Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[N:20][NH:21]2)=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:14][C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1ccc2cn[nH]c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]

Procedure:
4-Amino-3-nitrobenzoic acid (27 mmol) was coupled with 6-aminoindazole (30 mmol) using HBTU (30 mmol) in dry DMF as the solvent employing the general procedure D to afford 4-amino-N-(1H-indazol-6-yl)-3-nitrobenzamide which was used for further transformation without further purification.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].C(OC([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34](Cl)=[N:33]1)=O)(C)(C)C.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:34]4[C:35]5[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=5)[NH:32][N:33]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: CC(C)(C)OC(=O)n1nc(Cl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4n[nH]c5ccccc45)cc3CC[C@@H]12
Yield: 41.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol) , 1-(t-butoxycarbonyl)-3-chloroindazole (116 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 60 mg (16%) of the title compound as an oil. FDMS: m/e=377.
Reaction SMILES: [CH2:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3][S:2]1(=[O:13])=[O:12].[OH-].[K+].Cl[CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].CN(C)C=O>CO>[O:20]=[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:18][CH2:17][N:3]1[C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:1][S:2]1(=[O:12])=[O:13]
Reactant: O=C1NS(=O)(=O)Cc2ccccc21
Reactant: O=C(CCCl)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCN1C(=O)c2ccccc2CS1(=O)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
1H-2,3-Benzothiazin-4(3H)-one 2,2-dioxide (1 g, 5.08 mmol.) was added to a solution of powdery potassium hydroxide (334 mg, 5.08 mmol.) in methanol (4 mL). The mixture was then stirred at room temperature for 15 min. The solution was placed under reduced pressure to distill the solvent off to dryness. To the dried product were added 3-chloropropiophenone (856 mg, 5.08 mmol.) and dimethylformamide (8 mL). The mixture was heated to 120° C. for 6 hours under stirring. The reaction liquid was placed under reduced pressure to distill the solvent off. To the resulting residue was added water, and it was extracted with ethyl acetate. The extract solution was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The dried extract solution was placed under reduced pressure to distill the solvent off. The resulting oil was treated by silica gel column chromatography (chloroform) to give the desired compound (1.13 g, yield 68%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][NH:20][CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:23][N:24]([CH3:31])[CH2:25]/[CH:26]=[CH:27]/[C:28](O)=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][N:20]([C:28](=[O:29])/[CH:27]=[CH:26]/[CH2:25][N:24]([CH3:31])[CH3:23])[CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Clc1ccc(Nc2ncnc3sc4c(c23)CNC4)cc1Cl
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1Cc2sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c3c2C1

Procedure:
In analogy to Example 89, the title compound was prepared from N-(3,4-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 25A (65 mg, 0.19 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (45 mg, 0.27 mmol) to yield 24 mg (26%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(=O)(O)[O-].[Na+]>C(O)C.[Cl-].[Na+].O>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:13]#[N:14])=[C:18]([F:23])[CH:17]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Reactant: Nc1ccc(Cl)cc1F
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Cl)cc1F

Procedure:
To 3.5 g of 4-chloro-6-fluoro-[1.7]naphthyridine-3-carbonitrile in 100 mL of absolute ethanol was added 2.3 mL of 4-chloro-2-fluoroaniline. After stirring the reaction under an inert atmosphere for 24 hours, the reaction mixture was poured into a mixture of brine and saturated aqueous sodium bicarbonate and the resultant crystals were filtered and washed with water. The product was then recrystallized from chloroform/ethyl acetate/hexanes. Drying in vacuo yielded 1.9 (40%) of 4-(4-chloro-2-fluoro-phenylamino)-6-fluoro-[1.7]naphthyridine-3-carbonitrile as yellow needles: melting point 249-252° C.; mass spectrum (m/e): M+H 316.9.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:7][SiH:8]([CH3:10])[Cl:9]>>[CH2:1]([Si:8]([CH3:10])([CH3:7])[Cl:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCC=C
Reactant: C[SiH](C)Cl
Product: C=CCCCC[Si](C)(C)Cl
Reaction time: 48 h
Yield: 68 %

