Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[N:8]=2)[N:3]=1.[C:13](=[O:16])([OH:15])[O-].[Na+].CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]3[N:33]=[C:32]([C@@H:34]4[CH2:39][C@@H:38]5[C@@H:36]([CH2:37]5)[N:35]4[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[NH:31][C:30]=3[CH:47]=2)O1>O1CCOCC1.O.CO.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>[C:43]([O:15][C:13]([N:35]1[C@H:34]([C:32]2[NH:31][C:30]3[CH:47]=[C:26]([C:2]4[N:3]=[C:4]5[C:9](=[CH:10][CH:11]=4)[N:8]=[C:7]([C:27]4[CH:26]=[CH:47][C:30]6[NH:31][C:32]([C@@H:34]7[CH2:39][C@@H:38]8[C@@H:36]([CH2:37]8)[N:35]7[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[N:33][C:29]=6[CH:28]=4)[CH:6]=[CH:5]5)[CH:27]=[CH:28][C:29]=3[N:33]=2)[CH2:39][C@@H:38]2[C@H:36]1[CH2:37]2)=[O:16])([CH3:46])([CH3:44])[CH3:45]
Reactant: Clc1ccc2nc(Cl)ccc2n1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Reactant: O=C([O-])O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2cc(-c3ccc4nc(-c5ccc6nc([C@@H]7C[C@H]8C[C@H]8N7C(=O)OC(C)(C)C)[nH]c6c5)ccc4n3)ccc2[nH]1
Temperature: 110 °C
Reaction time: 2 h
Yield: 19.9 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (17.4 mg, 0.015 mmol) was added to a solution of 2,6-dichloro-1,5-naphthyridine (30 mg, 0.151 mmol), sodium bicarbonate (38.0 mg, 0.452 mmol) and (1R,3S,5R)-tert-butyl 3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (141 mg, 0.332 mmol) in dioxane (1.0 mL) and H2O (0.2 mL) and the mixture was heated and stirred at 110° C. for 2 h. The reaction was diluted with MeOH, filtered, concentrated and purified by prep HPLC (H2O-MeOH with 10 mM NH4OAc buffer) to yield tert-butyl (1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-6-yl)-1,5-naphthyridin-2-yl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (22.3 mg, 0.030 mmol) as a white solid. LC-MS retention time 2.11 min; m/z 725 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water:10% methanol:0.1% TFA. Solvent B=10% water:90% methanol:0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1)#[CH:2].[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=1>C(N(CC)CC)C.C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=2)[CH:17]=1
Reactant: Brc1cncc(Br)c1
Reactant: C#Cc1cccc(OC)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cccc(C#Cc2cncc(Br)c2)c1
Temperature: 70 °C
Yield: 70.7 %

Procedure:
Add 1-ethynyl-3-methoxybenzene (0.56 g, 4.22 mmol) to a mixture of 3,5-dibromopyridine (1.00 g, 4.22 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.06 g, 0.08 mmol) and copper (I) iodide (0.03 g, 0.17 mmol) in triethylamine (8 mL) and heat at 70° C. for 2 h. Cool to room temperature, dilute with ethyl acetate and an aqueous saturated solution of ammonium chloride, and separate the layers. Wash the organic layer with an aqueous saturated solution of sodium chloride, dry (magnesium sulfate), filter and concentrate. Purify the resulting residue by silica gel chromatography, eluting with 2.5% ethanol in 50:50 chloroform/hexanes, to give the title compound (0.86 g, 71%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:13](=O)[CH2:14][C:15](=O)[C:16]([F:19])([F:18])[F:17])[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].[NH2:24][C:25]1[C:29]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=2)=[CH:28][NH:27][N:26]=1>>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]([C:16]([F:19])([F:18])[F:17])[N:26]3[N:27]=[CH:28][C:29]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=4)=[C:25]3[N:24]=2)[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)c(C(F)(F)F)c1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(C(F)(F)F)c4)nc23)ccn1
Yield: 37.9 %

