Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2].[Br:14]Br>CC(O)=O>[CH:1]([C:4]1[NH:5][C:6]2[C:12]([Br:14])=[C:11]([NH2:13])[CH:10]=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2ccc(N)cc2[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)c1nc2ccc(N)c(Br)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of 0.95 g (5.4 mmol) of 2-isopropyl-5-aminobenzimidazole in 50 ml of AcOH was added 0.19 ml (3.7 mmol) of Br2 dropwise and resulting reaction mixture was stirred for 1 h at 25° C. Reaction mixture was concentrated in vacuo and purified on silica gel column chromatography (5% MeOH/EtOAC) to yield 0.89 g (3.5 mmol, 95%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[CH3:11].[C:13](B1OC(C)(C)C(C)(C)O1)([CH3:15])=[CH2:14].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:13]([CH3:15])=[CH2:14])=[CH:6][C:5]=1[CH3:11]
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=C(C)c1ccc(C(=O)OC)c(C)c1
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 88.5 %

Procedure:
4-Bromo-2-methyl-benzoic acid methyl ester (4 g, 17.46 mmol), isopropenylboronic acid pinacol ester (3.228 g, 19.21 mmol) and cesium carbonate (19.913 g, 61.11 mmol) were treated with a degassed solution of 15 ml dioxane/5 ml water. After 5 min stirring [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex (0.718 g, 0.873 mmol) was added and heated to 120° C. for 40 min in the microwave. The reaction mixture was filtered over cellulose; washed with 20 ml dioxane and concentrated in vacuo. The residue was purified by 120 g silica gel chromatography (gradient elution 0-50% ethyl acetate in hexane during 50 min) to yield 4-Isopropenyl-2-methyl-benzoic acid methyl ester (2.94 g, 15.45 mmol). MS (ESI) 191.3 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C[Al](C)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: C1COCCN1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1C
Agent: C[Al](C)C
Product: Cc1cc(F)ccc1-c1nc(N2CCOCC2)nc2c1ccc(=O)n2-c1ccccc1C

Procedure:
Following the general procedure outlined in Example 193, the product of Example 121 (100 mg, 0.22 mmol), morpholine (58 mg, 0.66 mmol) and trimethylaluminum (0.33 mL, 0.66 mmol) were reacted to give the desired product, 61 mg (64%). LC-MS: 431.2 (MH+, m/z), 2.46 (Rt, min).
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]1([C:19]2[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[N+:10]([C:3]1[CH:4]=[C:5]([C:7](=[O:9])[CH3:8])[S:6][C:2]=1[S:25][C:22]1[CH:21]=[CH:20][C:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:24][CH:23]=1)([O-:12])=[O:11]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Sc1ccc(-c2ccccc2)cc1
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(-c3ccccc3)cc2)s1

Procedure:
Prepared according to the procedure described for example 1 from 1-(5-Chloro-4-nitro-2-thienyl)ethanone (82 mg, 0.4 mmol) and 4-phenylbenzenthiol (74 mg, 0.4 mmol). The title compound was obtained as a solid (30 mg, 21% yield). 1H NMR (400 MHz, CDCl3) δ: 8.09 (1H, s), 7.74 (2H, m) 7.65 (2H, m), 7.52 (2H, m), 7.44 (2H, m), 2.49 (3H, s). MS m/z: 355.9 [M+H]+.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=1)[C:3](=O)[CH3:4].[NH2:16][C:17]([NH2:19])=[S:18]>C(O)C>[C:12]([C:8]1[N:7]=[C:6]([C:2]2[S:18][C:17]([NH2:19])=[N:16][C:3]=2[CH3:4])[CH:11]=[CH:10][N:9]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(=O)C(Br)c1ccnc(C(C)(C)C)n1
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1nc(N)sc1-c1ccnc(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Bromo-1-(2-tert-butyl-pyrimidin-4-yl)-propan-2-one (1 g, 37 mmol) is stirred in ethanol (40 ml) at 70° C. Thiourea (280 mg, 37 mmol) is added and stirring continued for 1 hour at 70° C. After cooling to room temperature the mixture is filtered to afford the titled compound as the hydrobromide salt. If required, the product is dissolved in 1M aqueous hydrochloric acid and the solution is brought to pH 8 by addition of sodium hydroxide solution to precipitate the titled compound as the free base.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[O:7][C:6]=2[C:5]([Cl:13])=[CH:4][C:3]=1[F:14].Cl[C:16](OC(Cl)(Cl)Cl)=[O:17]>C1(C)C=CC=CC=1>[Cl:13][C:5]1[C:6]2[O:7][C:8]([CH3:11])([CH3:12])[O:9][C:10]=2[C:2]([N:1]=[C:16]=[O:17])=[C:3]([F:14])[CH:4]=1
Reactant: CC1(C)Oc2c(Cl)cc(F)c(N)c2O1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1(C)Oc2c(Cl)cc(F)c(N=C=O)c2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.5 g (0.0069 mole) of 4-amino-7-chloro-2,2-dimethyl-5-fluoro-1,3-benzodioxole in 50 mL of toluene was added slowly 0.41 mL (0.0035 mole) of trichloromethyl chloroformate. This mixture was stirred at ambient temperature for one hour and then was heated at reflux for approximately 16 hours. At the conclusion of this period the solvent was evaporated from the reaction mixture under reduced pressure, leaving 7-chloro-2,2-dimethyl-5-fluoro-1,3-benzodioxol-4-yl isocyanate as a residue which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.CN(C=O)C>O>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:25]2[CH2:24][CH2:23][N:22]([C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=3)[CH2:27][CH2:26]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: Clc1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@](O)(CN1CCN(c2ccc(Cl)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 72.5 °C
Reaction time: 5 h
Yield: 86.7 %

