Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]([CH2:31][CH:32]([OH:36])[CH2:33][C:34]#[N:35])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][C:15]([C:17]1([C:20]3[CH:30]=[CH:29][C:23]4[O:24][C:25]([F:28])([F:27])[O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]1)=[O:16])=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C=O)C>[C:1]([C:5]1[N:6]([CH2:31][CH:32]([OH:36])[CH2:33][C:34]2[N:39]=[N:40][NH:41][N:35]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][C:15]([C:17]1([C:20]3[CH:30]=[CH:29][C:23]4[O:24][C:25]([F:28])([F:27])[O:26][C:22]=4[CH:21]=3)[CH2:18][CH2:19]1)=[O:16])=[CH:9][CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2n1CC(O)CC#N
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2n1CC(O)Cc1nn[nH]n1

Procedure:
To a solution of N-(2-tert-butyl-1-(3-cyano-2-hydroxypropyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (27 mg, 0.054 mmol) in anhydrous DMF (1.2 mL) were successively added NH4Cl (35 mg, 0.65 mmol) and NaN3 (43 mg, 0.65 mmol) at room temperature. The reaction mixture was stirred for 4 h at 110° C. in the microwave, at which stage 50% of the starting material was converted to the desired product. The reaction mixture was purified by preparative HPLC to provide N-(2-tert-butyl-1-(2-hydroxy-3-(2H-tetrazol-5-yl)propyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo-[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H+) 539.0.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:4]1.[CH3:17][N:18]=[C:19]=[O:20]>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:5]2[CH2:6][CH2:7][O:8][CH:3]([CH2:2][NH:1][C:19]([NH:18][CH3:17])=[O:20])[CH2:4]2)=[CH:11][CH:12]=1
Reactant: CN=C=O
Reactant: NCC1CN(Cc2ccc(F)cc2)CCO1
Product: CNC(=O)NCC1CN(Cc2ccc(F)cc2)CCO1
Yield: 65 %

Procedure:
This compound was synthesized from 2-aminomethyl-4-(p-fluorobenzyl)morpholine and methyl isocyanate according to the same procedure as in Example 21. Yield=65%.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@@:16]43[O:37][C@H:17]4[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(C)=O>[C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C:16]=3[C:17](=[O:37])[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCC[C@@H](C)[C@H]1C[C@@H]2O[C@@]23C2=CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]2CC[C@]13C
Solvent: CC(C)=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
A 5.0 g amount of (3β,5α,15α)-14,15-epoxycholest-7-en-3-ol benzoate (3) (Example 2) was suspended and stirred in 50 ml of acetone and the procedure of Example 6 was followed throughout to obtain 4.8 g of the desired product.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH2:16]([O:18][C:19](=[O:32])[CH2:20][NH:21][C:22]([C:24]1[C:28]([CH3:29])=[C:27]([CH:30]=O)[NH:26][CH:25]=1)=[O:23])[CH3:17]>N1CCCCC1.C(O)C>[CH2:16]([O:18][C:19](=[O:32])[CH2:20][NH:21][C:22]([C:24]1[C:28]([CH3:29])=[C:27]([CH:30]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([S:3](=[O:5])(=[O:4])[NH:2][CH3:1])[CH:7]=3)[NH:11][C:10]2=[O:15])[NH:26][CH:25]=1)=[O:23])[CH3:17]
Reactant: CCOC(=O)CNC(=O)c1c[nH]c(C=O)c1C
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)CNC(=O)c1c[nH]c(C=C2C(=O)Nc3ccc(S(=O)(=O)NC)cc32)c1C
Temperature: 90 °C