Procedure:
Reaction of 1-(3,4-bis-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (176 mg, 0.5 mmol), prepared from commercially available 3,4-bis-trifluoromethyl-acetophenone [CAS No. 129604-25-7] according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2-methyl-pyridine, as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (93 mg, 38%). MS (ISP) 491.3 [(M+H)+]; mp 223° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[C@@H:17]2[CH2:22][CH2:21][CH2:20][C@H:19]([N:23]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:18]2)=[O:9])[CH:5]=[CH:4][C:3]=1[F:34].[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1B(O)O.C(N(CC)CC)C>CCO.C1(C)C=CC=CC=1>[NH2:23][C@H:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[NH:10][C:8](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([F:34])=[C:2]([C:37]3[C:36]([F:35])=[CH:41][CH:40]=[CH:39][C:38]=3[F:42])[N:7]=2)[CH2:18]1
Reactant: O=C(Nc1cnccc1[C@@H]1CCC[C@H](N2C(=O)c3ccccc3C2=O)C1)c1ccc(F)c(Br)n1
Reactant: OB(O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: N[C@H]1CCC[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C1

Procedure:
A solution of 6-bromo-N-(4-((1R,3S)-3-(1,3-dioxoisoindolin-2-yl)-cyclohexyl)pyridin-3-yl)-5-fluoropicolinamide (1.0 equiv), 2,6-difluorophenyl boronic acid (3.0 equiv.), tetrakistriphenylphosphine (0.2 equiv.) and triethylamine (3.0 equiv.) in 1:1 EtOH/toluene (0.1 M) was heated at 120° C. with microwave irradiation for 1200 seconds. Upon cooling, removal of the volatiles in vacuo, the Suzuki product was directly purified by reverse phase HPLC. The product fraction was lyophilized and the resulting phthalimide group was deprotected as described in Method 9 yielding, after RP HPLC purification and lyophilization, N-(4-((1R,3S)-3-aminocyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide as the TFA salt. LCMS (m/z): 427.2 (MH+); LC Rt=2.26 min.
Reaction SMILES: [CH2:1]([N:3]1C=CC(=O)C(OCC2C=CC=CC=2)=C1COC)C.[CH3:21][O:22][CH:23]([C:26]1O[C:28]([CH3:41])=[CH:29][C:30](=[O:40])[C:31]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:24][CH3:25].CN>>[CH3:1][N:3]1[C:28]([CH3:41])=[CH:29][C:30](=[O:40])[C:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:26]1[CH:23]([O:22][CH3:21])[CH2:24][CH3:25]
Reactant: CCC(OC)c1oc(C)cc(=O)c1OCc1ccccc1
Reactant: CCn1ccc(=O)c(OCc2ccccc2)c1COC
Agent: CN
Product: CCC(OC)c1c(OCc2ccccc2)c(=O)cc(C)n1C
Yield: 37.6 %

Procedure:
In an analogous procedure in the preparation of 1-ethyl-2-methoxymethyl-3-benzyloxy-pyridin-4( 1H)-one using 2-(1-methoxypropyl)-3-benzyloxy-6-methyl-pyran-4(1H)-one 4.32 g (15 mmol, 1 eq.) and 3.49 g (45 mmol, 3 eq.) of 40% aqueous methylamine yielded the title compound (1.7 g, 37.6%) after purification by column chromatography on silica gel (eluant: 15% CH3OH/85% CHCl3) as a yellow oil.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)([N:3]1[CH:7]=[CH:6]N=[CH:4]1)=O.[C:13]([OH:16])(=[O:15])C.[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1>C(OCC)(=O)C>[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][N:18]1[C:13]([O:16][C:20]1[CH:21]=[C:22]2[C:12](=[CH:11][CH:19]=1)[N:8]([CH3:9])[C@H:1]1[N:3]([CH3:4])[CH2:7][CH2:6][C@@:23]21[CH3:24])=[O:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: c1ccc2c(c1)CCNC2
Reactant: CC(=O)O
Solvent: CCOC(C)=O
Product: CN1CC[C@@]2(C)c3cc(OC(=O)N4CCc5ccccc5C4)ccc3N(C)[C@@H]12
Reaction time: 8 h
Yield: 161 %

