Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[CH3:26])[N:19]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[C:18]1=[O:34])[CH3:16].CC(C)([O-])C.[K+].O>CC(N(C)C)=O>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[CH3:26])[N:19]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:29][CH:28]=2)[C:18]1=[O:34])[CH3:16]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(C)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2nccc(C)c21
Temperature: 95 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
120s′) A solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (78.4 g, 371.33 mmol) in DMA (420 mL) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100.0 g, 371.33 mmol) and potassium tert-butoxide (51.5 g) in DMA (370 mL) at room temperature. The mixture was stirred at 90-100° C. for 1 h. Water (780 mL) was added at 90-100° C. The precipitate was collected at room temperature and dried under reduced pressure to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (127.7 g) as crystals. The obtained crystals (125.0 g) were dissolved in DMSO (1375 mL) at 90-95° C. To the solution was slowly added EtOH (1250 mL) at 80-95° C., and then the mixture was allowed to cool to room temperature. The solid was collected by filtration and washed with EtOH (625 mL) to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (103.9 g) as crystals.
Reaction SMILES: [C:1]([N:5]1[C:9]([Cl:10])=[C:8]([CH:11]=[O:12])[C:7]([C:13]([F:16])([F:15])[F:14])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO>[C:1]([N:5]1[C:9]([Cl:10])=[C:8]([CH2:11][OH:12])[C:7]([C:13]([F:14])([F:16])[F:15])=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(C(F)(F)F)c(C=O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)n1nc(C(F)(F)F)c(CO)c1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
A solution of 39.9 g (156.9 mmoles) of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 300 ml of methanol was cooled to 0° C. Thereto was gradually added 6.5 g (172.6 mmoles) of sodium borohydride. The mixture was stirred at room temperature for 3 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 37.7 g (yield: 93.6%) of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.
Reaction SMILES: [CH:1]1([C:6]2[C:15]([CH:16]([F:27])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[C:14]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:13]3[C:12](=[O:35])[CH2:11][C:10]([CH3:37])([CH3:36])[CH2:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Li].[Cl-].[NH4+].[C:42]1(C)C=CC=CC=1>CCOCC>[CH:1]1([C:6]2[C:15]([CH:16]([F:27])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][CH:18]=3)=[C:14]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[C:13]3[C:12]([CH3:42])([OH:35])[CH2:11][C:10]([CH3:37])([CH3:36])[CH2:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccccc1
Reactant: CC1(C)CC(=O)c2c(nc(C3CCCC3)c(C(F)c3ccc(C(F)(F)F)cc3)c2-c2ccc(F)cc2)C1
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(C)Cc2nc(C3CCCC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)cc3)c2C(C)(O)C1
Temperature: -78 °C

Procedure:
514 mg (1 mmol) of the keto compound from Example XI are dissolved in 50 ml of ether p.a. (which had been dried over a molecular sieve), and the mixture is cooled under argon to −78° C. and admixed dropwise with 3.1 ml (5 mmol, 5 eq.) of methyllithium (1.6 molar solution in ether). The solution is subsequently stored at −30° C. (deep freezer) for 20 hours. The solution is then cooled to −78° C. and admixed with 20 ml of ammonium chloride solution and 40 ml of toluene p.a. The cooling bath is removed and the solution is allowed to warm to room temperature. The organic phase is separated off, the aqueous phase is extracted twice with toluene and the combined organic phases are dried over Na2SO4, filtered and concentrated. The residue—dissolved in toluene—is chromatographed over 500 ml of silica gel using cyclohexane with a little added ethyl acetate as eluent.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]1([C:14]2([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24]>N1C=CC=CC=1>[C:8]1([C:14]2([NH:20][C:23](=[O:24])[C:22]([CH3:27])([CH3:26])[CH3:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC1(c2ccccc2)CCCCC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)NC1(c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
Into a 200 ml four-necked flask, there were charged toluene (150 ml), 1-phenylcyclohexylamine (10.5 g) and pyridine (5.2 g), and trimethylacetyl chloride (7.2 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, the reaction mixture was washed with water to remove pyridine hydrochloride. The toluene layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 9.8 g of N-(1-phenylcyclohexyl)trimethylacetamide. M.P., 129°-130.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12][S:13][C:14]2[NH:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:12][S:13]([C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)=[O:31])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Yield: 39.5 %