Procedure:
A mixture of 5-methylaminosulfonyl-2-oxindole (0.06 g, 0.22 mmol), [(5-formyl-4-methyl-1H-pyrrole-3-carbonyl)-amino]-acetic acid ethyl ester (0.075 g, 0.27 mmol) and piperidine (2 drops) in ethanol (5 mL) was heated in a sealed tube at 90° C. for 12 hrs. After cooling, the precipitate was collected by vacuum filtration, washed with ethanol, triturated with dichloromethane/ether and dried to give 0.035 g (36%), of the title compound as a yellowish brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:11]2[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9]C)#[N:2].BrB(Br)Br>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([C:11]2[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[OH:9])#[N:2]
Reactant: CCOC(=O)c1cc(-c2ccc(OC)c(C#N)c2)no1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2ccc(O)c(C#N)c2)no1
Reaction time: 2 h

Procedure:
Ethyl 3-(3-cyano-4-methoxyphenyl)-5-isoxazolecarboxylate and tribromoborane were dissolved in a dichloromethane solution, followed by stirring for 2 hours under ice-cooling. Further, the mixture was stirred at 40° C. for 30 minutes to obtain ethyl 3-(3-cyano-4-hydroxyphenyl)-5-isoxazolecarboxylate. APN: 257.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:13][OH:14]>CO>[F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:3]=1[C:4](=[N:13][OH:14])[NH2:5]
Reactant: NO
Reactant: N#Cc1ccc(CO)cc1F
Agent: Cl
Solvent: CO
Product: NC(=NO)c1ccc(CO)cc1F
Temperature: 50 °C
Reaction time: 16 h
Yield: 42.8 %

Procedure:
To a solution of 2-fluoro-4-hydroxymethylbenzonitrile (CAS 222978-02-1) (2.5 g, 16.5 mmol) in methanol (30 mL) was added hydroxylamine hydrochloride (3 mL, 50 mmol). After heating to 50° C. with stirring for 16 h, the reaction mixture was cooled to RT and concentrated to afford 1.3 g of Intermediate 5.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19]([O:21]C)=[O:20])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[ClH:23]>>[ClH:23].[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[C:12]([C:19]([OH:21])=[O:20])=[CH:11][N:10]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1cnc(NC2CCN(C)CC2)nc1C(F)(F)F
Agent: Cl
Product: CN1CCC(Nc2ncc(C(=O)O)c(C(F)(F)F)n2)CC1
Reaction time: 31.5 h

Procedure:
A mixture of methyl 2-[(1-methylpiperidin-4-yl)amino]-4-(trifluoromethyl)pyrimidine-5-carboxylate (322 mg) and 6 M hydrochloric acid (3 mL) was stirred for 31.5 hours under heating with reflux. The reaction liquid was concentrated under reduced pressure, and the residue was solidified from a mixed solvent of diisopropyl ether and ethyl acetate, and then the obtained solid was washed with ethyl acetate to obtain 2-[(1-methylpiperidin-4-yl)-amino]-4-(trifluoromethyl)pyrimidine-5-carboxylic acid hydrochloride (297 mg) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:3]=1[NH:4][CH2:5][C:6]1[NH:7][CH2:8][CH2:9][N:10]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([N:10]2[CH2:9][CH2:8][N:7]=[C:6]2[CH2:5][NH:4][C:3]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:2]=2[CH3:1])=[O:25])=[CH:19][CH:18]=1
Reactant: Cc1cccc(NCC2=NCCN2)c1C
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: Cc1cccc(NCC2=NCCN2C(=O)Nc2ccc(Cl)cc2)c1C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
2-(2,3-Dimethylanilinomethyl)-2-imidazoline (4.20 g; 0.024 moles) was stirred in methylene chloride (90 ml), cooled to 0° C. and a solution of 4-chlorophenyl isocyanate (3.66 g; 0.024 moles) in methylene chloride (10 ml) was then added dropwise. A white precipitate formed rapidly. Stirring was continued for 2 to 3 hours after the addition at 0° C., the reaction mixture then allowed to reach ambient temperature and stirring was continued overnight. The reaction mixture was then evaporated to dryness under reduced pressure and the solid residue so obtained recrystallised from propan-2-ol to yield white crystals of 1-(N-(4-chlorophenyl)-carbamoyl)-2-(2,3-dimethylanilinomethyl)-2-imidazoline m.p. 153°-155° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>C1COCC1.O.[Fe]>[Cl:18][C:13]1[CH:12]=[C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(F)cc(Cl)c2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Oc2cc(F)cc(Cl)c2)cc1
Yield: 95.6 %