Procedure:
5-Hexenyldimethylchlorosilane was prepared by combining 1,5-hexadiene (164 g) and 0.05 g of platinum complex ##STR8## in a flask equipped with a condenser, addition-funnel and a thermometer. Dimethylchlorosilane (92 g) was added at such a rate that the pot temperature did not rise above 40° C. The mixture was allowed to stand at room temperature for 48 hours. The product was isolated in 68% yield by distillation under reduced pressure (bp 39°-40° C./2.2 mm Hg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][Cl:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CCCCl)C1
Reaction time: 16 h
Yield: 88.6 %

Procedure:
A mixture of 3-aminoazetidine-1-carboxylic acid tert-butyl ester (730 mg, 4.24 mmol) and triethylamine (1.74 mL, 1.29 g, 12.72 mmol) in DCM (10 mL) was cooled to 0° C. before the addition of 4-chlorobutyrylchloride (523 μL, 657 mg, 4.66 mmol). The resulting mixture was stirred for 16 h then quenched with H2O and extracted with DCM. The combined organic extracts were washed with brine then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 30-70%) affording 3-(4-Chlorobutyrylamino)azetidine-1-carboxylic acid tert-butyl ester as a brown oil (1.04 g, 89%).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[CH:19][C:20]3[O:24][C:23]([C:25](O)=[O:26])=[CH:22][C:21]=3[CH:28]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C(Cl)CCl.Cl.C[O:39][C:40](=[O:43])[CH2:41][NH2:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:32][C:2]([CH3:1])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[CH:19][C:20]3[O:24][C:23]([C:25]([NH:42][CH2:41][C:40]([OH:39])=[O:43])=[O:26])=[CH:22][C:21]=3[CH:28]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29]
Reactant: COC(=O)CN
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)O)cc2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)NCC(=O)O)cc2c1
Yield: 48.6 %

Procedure:
5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-2-carboxylic acid (730 mg, 1.672 mmol) in CH2Cl2 (30 mL) and DMAP (612 mg, 5.02 mmol), EDC (481 mg, 2.51 mmol), and glycine methyl ester hydrochloride (313 mg, 2.51 mmol) are reacted and hydrolyzed analogous to Example 7 to yield title compound (401 mg, 47%).
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([NH:28][C:29]1[N:34]=[CH:33][C:32]([C:35](Cl)=[O:36])=[CH:31][CH:30]=1)=[O:27]>ClCCl>[S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([C:35]([C:32]3[CH:31]=[CH:30][C:29]([NH:28][C:26](=[O:27])[CH2:25][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH3:18])=[N:34][CH:33]=3)=[O:36])[C:4]=2[CH:3]=[CH:2]1
Reactant: Cc1ccccc1CC(=O)Nc1ccc(C(=O)Cl)cn1
Reactant: c1cc2c(s1)CCCCN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1CC(=O)Nc1ccc(C(=O)N2CCCCc3sccc32)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled (0° C.) mixture of 0.306 g of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine and 1.11 μl of triethylamine in 5 ml of dichloromethane is added 1.2 g of 6-[(2-methylphenylacetyl)amino]pyridine-3-carbonyl chloride. The mixture is stirred at room temperature for 16 hours and diluted with 50 ml of dichloromethane. The mixture is washed with H2O, 1N NaHCO3, H2O, brine and dried (Na2SO4). The solution is concentrated to dryness under vacuum and the residue chromatographed on silica gel to give the product as a solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:8]
Reactant: O=C(Cl)Cc1cccs1
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=C(Cc1cccs1)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(2-Thienyl)acetyl chloride (16 g) was added slowly to a stirred mixture of morpholine (17.5 ml) and methylene chloride (150 ml). A further portion (5 ml) of morpholine was added and the mixture was stirred at ambient temperature for 4 hours. The reaction mixture was washed in turn with 2M aqueous hydrochloric acid, a saturated aqueous sodium bicarbonate solution and brine. The organic phase was dried and evaporated. The residue was triturated under a mixture of hexane and diethyl ether to give N-[2-(2-thienyl)acetyl]morpholine (20.9 g).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1([C@@H:11]2[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1.Cl[C:19]1[C:24]([Cl:25])=[C:23]([CH2:26][CH3:27])[N:22]=[CH:21][N:20]=1>CN(C)C=O.O>[CH3:7][C:8]1([C@@H:11]2[CH2:16][CH2:15][C@H:14]([NH:17][C:19]3[C:24]([Cl:25])=[C:23]([CH2:26][CH3:27])[N:22]=[CH:21][N:20]=3)[CH2:13][CH2:12]2)[CH2:9][CH2:10]1
Reactant: CC1([C@H]2CC[C@@H](N)CC2)CC1
Reactant: CCc1ncnc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ncnc(N[C@H]2CC[C@@H](C3(C)CC3)CC2)c1Cl
Temperature: 80 °C
Reaction time: 4 h

