Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][CH:9]([CH3:33])[CH2:10][N:11]1[C:23]2[CH:22]=[CH:21][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2.Br[C:35]1[CH:36]=[CH:37][C:38]2[N:39]([CH2:49][CH:50]([CH3:52])[CH3:51])[C:40]3[C:45]([C:46]=2[CH:47]=1)=[CH:44][C:43]([Br:48])=[CH:42][CH:41]=3.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:48][C:43]1[CH:44]=[CH:45][C:40]2[N:39]([CH2:49][CH:50]([CH3:51])[CH3:52])[C:38]3[C:37]([C:41]=2[CH:42]=1)=[CH:36][C:35]([C:15]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:10][CH:9]([CH3:33])[CH3:8])[C:23]4[C:18]([C:17]=2[CH:16]=1)=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:47][CH:46]=3
Reactant: CC(C)Cn1c2ccccc2c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)Cn1c2ccccc2c2cc(-c3ccc4c(c3)c3cc(Br)ccc3n4CC(C)C)ccc21
Temperature: 90 °C
Reaction time: 12 h
Yield: 34.5 %

Procedure:
Toluene (30 ml) and H2O (10 ml) were added into a mixture of 4 (1.2 g, 3.43 mmol), 2 (3.27 g, 8.59 mmol), Pd(PPh3)4 (0.22 g, 0.17 mmol) and Na2CO3 (3.43 g, 34 mmol). The reaction mixture was stirred at 90° C. for 12 hours, cooled to room temperature, and then extracted with methylene chloride. The organic extracts were combined, washed with water, and dried over MgSO4. Upon evaporating off the solvent, the crude product was purified by gradient column chromatography on silica gel with hexane/methylene chloride 9:1 to 3:1 (v/v) to yield 5 (0.62 g, 34%) as a white powder. 1H NMR (400 MHz, CDCl3, 298 K): δ(ppm) 8.40-8.33 (dd, 2H), 8.30-8.28 (d, 1H), 8.21-8.35 (d, 1H), 7.88-7.76 (m, 2H), 7.56-7.40 (m, 5H), 7.33-7.20 (m, 2H), 4.14-4.09 (m, 4H), 2.46-2.37 (m, 2H), 1.10-0.90 (m, 12H).
Reaction SMILES: C(=O)(O)[O-].[K+].[CH3:6][NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:16][C:17]1[C:18](=[O:23])[S:19][S:20][C:21]=1Cl>CO>[Cl:16][C:17]1[C:18](=[O:23])[S:19][S:20][C:21]=1[N:7]([CH3:6])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CNCCc1ccccc1
Reactant: O=c1ssc(Cl)c1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Product: CN(CCc1ccccc1)c1ssc(=O)c1Cl
Temperature: 20 °C
Reaction time: 20 h
Yield: 31.3 %

Procedure:
Potassium bicarbonate (6 g) and a solution of N-methylphenethylamine (8 g) in methanol (150 cc) are added to a solution of 4,5-dichloro-1,2-dithiol-3-one (11.2 g) in methanol (350 cc). The reaction mixture is stirred at a temperature of about 20° C. for 20 hours, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue is dissolved in methylene chloride (210 cc); the solution obtained is washed 3 times with distilled water (60 cc in total), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The crystals obtained are recrystallized from a mixture of isopropyl ether and ethyl acetate (75/25 by volume); 4-chloro-5-[N-methyl-N-(2-phenylethyl)-amino]-1,2-dithiol-3-one (5.3 g) is thus obtained in the form of yellow crystals of m.p. 75° C.
Reaction SMILES: [CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>>[CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)[S:46]([CH3:45])(=[O:48])=[O:47]
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)S(C)(=O)=O)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 31 in Step A and methylsulfonyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [I-].[CH2:2]([N+:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]2[C:18]([CH3:21])=[CH:19][S:20][C:10]=12)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:22][O-:23].[Na+]>CO>[CH2:2]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11](/[C:18](/[CH3:21])=[CH:19]\[S:20][CH3:10])[C:22]1=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC[n+]1c2ccccc2n2c(C)csc21
Reactant: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCn1c(=O)n(/C(C)=C\SC)c2ccccc21
Temperature: 25 °C
Yield: 83.1 %

