Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][N:10]2[C:20](=[O:21])[CH2:19][NH:18][C:17](=O)[CH:16]=[C:11]23)[N:3]=[CH:2]1.ClCCCl.[CH3:27][O:28][CH2:29][C:30]1[N:31]=[CH:32][NH:33][CH:34]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:27][O:28][CH2:29][C:30]1[N:31]=[CH:32][N:33]([C:17]2[CH:16]=[C:11]3[C:12]4[C:7]([CH2:8][CH2:9][N:10]3[C:20](=[O:21])[CH2:19][N:18]=2)=[C:6]([C:4]2[N:3]=[CH:2][S:1][CH:5]=2)[CH:15]=[CH:14][CH:13]=4)[CH:34]=1
Reactant: O=C1C=C2c3cccc(-c4cscn4)c3CCN2C(=O)CN1
Reactant: COCc1c[nH]cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: COCc1cn(C2=NCC(=O)N3CCc4c(cccc4-c4cscn4)C3=C2)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 13.1 %

Procedure:
Example 101. To a stirred solution of 9-(thiazol-4-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (160 mg, 0.51 mmol) in 1,2-dichloroethane (4 mL) POCl3 (0.096 mL, 1.03 mmol) was added and the resulting suspension was stirred at 100° C. for 1 h. The reaction mixture was cooled to rt and concentrated under reduced pressure to dryness. For complete removal of POCl3 the residue was taken up in toluene and evaporated twice again and dried under high vacuo. The resulting crude chloro compound was dissolved in 1,2-dichloroethane (4 mL), 4-(methoxymethyl)-1H-imidazole (172 mg, 1.53 mmol) was added and the mixture was stirred at 100° C. for 2 h. The reaction mixture was allowed to warm to rt and diluted with DCM. Saturated aqueous NaHCO3 solution was added and the mixture was extracted twice with DCM. The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by SFC (column: Reprosil 70 NH2, 5 μm, 250×30 mm, Dr. Maisch; eluent: 14% MeOH/CO2 for 1 min, then from 14% MeOH/CO2 to 19% MeOH/CO2 in 6 min; flow 100 mL/min; UV detection at 220 nm) to yield the title compound as white powder (27 mg). UPLC-MS: MS 406.2 (M+H+); UPLC rt 0.78 min. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.14 (t, J=5.9 Hz, 2 H), 3.42 (s, 3 H), 3.85 (t, J=6.1 Hz, 2 H), 4.39 (br. s., 2 H), 4.44 (s, 2 H), 6.61 (s, 1 H), 7.37-7.50 (m, 3 H), 7.68 (d, J=7.8 Hz, 1 H), 7.72 (d, J=7.8 Hz, 1 H), 8.04 (s, 1 H), 8.95 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:17]([CH3:20])([CH3:19])[CH3:18])[NH:5][C:6]=1[C:7]([N:9]1[CH2:15][CH2:14][C:13](=[O:16])[NH:12][CH2:11][CH2:10]1)=[O:8].[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>C1COCC1.C(OCC)(=O)C>[C:17]([C:4]1[NH:5][C:6]([C:7]([N:9]2[CH2:15][CH2:14][C:13](=[O:16])[NH:12][CH2:11][CH2:10]2)=[O:8])=[C:2]([NH:1][C:30]([NH:29][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=2[Cl:21])=[O:31])[CH:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1cc(N)c(C(=O)N2CCNC(=O)CC2)[nH]1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)c(C(=O)N2CCNC(=O)CC2)[nH]1
Temperature: 70 °C
Yield: 50 %