Procedure:
To a solution of 3-chloro-5-fluorophenyl 4-nitrophenyl ether (Intermediate 5, 2.38 g) in THF (40 mL) and water (10 mL) was added Fe power (11.2 g, 200 mmol) and ammonium chloride (10.7 g, 200 mmol). The reaction mixture was heated at reflux for 4 hours. After filtration, the solvent was concentrated to give a residue and poured into 50 mL of water. The mixture was extracted with ethyl acetate (3 times 50 mL) and the combined organic phases were washed and dried over magnesium sulphate. Removal of the solvent afforded the title compound (2.02 g) which was directly used in the next step.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].Br[CH2:10][C:11]([CH3:13])=[CH2:12]>CN(C=O)C>[CH3:7][C:4]([NH2:3])([CH3:8])[CH2:5][O:6][CH2:12][C:11]([CH3:13])=[CH2:10]
Reactant: CC(C)(N)CO
Reactant: C=C(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)COCC(C)(C)N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of NaH (60% dispersion in mineral oil, 2.0 g, 50 mmol, 1 equiv) in DMF at 0° C. was added 2-amino-2-methyl-1-propanol (4.8 ml, 50 mmol, 1 equiv) and after 1 h 3-bromo-2-methyl-1-propene (5.5 ml, 55 mmol, 1.1 equiv). The resulting solution was stirred at room temperature for 15 h then partitioned between AcOEt and H2O. The two layers were separated and the organic phase was washed with H2O and brine, dried over MgSO4 and distillated (45° C., P=150 mbar) to give 2-methyl-1-[(2-methyl-2-propen-1-yl)oxy]-2-propanamine (F71) as a light pink solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[CH2:28][OH:29])=[CH:18][CH:17]=1.C(Cl)(Cl)Cl.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[Cl-].[S:48]1[CH:52]=[CH:51][CH:50]=[C:49]1[Zn+]>CN(C)C=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:29][CH2:28][CH:24]1[CH2:25][CH2:26][CH2:27][N:23]1[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][CH:14]=[C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:49]4[S:48][CH:52]=[CH:51][CH:50]=4)[CH:3]=3)[C:8](=[O:12])[NH:7][C:6]2=[O:13])=[CH:17][CH:18]=1
Reactant: O=C1NC(=O)c2ccc(Br)cc2C1=CNc1ccc(CN2CCCC2CO)cc1
Reactant: [Zn+]c1cccs1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C1NC(=O)c2ccc(-c3cccs3)cc2C1=CNc1ccc(CN2CCCC2CO)cc1
Reaction time: 2 h
Yield: 38.1 %