Procedure:
257 mg of 9-heptyl-3-methyl[1,3]thiazolo[3,2-a]benzimidazol-9-ium iodide (0.620 mmol) were solubilised in methanol (40 mL), then 268 mg (8 eq) of NaOMe were added and the solution stirred at room temperature. After 48 h the solvent was evaporated, water was added (20 mL) and the mixture extracted with CH2Cl2 (3×20 mL). The organic layer was dried with MgSO4 and evaporated under reduced pressure to afford 1-heptyl-3-[(1Z)-1-(methylsulfanyl)prop-1-en-2-yl]-1,3-dihydro-2H-benzimidazol-2-one as a pale green oil (164 mg, 83%). Rf=0.65 (CH2Cl2/AcOEt 8:2); 1H NMR (300 MHz, CDCl3) δ=0.82-0.87 (3H, m, CH3), 1.14-1.44 (8H, m, 4-CH2), 1.75 (2H, quint, J=7.1, CH2), 2.12 (3H, d, J=1.2, CH3), 2.21 (3H, s, SCH3), 3.86 (2H, t, J=7.3, CH2), 6.21 (1H, q, J=1.2, H5), 6.80-7.14 (4H, m, Ar). 13C NMR (75 MHz, CDCl3) δ=13.86, 16.67, 20.20, 22.34, 26.52, 28.07, 28.70, 31.49, 40.91, 107.64, 108.80, 120.69, 121.15, 126.53, 127.23, 127.39, 129.52, 151.96; HRMS m/z C18H27N2OS [M+H]+ calcd: 319.1839, found: 319.1838.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:11][N:12]1[C:16]([CH3:17])=[C:15]([NH2:18])[CH:14]=[N:13]1.C(O)(C(F)(F)F)=O>COCCO>[Br:1][C:2]1[C:3]([NH:9][CH3:10])=[N:4][C:5]([NH:18][C:15]2[CH:14]=[N:13][N:12]([CH3:11])[C:16]=2[CH3:17])=[N:6][CH:7]=1
Reactant: CNc1nc(Cl)ncc1Br
Reactant: Cc1c(N)cnn1C
Solvent: O=C(O)C(F)(F)F
Solvent: COCCO
Product: CNc1nc(Nc2cnn(C)c2C)ncc1Br
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 17.1 %

Procedure:
To a mixture of 5-bromo-2-chloro-N-methylpyrimidin-4-amine (0.201 g, 0.903 mmol) and 1,5-dimethyl-1H-pyrazol-4-amine (0.12 g, 1.08 mmol) in 2-methoxyethanol (2 mL) was added TFA (0.070 mL, 0.9 mmol). The reaction was stirred in a sealed tube at 100° C. for 90 minutes. The resulting precipitate was collected by filtration. The isolated solid was further purified by reverse phase HPLC to give 5-bromo-N2-(1,5-dimethyl-1H-pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine (46 mg, 17%). LCMS (Method A): [MH+]=297.0 at 2.57 min. 1H-NMR (DMSO): δ 8.28 (s, 1H), 7.84 (s, 1H), 7.49 (s, 1H), 6.79 (d, J=3.4, 1H), 3.67 (s, 3H), 2.82 (d, J=3.6, 3H), 2.14 (s, 3H). Ki=0.017 μM.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Reactant: C1CCNCC1
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(C(=O)N4CCCCC4)c3)c2o1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 149) and 20.0 mg (0.23 mmol) of piperidine are reacted together by general method E. 16.4 mg (27.6% of theory) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.B([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(O)O>O>[CH3:13][O:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[N:3]=[CH:4]2)=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: COc1ccc2cc(Cl)ncc2c1
Solvent: O
Product: COc1ccc2cc(-c3ccc(C(=O)O)cc3)ncc2c1