Procedure:
The previously prepared 1-(4-amino-2-tert-butyl-1H-pyrrole-5-carbonyl)-1,4-diazepan-5-one (8 mg, 0.03 mmol) and 2,3 dichlorophenyl isocyanate (5 mg, 0.03 mmol) were dissolved in THF (2 mL) and heated at 70° C. for 2 hours. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried and the solvent eliminated under vacuum. The crude product was purified by preparative thin layer chromatography using a mixture of dichloromethane:methanol 9:1 as elution solvent to afford 7.0 mg of 1-(5-tert-butyl-2-(5-oxo-1,4-diazepane-1-carbonyl)-1H-pyrrol-3-yl)-3-(2,3-dichloro-phenyl)urea as a white solid. 1H NMR (400 MHz, acetone-d6): δ (ppm) 9.60 (bs, 1H); 8.60 (d, 2H); 8.26 (d, 1H); 7.30 (t, 1H); 7.20 (d, 1H); 6.84 (t, 1H); 6.59 (d, 1H); 3.76 (m, 2H); 3.70 (m, 2H); 3.40 (m, 2H); 2.61 (m, 2H); 1.37 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[NH:4][N:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:7]([C:6]1[C:2]([NH:1][C:22](=[O:24])[CH3:23])=[N:3][NH:4][C:5]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)#[N:8]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1c(N)n[nH]c1N1CCN(Cc2ccccc2)CC1
Product: CC(=O)Nc1n[nH]c(N2CCN(Cc3ccccc3)CC2)c1C#N

Procedure:
A 2.82 g (0.01 mole) amount of 3-amino-5-(4-benzyl-1-piperazinyl)-4-pyrazolecarbonitrile (prepared as described in Example 8) was added to 50 ml of acetic anhydride with stirring. After nearly complete solution a heavy precipitate was formed. The mixture was stirred for 18 hours at room temperature beneath a drying tube containing a desicant.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[Br:19]N1C(=O)CCC1=O>>[Br:19][C:7]1[CH:6]=[C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: CN(C)S(=O)(=O)c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: CN(C)S(=O)(=O)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
A solution of 4-fluoro-N,N-dimethylbenzenesulfonamide (1.80 g; 8.86 mmol) in conc. sulfuric acid (7 ml; 130 mmol) was treated with N-bromosuccinimide (1 730 mg; 9.74 mmol) and stirred at RT for 3 h. The reaction mixture was carefully poured on crushed ice, extracted with AcOEt and the organic phase was washed with a 0.1 N solution of NaOH in water twice, then with brine twice. The organic phase was dried on MgSO4, filtered and concentrated under reduced pressure to give the title compound as a white solid (2.04 g, 82%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH:16]([OH:17])[CH:15]([Cl:18])[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][C:5]=2[CH2:4]1>FC(F)(F)C(O)=O>[ClH:18].[NH2:2][CH:3]1[C:16](=[O:17])[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][C:5]=2[CH2:4]1
Reactant: NC1Cc2ccc3ccccc3c2C(Cl)C1O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: NC1Cc2ccc3ccccc3c2CC1=O
Yield: 48.8 %

Procedure:
2-Amino-4-chloro-1,2,3,4-tetrahydro-3-phenanthrenol, hydrochloride (40 mg) was refluxed in trifluoroacetic acid (17 ml) for 31/2hours. The solvent was removed in vacuo and the residue was crystallized from a cyclohexane/ethyl acetate mixture to yield the title compound (17 mg) as a cream colored powder.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:3]=1.[CH:14]1(/[C:17](/O)=[CH:18]/[C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1>C(O)(=O)C>[CH:14]1([C:17]2[CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]3[C:2]([CH3:1])=[N:3][N:4]([CH:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[C:5]=3[N:7]=2)[CH2:15][CH2:16]1
Reactant: Cc1cc(N)n(C2CCOCC2)n1
Reactant: CCOC(=O)C(=O)/C=C(\O)C1CC1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CCOCC1
Temperature: 117 °C