Procedure:
To the ethyl acetate solution (which contained (-)-eseroline) was added, under N2, 13.17 g (1.0 equiv) of 1,1'-carbonyldiimidazole, as a solid, in several portions. This was followed by the addition of 13.16 g (3.0 equiv) of glacial acetic acid and 10.81 g (1.07 equiv) of 1,2,3,4-tetrahydroisoquinoline in 20 mL of ethyl acetate. After stirring overnight, the reaction mixture was extracted with 200 mL of water. The ethyl acetate solution was further extracted twice with 100 mL of 0.5N sodium hydroxide solution, and 100 mL of water. After drying over anhydrous sodium sulfate, the ethyl acetate solution was concentrated under reduced pressure to give 24.66 g (80.5%) of crude product.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[CH2:27][CH:28]=O>C(O)C>[ClH:1].[CH3:2][C:3]1[CH:14]=[C:13]2[C:6](=[CH:5][CH:4]=1)[NH:7][C:8]1[CH:28]([CH2:27][C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:25]=[CH:26][C:17]=3[O:16][CH3:15])[NH:12][CH2:11][CH2:10][C:9]2=1
Reactant: COc1ccc2ccccc2c1CC=O
Reactant: Cc1ccc2[nH]cc(CCN)c2c1
Agent: Cl
Solvent: CCO
Product: COc1ccc2ccccc2c1CC1NCCc2c1[nH]c1ccc(C)cc21
Temperature: 25 °C

Procedure:
To a stirred solution of 5-methyltryptamine hydrochloride (947 mg, 4.49 mmol.) in 20 mL of ethyl alcohol was added (2-methoxy-1-naphthyl)-acetaldehyde (1.0 g, 4.99 mmol.). The solution was heated to reflux under nitrogen atmosphere for 40 hours. The reaction mixture was cooled to ambient temperature and the crude product isolated by filtration. Recrystallization from ethyl alcohol/2-butanone afforded product as a pale solid (705 mg). (mp. 245.3° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16](OCC)[O:17]CC)=O)=[C:4]([O:23][N:24]=C(C)C)[CH:3]=1.Cl.O>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:16]=[O:17])=[N:24][O:23][C:4]=2[CH:3]=1
Reactant: CCOC(OCC)c1ccccc1C(=O)c1ccc(Br)cc1ON=C(C)C
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=Cc1ccccc1-c1noc2cc(Br)ccc12
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 95.8 %

Procedure:
To a stirred solution of (4-bromo-2-(propan-2-ylideneaminooxy)phenyl)(2-(diethoxymethyl)phenyl)methanone (Compound 3a) (18 g) in ethanol (50 mL) at 70° C. was added 2M hydrochloric acid (25 mL). The mixture was stirred at 70° C. for 20 min forming a thick suspension. Water (500 mL) was added and the resultant solid filtered off and dried in vacuo at 50° C. to give the title compound (12 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:35]=[CH:34][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([NH:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[C:20]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[N:19]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:2][C:3]2[CH:35]=[CH:34][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([NH:17][C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[C:20]([C:28]5[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=5)[N:19]=4)[CH:11]=3)=[O:8])=[CH:5][CH:4]=2)[CH2:39][CH2:38]1
Reactant: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Temperature: 25 °C
Yield: 41 %

Procedure:
To a stirring mixture of 4-chloromethyl-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide (48 mg, 0.096 mmol) and 1-methylpiperazine (16 μl, 0.0.144 mmol) in anhydrous tetrahydrofuran (5 ml) was added N,N-diisopropylethylamine (200 μl). The mixture was refluxed for 20 h. The mixture was cooled to room temperature and then rotary evaporated to dryness. The residue was purified by column chromatography and isolated as a tan solid (22 mg, 41%). 1H NMR (CDCl3): 8.77 (dd, J=1.8, 4.5 Hz, 2H), 8.29 (dd, J=1.5, 4.5 Hz, 2H), 8.01 (s, 1H), 7.85 (s, 1H), 7.83 (d, J=8.1 Hz, 2H), 7.47 (d, J=7.8 Hz, 2H), 7.37 (dd, J=1.5, 8.4 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.04 (s, 1H), 6.74 (s, 1H), 3.57 (s, 2H), 2.47 (s, 8H), 2.29 (s, 6H).
Reaction SMILES: C([C:5]1N=C(N2CCC(F)(F)C2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])N=2)[N:10]=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].ClCC1N(C2CC2)N=NN=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[C:31](=[N:33][N:34]([CH2:8][C:9]3[N:10]([CH3:5])[C:14]([CH3:15])=[N:12][N:11]=3)[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Agent: ClCc1nnnn1C1CC1
Product: Cc1nnc(Cn2nc3nc(C(C)(C)C)nc(N4CC5(COC5)C4)c3n2)n1C

