Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[H-].[Na+].Cl[CH2:32][C:33]1[O:34][CH:35]=[CH:36][CH:37]=1>C(OCC)(=O)C.CCCCCC.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:32][C:33]3[O:34][CH:35]=[CH:36][CH:37]=3)[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: ClCc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2Cc2ccco2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (1.7 g, 5.37 mmol), tetrahydrofuran (45 mL), and dimethylformamide (5 mL). Cool in an ice-bath. Add sodium hydride (0.32 g, 60%n in oil, 8.06 mmol). After 15 minutes, warm to ambient temperature. When gas evolution ceases add 2-(chloromethyl)furan (0.94 g, 8.06 mmol). After 18 hours, cool the reaction mixture, quench by the addition of a saturated aqueous ammonium chloride solution. Evaporate to remove most of the tetrahydrofuran, dilute with ethyl acetate, and extract with water, a saturated aqueous sodium bicarbonate solution, and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 50% ethyl acetate/hexane to give 1-(t-butoxycarbonyl)-4-(fur-2-ylmethyl-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.47 (silica gel, ethyl acetate) Elemental Analysis Calculated for C22H28N4O3: C, 66.66; H, 7.17; N, 14.04. Found C, 66.65; H, 7.12; N, 14.13.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:32](OC)=[O:33])=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:20]3[C:21]([C:28]([F:31])([F:30])[F:29])=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:17][CH2:18][CH2:19][N:12]21.Cl.[Cl-].[NH4+]>C(O)C.O1CCCC1>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:21]([C:28]([F:30])([F:29])[F:31])=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH2:32][OH:33])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(CO)c23)c(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of calcium chloride (670 mg, 6.04 mmol) in ethanol (15 mL) was added sodium tetrahydroborate (457 mg, 12.08 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hr. A solution of methyl 9-chloro-1-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (1.33 g, 3.02 mmol) in tetrahydrofuran (15 mL) was added dropwise to the mixture at 0° C. The mixture was stirred at 0° C. for 12 hr. 1N HCl (ca. 9.0 mL) was added to the reaction mixture at 0° C., and the aqueous ammonium chloride was added to the mixture. The solvent was removed in vacuo. The precipitated solid was collected by filtration, washed with water and diisopropyl ether to give the title compound (1.33 g, 3.02 mmol, quant) as a white solid.
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:29])[C@H:17]([NH:24][C:25]([O:27][CH3:28])=[O:26])[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:10])C1C=CC=CC=1>CO.[Pd]>[CH3:28][O:27][C:25]([NH:24][C@H:17]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:29])=[O:26]
Reactant: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C1CCCCC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)C1CCCCC1
Yield: 88.1 %

Procedure:
1.17 g 1-[(R)-methoxycarbonylamino-cyclohexyl-acetyl]-pyrrolidine-2-(S)-carboxylic acid benzyl ester were dissolved in 90 mL of methanol and hydrogenated for 3 h at room temperature using 0.8 g palladium on charcoal (10%) as catalyst. Filtration followed by concentration in vacuo affords 0.80 g (89%) of the title compound as a colorless oil. (−)-APCI-MS: 311 ([M−H]−).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH2:11]1.N(CCO)(CCO)CCO.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>C(Cl)(Cl)Cl>[CH2:39]([O:38][C:36]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH2:11]1)=[O:37])[CH3:40]
Reactant: CN1CCC2(CC1)CN(c1ccccc1N)c1ccccc12
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: OCCN(CCO)CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Nc1ccccc1N1CC2(CCN(C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A slurry of 10.36 g of 1-(2-aminophenyl)-1'-methylspiro[indoline-3,4'-piperidine] dihydrochloride of Example 1b in 60 ml of chloroform is treated portionwise with 12.3 ml of triethanolamine. The resulting mixture is cooled in an ice bath and treated dropwise over 40 minutes with a solution of 2.7 ml of ethyl chloroformate in 20 ml of chloroform. After stirring at room temperature for 1 hour, an additional 3.0 ml of ethyl chloroformate is added and the mixture is permitted to stand 16 hours. The product is washed thrice with water, brine, dried over anhydrous sodium sulfate, concentrated and pumped on under high vacuum to give a crude carbamate. Chromatography on silica gel (100 g) using ether-methylene chloride affords an oil. The material crystallizes on prolonged standing to yield 1-[2-(ethoxycarbonyl)aminophenyl]-1'-methylspiro[indoline-3,4'-piperidine], mp 99.5°-101.0° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH2:11][C:12]([N:14]=[C:15]=[S:16])=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClC(Cl)C(Cl)Cl>[S:16]=[C:15]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:11][C:12](=[O:13])[NH:14]1
