Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:8])(=[NH:7])[CH3:6].[CH3:9][O:10][C:11](=O)[CH2:12][C:13]([CH2:15][O:16]C)=O.Cl>CO>[CH3:6][C:5]1[N:8]=[C:12]([CH2:11][O:10][CH3:9])[CH:13]=[C:15]([OH:16])[N:7]=1
Reactant: COCC(=O)CC(=O)OC
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1cc(O)nc(C)n1
Temperature: 50 °C
Yield: 58.4 %

Procedure:
968 g (4 mol) of sodium methylate in methanol were added to a solution of 187 g (2 mol) of acetamidine hydrochloride and 292 g (2 mol) of γ-methoxyacetoacetic acid methyl ester in 1,000 ml of methanol at 5° C., the mixture was warmed for 3 hours at 50° C. and the solvent was then stripped off under reduced pressure. The residue was dissolved in 500 ml of ice-water and brought to pH ca.6 with concentrated hydrochloric acid, while cooling externally, the precipitate was filtered off, washed with ether and then dried in a desiccator over phosphorus pentoxide. 180 g (58% of theory) of 2-methyl-4-methoxymethyl-6-hydroxy-pyrimidine were obtained in the form of a white powder of melting point 168°-170° C.
Reaction SMILES: [C:1]([CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:8]1[CH:23]1[CH2:25][CH2:24]1)([O:3]C)=[O:2].[OH-].[Na+].CO>O>[C:1]([CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:8]1[CH:23]1[CH2:25][CH2:24]1)([OH:3])=[O:2]
Reactant: COC(=O)CCn1c(C2CC2)c(Cc2cccnc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCn1c(C2CC2)c(Cc2cccnc2)c2ccccc21
Yield: 57.4 %

Procedure:
A mixture of 1-(2-carbomethoxyethyl)-2-cyclopropyl-3-(3-pyridylmethyl)indole (1.0 g), sodium hydroxide (0.18 g), methanol (1 ml) and water (10 ml) was heated under reflux for six hours. The resulting solution was evaporated to dryness and the residue was dissolved in a small volume of water. Acidification with acetic acid gave a solid which was filtered off, washed with water, dried and crystallised from isopropanol/petrol (b.p. 60°-80°) to give 1-(2-carboxyethyl)-2-cyclopropyl-3-(3-pyridylmethyl)indole (0.55 g), m.p. 159°-160°.
Reaction SMILES: [CH3:1][C@@:2]12[CH2:14][CH2:13][C@@H:12]3[C@:7]([CH3:17])([CH2:8][CH2:9][CH2:10][C:11]3([CH3:16])[CH3:15])[C@@H:6]1[C@@H:5]([OH:18])[CH:4]([OH:19])[O:3]2.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C1C=CC=CC=1.C(OCC)C>[CH:4]([O:3][C@:2]1([CH3:1])[CH2:14][CH2:13][C@@H:12]2[C@:7]([CH3:17])([CH2:8][CH2:9][CH2:10][C:11]2([CH3:15])[CH3:16])[C@H:6]1[CH:5]=[O:18])=[O:19]
Reactant: CC1(C)CCC[C@@]2(C)[C@H]1CC[C@@]1(C)OC(O)[C@H](O)[C@@H]21
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC1(C)CCC[C@]2(C)[C@@H](C=O)[C@](C)(OC=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
To a solution of 0.30 g (1.1 mmol) of lactols 9S and 9R in 15 mL of benzene under argon was added 0.60 g (1.3 mmol) of lead tetraacetate. After the mixture was stirred at 25° C. for 4 h, it was diluted with diethyl ether, the organic layer was washed with water, and brine, dried (MgSO4), concentrated, and column chromatographed on silica gel using a gradient mixture of hexane and diethyl ether as eluent to give 0.25 g (85% yield) of aldehyde 11. [α]22D=−54.4° (c 0.25, CHCl3); 1H NMR (CDCl3) δ 9.98 (d, J=4Hz, 1H, CHO), 7.92 (s, 1H, OCHO), 2.55 (dd, J=9.6, 3.2Hz, 1H, C4a-H), 2.49 (d, J=4Hz, 1H, C1-H), 1.85 (s, 3H, Me), 1.84˜0.90 (m, 10H), 1.18 (s, 3H, Me), 0.89 (s, 3H, Me), 0.83 (s, 3H, Me); 13C NMR (CDCl3) δ 204.2 (C═O), 160.1 (C═O), 85.9, 68.9, 55.1, 41.7, 40.0, 39.9, 39.1, 33.4, 22.3, 21.6, 21.5, 20.0, 18.1, 17.2.
Reaction SMILES: Cl.[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6]([NH2:17])[C:5]=2[CH:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][C@H:27]1[CH2:32]N[CH2:30][CH2:29][NH:28]1.C(N(CC)C(C)C)(C)C.CS(C)=O>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][C@@H:27]1[NH:28][CH2:29][CH2:30][N:17]([C:6]2[C:5]3[CH:4]=[C:3]([CH3:2])[S:12][C:11]=3[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=2)[CH2:32]1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: Clc1ccccc1CC[C@H]1CNCCN1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2Cl)C1
Temperature: 105 °C
Reaction time: 64 h
Yield: 48.4 %