Procedure:
A mixture of 3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine (380 mg, 2.097 mmol), ethyl (3Z)-4-cyclopropyl-4-hydroxy-2-oxo-3-butenoate (386 mg, 2.097 mmol) and acetic acid (50 mL) were heated at 117° C. for 2 hours. The solvent was removed in vacuo, and the crude residue was purified via silica gel chromatography (eluent: 0 to 25% EtOAc:Hex). The desired product was collected as a solid, 300 mg (43%). LCMS E-S (M+H)=330.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.12 (m, 4 H), 1.37 (t, J=7.20 Hz, 3 H), 1.82 (dd, J=12.51, 2.40 Hz, 2 H), 2.16 (qd, J=12.21, 4.55 Hz, 2 H), 2.29-2.42 (m, 1 H), 2.54 (s, 3 H), 3.47-3.60 (m, 2 H), 3.99 (dd, J=11.37, 3.79 Hz, 2 H), 4.42 (q, J=7.24 Hz, 2 H), 4.92 (tt, J=11.59, 4.20 Hz, 1 H), 7.46 (s, 1 H).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([CH:23]4[CH2:27][CH2:26][C:25](=O)[CH2:24]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.Cl.[NH:31]1[CH2:34][CH2:33][CH2:32]1>>[F:1][C:2]1([F:29])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([CH:23]4[CH2:27][CH2:26][CH:25]([N:31]5[CH2:34][CH2:33][CH2:32]5)[CH2:24]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: C1CNC1
Reactant: O=C1CCC(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)C1
Agent: Cl
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3CCC(N4CCC4)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 133 using 6-chloro-2-(3-oxo-cyclopentyl)-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, and azetidine hydrochloride. 1H NMR (400 MHz, DMSO-d6): δ 10.08 (m, 1H), 8.81 (t, J=4.41 Hz, 1H), 8.06-8.03 (m, 1H), 8.00-7.96 (m, 1H), 7.81-7.77 (m, 1H), 7.62-7.58 (m, 1H), 4.17-4.06 (m, 5H), 4.06-4.04 (m, 1H), 3.29-3.26 (m, 2H), 2.50-2.44 (m, 5H), 2.07-2.03 (m, 3H), 1.90-1.84 (m, 7H), 1.78-1.74 (m, 1H), 1.31-1.27 (m, 2H). m/z: 462.3 [M+H]+
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Cl.O>CN(C)C=O>[CH:3]1([CH2:9][O:10][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OCC1CCCCC1
Reactant: ClCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: BrCCCCCOCC1CCCCC1
Yield: 419.4 %

Procedure:
60% Sodium hydride (1.16 g) was suspended in dimethylformamide (40 ml), and a solution of cyclohexanemethanol (0.3 g) in dimethylformamide (10 ml) was dropwise added under ice-cooling with stirring, which was followed by stirring at room temperature for 1 hr. The mixture was again ice-cooled, and a solution of 1-bromo-5-chloropentane (4.88 g) in dimethylformamide (10 ml) was dropwise added, which was followed by stirring at room temperature for 2.5 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 2.9 g of 5-(cyclohexylmethoxy)pentyl bromide.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[C:16](=[O:17])[CH:15]3[CH2:18][CH2:19][CH:12]2[CH2:13][CH2:14]3)=[CH:5][CH:4]=1)#[CH:2].C([Li])CCC.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[O:17]=[C:16]1[CH:15]2[CH2:18][CH2:19][CH:12]([CH2:13][CH2:14]2)[N:11]1[CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:21][CH:20]=1
Reactant: CCOC(=O)Cl
Reactant: C#Cc1ccc(OCCCN2C(=O)C3CCC2CC3)cc1
Agent: [Li]CCCC
Product: CCOC(=O)C#Cc1ccc(OCCCN2C(=O)C3CCC2CC3)cc1