Procedure:
(R)-2-Chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (20 g, 91.9 mmol) and 1-(4-chlorophenyl)piperazine (20.8 g, 0.11 mol) were added to DMF (200 ml) followed by stirring at 70-75° C. for 5 hours. The reaction mixture was allowed to return to room temperature, poured into water, and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=20/1) to afford (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-chlorophenyl)piperazin-1-yl]propan-2-ol (33.0 g, yield 87%) as a yellow amorphous form.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].NC1C=CC([N+]([O-])=O)=C[C:15]=1[S:23](N)(=[O:25])=[O:24].CS(O)(=O)=O.CS(Cl)(=O)=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:23]([CH3:15])(=[O:25])=[O:24])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:10])=[O:11]
Reactant: Nc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Reactant: Nc1ccc(N)c(S(N)(=O)=O)c1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)O
Product: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1

Procedure:
The 2-chloro-5-nitro-benzenesulfonamide intermediate (prepared as described in scheme 14) can be treated with a benzylic amine, such as benzylamine, to displace the chloro moiety. Hydrogenation under standard conditions in the presence of an acid (e.g., methanesulfonic acid) can be used to remove the benzylic group and to reduce the nitro group at the same time to afford the 2,5-diamino-benzenesulfonamide intermediate as a salt. Alternatively, the 2,5-diamino-benzenesulfonamide salt can be prepared by reduction of the 2-amino-5-nitro-benzenesulfonamide (prepared as described in schemes 14 and 15) under standard hydrogenation conditions in the presence of an acid (e.g., methanesulfonic acid). Subsequent reaction with methanesulfonyl chloride affords the desired 2-amino-5-methanesulfonylamino-benzenesulfonamide intermediate.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[CH:4]([NH2:7])[CH2:5][CH3:6].[C:10](Cl)(=[O:13])[CH:11]=[CH2:12]>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:8][CH3:9])[CH:4]([NH:7][C:10](=[O:13])[CH:11]=[CH2:12])[CH2:5][CH3:6]
Reactant: C=CC(=O)Cl
Reactant: CCC(N)C(OC)OC
Solvent: ClCCl
Product: C=CC(=O)NC(CC)C(OC)OC
Yield: 68.9 %

Procedure:
Using the standard procedure for ABDA-Et, 16.5 g (0.124 mol) of the above aminobutyraldehyde dimethyl acetal was reacted with 11.2 g (0.124 mol) of acryloyl chloride in 40 mL of CH2Cl2 /30 g of 14N NaOH. The product mixture was adjusted to pH 10.0 and worked up as usual to yield 16 g of oil showing predominantly a single component by gc at 7.00 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]#[C:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.[N+:20](=[CH:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24])=[N-:21]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[C:22]([C:23](=[O:24])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:20][NH:21][C:10]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: [N-]=[N+]=CC(=O)c1ccccc1
Reactant: CCOC(=O)C#CC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]nc(C(=O)c2ccccc2)c1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Yield: 74.3 %