Procedure:
To a mixture of 6-Bromo-4-{[4-(2-hydroxymethyl-pyrrolidin-1-ylmethyl)-phenylamino]-methylene}-4H-isoquinoline-1,3-dione (100 mg, 0.2 mmol) in N,N-dimethylformamide (1 mL) is added Pd2(dba)3.CHCl3 (10 mg, 0.01 mmol) and P(tBu)3 (20 μL, 1 M solution in N,N-dimethylformamide, 0.02 mmol). After degassing the mixture, 2-thienyl zinc chloride (2.2 mL, 0.5 M solution in THF, 1.1 mmol) is then added and the resulting mixture is stirred for 2 h. N,N-dimethylformamide is then removed and the residue is purified through chromatography to provide the title compound (35 mg, 38%). MS (ESI): 460.1 (M+1)+1.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([CH2:7][C@H:8]2[CH2:19][CH2:18][C:17]3[S:16][C:15]4[N:14]=[CH:13][N:12]=[C:11]([O:20][CH:21]5[CH2:26][CH2:25][CH:24]([N:27](C)[C:28](=O)OC(C)(C)C)[CH2:23][CH2:22]5)[C:10]=4[C:9]2=3)[C:4](=[O:36])[NH:3]1.Cl>ClCCl>[CH3:28][NH:27][CH:24]1[CH2:25][CH2:26][CH:21]([O:20][C:11]2[C:10]3[C:9]4[C@@H:8]([CH2:7][C@H:5]5[NH:6][C:2](=[O:1])[NH:3][C:4]5=[O:36])[CH2:19][CH2:18][C:17]=4[S:16][C:15]=3[N:14]=[CH:13][N:12]=2)[CH2:22][CH2:23]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H]2NC(=O)NC2=O)CC4)CC1
Agent: Cl
Solvent: ClCCl
Product: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H]2NC(=O)NC2=O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
To a solution of tert-butyl N-(4-[[(3R)-3-[[(4R)-2,5-dioxoimidazolidin-4-yl]methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (45 mg, 0.09 mmol, 1.00 equiv) in dichloromethane (3 mL) was added hydrogen chloride (conc., 0.5 mL) at 0° C. under nitrogen. The resulting solution was stirred for 2 h at room temperature and evaporated under reduced pressure. The crude product (45 mg) was purified by preparative HPLC under the following conditions (Waters): column: XBridge Shield RP18 OBD column: 5 um, 19*150 mm; mobile phase: water with 0.03% NH3.H2O and CH3CN (16% CH3CN up to 22% in 11 min, up to 100% in 2 min, down to 16% in 2 min); UV detection at 254 and 220 nm. The product-containing fractions were collected and concentrated to remove CH3CN and water under reduced pressure. The residue was lyophilized overnight to give (5R)-5-[[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methyl]imidazolidine-2,4-dione (16.5 mg) as a white solid. MS: m/z 416 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 1.20-1.40 (m, 2H), 1.50-1.65 (m, 2H), 1.72-1.95 (m, 1H), 2.00-2.37 (m, 6H), 2.45 (s, 3H), 2.56-2.68 (m, 2H), 2.98-3.05 (m, 1H), 3.08-3.15 (m, 1H), 3.50 (t, 1H, J=1.5 Hz), 4.19 (dd, 2H, J=11.7, 2.7 Hz), 5.20-5.30 (m, 1H), 8.42 (s, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11](O)=[O:12])[C:2]=1[C:14]([OH:16])=O.[NH2:17]C(N)=O>O>[C:11]1(=[O:12])[C:3]2[C:2](=[N:1][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH:4]=2)[C:14](=[O:16])[NH:17]1
Reactant: O=C(O)c1cc2ccccc2nc1C(=O)O
Reactant: NC(N)=O
Solvent: O
Product: O=C1NC(=O)c2nc3ccccc3cc21
Yield: 38.2 %

Procedure:
Quinoline-2,3-dicarboxylic acid (1.29 g) and urea (709 mg) were ground together and heated at 170° for 3 h. The cooled mass was treated with water (50 mL) and triturated. The resulting solid was filtered, washed with water, and air dried to give the title compound as a white solid (450 mg). M.p.>300°.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21]C)=[O:20])[CH:17]=4)[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[OH-].[K+]>CO.O>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=4)[NH:12][CH:11]=3)[CH:7]=[N:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)c(-c1cncc(C3CC3)n1)cn2S(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2[nH]cc(-c3cncc(C4CC4)n3)c2c1
Temperature: 60 °C
Yield: 94.8 %