Procedure:
In the a) route at scheme 2,2-azabicyclo[2.2.2]octan-3-one(isoquinuclidine-3-one) (4) is treated with sodium hydride (NaH) in DMF, then it is reacted with the intermediate as above (3) in the presence of potassium iodide to yield 2-[3-(4-ethynylphenoxy)propane-1-yl]-2-azabicyclo[2.2.2]octane-3-one (compound 5). Further, compound 5 is treated with n-butyl lithium (n-BuLi), then it is reacted with ethyl chloroformate to obtain ethyl 4-[3-(3-oxo-2-azabicyclo[2.2.2]octan-2-yl)propoxy]phenylpropiolate (compound 6). Then 4-[3-(3-oxo-2-azabicyclo[2.2.2]octan-2-yl)propoxy]phenylpropiolic acid (compound 7) is provided by the hydrolysis of compound 6 using 10% sodium hydroxide in water solution (10% NaOHaq).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])=[C:14]([CH3:24])[CH:13]=1.[CH3:25][N:26]1[CH2:31][CH2:30][C:29]2([C:42]3[C:34](=[CH:35][C:36]4[CH2:37][CH2:38][NH:39][C:40]=4[CH:41]=3)[O:33][CH2:32]2)[CH2:28][CH2:27]1>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH:27]2[CH2:28][C:29]3([C:42]4[C:34](=[CH:35][C:36]5[CH2:37][CH2:38][NH:39][C:40]=5[CH:41]=4)[O:33][CH2:32]3)[CH2:30][CH2:31][N:26]2[CH3:25])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])=[C:14]([CH3:24])[CH:13]=1
Reactant: COC(=O)c1ccc(-c2ccc(N3CCCC3=O)c(C)c2)c(C)c1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Product: Cc1cc(C(=O)C2CC3(CCN2C)COc2cc4c(cc23)NCC4)ccc1-c1ccc(N2CCCC2=O)c(C)c1

Procedure:
The title compound was prepared from methyl 2,3'-dimethyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-carboxylate (D32) and 1'-methyl-2,3,6,7-tetrahydrospiro[filro[2,3-f]indole-3,4'-piperidine] (D7) following the method of Example 1. This was obtained as a yellow oil (77%), which was converted to its hydrochloride salt, crystallising from acetone.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:29][CH2:30][CH2:31][C:32]([F:35])([F:34])[F:33])[C:10]3[N:11]([C:13]([C:16]4[CH:27]=[CH:26][C:19]([C:20](NC5CC5)=[O:21])=[C:18]([CH3:28])[CH:17]=4)=[CH:14][N:15]=3)[N:12]=2)=[CH:4][CH:3]=1.Br.[OH2:39]>>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:29][CH2:30][CH2:31][C:32]([F:33])([F:35])[F:34])[C:10]3[N:11]([C:13]([C:16]4[CH:27]=[CH:26][C:19]([C:20]([OH:21])=[O:39])=[C:18]([CH3:28])[CH:17]=4)=[CH:14][N:15]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2cnc3c(NCCC(F)(F)F)cc(Oc4ccc(Cl)cc4)nn23)ccc1C(=O)NC1CC1
Reactant: O
Agent: Br
Product: Cc1cc(-c2cnc3c(NCCC(F)(F)F)cc(Oc4ccc(Cl)cc4)nn23)ccc1C(=O)O

Procedure:
A mixture comprising 300 mg (566 μmol) 4-{6-(4-chlorophenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide and 13.4 mL hydrobromic acid was heated at 120° C. for 2.5 days. Water was added, the precipitate filtered off to give the crude title compound that was used without further purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O.O>[CH2:14]([O:10][C:7]1[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][C:6]=1[N+:11]([O-:13])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
60% Sodium hydride dispersion in oil (4.4 g, 0.11 mol) was added in portions over 15 minutes to a stirred solution of 4-chloro-2-nitrophenol (17.4 g, 0.10 mol) in dimethylformamide (200 ml) at 0°-5° C. The mixture was stirred for 15 minutes then benzyl chloride (12.7 g, 0.10 mol) was added dropwise over 5 minutes. The mixture was stirred for 5 days at room temperature, diluted with water and extracted with ether. The extract was washed three times with water, dried and evaporated and the residue was triturated with petroleum spirit.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[N:18]=[C:17]([NH2:19])[N:16]=[C:15]([NH2:20])[CH:14]=1>O.C(O)(=O)C>[CH3:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[N:18]=[C:17]([NH2:19])[N:16]=[C:15]([NH2:20])[C:14]=1[N:1]=[O:3]
Reactant: COCCOCCOc1cc(N)nc(N)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COCCOCCOc1nc(N)nc(N)c1N=O
Reaction time: 2 h
Yield: 349.9 %