Reactant: O=C(Cc1ccccc1)N=C=S
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)C(Cl)Cl
Product: O=C1Cc2ccccc2C(=S)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
To a 250 mL round bottom flask was added anhydrous aluminum chloride powder (21.6 g, 162.2 mmol) and 1,1,2,2-tetrachloroethane (20 mL). The resulting solution was cooled to 0° C. under Ar and then a solution of phenylacetyl isothiocyanate (12.5 g, 70.5 mmol) in 1,1,2,2-tetrachloroethane (10 mL) was added dropwise via addition funnel over a period of 10 min. Upon completion of addition, the reaction mixture was stirred at 95° C. for 1 h during which time the slurry became a dark brown solution. The reaction mixture was then allowed to cool to RT. Once at the prescribed temperature, the reaction mixture was carefully quenched with a solution of cold HCl (250 mL, 2.4 N). The resultant beige precipitate was collected by vacuum filtration, air dried for 0.5 h and then recrystallized from glacial AcOH and decolorizing charcoal to yield the title compound as an orange crystalline solid (7.2 g, 40.6 mmol, 58%). 1H NMR (400 MHz, CDCl3): δ ppm 3.29 (s, 1H), 11.78 (s, 1H), 8.57 (d, 1H, J=8.35 Hz), 7.59-LC/MS m/z [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([CH3:15])([CH3:14])[C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9].[C:21]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:22][C:23]([CH3:25])=O.Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[NH2:20][C:19]1[C:3]2[C:2](=[CH:18][CH:17]=[CH:16][C:4]=2[O:5][CH2:6][C:7]([CH3:15])([CH3:14])[C:8](=[O:9])[NH:10][CH2:11][CH2:12][CH3:13])[N:1]=[C:23]([CH3:25])[C:22]=1[C:21]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCNC(=O)C(C)(C)COc1cccc(N)c1C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCNC(=O)C(C)(C)COc1cccc2nc(C)c(C(=O)OCC)c(N)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of 3-(3-amino-2-cyanophenoxy)-2,2-dimethyl-N-propylpropan-amide (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221, 1.38 g, 5.0 mmol) and ethyl acetoacetate (0.66 g, 5.0 mmol) in dry toluene (150 mL) was added SnCl4 (2.61 g, 10.0 mmol) dropwise via syringe at room temperature under nitrogen. After 1 hr at room temperature, the reaction mixture was refluxed for an additional 5 hrs. The solution was cooled to room temperature and the solvent removed under reduced pressure. The residue was diluted with EtOAc, and aqueous NaOH (2N) was added at room temperature to pH >8. The solution was filtered and the organic layer separated. The aqueous layer was extracted with EtOAc (5×). The combined organic layers was washed with brine, and dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel (0.5% MeOH in EtOAc) to give the title compound as an off-white solid (1.63 g, 84%). 1H NR (400 MHz, DMSO-d6) δ 0.73 (t, J=7.6 Hz, 3H), 1.25 (s, 6H), 1.32 (t, J=7.4 Hz, 3H), 1.35-1.42 (m, 2H), 2.54 (s, 3H), 3.00-3.05 (m, 2H), 4.12 (s, 2H), 4.31 (q, J=7.4 Hz, 2H), 6.87 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.80 (t, J=5.6 Hz, 1H), 8.08 (s, 2H). MS 388 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:13](Cl)(=[O:17])[C:14]([CH3:16])=[CH2:15]>C(Cl)Cl>[C:13]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10])(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: CS(=O)(=O)Nc1ccccc1O
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1ccccc1NS(C)(=O)=O
Reaction time: 2 h

Procedure:
To a solution of 10.12 g (0.10 mol) of triethylamie, 18.72 g (0.10 mol) of N-(2-hydroxyphenyl)methanesulfonamide and 300 ml of methylene chloride cooled to 0° C. was added a solution of 10.45 g (0.10 mol) of methacryloyl chloride in 100 ml of methylene chloride over a 15-minute period. After stirring 2 hours at reduced temperature, the solution was washed three times with water, dried over magnesium sulfate and concentrated to an oil. On cooling and scratching, the oil crystallized. Recrystallization from 1:1 benzene:hexane gave a white solid which was collected, washed with 1:1 benzene:hexane, and dried at room temperature in vacuo. The yield of N-(2-methacryloyloxyphenyl)methanesulfonamide was 10.4 g (40.7 percent); m.p.=88° to 90° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>ClCCl>[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
Into a 5000-mL 4-necked round-bottom flask, was placed aniline (93 g, 1.0 mol, 1.0 equiv.), triethylamine (202 g, 2.0 mol, 2.0 equiv.) and dichloromethane (2,000 mL). This was followed by the addition of 4-fluorobenzoyl chloride (174 g, 1.1 mol, 1.1 equiv.) dropwise with stirring at 0° C. The mixture was stirred at room temperature for 3 hours. The resulting solution was concentrated under vacuum. The solid was filtered out. The filter cake was washed with 1×200 mL of dichloromethane and 3×500 mL of water. This resulted in 200 g (93%) of 4-fluoro-N-phenylbenzamide as white solid. MS (ESI) m/z 216 ([M+H]+).