Procedure:
An orange-brown suspension of methyl 3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indole-5-carboxylate (353.7 mg, 0.790 mmol) and KOH (310 mg, 5.53 mmol) in a mixture of MeOH (6.0 mL) and water (1.20 mL) was heated at 60° C. for 6 h. The mixture was subsequently cooled to RT and MeOH was removed in vacuo. 1.0 N aq HCl (4.0 mL) was added to the resulting slurry, and the precipitated solid was collected by vacuum filtration, washed with water (10 mL), and dried in vacuo to provide 3-(6-cyclopropylpyrazin-2-yl)-1H-indole-5-carboxylic acid (209.2 mg, 0.749 mmol, 95%) as a yellow solid: MS (ESI, pos. ion) m/z: 280.1 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.96 (1H, br. s.), 9.12 (1H, s), 8.91 (1H, s), 8.33-8.40 (2H, m), 7.80 (1H, dd, J=8.3, 1.2 Hz), 7.51 (1H, d, J=8.5 Hz), 2.23 (1H, br. s.), 1.17 (2H, br. s.), 1.11 (2H, m, J=7.9 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>ClCCl.CO.CCOCC>[ClH:23].[NH:8]1[CH2:13][CH2:12][CH:11]([S:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)N2CCOCC2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: O=S(=O)(C1CCNCC1)N1CCOCC1
Reaction time: 8 h

Procedure:
To a solution of 4-(morpholine-4-sulfonyl)-piperidine-1-carboxylic acid tert-butyl ester in dichloromethane (10 ml) and methanol (10 ml) was added 2M hydrogen chloride in ether (2 μL). The reaction mixture was stirred overnight. The solvents were removed in vacuo to yield 4-(piperidine-4-sulfonyl)-morpholine hydrochloride salt.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([F:12])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:18][O:19][B:20](OC)[O:21][CH3:22]>O1CCCC1>[CH3:18][O:19][B:20]([O:21][CH3:22])[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([F:12])=[CH:4][CH:3]=1
Reactant: COB(OC)OC
Reactant: Fc1ccc(Br)c2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COB(OC)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 1-bromo-4-fluoronaphthalene (0.5 g) in 10 mL of tetrahydrofuran at -78° C. under nitrogen was added n-butyllithium (1.6M, 1.53 mL) dropwise. The solution was allowed to stir for 5 minutes, then trimethoxyborane (0.33 mL) was added dropwise. The solution was allowed to warm to room temperature and the solvent removed under reduced pressure to give a solid, dimethoxy-(4-fluoronaphth-1-yl)borane, a compound of formula (7).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:19]([CH2:20][NH:21][CH2:22][CH3:23])=[CH:18][C:17]([CH3:24])=[CH:16][N:15]=2)[CH:7]=1)[CH3:2].FC(F)(F)C([O-])=O.[C:33](Cl)(=[O:42])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:19]([CH2:20][N:21]([CH2:22][CH3:23])[C:33](=[O:42])[CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:18][C:17]([CH3:24])=[CH:16][N:15]=2)[CH:7]=1)[CH3:2]
Reactant: CCNCc1cc(C)cnc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ncc(C)cc2CN(CC)C(=O)CCc2ccccc2)c1

Procedure:
[3-(3-Ethylaminomethyl-5-methyl-pyridin-2-yl)-4-methoxy-phenyl]-acetic acid ethyl ester, trifluoroacetate (0.36 mmol) was reacted with hydrocinnamoyl chloride (0.06 mL, 0.44 mmol) and triethylamine (0.15 mL, 1.09 mmol) in CH2Cl2 to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:27][N:28]([CH3:37])[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:33]([C:32]3[CH:35]=[CH:36][C:29]([N:28]([CH3:37])[CH3:27])=[CH:30][CH:31]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3c(F)cccc3Cl)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(Cc5c(F)cccc5Cl)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-chloro-4-(4-(2-chloro-6-fluorobenzyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.045 g, 0.11 mmol), ethanol (3.2 ml), and 4-dimethylaminobenzaldehyde (0.022 g, 0.15 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.4 ml, 0.4 mmol). The reaction mixture was heated at 70° C. for 6 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column, which was eluted with diethyl ether/dichloromethane (v/v; 1:1). The title compound was isolated as a pale yellow solid after trituration with diethyl ether (0.09 g, 16%); 1H-NMR (500 Mz, DMSO-d6) 2.68 (br s, 4H, piperazine N(CH2)2), 2.99 (s, 6H, N(CH3)2), 3.63 (br s, 4H, piperazine N(CH2)2), 3.70 (s, 2H, NCH2), 6.80 (d, J=8.56 Hz, 2H) and 8.00 (d, J=8.55 Hz, 2H) (3,5-C6H4—NMe2 and 2,6-C6H4—NMe2) 7.26 (t, J=9.78 Hz, 1H) and 7.40 (m, 2H) (ArH), 8.03 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.12 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2nccc3ccccc23)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn(-c2nccc3ccccc23)c2ccccc12
Yield: 104.8 %