Procedure:
A solution of 9.11 g (0.013 mol) of sodium nitrite in 40 ml of water was added in drops to a solution of 22.8 g (0.100 mol) of 6-[2-(2-methoxyethoxyl)ethoxy]pyrimidine-2,4-diamine in 200 ml of acetic acid (10% in water) over 1 h at 3-5° C. while stirring was performed. Then stirring was performed further for 2 h at room temperature. The resulting precipitate was sucked off, post-washed with water, and dried, whereby 6-[2-(2-methoxyethoxyl)ethoxy]-5-nitrosopyrimidine-2,4-diamine (11.7 g, 45%) was obtained as a purple solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.C([Li])CCC.CON(C)[C:21]([CH:23]1[CH2:26][CH:25]([NH:27][C:28]2[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:24]1)=[O:22]>O1CCCC1>[CH3:1][O:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:21]([CH:23]1[CH2:24][CH:25]([NH:27][C:28]2[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:26]1)=[O:22]
Reactant: COCn1cnc2ccccc21
Reactant: CON(C)C(=O)C1CC(Nc2ncccc2[N+](=O)[O-])C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCn1c(C(=O)C2CC(Nc3ncccc3[N+](=O)[O-])C2)nc2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
To a solution of 1-(methoxymethyl)-1H-benzo[d]imidazole (1.5 g, 9.04 mmol) in dry tetrahydrofuran (20 mL) at −78° C. was added butyllithium (2.5 M in hexane, 3.7 mL, 9.16 mmol). The solution was stirred at −78° C. for 30 min and a solution of N-methoxy-N-methyl-3-((3-nitropyridin-2-yl)amino)cyclobutanecarboxamide (1.92 g, 6.87 mmol) in dry tetrahydrofuran (20 mL) was added dropwise via cannula. The reaction mixture was stirred at −78° C. for 30 minutes and then warmed to room temperature and quenched with water. The reaction mixture was extracted with ethyl acetate (3×30 mL) and the organic phases were combined and washed with water (20 mL), then brine (20 mL). The organic was dried over magnesium sulfate and concentrated to get a residue, which was purified by flash column chromatography on silica gel (10% to 40% ethyl acetate in hexanes) to give (1-(methoxymethyl)-1H-benzo[d]imidazol-2-yl)(3-((3-nitropyridin-2-yl)amino)-cyclobutyl)methanone (1.17 g, 3.07 mmol, 80% yield) as solid.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1.Cl.[NH2:20][OH:21].[OH-].[Na+].Cl>C(O)C.O>[OH:21][N:20]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1
Reactant: CC(C(=O)O)c1ccc(CC2CCCC2=O)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc(CC2CCCC2=NO)cc1
Temperature: 0 °C
Yield: 88 %