Procedure:
Followed the procedure described in Compound IV-8 step 1, starting with 3-chloro-7-methoxyisoquinoline (Intermediate 12) and 4-boronobenzoic acid with an alternative isolation procedure: After reaction was complete, the reaction mixture was diluted with H2O (10 mL). The aqueous layer was extracted with EtOAc/MeOH (v/v=10:1, 30 mL×2). Then the aqueous layer was acidified with 2M HCl to pH=6. The precipitate was collected by filtration and washed with MeOH (10 mL), dried under high vacuum to give the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6](O)=[O:7].C(Cl)(=O)C(Cl)=O.[CH3:18][NH2:19]>CN(C=O)C.C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][CH3:18])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: CN
Reactant: O=C(O)c1ccc(F)cc1O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(F)cc1O
Reaction time: 2 h

Procedure:
DMF (2 drops) was added to a mixture of 4-fluorosalicylic acid (2 g, 12.8 mmol) and oxalyl chloride (2.85 mL, 32.0 mmol) in THF (15 mL). The reaction was stirred for 2 hours then reduced in vacuo. The residue was dissolved in THF (10 mL) and added dropwise to 2M methylamine in THF (32 mL) at 0° C. The reaction was stirred at RT for 72 hours and the THF removed in vacuo. The residue was partitioned between ethyl acetate (80 mL) and water (80 mL). The aqueous layer was further extracted into ethyl acetate (80 mL) and the combined organics washed with brine (50 mL), dried (MgSO4), and reduced in vacuo to give a white solid. The material was chromatographed on silica, eluting with 5-40% ethyl acetate in isohexane, to give the desired compound as a white solid (1.43 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-nitro-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-nitro-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)OCC)C.C[O-].[Na+].[CH2:19]([O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=O)[CH:24]=1)[CH3:20].C1(C)C=CC=CC=1>O1CCCC1>[CH2:19]([O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[CH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:24]=1)[CH3:20]
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: CCOC(=O)c1cccc(C=O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(C=Cc2ccccc2)c1
Temperature: 0 °C
Yield: 37.7 %

Procedure:
45.6 g (0.2 mol) of benzylphosphonic acid diethyl ester, dissolved in 50 ml of tetrahydrofuran, were added dropwise to a mixture of 300 ml of tetrahydrofuran and 46.4 g (0.22 mol) of a methanolic sodium methylate solution at 0°-5° C., whilst stirring. The mixture was subsequently stirred at 0° C. for 2 hours and 35.6 g (0.2 mol) of 3-formyl-benzoic acid ethyl ester, dissolved in 50 ml of tetrahydrofuran, were then added dropwise, also at 0° C. and whilst stirring. The reaction mixture was then stirred at 20°-25° C. for 12 hours, 300 ml of toluene were subsequently added and the mixture was then extracted by shaking twice with 600 ml of water each time. The organic phase was separated off and dried over magnesium sulphate and the solvent was distilled off under a waterpump vacuum. The oily residue was distilled at 160°-190° C. and under a pressure of 3 mm Hg. The semi-crystalline product thus obtained was dissolved in a little petroleum ether and the solution was cooled to 0° C. The crystals which had precipitated were filtered off and dried. 19 g (37.7% of theory) of 3-(2-phenyl-vinyl)-benzoic acid ethyl ester were obtained as colourless crystals with the melting point 82° C. (isomer mixture, about 90% transconfiguration). ##STR65##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([C:10]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])=[O:11])[C:6]=2[CH:19]=1.[Mg].[Cl-].[NH4+]>CO.BrCCBr>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH2:8][CH:7]([C:10]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])=[O:11])[C:6]=2[CH:19]=1
Reactant: CCCN(CCC)C(=O)c1csc2ccc(N)cc12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CO
Solvent: BrCCBr
Product: CCCN(CCC)C(=O)C1CSc2ccc(N)cc21
Reaction time: 4 h

Procedure:
30 g of 5-amino-N,N-dipropyl-3-benzothiophencarboxamide were dissolved in 250 ml of dry methanol. 15 g of magnesium turnings were added (eventually activated by addition of a few drops of 1,2-dibromoethane). The mixture was stirred at 30°-35° C. for 4 hours with periodically cooling to keep the temperature down. 2 l of a saturated ammonium chloride solution were added and the product extracted with ethyl acetate. The organic phase was separated, washed with water, dried (MgSO4) and the solvent evaporated. Isopropyl ether was added, and by cooling the title compound precipitated and was filtered off. Yield: 20 g. M.P. 100° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:17])=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:18](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(=O)CC>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][N:9]2[CH3:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2cc(F)ccc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)c1cn(C)c2cc(F)ccc2c1=O