Procedure:
A solution of ethyl 4-(4-chloro-2-nitrophenyl)-4-oxo-2-butynoate (prepared as described in Example 48(a)) (1.2 g, 4.11 mmol) and diazoacetophenone (1.2 g, 8.22 mmol, prepared as described in Org. Syn. Coll. Vol. VI, pp. 386-388) in tetrahydrofuran (THF) (21.6 mL) was stirred at room temperature for 16 hours. The reaction was concentrated by rotary evaporation and purified by flash chromatography eluting with hexanes:ethyl acetate (90:10, 80:20, 70:30) to give the title compound (1.3 g, 74.3%); Rf 0.38 (1:1 ethyl acetate:hexanes).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH2:9][C@H:8]([NH:17]C(=O)OC(C)(C)C)[C:7]1=[O:25].[ClH:30]>O1CCOCC1>[ClH:30].[NH2:17][C@@H:8]1[C:7](=[O:25])[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([F:1])[CH:28]=[C:27]([F:29])[CH:26]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CSc2ccccc2N(Cc2cc(F)cc(F)c2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CSc2ccccc2N(Cc2cc(F)cc(F)c2)C1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.59 g of 2 (3.78 mmol) are placed in a 100 mL round-bottomed flask and 25 mL of a solution of hydrogen chloride in dioxane (4 M) are added. The medium is stirred for 5 hours at room temperature under argon. After evaporating off the solvent, 1.44 g of amine 3 are obtained in hydrochloride form, which product is used directly for the following step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:10][CH2:11][CH2:12][OH:13].[OH-].[Na+]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: Cc1cccc(O)c1
Reactant: OCCCCl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(OCCCO)c1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A stirred solution of 25 grams (0.23 mole) of 3-methylphenol and 18.8 grams (0.20 mole) of 3-chloropropan-1-ol in 100 mL of aqueous 10% sodium hydroxide was heated at reflux for about 40 minutes. After this time, the reaction mixture was cooled to ambient temperature and extracted with three 100 mL portions of diethyl ether. The combined extracts were then washed with three 50 mL portions of an aqueous dilute sodium hydroxide solution and dried with sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure, yielding 29 grams of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][C@H:15]([OH:27])[C:16]1[CH:25]=[CH:24][C:19]2[C:20](=[O:23])[O:21][CH2:22][C:18]=2[C:17]=1[CH3:26])(C)(C)C.[ClH:29]>O1CCOCC1>[ClH:29].[NH2:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][C@@H:15]([C:16]1[CH:25]=[CH:24][C:19]2[C:20](=[O:23])[O:21][CH2:22][C:18]=2[C:17]=1[CH3:26])[OH:27]
Reactant: Cc1c([C@@H](O)CN2CCCC2CNC(=O)OC(C)(C)C)ccc2c1COC2=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c([C@@H](O)CN2CCCC2CN)ccc2c1COC2=O

Procedure:
A suspension of the faster eluting diastereomer of tert-butyl({1-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]pyrrolidin-2-yl}methyl)carbamate (710 mg, 1.82 mmol) in dioxane (2.0 mL) was treated with a solution of hydrochloric acid in dioxane (4.0 M, 2.0 mL). After shaking sixteen hours, the solvents were removed in vacuo to provide 5-[(1R)-2-[2-(aminomethyl)pyrrolidin-1-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one hydrochloride which was carried on without purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([Cl:12])=[CH:4][C:3]=1[F:13].Cl[C:15](OC(Cl)(Cl)Cl)=[O:16]>C1(C)C=CC=CC=1>[Cl:12][C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][O:10][C:11]=2[C:2]([N:1]=[C:15]=[O:16])=[C:3]([F:13])[CH:4]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(F)cc(Cl)c2c1OCCC2
Solvent: Cc1ccccc1
Product: O=C=Nc1c(F)cc(Cl)c2c1OCCC2
Yield: 99.8 %