Reaction SMILES: C(OC[O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[C:20]([CH3:35])=[N:21][N:22]4[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=3)=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1)C.FC(F)(F)C(O)=O>ClCCl>[OH:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[C:20]([CH3:35])=[N:21][N:22]4[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=3)=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: CCOCOc1ccn2c(C(=O)Nc3cccc4c3c(C)nn4Cc3cccc(C)n3)cnc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(O)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
7-(Ethoxymethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (11.2 mg, 0.02 mmol) was dissolved in dichloromethane (0.9 mL) and treated with trifluoroacetic acid (0.1 mL). The mixture was stirred at ambient temperature for 2 hours. The mixture was concentrated and dried under high vacuum to give 7-hydroxy-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (8 mg). MS m/z 413.2 (M+1, APCI+).
Reaction SMILES: [CH:1]1[N:9]=[C:8](Br)[C:7]2[C:3](=[N:4][S:5][N:6]=2)[C:2]=1[Br:11].[CH2:12]([C:24]1([CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[C:47]2[CH:46]=[C:45]([Sn](CCCC)(CCCC)CCCC)[S:44][C:43]=2[C:26]2[S:27][C:28]([Sn:30]([CH2:39][CH2:40][CH2:41][CH3:42])([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:29][C:25]1=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>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.C1(C)C=CC=CC=1>[Br:11][C:2]1[C:3]2[C:7](=[N:6][S:5][N:4]=2)[C:8]([C:45]2[S:44][C:43]3[C:26]4[S:27][C:28]([Sn:30]([CH2:39][CH2:40][CH2:41][CH3:42])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:29][C:25]=4[C:24]([CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:47]=3[CH:46]=2)=[N:9][CH:1]=1
Reactant: Brc1cnc(Br)c2nsnc12
Reactant: CCCCCCCCCCCCC1(CCCCCCCCCCCC)c2cc([Sn](CCCC)(CCCC)CCCC)sc2-c2sc([Sn](CCCC)(CCCC)CCCC)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCC1(CCCCCCCCCCCC)c2cc(-c3ncc(Br)c4nsnc34)sc2-c2sc([Sn](CCCC)(CCCC)CCCC)cc21
Temperature: 75 °C
Reaction time: 10 h
Yield: 32.1 %

Procedure:
To a solution of 4,7-dibromo-pyridal[2,1,3]thiadiazole (0.28 g, 0.95 mmol) and 1a (1.04 g, 0.95 mmol) in freshly distilled toluene (10 ml) was added Pd(PPh3)4 (109.8 mg, 0.095 mmol) under nitrogen, and then capped with a rubber septum. The reaction mixture was stirred at 75° C. for 10 hours. The solvent was removed and purified by column chromatography (silica was pretreated by 10 v/v % triethylamine/hexane solution) with hexane as eluent. The column separation was repeated for 3 times to give 0.31 g of viscous purple oil, yield 30%. 1H NMR (500 MHz, CD2Cl2) δ (ppm): 8.55 (s, 1H), 8.53 (s, 1H), 7.01 (s, 1H), 1.95-1.91 (m, 4H), 1.63-1.56 (m, 6H), 1.37-1.31 (m, 6H), 1.26-1.12 (m, 42H), 1.08-0.97 (m, 4H), 0.91-0.82 (m, 15H); 13C NMR (CDCl3, 125 MHz) δ (ppm): 163.11, 160.01, 156.33, 148.10, 147.92, 145.92, 143.99, 142.26, 141.81, 140.27, 129.80, 127.62, 106.17, 37.85, 31.88, 29.96, 29.61, 29.52, 29.34, 29.31, 28.98, 27.21, 24.57, 22.66, 13.85, 13.44, 10.95.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][N:5]1[C:10]([CH3:11])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:8](=[O:17])[C:7](Br)=[C:6]1[CH3:19].[F:25][C:26]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.[OH-].[Ba+2].[OH-]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC=CC=1.C(O)C.COCCOC>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][N:5]1[C:10]([CH3:11])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:8](=[O:17])[C:7]([C:27]2[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:26]=2[F:25])=[C:6]1[CH3:19]