Procedure:
A mixture of ethyl 7-fluoro-4-hydroxyquinoline-3-carboxylate (4.7 g), anhydrous potassium carbonate (3.0 g), dimethyl sulphate (2.52 g) and butanone (200 ml) can be boiled under reflux for 14 hours. The solvent can be evaporated and the residue can be triturated with dichloromethane (150 ml). The mixture can be filtered and the filtrate evaporated to a small volume. Diethyl ether can be added, causing a solid to precipitate. The solid can be collected, washed with ether, dried and recrystallised from industrial methylated spirit to give the compound ethyl 7- fluoro-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate, m.p. 164° C.-166° C.
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.Cl.[CH2:7]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:22]3[CH2:28][CH2:27][NH:26][CH:25]([CH3:29])[C:23]=3[N:24]=2)=[CH:15][CH:14]=1)=[O:11])[CH3:8].C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:7]([NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[C:22]3[CH2:28][CH2:27][N:26]([CH:3]4[CH2:2][O:1][CH2:4]4)[CH:25]([CH3:29])[C:23]=3[N:24]=2)=[CH:17][CH:18]=1)=[O:11])[CH3:8]
Reactant: O=C1COC1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C2COC2)C3C)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
3-oxetanone (0.38 mL, 5.2 mmol) and 1-ethyl-3-(4-(8-methyl-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride salt (451 mg, 1.04 mmol) were mixed in 1,2-Dichloroethane (6.2 mL) and N,N-Diisopropylethylamine (0.73 mL, 4.2 mmol). The reaction was stirred at 70° C. for 1 h and at 80° C. for 30 minutes. Sodium triacetoxyborohydride (0.71 g, 3.3 mmol) was added to the reaction, and the mixture was stirred at 80° C. for 30 minutes. The reaction mixture was quenched with NaHCO3 and water, which was extracted by CHCl3. The organic layers were combined, washed by water and brine (final pH ˜9), dried over Magnesium sulfate and evaporated. The residue was purified to give the desired product sk (269 mg, 57% yield) as white powder: 1H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 8.18 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 6.14 (t, J=5.5 Hz, 1H), 4.62 (m, 3H), 4.53 (t, J=6.2 Hz, 1H), 4.04 (p, J=6.7 Hz, 1H), 3.81-3.64 (m, 5H), 3.54-3.35 (m, 4H), 3.17-3.03 (m, 2H), 2.67 (m, 4H), 1.29 (d, J=6.8 Hz, 3H), 1.06 (t, J=7.2 Hz, 3H); LC-MS m/z=453 (M+H).
Reaction SMILES: S([O-])(O)=O.[Na+].[CH2:6]([O:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14]([CH:17]=O)[NH:13][C:12]=1[CH3:19])=[O:10])[CH3:7].[NH2:20][C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][C:34]=1[NH2:35])[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[CH2:6]([O:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14]([C:17]2[NH:20][C:21]3[CH:22]=[C:23]([C:24](=[O:25])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:32]=[CH:33][C:34]=3[N:35]=2)[NH:13][C:12]=1[CH3:19])=[O:10])[CH3:7]
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1C
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(C)[nH]c(-c2nc3ccc(C(=O)c4ccccc4)cc3[nH]2)c1C
Temperature: 120 °C
Reaction time: 10 h
Yield: 85.6 %

