigorous foaming ceased. The reaction mixture was added with chloromethyl methyl ether (0.59 g) and stirred for 5 hours at room temperature, which was then poured into ice-water, extracted with ethyl acetate, washed with water and dried on anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The thus obtained residue was purified by column chromatography (silica gel; ethyl acetate/n-hexane=3/1) and recrystallized from acetonitrile to give the compound of interest (620 mg). M.P.: 105.5-107.9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:8]2[O:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])[CH:7]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>ClCCCl>[C:24]([N:10]1[C:9](=[O:14])[CH:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:15][CH3:16])[O:12][C:11]1=[O:13])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: COc1ccc(Cl)cc1C1OC(=O)NC1=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C1OC(=O)N(C(C)=O)C1=O
Reaction time: 0.02 h

Procedure:
At room temperature, 5-(5-chloro-2-methoxyphenyl)-oxazolidine-2,4-dione (1.21 g., 5 mmoles) was suspended in 25 ml. of 1,2-dichloroethane. Triethylamine (505 mg., 0.7 ml., 5 mmoles) was added and the mixture stirred for 1 minutes to achieve solution. Acetyl chloride (393 mg., 0.36 ml., 5 mmoles) was added and the mixture stirred for 1 hour. The reaction mixture was concentrated to 5 ml., and solids precipitated by the addition of about 25 ml. of ether. The isolated solids were distributed between chloroform and saturated sodium bicarbonate. The organic phase was separated, washed with fresh bicarbonate and then with brine, dried over anhydrous magnesium sulfate and evaporated to yield 3-acetyl-5-(5-chloro-2-methoxyphenyl)oxazolidine-2,4-dione [910 mg., 64%; m.p. 161°-164° C.; pnmr/DMSO-d6 /delta 2.5 (s, 3H), 3.9 (s, 3H), 6.0 (s, 1H, 7.4 (m, 3H)].
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[CH3:12][NH:13][C@H:14]1[CH2:33][N:18]2[C:19]3[C:24]([C:25]([CH2:26][C:27]([O:29]CCC)=[O:28])=[C:17]2[CH2:16][CH2:15]1)=[CH:23][CH:22]=[CH:21][CH:20]=3>>[CH3:12][N:13]([C:1](=[O:11])[CH:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:3])[C@H:14]1[CH2:33][N:18]2[C:19]3[C:24]([C:25]([CH2:26][C:27]([OH:29])=[O:28])=[C:17]2[CH2:16][CH2:15]1)=[CH:23][CH:22]=[CH:21][CH:20]=3
Reactant: CC(C(=O)O)c1ccccc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CC(C(=O)N(C)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1)c1ccccc1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from hydratropic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 391.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:16]2[C:17]([CH3:26])=[C:18]([CH:23]=[CH:24][CH:25]=2)[O:19][CH2:20][C:21]#[N:22])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7](=[O:15])[C:6]=12.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+].Cl>O.CN(C)C=O>[NH2:1][C:2]1[N:3]([C:16]2[CH:25]=[CH:24][CH:23]=[C:18]([O:19][CH2:20][C:21]3[NH:29][N:28]=[N:27][N:22]=3)[C:17]=2[CH3:26])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7](=[O:15])[C:6]=12
Reactant: Cc1c(OCC#N)cccc1-n1nc2c(c1N)c(=O)[nH]c1ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(OCc2nnn[nH]2)cccc1-n1nc2c(c1N)c(=O)[nH]c1ccccc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
A mixture of [3-(3-amino-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)-2-methylphenoxy]acetonitrile (65 mg), sodium azide (37 mg), ammonium chloride (30 mg) and N,N-dimethylformamide (6 ml) was stirred at 60° C. for 3 hours and then at 100° C. for 2 days. After cooling to room temperature, the reaction mixture was diluted with water, and then pH of the reaction mixture was adjusted to about 2 by adding 1N hydrochloric acid. The precipitated solid was collected by filtration, washed with water, and dried to obtain the target compound (72 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[NH:10][CH:9]=[C:8]([C:11]([O:13]C)=[O:12])[CH:7]=1)=[O:5].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[NH:10][CH:9]=[C:8]([C:11]([OH:13])=[O:12])[CH:7]=1)=[O:5]
Reactant: COC(=O)c1c[nH]c(C(=O)c2ccc(Cl)cc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(C(=O)c2ccc(Cl)cc2Cl)c1

Procedure:
Methyl 5-(2,4-dichlorobenzoyl)pyrrole-3-carboxylate (3.0 g.) was refluxed for 2.5 hours in 35 ml. of methanol and 35 ml. of 1N sodium hydroxide. The methanol was evaporated, and approximately one volume of water was added to the aqueous residue. The mixture was extracted twice with ether, and acidified with conc. hydrochloric acid to yield 2.12 g. of crude product, recovered by filtration. Recrystallization from methanol, which included an activated carbon treatment, afforded purified 5-(2,4-dichlorobenzoyl)pyrrole-3-carboxylic acid (1.06 g., m.p. 245°-249° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([NH2:27])[CH:22]=[CH:21]2.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.O>[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([NH:27][C:14]([C:11]1[CH:10]=[N:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:13][CH:12]=1)=[O:15])[CH:22]=[CH:21]2
Reactant: O=C(Cl)c1cnc(-c2cccc(F)c2)nc1
Reactant: Nn1ccc2cc(F)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nn1ccc2cc(F)ccc21)c1cnc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid chloride (1 mmol) in EtOAc (20 mL) is added to a stirred solution of 5-fluoro-indol-1-ylamine (1 mmol) and potassium carbonate (1 mmol) in EtOAc (10 mL) and H2O (20 mL) at rt and the reaction mixture is stirred at rt overnight. EtOAc is evaporated in vacuo, and the resulting solid is collected by filtration to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide (148 mg, 42%) as a solid. MS: 351 (M+H); 1H NMR (300 MHz, CDCl3): δ 6.56 (m, H) 7.02 (m, H), 7.12-7.34 (m, 3H), 7.51 (m, H), 8.24 (d, H), 8.34 (s, H), 8.92 (br, H), 9.24 (br, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])[CH:4]=1.[CH2:23]1COCC1.C[O-].[Na+].C=O>C(OCC)(=O)C.O.CO.C(N(CC)CC)C.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][C:11](=[CH2:23])[C:12]2=[O:22])[CH:4]=1
Reactant: C1CCOC1
Reactant: COC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Agent: C=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: C=C1C[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@]2(C)C1=O
Reaction time: 8 h

Procedure:
3-Methoxyandrosta-3,5-diene-17-one (I, 2.0 g) was mixed with THF (22 ml). Diethyloxylate (1.45 ml) was added and the mixture cooled in an ice bath. Sodium methoxide (25%, 1.83 ml) was added dropwise with stirring. The mixture was stirred, and after removing the ice bath for one hour TLC showed the reaction to be complete. The reaction mixture was cooled in an ice bath, acetic acid (0.1 ml) was added, followed by triethylamine (0.7 ml) and methanol (2.8 ml). Formaldehyde (37%, 0.3 g) was added and the mixture stirred for 40 min. Then formaldehyde (37% aqueous, 0.61 g) was added and the mixture stirred at 20°-25° for about 45 minutes. TLC showed the reaction to be done. Water (10 ml) and ethyl acetate (10 ml) were added and the mixture stored at about -20° overnight. The mixture was warmed, the layers are separated, and the organic layer was washed twice with saline. The aqueous layer was extracted with ethyl acetate, the ethyl acetate washed with saline, and the organic extracts combined and dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound.