Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:8][CH:9]=O.[NH:17]1[C:25]2[C:20](=[C:21]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.ClCCCl.C(O)(=O)C>[NH:17]1[C:25]2[C:20](=[C:21]([N:26]3[CH2:31][CH2:30][N:29]([CH2:9][CH2:8][CH:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=4)[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:28][CH2:27]3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1
Reactant: O=CCC(c1ccccn1)c1ccccn1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: c1ccc(C(CCN2CCN(c3cccc4[nH]ccc34)CC2)c2ccccn2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 13 %

Procedure:
A mixture of 1.15 g of Compound 16B, 1.2 g of 1-(4-indolyl)piperazine (prepared as described in EP 138,280), 1.24 mL of acetic acid, 1.71 g of sodium triacetoxyborohydride and 85 mL of 1,2-dichloroethane was stirred at room temperature for 24 h. Afterwards it was diluted with water and alkalinized with sodium carbonate. The organic layer was dried on sodium sulphate and evaporated to dryness affording 1.53 g of crude, which was purified by flash chromatography (ethyl acetate-2.2 N methanolic ammonia, gradient from 9.4:0.6 to 9.2:0.8) affording 0.28 g (13%) of the title product as an oil.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:26])[CH2:22][C:23](O)=[O:24])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.N.CC#[N:36]>CN(C=O)C.C1(C)C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:26])[CH2:22][C:23]([NH2:36])=[O:24])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC#N
Reactant: COc1ccc(C2CCN(C(=O)CC(=O)O)CC2)cc1OC1CCCC1
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(C2CCN(C(=O)CC(N)=O)CC2)cc1OC1CCCC1

Procedure:
In the same manner as Example, 9, 3-[4-(3-cyclopentyloxy-4-methoxyphenyl)piperidin-1-yl]-3-oxo-propionic acid (0.70 mmol, 0.25 g), oxalyl chloride (0.77 mmol, 0.385 mL; 2M solution in CH2Cl2), DMF (4 drops) and saturated NH3 /CH3CN solution (10 mL) in dry toluene (10 mL) afforded a solid which was triturated in Et2O/hexane to give the title compound as a white solid, mp=132°-133° C. (0.40 mmol, 0.150 g, 60%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]=[CH:15][N:16]=[C:17](O)[C:18]=3[N:19]=2)[CH:7]=[CH:8][CH:9]=1.O=S(Cl)[Cl:25]>>[Cl:25][C:17]1[C:18]2[N:19]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:22])([F:21])[F:1])[CH:5]=3)[CH:11]=[CH:12][C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: Oc1ncnc2ccc(-c3cccc(OC(F)(F)F)c3)nc12
Reactant: O=S(Cl)Cl
Product: FC(F)(F)Oc1cccc(-c2ccc3ncnc(Cl)c3n2)c1

Procedure:
A solution of 6-(3-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-ol (1.2 g, 3.9 mmol) in SOCl2 (10 mL) was refluxed for 2 hours. The reaction was concentrated under reduce pressure, and the residue was chased with toluene (10 mL) to obtain 4-chloro-6-(3-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidine as a brown solid. Used as is without further purification.
Reaction SMILES: [C:1]([NH:4][CH:5](OCC)[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].B(Br)(Br)Br.[NH2:23][OH:24]>>[C:1]([NH:4][CH:5]([NH:23][OH:24])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(NC(C)=O)C(=O)NCc1ccccc1
Reactant: NO
Agent: BrB(Br)Br
Product: CC(=O)NC(NO)C(=O)NCc1ccccc1

Procedure:
Using 2-acetamido-N-benzyl-2-ethoxyacetamide (2.00 g, 8.0 mmol), BBr3 (1M in CH2Cl2, 8.8 mL, 8.8 mmol), and anhydrous NH2OH (5-6 equiv) gave an oily residue. The residue was separated in three components by flash chromatography on SiO2 gel (7.5% MeOH/CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:44]1([CH2:50][C:51]([NH:53][NH2:54])=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C>[C:44]1([CH2:50][C:51]([NH:53][NH:54][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: NNC(=O)Cc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccccc1)NNC(=O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 8, 50 mg, 0.25 mmol) in DMF (10 mL) was added DIPEA (89 μL, 0.51 mmol), HOBt (34 mg, 0.25 mmol), EDCI (63 mg, 0.33 mmol) and phenylacetic acid hydrazide (38 mg, 0.25 mmol) and the mixture was stirred at rt for 72 h. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (3×30 mL). The combined organics were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude material was chromatographed on silica gel eluting with methanol/dichloromethane (1:19) to give the title compound. m/z (ES+)=329 [M+H]+; RT=3.07 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]([NH2:10])[CH2:8][CH3:9].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:36]([O:35][C:33]([N:10]([CH:7]([CH2:8][CH3:9])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])=[O:34])[CH3:37]
Reactant: CCOC(=O)Cl
Reactant: CCC(N)Cc1cccs1
Reactant: CCOC(=O)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)OCC)C(CC)Cc1cccs1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 70.5 %

Procedure:
To a solution of 1-(thiophen-2-yl)butan-2-amine (2.1 g, 13.72 mmol) in methylene chloride (40 mL) was added ethyl glyoxylate (2.80 g, 13.72 mmol) at RT. One drop of acetic acid was added, the mixture stirred at RT for 75 min, and sodium triacetoxyborohydride (4.36 g, 20.58 mmol) was added. The reaction was stirred at RT for 15 hours before quenching the reaction by adding 5 mL of acetic acid. The volatiles were removed under reduced pressure and the residue dissolved in 40 mL THF. Saturated sodium bicarbonate (40 mL) was added carefully, followed by the addition of ethyl chloroformate (2.978 g, 2.624 mL, 27.44 mmol). Solid NaHCO3 was subsequently added portionwise until gas evolution ceased. The reaction was stirred at RT overnight and extracted with EtOAc (2×). The organics were dried over Na2SO4, the volatiles removed under reduced pressure, and there resulting yellow oil purified by silica gel chromatography, using a 0-35% EtOAc/hexanes gradient as eluant, to produce ethyl 2-(ethoxycarbonyl-(1-(thiophen-2-yl)butan-2-yl)amino)acetate (Compound 1035, 3.03 g) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]([Cl:18])=[N:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][Si](C=[N+]=[N-])(C)C>CO.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([O:17][CH3:19])=[O:16])=[CH:13][C:12]([Cl:18])=[N:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(Cl)ncc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To 5.4 g of 5-tert-butoxycarbonylamino-2-chloro-isonicotinic acid in 50 mL of methanol and 100 mL of chloroform was at 0° C. was added 15 mL of 2 M (trimethylsilyl)diazomethane in hexanes. After allowing the reaction to warm to ambient temperature and stirring for 2 hours, the solvents were removed and the crude product purified by passing through a plug of silica gel with chloroform. The product was then recrystallized from hexanes to give 5.8 g (100%) of 5-tert-butoxycarbonylamino-2-chloro-isonicotinic acid, methyl ester: mp=90-96° C. (decomposed); mass spectrum (m/e): M+H 287.1.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]2[C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH2:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:17]([NH:20]C1C=CC=C2C=1C(=O)CCC2)(=[O:19])[CH3:18]>>[C:1]([NH:4][C:5]1[C:10]2[C:11](=[O:16])[CH:12]([NH:20][C:17](=[O:19])[CH3:18])[CH2:13][CH2:14][CH2:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1C(=O)CCCC2
Reactant: CC(=O)Nc1cccc2c1C(=O)CCC2
Product: CC(=O)Nc1cccc2c1C(=O)C(NC(C)=O)CCC2

Procedure:
The reaction was carried out in the same manner as in Example 1-(2), except that 270 mg of the compound prepared in (2) above was used instead of 8-acetylamino-1-tetralone of Example 1-(2). The reaction mixture obtained by the post-treatment was further reacted in the same manner as in Example 1-(3) and post-treated to produce 126 mg of the title compound.
Reaction SMILES: [C:1]([C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=O)([CH3:4])([CH3:3])[CH3:2].[CH3:14][NH:15][NH2:16].S(=O)(=O)(O)O>C(O)C>[CH3:14][NH:15][N:16]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: CC(C)(C)C(=O)c1ccc(Cl)cc1
Reactant: CNN
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CNN=C(c1ccc(Cl)cc1)C(C)(C)C

Procedure:
29.5 g ofg 4-chlorophenyl tert.-butyl ketone (0.15 mol) in 750 ml ethanol was heated under reflux with an excess (118 ml) of methl hydrazine and 3 ml of concentrated sulphuric acid for 4.5 hours. It was concentrated almost to dryness and the added to water. After extraction with methylene chloride and then drying and concentrating the extract in vacuo, there was obtained an oil which eventually crystallised. The resulting crude product used immediately.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[C:9]2[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:19][C:8]=2[C:7]=1[OH:26])=[O:5])C.[NH2:27][CH2:28][C:29]([OH:31])=[O:30]>C[O-].[Na+].CO>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:10]1[C:9]2[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:19][C:8]=2[C:7]([OH:26])=[C:6]([C:4]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5])[N:11]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(-c2ccco2)c2nc(-c3ccccc3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1nc(-c2ccco2)c2nc(-c3ccccc3)sc2c1O
Temperature: 25 °C
Yield: 53 %

Procedure:
A mixture of 4-furan-2-yl-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (78 mg, 0.21 mmole) and glycine (320 mg, 4.26 mmole) in 0.5 M sodium methoxide/methanol (8.1 ml) was refluxed for 4 days before it was cooled to room temperature and concentrated in vacuo. Water (100 ml) and 0.1 N HCl (2.5 ml) were added to the residue and the suspension was extracted with dichloromethane (3×50 ml) and methyl tert-butyl ether (1×50 ml). The resulting yellow-green aqueous solution was acidified to pH=2 with 0.1 N HCl (3.5 ml). The resulting suspension was extracted with dichloromethane, washed with brine, dried over sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (44 mg). 1H NMR (DMSO-d6, 200 MHz): δ=9.17 (t, 1H), 8.25 (m, 2H), 7.94 (m, 1H), 7.82 (m, 1H), 7.64 (m, 3H), 6.76 (m, 1H), 4.08 (d, J=6.2 Hz, 2H); MS: (+) m/z 395.94 (M+1), (−) m/z 393.94 (M−1).
Reaction SMILES: Cl.[CH2:2]([NH:9][OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=O.[C:13](=O)(O)[O-].[Na+].[P:18]([O-:35])([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:2]([N:9]([CH2:13][P:18](=[O:35])([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C([O-])O
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: ONCc1ccccc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=P(CN(O)Cc1ccccc1)(OCc1ccccc1)OCc1ccccc1
Temperature: 59 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
A mixture of 2.0 g (12.5 mmol) of N-benzylhydroxylamine hydrochloride, 0.75 g (25 mmol) of paraformaldehyde, 1.0 g (12 mmol) of sodium bicarbonate and 40 ml of tetrahydrofuran (THF) is stirred at 59° C. for one hour. To the resultant mixture is then added dropwise over a three-hour period a solution of 3.6 g (13.7 mmol) of dibenzyl phosphite in 40 ml of THF. The reaction mixture is then stirred for 14 hours at 55° C. The reaction mixture is concentrated in vacuo to 20 ml volume and 500 ml of ethyl acetate is added. The organic phase is separated and washed sequentially with a saturated solution of sodium bicarbonate and a saturated solution of sodium chloride. The organic phase is dried over anhydrous magnesium sulfate and the solvent removed in vacuo. The residue is purified by column chromatography (silica gel, 20:1, methylene chloride:ethyl acetate eluent) followed by recrystallization from a mixture of methylene chloride, ethyl acetate and hexane to give 1.95 g (40% yield) of a white solid melting at 62°-64° C.
Reaction SMILES: CCN(C(C)C)C(C)C.Br[CH2:11][C:12]([C:14]1[CH:23]=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=2)[N:15]=1)=[O:13].[C:25]([O:29][C:30]([N:32]1[C@H:37]([C:38]([OH:40])=[O:39])[CH2:36][C@@H:35]2[C@H:33]1[CH2:34]2)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(#N)C>[C@@H:33]12[CH2:34][C@@H:35]1[CH2:36][C@@H:37]([C:38]([O:40][CH2:11][C:12]([C:14]1[CH:23]=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=3)[N:15]=1)=[O:13])=[O:39])[N:32]2[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Reactant: O=C(CBr)c1cnc2cc(Br)ccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)OCC(=O)c1cnc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
DIPEA (0.040 mL, 0.227 mmol) was added to a solution of 2-bromo-1-(6-bromoquinoxalin-2-yl)ethanone (50 mg, 0.152 mmol) and (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (37.9 mg, 0.167 mmol) in acetonitrile (1.5 mL) and the mixture was stirred at rt for 16 h. The solvent was evaporated and the residue was partitioned between EtOAc (20 mL)/aq. sat. NaHCO3 (5 mL). The organic layer was dried (MgSO4), filtered and concentrated to yield crude (1R,3S,5R)-3-(2-(6-bromoquinoxalin-2-yl)-2-oxoethyl) 2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (63 mg) as orange solid. LC-MS retention time 2.74 min; m/z 476 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water:10% methanol:0.1% TFA. Solvent B=10% water:90% methanol:0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:16][N:17]([CH3:32])[C:18]([C:20]1[CH:21]=[N:22][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:24][CH:25]=1)=[O:19].CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH3:16][N:17]([CH3:32])[C:18]([C:20]1[CH:21]=[N:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1)=[O:19]
Reactant: CN(C)C(=O)c1ccc(N2CCNCC2)nc1
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(N2CCN(C(=O)/C=C/C(F)(F)F)CC2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.3 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (32 mg, 0.23 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (20 μl, 0.23 mol) and one drop of DMF were added and the resulting solution was stirred at room temperature for 10 minutes. This solution was added to a solution of N,N-dimethyl-6-piperazin-1-yl-pyridine-3-carboxamide (35 mg, 0.15 mmol) and DIPEA (80 μl, 0.5 mmol) in anhydrous DCM (2 ml) and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 39 mg of a solid (0.11 mmol, yield 48%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(#N)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1nc(Cl)nc(OC)n1
Solvent: CC#N
Product: COc1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(OC)n1
Yield: 100 %