Procedure:
0.333 g (7.94 mmol) of lithium hydroxide monohydrate and 60 cm3 of water are added at 25° C. to 1.2 g (3.97 mmol) of 3-methoxycarbonyl-1-(isoquinol-1-yl)-1H-indole dissolved in 60 cm3 of tetrahydrofuran. After stirring at reflux for 22 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 30 cm3 of water and then triturated with 8 cm3 of 5N hydrochloric acid. After filtering off and drying the solid residue under reduced pressure (2.7 kPa) at 40° C., 1.2 g of 3-carboxy-1-(isoquinol-1-yl)-1H-indole are obtained in the form of a white solid. Mass spectrum (EI): m/e 288 (M+·), m/e 243.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[S:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([Cl:28])[CH:27]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:23]=[C:22]([Cl:21])[CH:27]=[C:26]([Cl:28])[CH:25]=3)[CH2:34][CH2:33]2)=[S:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)nc1NC(=S)Oc1ccccc1
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Product: COc1nc(C)c(C)nc1NC(=S)N1CCN(c2cc(Cl)cc(Cl)c2)CC1
Yield: 70.8 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)thiocarbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 28 to obtain the titled compound.
Reaction SMILES: [CH2:1]([CH:3]1[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH2:6][CH2:5][NH:4]1)[CH3:2].[CH2:12]([NH:14][C:15](=[NH:18])SC)[CH3:13].Br>C(#N)C>[CH2:1]([CH:3]1[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH2:6][CH2:5][N:4]1[C:15](=[NH:18])[NH:14][CH2:12][CH3:13])[CH3:2]
Reactant: CCNC(=N)SC
Reactant: CCC1NCCc2[nH]cnc21
Agent: Br
Solvent: CC#N
Product: CCNC(=N)N1CCc2[nH]cnc2C1CC

Procedure:
A solution of 1.5 g of 4-ethyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 1.18 g of N-ethyl-S-methyl-isothiourea in 15 ml of acetonitrile is refluxed for 8 h. After evaporation to dryness the residue is treated with one equivalent of ethanolic hydrogen bromide. After cooling, 1.5 g of 4-ethyl-5-(N-ethyl-guanyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine monohydrobromide, m.p. 275°, are collected.
Reaction SMILES: Cl.[S:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:4][CH2:3]1.[F:13][C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17]>>[F:13][C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([N:4]1[CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7][S:2][CH2:3]1)=[O:17]
Reactant: O=C(O)c1cccnc1F
Reactant: CCOC(=O)C1CCSCN1
Agent: Cl
Product: CCOC(=O)C1CCSCN1C(=O)c1cccnc1F
Yield: 46.6 %

Procedure:
Ethyl N-(2-fluoronicotinoyl)-3,4,5,6-tetrahydro-2H-1,3-thiazine-4-carboxylate is prepared by the method described in European Patent Application EP 118321, but from 12.5 g of ethyl 3,4,5,6-tetrahydro-2H-1,3-thiazine-4-carboxylate hydrochloride and 13.5 g of 2-fluoronicotinic acid. 8.2 g of ethyl N-(2-fluoronicotinoyl)-3,4,5,6-tetrahydro-2H-1,3-thiazine-4-carboxylate are thus obtained in the form of light-yellow oil, employed as such in the following reaction.