Procedure:
1.8 g (13.0 mmol) of K2CO3 were placed in 10 ml of dimethylformamide, 1.3 g (8.5 mmol) of cis-4-(1-methylcyclopropyl)cyclohexylamine and 1.5 g (8.5 mmol) of 4,5-dichloro-6-ethylpyrimidine were added, and the mixture was stirred at 80° C. for 4 hours. For working up, the cooled reaction solution was taken up in water. Extraction was carried out with ether, and the combined organic phases were washed with water, dried and concentrated. For purification, the mixture was chromatographed on silica gel with petroleum ether/ethyl acetate 3:1. 1.8 g (71.1% of theory) were obtained of a colorless oil.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:17](=[O:26])[C:16]2([CH3:28])[CH3:27])=[O:14])=[C:8]([N+:10]([O-])=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)(Cl)(Cl)Cl>CO>[NH2:10][C:8]1[CH:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6][C:7]=1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])[C:17](=[O:26])[C:16]1([CH3:27])[CH3:28])=[O:14]
Reactant: CN(C)CCN1CCN(C(=O)c2sc(C(C)(C)C)cc2[N+](=O)[O-])C(C)(C)C1=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CO
Product: CN(C)CCN1CCN(C(=O)c2sc(C(C)(C)C)cc2N)C(C)(C)C1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
A mixture of 4-(2-tert-butyl-4-nitrothiophene-5-carbonyl)-1-(2-(dimethylamino)ethyl)-3,3-dimethylpiperazin-2-one (0.200 g, 0.49 mmol) and tin chloride dihydrate (0.55 g, 2.4 mmol) dissolved in 4 mL MeOH was stirred at 70° C. overnight. The reaction mixture was cooled down to room temperature, quenched with saturated NaHCO3 (40 mL), and extracted with ethyl acetate. The combined organic layers was dried, the solvent eliminated under vacuum and the residue purified by chromatographic column (silica gel, dichloromethane) to afford 0.090 g of 4-(4-amino-2-tert-butylthiophene-5-carbonyl)-1-(2-(dimethylamino)ethyl)-3,3-dimethylpiperazin-2-one as a tan solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[C:13]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:14]([N:17]3[CH2:22][CH2:21]O[CH2:19][CH2:18]3)[CH2:15][S:16][C@H:11]12)=[O:8].N1CCOC[CH2:42]1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[C:13]([C:23]([O:25][CH:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:24])=[C:14]([N:17]3[CH2:18][CH2:19][CH2:42][CH2:21][CH2:22]3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: C1COCCN1
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(N3CCOCC3)CS[C@H]12
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(N3CCCCC3)CS[C@H]12