Procedure:
To a solution of 2-(3-methyl-4-propoxy-2-pyridyl)methylthiobenzimidazole (1 g) in chloroform (20 ml) was added dropwise over 10 minutes under ice-cooling m-chloroperbenzoic acid (750 mg) dissolved in chloroform (10 ml). The solution was chromatographed directly on a column of silica gel (50 g), which was eluted with ethyl acetatehexane (1:1) and then with 5% methanol-ethyl acetate. From the eluate was removed the solvent. The residue was recrystallized from acetone-ether-hexane to give 415 mg of 2-[3-methyl-4-propoxy-2-pyridyl)methylsulfinylbenzimidazole.4/5H2O as crystals, m.p. 81°-83° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C.[CH2:19]([CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22]Br)[CH3:20]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:22][CH:21]([CH2:19][CH3:20])[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: CCCCC(CC)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCC(CC)COc1ccc(OC)cc1
Yield: 80.4 %

Procedure:
A mixture of 4-methoxyphenol (100.0 g, 0.8 mol), dry potassium carbonate (166.7 g, 1.2 mol), acetonitrile (800 mL), and 2-ethylhexyl bromide (173.8 g, 0.9 mol) was stirred mechanically and heated at reflux for 4 days. After cooling, the mixture was diluted with water (1.5 L), and then the organic phase was separated. The aqueous layer was extracted with hexane, and the combined organic layers were washed two times with 1.0 M NaOH and water. After drying over MgSO4, the solvent was removed under reduced pressure to give an orange oil. The crude product was distilled under reduced pressure to give 152 g (80%) of a clear oil. (bp 135-138° C. at 0.4 mmHg).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Cl:15][C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:15][C:16]1[N:17]=[N:18][C:19]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:20][CH:21]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(Cl)nn1
Yield: 81.8 %

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (342 mg, 1.7 mmol), prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), in anhydrous toluene (8.5 mL) was treated with 3,6-dichloropyridazine (256 mg, 1.7 mmol, Aldrich Chemical Company) and triethylamine (0.24 mL, 170 mg, 1.7 mmol). The reaction mixture was heated to reflux for 16 hours, concentrated under reduced pressure, and the residue purified on SiO2 (5%MeOH/CH2Cl2/1%NH4OH) to provide the title compound (432 mg, 81% yield) as a white solid. 1H NMR (CDCl3, 300 MHz) δ 1.42(s, 4.5H), 1.46(s, 4.5H), 1.91-2.05(m, 2H), 3.36-3.46 (m, 3H), 3.54-3.60 (m, 1H), 4.57(s, 0.5H), 4.70(s, 0.5H), 4.92(s, 0.5H), 5.07(s, 0.5H), 6.59(d, J=9.20 Hz, 1H), 7.34(d, J=9.56 Hz, 1H); MS (DCI/NH3) m/z 311 (M+H)+, 328(M+NH4)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:22])=[C:10]2[C:23](O)=[O:24])=[C:5]([O:26][C:27]([F:30])([F:29])[F:28])[CH:4]=1)#[N:2].C(OCC)(=O)C.C(N1C=CN=C1)([N:39]1C=CN=C1)=O.N>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:22])=[C:10]2[C:23]([NH2:39])=[O:24])=[C:5]([O:26][C:27]([F:28])([F:30])[F:29])[CH:4]=1)#[N:2]
Reactant: CCOc1nccc2c1C(c1ccc(C#N)cc1OC(F)(F)F)C(C(=O)O)=C(C)N2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1OC(F)(F)F)C(C(N)=O)=C(C)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.477 mmol) of the compound from Example 37A are introduced into 5 ml of ethyl acetate and, after addition of 96.7 mg (0.596 mmol) of 1,1′-carbonyldiimidazole, stirred at room temperature overnight (TLC check: insufficient reaction). Then 1 ml of DMF is added, and the mixture is stirred at room temperature for a further night (TLC check: complete conversion). The volatile components are removed in a rotary evaporator, and the residue is taken up in 4 ml of DMF. Then 663 μl of ammonia (28% by weight solution in water, 4.77 mmol) are added, and the reaction mixture is heated at 100° C. in a closed vessel overnight. After cooling, the solvent is removed under reduced pressure, and the residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 140 mg (70% of theory) of the title compound are obtained.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].N1CCCC1.[N:13]1([C:19]2[C:20]3[N:28]=[C:27]([CH:29]=O)[CH:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CO>[N:13]1([C:19]2[C:20]3[N:28]=[C:27](/[CH:29]=[C:5]4/[C:4](=[O:6])[NH:3][C:2](=[O:7])[S:1]/4)[CH:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=Cc1ccc2ncnc(N3CCCCC3)c2n1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1NC(=O)/C(=C/c2ccc3ncnc(N4CCCCC4)c3n2)S1
Temperature: 70 °C
Yield: 48.8 %