Procedure:
A mixture of 2-chloro-4,6-dimethoxy-[1,3,5]triazine (1.35 g, 7.68 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.00 g, 9.98 mmol, 1.3 equiv; commercially available) in acetonitrile (16 mL) was heated by microwave irradiation to 160° C. for 20 min. The organic phase was concentrated under reduced pressure and the residue extracted with ethyl acetate (3×50 mL) from a solution of 1 M NaOH (200 mL). The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure yielding 2.60 g (100%) of the title compound. MS (ISP): 340.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17](O)=[O:18])[CH:13]=3)[C:8]2=[O:20])=[CH:4][CH:3]=1.[N:23]1([CH2:28][CH2:29][NH2:30])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl-:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17]([NH:30][CH2:29][CH2:28][NH+:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[O:18])[CH:13]=3)[C:8]2=[O:20])=[CH:21][CH:22]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)N(Cc1ccc(Cl)cc1)C2=O
Reactant: NCCN1CCCC1
Product: O=C(NCC[NH+]1CCCC1)c1ccc2c(c1)C(=O)N(Cc1ccc(Cl)cc1)C2=O
Product: [Cl-]

Procedure:
2-(4-chloro-benzyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-carboxylic acid (100 mg, 0.316 mmol) and 2-pyrrolidin-1-yl-ethylamine (100 μL, 0.792 mmol) were reacted with each other. Target compound in the amount of 106 mg (75%) was obtained by following the procedure described in Example 1.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=3[N:10]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:9]2=[O:29])[CH2:4][CH2:3]1.[S:30](N)([NH2:33])(=[O:32])=[O:31]>COCCOC>[NH2:33][S:30]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=3[N:10]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:9]2=[O:29])[CH2:4][CH2:3]1)(=[O:32])=[O:31]
Reactant: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](N)CC3)c3ccc(C#N)cc32)cc1Cl
Reactant: NS(N)(=O)=O
Solvent: COCCOC
Product: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](NS(N)(=O)=O)CC3)c3ccc(C#N)cc32)cc1Cl