Procedure:
Sodium hydrogen sulfite (101 mg) and the 5-formyl-2,4-dimethyl-pyrrole-3-carboxylic acid ethyl ester (146 mg) obtained in Example 53 (1) were added to an N,N-dimethylacetamide (5 ml) solution of 3,4-diaminobenzophenone (160 mg). The mixture was heated to 120° C. and stirred for 10 hours. The reaction mixture was allowed to cool to room temperature, and then a 5% sodium carbonate (6 ml) was added and stirred at room temperature. The precipitate was collected by filtration to afford 5-(5-benzoylbenzimidazole-2-yl)-2,4-dimethylpyrrole-3-carboxylic acid ethyl ester (248 mg, 85%) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:8]([CH:16]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.[NH2:23][C:24]1[N:29]=[CH:28][C:27]([N:30]2[CH:36]3[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]3)[CH2:32][C:31]2=[O:39])=[CH:26][CH:25]=1>>[CH:16]1([N:8]2[C:6]3[N:7]=[C:2]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([N:30]5[CH:36]6[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]6)[CH2:32][C:31]5=[O:39])=[CH:28][N:29]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[C:9]2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(N2C(=O)CN3CCC2CC3)cn1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C(=O)CN5CCC4CC5)cn3)nc2n1C1CCCCCC1
Yield: 77 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide was combined with 4-(6-aminopyridin-3-yl)-1,4-diazabicyclo[3.2.2]nonan-3-one and gave 7-cycloheptyl-N,N-dimethyl-2-(5-(3-oxo-1,4-diazabicyclo[3.2.2]nonan-4-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (103 mg) in 77% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.73 (s, 1H), 8.66 (d, J=9.09 Hz, 1H), 8.17 (d, J=2.02 Hz, 1H), 8.14 (s, 1H), 7.55 (dd, J1=9.09 Hz, J2=2.53 Hz, 1H), 6.45 (s, 1H), 4.53 (m, 1H), 3.95 (s, 2H), 3.83 (m, 1H), 3.21 (m, 10H), 2.64 (m, 2H), 2.42 (m, 2H), 2.14-1.54 (m, 12H); HRMS m/z 517.3049 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)[CH2:7][CH2:6]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:50])=CC=1>>[CH3:1][CH:2]([CH2:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)[CH2:7][CH2:6]1)=[S:50]
Reactant: CC(CN1CCN(c2ccc(C(F)(F)F)cc2)CC1)C(=O)N1CCC(Nc2ccc(C#N)c(C(F)(F)F)c2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC(CN1CCN(c2ccc(C(F)(F)F)cc2)CC1)C(=S)N1CCC(Nc2ccc(C#N)c(C(F)(F)F)c2)CC1

Procedure:
4-(1-{2-Methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propionyl}-piperidin-4-ylamino)-2-trifluoromethyl-benzonitrile (15 mg; 0.026 mmol, prepared in accordance with Example 92) is reacted with Lawesson's reagent (5 mg; 0.013 mmol) according to the general conditions described in Example 109. The desired product is obtained following purification by preparative HPLC (9 mg; 0.015 mmol). The structure was confirmed using Protocol I-B. Calculated mass=584; observed mass=584; HPLC retention time=4.68 min
Reaction SMILES: [Cl:1][C:2]1[O:11][C:5]2=[C:6]([NH2:10])[N:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[Cl:12].[I:13]N1C(=O)CCC1=O>CC#N>[Cl:1][C:2]1[O:11][C:5]2=[C:6]([NH2:10])[N:7]=[CH:8][C:9]([I:13])=[C:4]2[C:3]=1[Cl:12]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nccc2c(Cl)c(Cl)oc12
Solvent: CC#N
Product: Nc1ncc(I)c2c(Cl)c(Cl)oc12
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
A solution of 2,3-dichlorofuro[2,3-c]pyridin-7-amine (5.7 g, 28.2 mmol) in MeCN (200 mL) was treated with N-iodosuccinimide (9.57 g, 42.3 mmol), added portionwise over 5-10 min. The mixture was heated at 60° C. for 16 h. After cooling to RT, the reaction was quenched with 20% aqueous sodium thiosulfate and stirred for 10 min. EtOAc (200 mL) was added and the phases separated. The organic phase was washed with 20% aqueous sodium thiosulfate (50 mL), then water (2×100 mL) and finally with brine. After drying over Na2SO4, the organic extracts were filtered and concentrated in vacuo. The material was purified using flash chromatography eluting with 2% MeOH in DCM to afford 3.8 g (41%) of the title compound. 1H NMR (300 MHz, DMSO-d6): δ 6.75 (br. s, 2H); 8.02 (s, 1H).