Procedure:
A mixture of 2,4-thiazolidinedione (3.4 g; 29.1 mmol; 1.80 eq.), pyrrolidine (269.80 μL; 3.2 mmol; 0.2 eq.) in MeOH (50 mL) was heated at 70° C. A solution of 4-(1-piperidinyl)pyrido[3,2-d]pyrimidine-6-carbaldehyde (Intermediate 1.7) (3.9 g; 16.2 mmol; 1 eq.) in MeOH (50 mL) was slowly added over 1.5 hour at 70° C. After 2 h under reflux after the addition, the reaction was complete. A precipitate was formed. The hot reaction mixture was filtered and the solid was washed with cold MeOH to give (5Z)-5-{[4-(1-piperidinyl)pyrido[3,2-d]pyrimidin-6-yl]methylene}-1,3-thiazolidine-2,4-dione (1) (2.70 g; 48%) as an orange powder in 98% HPLC purity.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:38])[C:15]([O:28][CH2:29][O:30][C:31]([O:33][CH2:34][C:35](O)=[O:36])=[O:32])=[C:16]2[C:21](=[O:22])[N:20]3[C@@H:23]([CH3:26])[CH2:24][O:25][C@@H:19]3[CH2:18][N:17]2[CH:27]=1)=[O:12].[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:45][NH2:46].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[C:31](=[O:32])([O:33][CH2:34][C:35](=[O:36])[NH:46][CH2:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=1)[O:30][CH2:29][O:28][C:15]1[C:14](=[O:38])[C:13]([C:11]([NH:10][CH2:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[O:12])=[CH:27][N:17]2[C:16]=1[C:21](=[O:22])[N:20]1[C@@H:23]([CH3:26])[CH2:24][O:25][C@@H:19]1[CH2:18]2
Reactant: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCOC(=O)OCC(=O)O)c3C(=O)N12
Reactant: NCc1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCOC(=O)OCC(=O)NCc4ccccn4)c3C(=O)N12

Procedure:
The title compound was prepared from ({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)acetic acid (64 mg, 0.119 mmol), (2-pyridinylmethyl)amine (0.02 mL, 0.179 mL), N,N-diisopropylethylamine (0.03 mL, 0.179 mL), and HATU (69 mg, 0.179 mmol), using a process similar to that described in example 16, step (a). Purification by silica gel chromatography yielded the title compound as a white solid. 1H NMR (CDCl3) δ 10.09 (m, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.38 (s, 1H), 7.75 (m, 1H), 7.59 (m, 1H), 7.34-7.26 (m, 2H), 7.14 (m, 1H), 6.78 (m, 2H), 6.04 (d, J=6.8 Hz, 1H), 5.87 (d, J=6.8 Hz, 1H), 5.27-5.22 (m, 2H), 4.80-4.52 (m, 5H), 4.32-4.22 (m, 3H), 3.82 (m, 1H), 3.61 (m, 1H), 1.26 (d, J=6 Hz, 3H). ES+ MS: 628 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:8]=2[CH:21]=1)([OH:3])=O.[C:22]1([S:28]([NH2:31])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C)C=O>[C:22]1([S:28]([NH:31][C:1]([C:4]2[CH:5]=[CH:6][C:7]3[N:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[Cl:20])[C:8]=3[CH:21]=2)=[O:3])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1nc2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Reactant: NS(=O)(=O)c1ccccc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Product: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
N,N'-carbonyldiimidazole (0.973 g) was added to a solution of 0.902 g of 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole in 20 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 1 hour. Subsequently, a solution of 0.943 g of benzenesulfonamide and 0.913 g of diazabicycloundecene in 5 ml of N,N-dimethylformamide was added thereto, and the mixture was stirred at 100° C. for 70 hours. The reaction solution was cooled, and the solvent was distilled off under reduced pressure. Water and chloroform were added to the residue, and 10% hydrochloric acid was added thereto while being stirred until the aqueous layer was acidified. The mixed solution was extracted twice with chloroform. The resulting organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, and the solvent was distilled off under reduced pressure. The residue was dissolved in a small amount of chloroform, and ethyl acetate was added to the solution for crystallization. The crystals were separated through filtration, and were dried to give 0.667 g of 6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole (163).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH2:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:17]1([CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24](O)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[C:10]1([CH:9]([NH:16][C:24](=[O:25])[CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ccc(CC(N)c2ccccc2)cc1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1ccc(CC(NC(=O)C(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.4 %