Procedure:
By the method of Example 1, Step F, 2.2 grams (0.011 mole) of 8-amino-5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran and 2.2 grams (0.011 mole) of trichloromethyl chloroformate were reacted in 50 mL of toluene, yielding about 2.5 grams of 5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran-8-yl isocyanate. The product was taken to the next step without further characterization.
Reaction SMILES: CI.[C:3]([O-])([O-])=O.[K+].[K+].[NH:9]([C:16]1[N:17]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:18]2[C:23]([C:24](=[O:26])[CH:25]=1)=[C:22]([CH3:27])[CH:21]=[C:20]([Cl:28])[N:19]=2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[Cl:28][C:20]1[N:19]=[C:18]2[C:23]([C:24](=[O:26])[CH:25]=[C:16]([N:9]([CH3:3])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:17]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:22]([CH3:27])[CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Cl)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(Cl)nc2c1c(=O)cc(N(C)c1ccccc1)n2-c1ccccc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
MeI (0.10 mL, 228 mg, 1.6 mmol) was added to a stirred suspension of K2CO3 (23.5 mg, 0.17 mmol) and 2-anilino-7-chloro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (50 mg, 0.14 mmol) in THF (3 mL). The suspension was heated to 40° C. and stirred was overnight. The reaction was quenched with water (5.0 mL) and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Recrystallization of the residue using EtOAc afforded 7-chloro-5-methyl-2-[methyl(phenyl)amino]-1-phenyl-1,8-naphthyridin-4(1H)-one (18 mg, 35%): LCMS RT: 2.24 min, MH+: 376.6, Rf=0.76 (4:1 Hex:EtOAc).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[CH3:20][C:21]([CH3:29])([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[NH2:22]>>[CH3:20][C:21]([NH:22][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[CH3:29]
Reactant: O=C(O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Reactant: Cc1nc(C(C)(C)N)no1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(N3CCCC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (Example 14 a) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (LC/MS): 386.2 [M+H]+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.[OH-].[K+]>[CH2:5]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]2[CH2:19][CH2:20][N:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:1]2=[O:2])[CH2:16][CH2:17]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: c1ccc(CN2CCC(NCCNc3ccccc3)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C1N(c2ccccc2)CCN1C1CCN(Cc2ccccc2)CC1
Yield: 66.4 %

Procedure:
With stirring, 15 g of phosgene are introduced at 5° to 10° C. in the course of 1 hour into a suspension of 10 g of 1-benzyl-4-(2-phenylamino-1-ethylamino)-piperidine in 100 ml of toluene and 48.5 ml of 3 N potassium hydroxide solution. After stirring for 2 hours at 5° to 10° C., the reaction mixture is made alkaline with 43 ml of 6 N potassium hydroxide solution and brought to room temperature. After it has been stirred for a further 15 hours at room temperature, the reaction mixture is filtered with suction and the residue is recrystallised from isopropanol-methanol to yield 7.2 g of 1-(1-benzyl-4-piperidinyl)-3-phenyl-2-imidazolidinone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]([N:16]=[C:17]=S)([CH3:15])[CH3:14]>C(OCC)(=O)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[S:9](=[O:11])(=[O:10])[N:12]=[C:17]([NH:16][CH:13]([CH3:15])[CH3:14])[NH:1][C:2]=2[CH:7]=1
Reactant: CC(C)N=C=S
Reactant: Nc1cc(F)ccc1S(N)(=O)=O
Solvent: CCOC(C)=O
Product: CC(C)NC1=NS(=O)(=O)c2ccc(F)cc2N1
Temperature: 140 °C
Yield: 13.8 %

Procedure:
A mixture of 2-amino-4-fluorobenzenesulfonamide (1.9 g, 10 mmol) and isopropyl isothiocyanate (6.4 ml, 60 mmol) was heated at 140° C. for 2.5 h. The mixture was cooled to room temperature and stirred with 50 ml of ethyl acetate for 20 min. The precipitate was isolated by filtration and washed with ethyl acetate to give 355 mg (14%) of the title compound; m.p. 266-269° C.; 1H-NMR (DMSO-d6): δ 1.18 (d, 6H, CH(CH3)2), 3.91 (m, 1H, CH(CH3)2), 7.00-7.13 (m, 2H, ArH), 7.16 (br.s, 1H, NH), 7.73 (dd, 1H, ArH), 10.4 (br.s, 1H, NH); MS: m/e 257 (M+, 25%); (C10H12N3F1O2S1) calc. C, 46.68; H, 4.70; N, 16.33; found C, 46.84; H, 4.88; N, 16.13.
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NN>CO.C(OCC)(=O)C>[C:1]1([C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH2:12][NH2:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ncsc1-c1ccccc1
Agent: NN
Solvent: CCOC(C)=O
Solvent: CO
Product: NCc1ncsc1-c1ccccc1
Reaction time: 8 h
Yield: 85.4 %