Procedure:
Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (607.1 mg, 2.28 mmol), (S)-2-[2-(2-chloro-phenyl)-ethyl]-piperazine (1.03 g, 4.57 mmol), N,N-diisopropylethylamine (295.3 mg, 2.28 mmol), DMSO (1.0 ml), and toluene (4.0 ml). Stir and heat the mixture at 105° C. After 64 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate and water. Remove the organic layer and wash it with 1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 482.4 mg (48%) of the title compound as a brown foam: mp 72°, dec; mass spectrum (ion spray): m/z=437.3.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[N:15]=1.O>O1CCOCC1>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[O:12][C:18]1[CH:19]=[CH:14][N:15]=[C:16]([NH:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[N:17]=1
Reactant: N#Cc1ccc(Nc2nccc(Cl)n2)cc1
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(Oc2ccnc(Nc3ccc(C#N)cc3)n2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.3 %

Procedure:
To a suspension of NaH (0.006 mol) in 1,4-dioxane (30 ml), 2,4,6-trimethyl-phenol (0.006 mol) was added. The mixture was stirred for 15 minutes at room temperature, and a clear solution formed. 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (0.004 mol) was added, and the reaction mixture was heated to reflux under Argon for 15 hours. The reaction mixture was allowed to cool to room temperature, 0.5 ml of water was added, followed by 4 g of silica gel, and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (eluent gradient: CH2Cl2:CH3OH 100:0:0 to 97:3). The pure fractions were collected and the solvent was evaporated, yielding 1.18 g (89.4%) of 4-[[4-(2,4,6-trimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile (comp. 20).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]1.CN1CCOCC1>C(#N)C.C([O-])(O)=O.[Na+]>[N:12]1([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]1
Reactant: COC(=O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
Benzyl chloroformate (11.0 mL, 0.0768 mol) was added into a solution of methyl piperidine-4-carboxylate (10.0 g, 0.0698 mol) and 4-methylmorpholine (15.4 mL, 0.140 mol) in acetonitrile (20.0 mL). After 30 min, the mixture was diluted with NaHCO3 (7.5%), extracted with ethyl acetate (AcOEt) (3×30 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated to afford 1-benzyl 4-methyl piperidine-1,4-dicarboxylate (12 gram) which was directly used in next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[CH3:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu]I>[CH3:13][C:14]1[N:15]=[CH:16][N:17]([C:2]2[CH:3]=[C:4]([NH2:5])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=2)[CH:18]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: Cc1c[nH]cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Temperature: 120 °C