Procedure:
2-(4-aminophenyl)-1-phenylethylamine (0.40 g, 1.9 mMol) and diphenylacetic acid (0.40 g, 1.9 mMol) were dissolved in dimethylformamide (DMF) (4 mL) at room temperature. To this was added HOBT (0.26 g, 1.9 mMol), NMM (0.19 g, 1.9 mMol) and EDCl (0.36 g) and the mixture was stirred at room temperature for 18 hours. The DMF was removed under vacuum and the oily residue was taken up in 100 mL ethyl acetate. The ethyl acetate was washed with saturated sodium bicarbonate and with brine, dried over magnesium sulfate, and evaporated to give 0.683 grams of a semi-solid. This was purified on 30 grams of flash-grade silica gel eluting with 100% dichloromethane to give 0.512 grams of the title compound, m.p. 161°-163° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[NH2:16][C@H:17]([CH3:23])[CH:18]([CH:20]1[CH2:22][CH2:21]1)[OH:19].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:16][C@H:17]([CH3:23])[CH:18]([CH:20]3[CH2:22][CH2:21]3)[OH:19])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: C[C@@H](N)C(O)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C(O)C1CC1
Temperature: 25 °C
Yield: 30.2 %

Procedure:
6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (272 mg, 0.989 mmol), (2R)-2-amino-1-cyclopropylpropan-1-ol hydrochloride (300 mg, 1.978 mmol) and DIPEA (0.691 ml, 3.96 mmol) were heated to 110° C. in NMP (3.297 ml) for 4 hrs. The reaction was then cooled to rt and ice-water added. After the ice had melted, the mixture was extracted with ethyl acetate (3×). The combined organics were then dried (MgSO4) and evaporated in vacuo before purifying by column chromatography using hexane ethyl acetate as eluent to give 6-bromo-4-(((2R)-1-cyclopropyl-1-hydroxypropan-2-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (111 mg, 0.299 mmol, 30.2% yield) as a mixture of diastereoisomers. 1H NMR (500 MHz, CCl3D) δ 7.93-7.78 (m, 1H), 7.68-7.52 (m, 1H), 6.93 (d, J=1.7 Hz, 1H), 5.44 (br. s., 1H), 4.53-4.27 (m, 1H), 4.13 (q, J=7.2 Hz, 1H), 2.99 (dd, J=9.2, 3.1 Hz, 1H), 1.48 (d, J=6.7 Hz, 3H), 1.27 (t, J=7.1 Hz, 2H), 1.14-0.99 (m, 1H), 0.65-0.53 (m, 2H), 0.43-0.27 (m, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5])[CH3:2]>C1COCC1.CCOC(C)=O.[Pd]>[NH2:19][C:15]1[CH:14]=[C:13]([C:9]2[S:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:11][C:10]=2[CH3:12])[CH:18]=[CH:17][CH:16]=1
Reactant: CCNC(=O)Nc1nc(C)c(-c2cccc([N+](=O)[O-])c2)s1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNC(=O)Nc1nc(C)c(-c2cccc(N)c2)s1
Reaction time: 2 h