Procedure:
Prepare a cold (0° C.) solution of 2-(5-phenylthiazol-4-ylmethyl)isoindole-1,3-dione (260 mg, 0.8 mmol) in methanol (15 mL). Add hydrazine (0.05 mL, 1.6 mmol). Warm the reaction to room temperature and stir overnight. Concentrate the reaction in vacuo. Dissolve the residue in ethyl acetate (25 mL) and filter to remove solids. Concentrate the filtrate in vacuo to an oil. Chromatograph (silica gel, 93:6:1 CHCl3/MeOH/concentrated NH4OH) to afford the title compound (130 mg). 1H NMR (CDCl3) δ 8.75 (s, 1H), 7.39-7.49 (m, 5H), 4.00 (s, 2H), 1.62 (br s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([OH:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:34]I)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:34][O:14][C:11]2[CH:10]=[N:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:13][N:12]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1cnc(-c2ccc(Cl)cc2)cn1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(F)cc2)C1
Product: CCOC(=O)C1(COc2cnc(-c3ccc(Cl)cc3)cn2)CCN(C(=O)c2ccc(F)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 5-(4-chloro-phenyl)-pyrazin-2-ol (Preparation 25) and 1-(4-fluoro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 12) to afford the racemate as a white solid (73 mg, 20%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([NH:15]C(=O)O)[N:11]=[CH:12][CH:13]=3)[C:8](=[O:19])[N:7]([CH3:20])[C:6]=2[CH:21]=1.Cl.C(=O)(O)[O-].[Na+].[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>CO>[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29].[NH2:15][C:10]1[N:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:8](=[O:19])[N:7]([CH3:20])[C:6]1[CH:21]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=1
Reactant: Cn1c(=O)c2c(NC(=O)O)nccc2c2ccc(Cl)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c2c(N)nccc2c2ccc(Cl)cc21
Yield: 27 %

Procedure:
A solution of (8-chloro-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-4-yl)carbamic acid (300 mg, 0.415 mmol) in conc. HCl (15 mL, 494 mmol) was heated at 90° C. for 2 h. The pH of the reaction mixture was adjusted to 8 with saturated sodium bicarbonate solution and extracted with DCM (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep. HPLC (0.1% TFA in MeOH) to yield 4-amino-8-chloro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (30 mg, 0.110 mmol, 27% yield) as a mono TFA salt. LC/MS (ESI) m/e 260.0 [(M+H)+, calcd for C13H11ClN3O 260.05]; LC/MS retention time (method B): tR=1.18 min; HPLC retention time (method A): tR=5.24 min; HPLC retention time (method B): tR=6.31 min; 400 MHz, 1H NMR (DMSO-d6) δ 9.95 (s, 1H), 8.75 (s, 1H), 8.56 (d, J=8.80 Hz, 1H), 8.23 (d, J=6.80 Hz, 1H), 7.82 (dd, J=6.80, 7.20 Hz, 2H), 7.54 (dd, J=2.00, 8.80 Hz, 1H), 3.72 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][C:8]3[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=3[N:6]=2)[CH2:2]1.[Cl:15][C:16]1[C:21](Cl)=[N:20][CH:19]=[CH:18][N:17]=1>CN(C=O)C.O>[Cl:14][C:12]1[CH:11]=[CH:10][C:8]2[NH:9][C:5]([CH:3]3[CH2:4][N:1]([C:21]4[C:16]([Cl:15])=[N:17][CH:18]=[CH:19][N:20]=4)[CH2:2]3)=[N:6][C:7]=2[CH:13]=1
Reactant: Clc1nccnc1Cl
Reactant: Clc1ccc2[nH]c(C3CNC3)nc2c1
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2[nH]c(C3CN(c4nccnc4Cl)C3)nc2c1
Temperature: 100 °C

Procedure:
A mixture of 2-azetidin-3-yl-5-chloro-1H-benzoimidazole (as prepared by Preparation 2) (1.0 g, 4.83 mmol) and 2,3-dichloro-pyrazine (0.71 g, 10.4 mmol) was dissolved in DMF (20 mL) and heated for 2 h at 100° C. The mixture was diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo to afford the product as a yellow solid.