Procedure:
A suspension of 3-bromo-5-(trifluoromethyl)aniline (4.8 g, 20 mmol), 4-methylimidazole (1.97 g, 24 mmol), potassium carbonate (3.04 g, 22 mmol), CuI (0.57 g, 3 mmol), and 8-hydroxyquinoline (0.44 g, 3 mmol,) in dry DMSO (20 mL) in a pressure tube was degassed by bubbling N2 into the suspension for 10 minutes while stirring. The tube was sealed tightly. The mixture was heated at 120° C. (oil bath temperature) for 15 h. The mixture was cooled down to 45-50° C. and 14% aq. NH4OH (20 mL) was added. The mixture was maintained at this temperature for 1 h. After cooling to rt, water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were passed through a short silica gel column to remove most of green/blue Cu salts. The filtrate was dried over sodium sulfate and concentrated on a rotavap. The crude product was recrystallized from EtOAc/hexanes, giving pure pale yellow needles. The mother liquor was concentrated and the residue was purified on silica gel column (5% methanol/methylene chloride), yielding a second crop as pale yellow needles.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:26]([O:29][CH2:30][C:31]1[C:32]([N:46]2[CH2:57][CH2:56][N:55]3[C:48](=[CH:49][C:50]4[CH2:51][C:52]([CH3:59])([CH3:58])[CH2:53][C:54]=43)[C:47]2=[O:60])=[N:33][CH:34]=[CH:35][C:36]=1B1OC(C)(C)C(C)(C)O1)(=[O:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:26]([O:29][CH2:30][C:31]1[C:32]([N:46]2[CH2:57][CH2:56][N:55]3[C:48](=[CH:49][C:50]4[CH2:51][C:52]([CH3:59])([CH3:58])[CH2:53][C:54]=43)[C:47]2=[O:60])=[N:33][CH:34]=[CH:35][C:36]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:28])[CH3:27]
Reactant: C[C@H]1COCCN1C(=O)c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOC[C@@H]4C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 47.1 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 257a (203 mg, 0.50 mmol), β-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (640 mg, 1.6 mmol), K3PO4 (212 mg, 1.0 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (18 mg, 0.025 mmol), sodium acetate (82 mg, 1.0 mmol), acetonitrile (10 mL), and water (0.2 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2.5 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with dichloromethane (20 mL) and water (20 mL). The aqueous layer was separated and extracted with dichloromethane (3×20 mL). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with 60:1 dichloromethane/methanol to afford 257b (160 mg, 47%) as black solid. MS-ESI: [M+H]+ 680.1
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=O)C1C=CC(OC)=CC=1.[C:31]1([C:37]2([CH2:42][CH2:43][OH:44])[CH2:41][CH2:40][NH:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:51][O:52][C:53]1[CH:61]=[CH:60][C:59]([O:62][C:63]([F:66])([F:65])[F:64])=[CH:58][C:54]=1[C:55](Cl)=[O:56]>C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C>[CH3:51][O:52][C:53]1[CH:61]=[CH:60][C:59]([O:62][C:63]([F:64])([F:65])[F:66])=[CH:58][C:54]=1[C:55]([N:39]1[CH2:40][CH2:41][C:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([CH2:42][CH2:43][OH:44])[CH2:38]1)=[O:56]
Reactant: OCCC1(c2ccccc2)CCNC1
Reactant: COc1ccc(OC(F)(F)F)cc1C(=O)Cl
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(OC(F)(F)F)cc1C(=O)N1CCC(CCO)(c2ccccc2)C1
Reaction time: 14 h

Procedure:
Combine (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt (1.7 g, 2.5 mmol) and sodium carbonate (1.32 g, 12.5 mmol) in ethyl acetate/water (1/1) (20 mL). Add a solution of 2-methoxy-5-trifluoromethoxybenzoyl chloride (0.64 g, 2.5 mmol) in ethyl acetate (10 mL). After 14 hours, separate the organic layer. Extract the aqueous layer four times with dichloromethane. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give the title compound: Rf=0.32 (silica gel, ethyl acetate).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:47][O:48][CH3:49])[C:21]([NH:23][CH:24]2[C:45](=[O:46])[N:26]3[CH:27]([C:31]([O:33][CH:34]([CH2:40][O:41][CH:42]([CH3:44])[CH3:43])[CH2:35][O:36][CH:37]([CH3:39])[CH3:38])=[O:32])[CH:28]=[CH:29][S:30][C@H:25]23)=[O:22])[N:19]=1)=[O:13].CSC>C(Cl)Cl>[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:47][O:48][CH3:49])[C:21]([NH:23][CH:24]2[C:45](=[O:46])[N:26]3[C:27]([C:31]([O:33][CH:34]([CH2:35][O:36][CH:37]([CH3:38])[CH3:39])[CH2:40][O:41][CH:42]([CH3:43])[CH3:44])=[O:32])=[CH:28][CH2:29][S:30](=[O:9])[C@H:25]23)=[O:22])[N:19]=1)=[O:13]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(COC(C)C)COC(C)C)C=CS[C@H]12)c1csc(NC=O)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CSC
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(COC(C)C)COC(C)C)=CCS(=O)[C@H]12)c1csc(NC=O)n1
Reaction time: 0.33 h