Procedure:
A mixture of 1-(trans-4-aminocyclohexyl)-3-(3-chloro-4-methoxybenzyl)-5-cyano-2,3-dihydro-1H-benzimidazol-2-one (90 mg) and sulfamide (42 mg) in ethylene glycol dimethyl ether (3 mL) was refluxed overnight. The mixture was concentrated in vacuo, and the residue was partitioned between chloroform and water. The separated organic layer was washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was subjected to a preparative thin-layer chromatography eluting with a mixture of chloroform and methanol (10:1). The obtained crystals were collected by filtration and washed with diethyl ether to give 1-(trans-4-aminosulfonamidocyclohexyl)-3-(3-chloro-4-methoxybenzyl)-5-cyano-2,3-dihydro-1H-benzimidazol-2-one (41 mg) as powders.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21]C)[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:5][C:4]=2[N:3]=1>ClCCl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][OH:21])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25]([N:27]([CH3:28])[CH3:29])=[O:26])=[CH:5][C:4]=2[N:3]=1
Reactant: COCc1nc2c(N)nc3cc(CCC(=O)N(C)C)ccc3c2n1CC(C)(C)O
Solvent: ClCCl
Product: CN(C)C(=O)CCc1ccc2c(c1)nc(N)c1nc(CO)n(CC(C)(C)O)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
A stirring solution of 3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N,N-dimethylpropanamide (523 mg, 1.31 mmol) in dichloromethane (125 mL) was sealed with a septum and purged with nitrogen gas. The solution was cooled in an ice/water bath and a 1.0 M solution of boron tribromide in dichloromethane (6.6 mL) was added via syringe. The resulting mixture was stirred for 18 hours while warming to ambient temperature. Methanol (50 mL) was added and the mixture was concentrated under reduced pressure. The resulting solid was dissolved in a 2.0 M solution of ammonia in methanol (75 mL) and the solution was concentrated under reduced pressure to yield a solid. This step was repeated two more times with silica gel (1 tbsp) being added prior to the final concentration. The sample absorbed on silica was purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient; 0-25% CMA over 1200 mL, followed by 25-40% CMA over 1300 mL) to provide 298 mg of 3-[4-Amino-2-(hydroxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N,N-dimethylpropanamide as a white crystalline solid, mp 228-230° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2(C3C=CC(NCCN(C)C)=CC=3)[NH:15][C:10]3[CH:11]=[N:12][CH:13]=[CH:14][C:9]=3[NH:8]2)=[N:4][O:5][N:6]=1.[H-].[Na+].Cl.C[N:32]([CH3:36])[CH2:33][CH2:34]Cl.[CH3:37][N:38]([CH:40]=O)[CH3:39]>>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:9]3[CH:10]=[CH:11][C:33]([NH:32][CH2:36][CH2:40][N:38]([CH3:39])[CH3:37])=[CH:34][CH:14]=3)[C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:15]=2)=[N:4][O:5][N:6]=1
Reactant: CN(C)CCCl
Reactant: CN(C)CCNc1ccc(C2(c3nonc3N)Nc3ccncc3N2)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCNc1ccc(-n2c(-c3nonc3N)nc3cnccc32)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 4 %

Procedure:
To a solution containing 500 mg the product from Step 1 (1.7 mmol) in 10 mL DMF was added 200 mg of NaH (60% dispension in oil, 5.1 mmol). After 2 hours at room temperature, 246 mg of 2-(dimethylamino)ethyl chloride hydrochloride (1.7 mmol) was added, and the reaction mixture was heated to 60° C. for 5 hours. The solvent was evaporated in vacuo to yield a residue which was partitioned between ethyl acetate and brine. The organic phase was dried over anhydrous sodium sulphate, filtered, and concentrated in vacuo. Purification of the residue by Gilson reverse-phase HPLC afforded the title compound (24 mg, 4%). MS (ES+) m/e 365 [M+H]+.