Procedure:
By employing the procedures and starting material of Example 2 and substituting piperidine for morpholine the title compound was prepared.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[N+:15]([C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:29])[C:26](O)=[O:27])[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:26](=[O:27])[C:25]([NH:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=3)=[O:29])[CH2:11][CH2:12]2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)C(=O)Nc1cccc([N+](=O)[O-])c1
Solvent: CCOCC
Product: O=C(Nc1cccc([N+](=O)[O-])c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 4-(4-fluoro-benzyl)-piperidine and N-(3-nitro-phenyl)-oxalamic acid (Example 10a according to the method described in Example 2. Melting Point: 135-138° C. (diethylether)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([F:11])[CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][C:22]([C:24]([NH:26][CH:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])=[O:25])=[N:21][CH:20]=2)=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:23][C:22]([C:24]([NH:26][C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])=[O:25])=[N:21][CH:20]=3)=[CH:15][CH:14]=2)=[C:4]([F:11])[CH:3]=1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(N)cc2)o1)C(C)C
Reactant: O=C=Nc1ccc(Cl)cc1F
Product: COC(=O)[C@@H](NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccc(Cl)cc3F)cc2)o1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 1, using 4-chloro-2-fluoro-1-isocyanatobenzene (0.533 mmol) and intermediate 1. 1H-NMR (DMSO-d6, 300 MHz): δ 9.356 (s, 1H), 9.017-8.990 (d, 1H), 8.733 (s, 1H), 8.208-8.149 (m, 1H), 7.826 (s, 1H), 7.809-7.780 (d, J=8.7 Hz, 2H), 7.623-7.593 (d, J=9 Hz, 2H), 7.514-7.470 (d, J=2.1, 11.1 Hz, 1H), 7.270-7.241 (dd, J=0.6, 8.7 Hz, 1H), 4.328-4.277 (m, 1H), 3.680 (s, 3H), 2.286-2.217 (m, 1H), 0.979-0.957 (d, J=6.6 Hz, 6H); MS (ESI) m/z 487 (M−H), 489 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:9][CH2:10][CH2:11][C:12](Cl)=[O:13]>ClCCl.O>[Cl:9][CH2:10][CH2:11][C:12]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])=[O:13]
Reactant: Nc1ccccc1F
Reactant: O=C(Cl)CCCl
Solvent: ClCCl
Solvent: O
Product: O=C(CCCl)Nc1ccccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-fluoroaniline (15 g, 0.135 mol) in dichloromethane (100 mL) was added 3-chloropropanoyl chloride (15.168 mL, 0.135 mol) under cooling condition (0° C.) with constant stirring. Reaction mass was allowed to stir at room temperature for 2 h. The reaction mixture was diluted with water (200 mL) and extracted with dichloromethane (4×100 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to obtain the title compound. MS (M+1): 201.9.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:14]([O:16][C:17]([C:19]1[S:20][C:21]([Cl:25])=[CH:22][C:23]=1[OH:24])=[O:18])[CH3:15]>C(C(C)=O)C>[CH2:14]([O:16][C:17]([C:19]1[S:20][C:21]([Cl:25])=[CH:22][C:23]=1[O:24][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:18])[CH3:15]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)c1sc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc(Cl)sc1C(=O)OCC
Temperature: 30 °C
Yield: 101.5 %

Procedure:
1.07 g of potassium carbonate and 1.3 g of ethyl bromoacetate were added to a solution of 1.6 g of the product of Step A in 50 ml of methyl ethyl ketone and the mixture was refluxed for an hour and was cooled to 30° C. The mixture was filtered and the filtrate was evaporated to dryness. The residue was taken up in ethyl acetate and the solution was washed with water, dried and evaporated to dryness to obtain 2.3 g of ethyl (2-ethoxycarbonyl-5-chloro-3-thienyl)-oxyacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:5]=[CH:6][C:7]=1[NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1.[C:20](N1C=CN=C1)(N1C=CN=C1)=[S:21].O>CN(C)C=O>[OH:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([N:8]2[C:7]3[CH:6]=[CH:5][C:4]([C:16]([F:17])([F:18])[F:19])=[CH:3][C:2]=3[NH:1][C:20]2=[S:21])[CH2:10][CH2:11]1
Reactant: Nc1cc(C(F)(F)F)ccc1N[C@H]1CC[C@H](O)CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O[C@H]1CC[C@H](n2c(=S)[nH]c3cc(C(F)(F)F)ccc32)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-amino-4-(trans-4-hydroxycyclohexylamino)benzotrifluoride (300 mg) in N,N-dimethylformamide (3 mL) was added 1,1′-thiocarbonyldiimidazole (234 mg), and the mixture was stirred at room temperature under nitrogen atmosphere for 15 hours. Water was added to the mixture, and the resulting precipitate was collected by filtration. The obtained solid was washed successively with water and diethyl ether to give 1-(trans-4-hydroxycyclohexyl)-5-trifluoromethyl-2,3-dihydro-1H-benzimidazol-2-thione (242.8 mg) as a pale brown solid.
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.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH2:22][NH:21][C:20]([CH3:29])([CH3:28])[CH2:19]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[C:20]([CH3:29])([CH3:28])[CH2:19][C:18]4[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=4)[CH2:22]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1cc2c(cc1OC)CC(C)(C)NC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: COc1cc2c(cc1OC)CC(C)(C)N(C(=O)c1cc3ncc(Cl)cn3n1)C2