Procedure:
To a solution of 1.5 g of 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propionic acid in 10 ml of ethanol was added a solution of 0.43 g of hydroxylamine hydrochloride in 2 ml of water, subsequently a solution of 0.76 g of sodium hydroxide in 2 ml of water, and the mixture was heated under reflux for 3 hours. The reaction mixture was poured into an ice-water, acidified by addition of hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent removed by distillation to give 1.4 g of crystals of the desired compound. Recrystallization of the product from a mixture of ether-n-hexane afforded colorless crystals, m.p. 146°-148° C.
Reaction SMILES: [OH:1][CH2:2][C@:3]([C:6]1[CH:24]=[CH:23][C:9]([C:10]([NH:12][C:13]2[N:18]=[CH:17][C:16]3[CH:19]=[CH:20][N:21]([CH3:22])[C:15]=3[CH:14]=2)=[O:11])=[CH:8][CH:7]=1)([OH:5])[CH3:4].C1C(=O)N([Cl:32])C(=O)C1>CN(C=O)C>[Cl:32][C:19]1[C:16]2[CH:17]=[N:18][C:13]([NH:12][C:10](=[O:11])[C:9]3[CH:23]=[CH:24][C:6]([C@@:3]([OH:5])([CH3:4])[CH2:2][OH:1])=[CH:7][CH:8]=3)=[CH:14][C:15]=2[N:21]([CH3:22])[CH:20]=1
Reactant: Cn1ccc2cnc(NC(=O)c3ccc([C@](C)(O)CO)cc3)cc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Cn1cc(Cl)c2cnc(NC(=O)c3ccc([C@](C)(O)CO)cc3)cc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
(S)-4-(1,2-dihydroxypropan-2-yl)-N-(1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide (650 mg, 2.0 mmol) was dissolved in DMF (25 ml) and NCS (270 mg, 2.0 mmol) was added to the mixture, which was stirred at 50° C. for 16 hours. The mixture was then poured into 50 ml ice water and was extracted into ethyl acetate (3×100 ml). Combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by preparatory HPLC (TFA mode, 15-50% ACN in water). Fractions containing the desired mono chlorinated product were combined, concentrated, washed with saturated NaHCO3 and brine, and then extracted into ethyl acetate (2×100 ml). Combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the title compound (S)—N-(3-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide (120 mg, 0.32 mmol, 16%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (s, 2H) 2.43-2.64 (m, 1H) 3.46 (dd, J=5.56, 2.53 Hz, 2H) 3.69-3.84 (m, 2H) 4.76 (t, J=5.81 Hz, 1H) 5.04 (s, 1H) 7.40-7.67 (m, 2H) 8.02 (d, J=8.59 Hz, 1H) 8.21-8.40 (m, 1H) 8.59 (s, 1H) 10.65 (s, 1H); ESI-MS: m/z 360 (M+H)+; m.p. 210-212° C.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1>O>[Cl:1][S:2]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:8]=1[O:7][CH3:6])[C:12]([OH:14])=[O:13])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(C(=O)O)cc1
Solvent: O
Product: COc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Reaction time: 3 h

Procedure:
To chlorosulfonic acid (20.00 ml) was added 4-methoxybenzoic acid (4.56 g) at 25° C. and stirred for 3 hours. Water was added at 0° C. to the reaction mixture, and the precipitated crystals were filtered, thereby giving 3.39 g of 3-chlorosulfonyl-4-methoxybenzoic acid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:10][C:11]([F:23])([F:22])[O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>>[F:10][C:11]([F:22])([F:23])[O:12][C:13]1[CH:18]=[C:17]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]#[N:9])[CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1cccnc1Cl
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: N#Cc1cccnc1-c1cccc(OC(F)(F)F)c1
Yield: 91 %

Procedure:
Prepared in 91% yield from 2-chloro-3-cyanopyridine and 3-trifluoromethoxyphenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 264.9 (M+H)+; 1H NMR (CDCl3) δ 7.37-7.45 (m, 2H), 7.57 (dd, J=8.0, 8.0 Hz, 1H), 7.82 (brs, 1H), 7.91 (d, J=7.8 Hz, 1H), 8.11 (dd, J=7.8, 1.7 Hz, 1H), 8.90 (dd, J=4.7, 1.7 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]2[NH:36][C:35]3[CH:37]=[C:38]([C:41]([F:44])([F:43])[F:42])[CH:39]=[CH:40][C:34]=3[N:33]=2)[CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:26]4[CH2:31][CH2:30][CH:29]([C:32]5[NH:36][C:35]6[CH:37]=[C:38]([C:41]([F:44])([F:43])[F:42])[CH:39]=[CH:40][C:34]=6[N:33]=5)[CH2:28][CH2:27]4)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: FC(F)(F)c1ccc2nc(C3CCNCC3)[nH]c2c1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: Cc1nc2nc(-c3ccc(CN4CCC(c5nc6ccc(C(F)(F)F)cc6[nH]5)CC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 120 h
Yield: 30 %

Procedure:
200 mg (0.64 mmol) 4-(2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde and 232 mg (0.64 mmol) 2-piperidine-4-yl-6-trifluoromethyl-1H-benzimidazole hydrochloride salt were treated as described in example 2.0. Additional NaBH(OAc)3 has been added after 24 and 26 hours (two equivalents each). After five days stirring at room temperature the solvents have been evaporated and the residue was purified via chromatography. 109 mg of the desired compound were obtained.