Procedure:
A stirred solution of 1-Ethyl-3-[4-methyl-5-(3-nitro-phenyl)-thiazol-2-yl]-urea (98c) (0.55 g, 1.8 mmol) in THF (25 ml) and EtOAc (50 ml) under Argon is treated with 10% palladium on carbon (1.0 g). The reaction mixture was placed under an atmosphere of hydrogen for 2 hours. The mixture was then filtered through Celite™ filter material and the solvent removed in vacuo to yield the titled compound.
Reaction SMILES: CO.[CH:3]1([O:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([CH3:45])=[CH:12][C:13](=[O:44])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([N:25]([CH2:33][C:34]4[CH:43]=[CH:42][C:37]5[O:38][CH2:39][CH2:40][O:41][C:36]=5[CH:35]=4)C(=O)OC(C)(C)C)[CH2:21][CH2:20]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4]1.[ClH:46].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:46].[CH:3]1([O:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([CH3:45])=[CH:12][C:13](=[O:44])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][CH:22]([NH:25][CH2:33][C:34]4[CH:43]=[CH:42][C:37]5[O:38][CH2:39][CH2:40][O:41][C:36]=5[CH:35]=4)[CH2:23][CH2:24]3)=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(OC3CC3)ccc12
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(OC3CC3)ccc12
Reaction time: 1.5 h

Procedure:
To 1 mL of methanol solution containing 85 mg of tert-butyl (1-(2-(7-cyclopropoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate, 1 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added at room temperature, and stirred for 1.5 hours. 1 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added, and further stirred for 30 min. Ethyl acetate was added, and the resulting solid was filtered to give 60 mg of 7-cyclopropoxy-1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-methylquinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: [C:1]([C@@:9]([CH2:41][OH:42])([OH:40])[C@:10]([C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([OH:31])[C@:11]([C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([OH:22])[C:12](C(=O)C1C=CC=CC=1)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:43].CC(O)=O>ClCCl>[Br:43][C:12]([C@:11]([C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C@:10]([C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C@:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH2:41][OH:42])[OH:40])[OH:31])[OH:22])=[O:13]
Reactant: Br
Reactant: O=C(C(=O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)c1ccccc1)[C@@](O)(CO)C(=O)c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(Br)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)c1ccccc1)[C@@](O)(CO)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Crude tetra-benzoyl-L-ribose 20 (17.0 g, 30.0 mmol) was dissolved in dichloromethane (150 mL) under an atmosphere of argon at 0° C. To this solution was added 33% HBr in AcOH (32.6 mL, 180.0 mmol of HBr) and the reaction was stirred for 30 min at 0° C. then brought to room temperature for 30 min. Dichloromethane (150 mL) was added and the reaction mixture was washed with 125 mL of cold water, dilute NaHCO3, two times with saturated NaHCO3 and brine then dried over Na2SO4 and concentrated in vacuo to give 21 as a off-white solid (13.3 g, 25.3 mmol, 84%). This material was used without further purification.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Br:5][C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:8]([CH2:20]Cl)[CH:7]=1.O>CN(C=O)C>[N:1]([CH2:20][C:8]1[CH:7]=[C:6]([Br:5])[CH:19]=[CH:18][C:9]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[N+:2]=[N-:3]
Reactant: ClCc1cc(Br)ccc1OCCN1CCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc(Br)ccc1OCCN1CCCC1
Temperature: 35 °C
Reaction time: 16 h

Procedure:
0.33 g (5.00 mmol) of sodium azide were added to a solution of 500 mg (1.57 mmol) of 1-[2-(4-bromo-2-chloromethylphenoxy)ethyl]pyrrolidine in 5 mL of DMF and the mixture was stirred for 16 hours at 35° C. Water was added and the phases were separated. The aqueous phase was exhaustively extracted with DCM, and the combined organic extracts were washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and evaporated down in vacuo. The crude product was used in the next reaction step without any further purification. Yield: 0.42 g (82% of theoretical); C13H17BrN4O (M=325.204); HPLC-MS: 5.62 minutes (method A).