Reactant: CCOC(=O)c1c(C)n(Cc2c(F)cccc2F)c(C)c(Br)c1=O
Reactant: COc1cccc(B(O)O)c1F
Agent: [Pd]
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccccc1
Solvent: COCCOC
Product: CCOC(=O)c1c(C)n(Cc2c(F)cccc2F)c(C)c(-c2cccc(OC)c2F)c1=O
Temperature: 90 °C

Procedure:
1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-bromo-5-ethoxycarbonyl-4-pyridone (1.5 g, 3.7 mmol) was evacuated in a pressure vessel with 2-fluoro-3-methoxyphenyl boronic acid (764 mg, 4.5 mmol) and tetrakis(triphenylphosphine) palladium (0) (428 mg, 370 μmol). A mixture of benzene/ethanol/1,2-dimethoxyethane (74 ml in a 10/1/11 ratio) and barium hydroxide (saturated aqueous, about 0.5M) was then added under vacuum, the vessel sealed under N2, and the reaction stirred at 90° C. for twelve hours, protected from light. The organic layer was concentrated and purified using flash silica chromatography (EtOAc/hexanes-1/4 to MeOH/CH2Cl2-2/98), with the product eluting as the third spot. The product was dried as an amber oil (1.12 g, 2.5 mmol, 68%). 1H NMR (CDCl3, 300 MHz) δ 6.80-7.80 (m, 6H), 5.29 (s, 2H), 4.37-4.33 (m, 2H), 3.87 (s, 3H), 3.38 (s, 3H), 2.26 (s, 3H), 1.35 (t, 3H); LCMS=446 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:18].N1CCCCC1.O>C(O)C>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[NH:11][C:10]2=[O:16])[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2cccnc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Solvent: O
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccnc4)c32)c1C
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of 4-pyridin-3-yl-1,3-dihydroindol-2-one (42 mg, 0.2 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (53 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated in a sealed tube at 80° C. for 2 hours, heating was stopped and the tube was shaken at room temperature for 2 days. A small amount of water was added to the reaction and the solid which formed was collected by vacuum filtration, washed with water and dried to give the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:5]2[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=2[N:7]=1.[CH3:19][C:20]1[O:24][N:23]=[C:22]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)=[O:27])[CH:21]=1>>[CH3:11][N:9]1[CH2:10][C:5]2[C:4]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]3[CH3:18])=[N:3][C:2]([C:32]3[CH:33]=[CH:34][C:29]([NH:28][C:26]([NH:25][C:22]4[CH:21]=[C:20]([CH3:19])[O:24][N:23]=4)=[O:27])=[CH:30][CH:31]=3)=[N:7][C:6]=2[CH2:8]1
Reactant: Cc1cc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)no1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C)C2
Product: Cc1cc(NC(=O)Nc2ccc(-c3nc4c(c(N5CCOC[C@@H]5C)n3)CN(C)C4)cc2)no1

Procedure:
Method as intermediate 5 using (S)-4-(2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 12) and 1-(5-methylisoxazol-3-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 15) as starting materials.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]([C:14](=[O:21])[C@@H:15]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[OH-].[Na+]>CO>[NH:16]1[C:17](=[O:20])[CH2:18][CH2:19][C@H:15]1[C:14]([N:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][C:4]([OH:22])=[O:3])=[O:21]
Reactant: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H]1CCC(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN(Cc1ccccc1)C(=O)[C@@H]1CCC(=O)N1
Reaction time: 0.08 h
Yield: 31.7 %

Procedure:
1.25 g N-(pyroglutamyl)-N-benzylglycine ethylester is dissolved in 5 ml methanol, treated with 3 ml 2N NaOH, and stirred for 5 min., after which the solution is concentrated to a small volume by removal of solvents. The residue is then dissolved in 10 ml H2O, acidified to pH2, extracted several times with ethyl acetate, and dried over anhydrous MgSO4. Following evaporation of solvent, the residue is chromatographed on silica gel (55 g) using chloroform/methanol/acetic acid (4:1:0.1). The first fractions give 0.36 g N-(pyroglutamyl)-N-benzylglycine as a white solid.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3].C(N(CC)CC)C.Cl[CH2:39][C:40]([NH:42][CH2:43][CH3:44])=[O:41]>C(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:43]([NH:42][C:40](=[O:41])[CH2:39][N:27]1[CH2:28][CH2:29][CH:24]([C:22]2[CH:21]=[CH:20][C:17]3[C:18]4[N:12]([CH:11]=[C:10]([C:9]5[N:5]([CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([CH3:30])[N:8]=5)[N:19]=4)[CH2:13][CH2:14][O:15][C:16]=3[CH:23]=2)[CH2:25][CH2:26]1)[CH3:44]
Reactant: CCNC(=O)CCl
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)CN1CCC(c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 54.3 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (150 mg, 0.35 mmol) in DCM (2 mL) was added triethylamine (107 μL, 0.77 mmol). The resultant mixture was stirred for 10 minutes before the addition of 2-chloro-N-ethyl-acetamide (46 mg, 0.38 mmol) and tetrabutylammonium iodide (13 mg, 0.04 mmol). The reaction was stirred at RT for 4 days before the reaction was washed with sodium hydrogen carbonate solution (sat. aq.). The aqueous phase was extracted with 10% MeOH in DCM (×3) and the combined organic layers dried (Na2SO4) then concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2, gradient 0-10% MeOH in DCM) affording 276 (91 mg, 0.19 mmol, 55%). LCMS: RT=2.75 min, [M+H]+=478. 1H NMR δ (ppm) (CDCl3): 8.43 (1 H, d, J=8.29 Hz), 7.59 (1 H, s), 7.16 (1 H, s), 7.00 (1 H, dd, J=8.34, 1.81 Hz), 6.88 (1 H, d, J=1.76 Hz), 5.91-5.80 (1 H, m), 4.48-4.44 (2 H, m), 4.42-4.37 (2 H, m), 3.37-3.26 (2 H, m), 3.06-2.88 (4 H, m), 2.57-2.47 (1 H, m), 2.38 (3 H, s), 2.30 (2 H, s), 1.87 (2 H, d, J=12.74 Hz), 1.76 (2 H, s), 1.54 (6 H, d, J=6.65 Hz), 1.15 (3 H, t, J=7.26 Hz).
Reaction SMILES: [NH2:1][CH2:2][C@@:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Cs+].[Cs+].[O:27]1[C:35]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]1[N:36]=[C:37](SC)SC>CN(C=O)C>[O:27]1[C:35]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]1[NH:36][C:37]1[O:11][C@:3]2([CH2:2][N:1]=1)[CH:8]1[CH2:7][CH2:6][N:5]([CH2:10][CH2:9]1)[CH2:4]2
Reactant: CSC(=Nc1nc2ncccc2o1)SC
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: c1cnc2nc(NC3=NC[C@@]4(CN5CCC4CC5)O3)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A 10 ml vial was charged with (S)-3-(aminomethyl)quinuclidin-3-ol.2HCl salt (8.53 mg, 0.044 mmol), DMF (2 ml), DIEA (7.74 μL, 0.04 mmol) and Cs2CO3(28.9 mg, 0.089 mmol) at room temperature, followed by dimethyl oxazolo[4,5-b]pyridin-2-ylcarbonimidodithioate (10.6 mg, 0.044 mmol). The resulting suspension was stirred at room temperature for 1 hr. LC/MS indicated complete consumption of starting material. The reaction mixture was diluted with MeOH and purified via preparative HPLC to afford the expected product, (R)—N-(oxazolo[4,5-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (13 mg, 0.038 mmol, 86% yield), as a white solid. 1H NMR (400 MHz, Acetone-d6) δ ppm 1.54-1.60 (m, 1H) 1.71-1.77 (m, 2H) 2.16-2.24 (m, 1H) 2.77-2.82 (m, 2H) 2.89 (t, J=7.91 Hz, 4H) 3.13-3.25 (m, 2H) 3.90 (d, J=10.29 Hz, 1H) 4.22 (d, J=10.29 Hz, 1H) 7.13 (dd, J=8.03, 5.02 Hz, 1H) 7.70 (dd, J=7.91, 1.13 Hz, 1H) 8.27 (dd, J=5.14, 1.13 Hz, 1H) 9.11 (br. s., 1H). MS (LC/MS) R.T.=0.443; [M+H]+=300.16.