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-3,3-dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:28])[C:13]3[C:14](=[C:16]([CH2:26][CH3:27])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:29]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:6][N:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:50][O:51][CH2:52]CCO>>[CH2:26]([C:16]1[N:17]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:18]=[C:13]2[C:12](=[O:28])[NH:11][C:10]([C:9]3[C:4]([O:3][CH2:1][CH2:2][CH2:50][O:51][CH3:52])=[N:5][CH:6]=[C:7]([S:29]([N:32]4[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]4)(=[O:30])=[O:31])[CH:8]=3)=[N:15][C:14]=12)[CH3:27]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Reactant: COCCCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCCCOC)[nH]c(=O)c2nn1Cc1ccccn1
Temperature: 90 °C
Reaction time: 18 h
Yield: 38 %

Procedure:
A mixture of the title compound of Example 1 (200 mg, 0.36 mmol), potassium bis(trimethylsilyl)amide (361 mg, 1.81 mmol) and 3-methoxypropan-1-ol (1.5 ml) was stirred at 90° C. for 18 hours, then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (97:3 to 95:5), to give the title compound (81 mg, 38%) as a foam. Found: C, 55.36; H, 6.11; N, 18.18. C28H36N8O5S; 0.50 H2O requires C, 55.52; H, 6.16; N, 18.50%. δ (CDCl3): 1.01 (3H,t), 1.29 (3H,t), 2.19 (2H,m), 2.40 (2H,q), 2.54 (4H,m), 3.02 (2H,q), 3.12 (4H,m), 3.39 (3H,s), 3.65 (2H,t), 4.76 (2H,t), 5.68 (2H,s), 7.09 (1H,d), 7.21 (1H,m), 7.62 (1H,m), 8.56 (1H,d), 8.62 (1H,s), 8.93 (1H,s), 10.84 (1H,s). LRMS: m/z 597 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=O)=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C(C)=CC=CC=1.P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[C:16]3[C:11](=[C:12]([CH3:17])[CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccccc1CCNC(=O)c1ccc(Cl)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1C
Product: Cc1cccc2c1CCN=C2c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
Thirty-six (36) grams of 1-(4-chlorobenzoylamino)-2-(2-methylphenyl)ethane was dissolved in 180 ml of xylene and 100 ml of phosphorus oxychloride. While the solution was heated with stirring, 80 g of phosphorus pentoxide was added gradually, and the mixture was heated under reflux. The reaction mixture was poured into ice water. The aqueous layer was separated, and made weakly alkaline with ammonia water. Recrystallization of the precipitated oily product from n-hexane afforded 31 g of 1-(4-chlorophenyl)-5-methyl-3,4-dihydroisoquinoline as colorless prisms having a melting point of 66° to 67° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]2[N:7]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)[CH2:8][CH2:9][CH:3]12>CO.[Pd]>[CH3:1][N:2]1[CH:3]2[CH:4]([N:7]([C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=3)[CH2:8][CH2:9]2)[CH2:5][CH2:6]1
Reactant: CN1CCC2C1CCN2c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CN1CCC2C1CCN2c1ccc(N)cc1

Procedure:
1-Methyl-4-(4-nitrophenyl)octahydropyrrolo[3,2-b]pyrrole was hydrogenated by method B using methanol as solvent and palladium on carbon (5%) as catalyst. The product with the molecular weight of 217.32 (C13H19N3); MS (ESI): 218 (M+H+) was obtained in this way.