Procedure:
A solution of m-chloroperbenzoic acid (70% purity: 3.2 g) in methylene chloride (50 ml) was dropwise added to a stirred solution of 2-isopropoxy-1-isopropoxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-cephem-4-carboxylate (syn isomer, 7.5 g) in methylene chloride (75 ml) at 2° to 5° C. over 25 minutes, and stirred at 0° to 5° C. for 20 minutes. Dimethylsulfide (1 ml) was added to the resultant mixture. The resultant mixture was washed with an aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride in turn. After drying the solution over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was triturated with diethylether (100 ml), and then the precipitates were collected by filtration to give 2-isopropoxy-1-isopropoxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate-1-oxide (syn isomer, 6.77 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([NH2:17])=[CH:10][CH:9]=3)[CH2:6]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([NH:35][CH3:36])(=[O:34])=[O:33])[C:22]([Cl:37])=[CH:21][N:20]=1.Cl.O1CCOCC1.[Na]>O>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([NH:35][CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:17][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[CH:7]2[CH2:16][CH:14]3[CH2:15][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:6]2)=[N:20][CH:21]=1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CC2CC(C1)c1cc(N)ccc12
Agent: Cl
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CC3CN(CCOC)C2)ncc1Cl
Temperature: 120 °C
Yield: 52.3 %

Procedure:
10-(2-Methoxy-ethyl)-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (45 mg, 0.19 mmol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (65 mg, 0.19 mmol) and 4N HCl in dioxane (53 μl, 0.21 mmol) were combined in a microwave tube. The reaction was heated to at 120° C. for 40 minutes in the microwave. The reaction was poured into water (50 ml) and saturated sodium bicarb (90 ml) and extracted 3 times with 25 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated to a brown oil. The crude reaction was purified on a 12 g Isco silica gel column using 0-15% methanol in methylene chloride as the eluent to yield 2-[5-chloro-2-(10-(2-methoxy-ethyl)-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide (52.57 mg, 43%) as a white foam. MP: 92-94° C., 1H-NMR (CDCl3) δ 9.10 (s, 1H), 8.50 (d, J=7.5 Hz, 1H), 8.13 (s, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.58 (m, 1H), 7.35 (s, 1H), 7.21 (d, J=7.8 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 6.95 (s, 1H), 4.61-4.53 (m, 1H), 3.36 (t, J=5.9 Hz, 2H), 3.29 (s, 3H), 3.08 (br s, 1H), 3.02 (br s, 1H), 2.85 (m, 2H), 2.64 (d, J=5.3 Hz, 3H), 2.57-2.45 (m, 4H), 2.27 (m, 1H), 1.71 (d, J=10.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].B(F)(F)F>C(#N)C>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[C:10]([C:17](=[O:19])[CH3:18])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2cc(-c3ccncc3)nn12
Reactant: CC(=O)OC(C)=O
Agent: FB(F)F
Solvent: CC#N
Product: CC(=O)c1c(-c2ccncc2)nn2c(Cl)cccc12
Temperature: 80 °C
Yield: 64.7 %

Procedure:
To a solution of 7-chloro-2-(4-pyridinyl)pyrazolo[1,5-a]pyridine (2.0 g, 8.7 mmol) in acetonitrile (50 mL) at room temperature was added acetic anhydride (2.0 mL, 21 mmol). Boron trifluoride diethyletherate (5.3 mL, 42 mmol) was added dropwise and the resulting solution was heated at 80° C. for 12 hours. The reaction mixture was cooled to room temperature and quenched by the dropwise addition of saturated sodium bicarbonate. The reaction mixture was extracted with ethyl acetate, and the organic phase phase washed with brine, dried (magnesium sulfate), filtered and concentrated. The residue was purified by silica gel chromatography (5:95 methanol-dichloromethane) to give 1-[7-chloro-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (1.53 g, 65%) as a red foam. 1H NMR (CDCl3): δ 8.82 (m, 2H), 8.45 (d, 1H), 7.62 (m, 2H), 7.54 (t, 1H), 7.25 (d, 1H), 2.26 (s, 3H); MS m/272 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:5][C:4]=1[CH:17]=[CH:18][C:19](=[O:24])[CH2:20][C:21](=[O:23])[CH3:22].[B]=O.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[CH:36]=O)[CH:29]=[CH:28]1.B(OC(C)C)(OC(C)C)OC(C)C.N1CCCCC1.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2/[CH:36]=[CH:22]/[C:21](=[O:23])[CH2:20][C:19](=[O:24])/[CH:18]=[CH:17]/[C:4]2[CH:5]=[CH:6][C:7]([O:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:8][C:3]=2[O:2][CH3:1])[CH:29]=[CH:28]1
Reactant: COc1cc(OCc2cccnc2)ccc1C=CC(=O)CC(C)=O
Reactant: O=Cc1cccc2cc[nH]c12
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCNCC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(OCc2cccnc2)ccc1/C=C/C(=O)CC(=O)/C=C/c1cccc2cc[nH]c12
Temperature: 70 °C
Yield: 17.7 %

Procedure:
In a 20 mL reaction vessel were placed 88 mg (0.27 mmol) of 6-[2-methoxy-4-(3-pyridylmethoxy)phenyl]hex-5-ene-2,4-dione and 26.4 mg (0.380 mmol) of boron oxide and they were dissolved in 1.76 mL of ethyl acetate. To the mixture under stirring at 70° C., 40 mg (0.27 mmol) of 1H-indole-7-carboxaldehyde and 124 μL (0.54 mmol) of triisopropyl borate were sequentially added. After the mixture was stirred at the same temperature for 1 hour, a solution of 5.4 μL (54 μmol) of piperidine in ethyl acetate (0.27 mL) was added and the mixture was further stirred for 1 hour. To the reaction mixture was added a 1:1 solution (0.8 mL) of 1 N hydrochloric acid and saturated brine at room temperature and the mixture was stirred for 5 minutes to 1 hour (further, the mixture was neutralized with a saturated sodium bicarbonate aqueous solution as needed). The resulting organic phase was directly subjected to purification by silica gel column chromatography (hexane/ethyl acetate or methylene chloride/methanol) to give 21.6 mg (18% yield) of the title compound as a yellow powder.
Reaction SMILES: [Br:1][CH:2]([Br:16])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[CH3:17][Si:18]([CH3:22])([CH3:21])[CH2:19][NH2:20].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(OC)(C)(C)C>[Br:1][CH:2]([Br:16])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:20][CH2:19][Si:18]([CH3:22])([CH3:21])[CH3:17])=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]
Reactant: O=C(O)c1ccc(C(Br)Br)c(C(F)(F)F)c1
Reactant: C[Si](C)(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: C[Si](C)(C)CNC(=O)c1ccc(C(Br)Br)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
4-(dibromomethyl)-3-(trifluoromethyl)benzoic acid (18.0 g, 49.7 mmol) was suspended in CH2Cl2. 1-(Trimethylsilyl)methanamine (5.1 g, 49.7 mmol) and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.5 g, 54.7 mmol) were added to the solution at 0° C. The reaction mixture was stirred at room temperature over night. The reaction mixture was diluted with t-BuOMe and washed with 2M HCl, H2O, and brine. After drying over MgSO4 and evaporation, the product was found to be 22.0 g (99%).
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:10]=1)[C:6]#[N:7].C(N(CC)CC)C.C[Si]([N:42]=[N+:43]=[N-:44])(C)C.[OH-].[Na+]>C(OC)(C)(C)C>[Br:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:3]=1[CH2:4][N:5]([CH2:8][C:9]1[CH:10]=[C:11]([C:19]([F:20])([F:21])[F:22])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:6]1[N:42]=[N:43][NH:44][N:7]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cc(CN(Cc2cc(C(F)(F)F)ccc2Br)c2nn[nH]n2)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To the product of step C (909 g, 1.80 mol) in methyl tert-butyl ether (9 L) was added triethylamine (2.5 L, 18 mol) followed by trimethylsilylazide (415 g, 3.60 mol). The resulting mixture was heated to 50° C. for 8 hours. An aliquot was checked by HPLC and starting material was still present. The mixture was cooled and trimethylsilylazide (50 g) was added. The mixture was again heated to 50° C. and stirred 3 hours. After cooling, 1N sodium hydroxide (9 L) was added. The layers were separated (added 150 ml ethanol to facilitate separation). The organics were washed with aqueous 10% citric acid solution (8 L, then 2 L) until washings were acidic. The organics were dried over sodium sulfate, filtered, and concentrated. The resulting solid turned white upon standing (976 g, 99% yield). 1H-NMR (CD3OD) δ 7.47 (m, 3H), 7.64 (d, 8.3 Hz, 1H), 7.44 (d, 2.1 Hz, 1H), 7.38 (dd, 2.1 Hz, 8.3 Hz, 1H), 4.88 (s, 2H), 4.86 (s, 2H). Mass Spec (ESI): M+1=548.0