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-cyclopropyl-1H-tetrazole and isolated as white solid. MS (m/e): 397.3 (MH+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:12](O)=[O:13])[C:6]([C:9](O)=[O:10])=[CH:7][CH:8]=1.B.CO>C1COCC1>[OH:13][CH2:12][C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:8]=[CH:7][C:6]=1[CH2:9][OH:10]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C(=O)O
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(C(F)(F)F)cc1CO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
To a solution of 4-trifluoromethylbenzene-1,2-dicarboxylic acid (5.85 g, 25 mmol) in THF (50 mL) at −78° C. was added borane in THF (1.0 M, 75 mL) and the mixture was stirred for 10 minutes. The mixture was then allowed to warm to room temperature and stirred overnight. Methanol (30 mL) was added and solvents were evaporated. The mixture was partitioned between ether and aqueous hydrochloric acid (1N). The organic layer was washed with brine and concentrated sodium bicarbonate solution. After the evaporation of solvents, colorless oil was obtained as (2-hydroxymethyl-4-trifluoromethyl-phenyl)-methanol (5.15 g). 1H-NMR (CDCl3) □ 7.58 (m, 2H), 7.51 (s 1H), 4.79 (s, 4H), 2.88 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH:7]2[CH:5]([CH2:6]2)[N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].CC#N.C(Cl)(Cl)(Cl)Cl.O.I([O-])(=O)(=O)=[O:26].[Na+]>[Ru](Cl)(Cl)Cl>[C:12]([O:11][C:9]([N:4]1[CH:3]([C:2]([OH:26])=[O:1])[CH2:8][CH:7]2[CH:5]1[CH2:6]2)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1C2CC2C[C@@H]1CO
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C(C(=O)O)CC2CC21
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.1 %

Procedure:
To a solution of (3R)-tert-butyl 3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (D32) (440 mg, 2.06 mmol) in a mixture MeCN/CCl4/H2O (6/6/9 ml), sodium periodate (1.76 g, 8.25 mmol) was added and the reaction stirred vigorously for 5 min before addition of Ruthenium trichloride (12.8 mg, 0.062 mmol). The resulting solution was stirred 18 hrs at RT then quenched by addition of isopropanol (6 ml). The resulting black mixture was diluted with Et2O (50 ml) and filtered through a celite pad. The filtrate was evaporated and the residue was dissolved in water, the pH was adjusted to pH˜9-10 with K2CO3 and the aqueous was washed with Et2O (3×30 ml). Aqueous was then acidified to pH˜4-5 and re-extracted with EtOAc (3×30 ml). Collected organics after solvent evaporation afforded the title compound (D33) (216 mg).
Reaction SMILES: CN([SiH3])[Si:3]([CH3:6])(C)[CH3:4].[F:8][C:9]([F:20])([F:19])[C:10]([O:12]C(=O)C(F)(F)F)=[O:11]>>[F:8][C:9]([F:20])([F:19])[C:10]([O:12][SiH:3]([CH3:6])[CH3:4])=[O:11]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CN([SiH3])[Si](C)(C)C
Product: C[SiH](C)OC(=O)C(F)(F)F

Procedure:
Additionally, for example when mixing tetramethyldisilazane as the silicon compound D with trifluoroacetic anhydride as the acid D, the trifluoroacetic anhydride immediately reacts therewith to form dimethylsilyl trifluoroacetate as the silicon compound B.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[OH-:20].[Na+].Cl>ClCCl>[C:14]1([C:12]2[C:11]([OH:20])=[CH:8][C:7]3[C:2](=[N:3][CH:4]=[CH:5][CH:6]=3)[N:1]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [OH-]
Reactant: Nc1ncccc1C=O
Reactant: O=C(CCl)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cc2cccnc2nc1-c1ccccc1
Reaction time: 72 h
Yield: 13 %

Procedure:
2-Amino-pyridine-3-carbaldehyde (100 mg) and 2-chloro-1-phenyl-ethanone (127 mg) were suspended in a 5 N aqueous sodium hydroxide solution (0.6 ml), and the suspension was hermetically sealed and, in this state, was allowed to stand for 3 days. The reaction solution was neutralized with 10% hydrochloric acid. Dichloromethane was then added thereto, and the mixture was extracted. The dichloromethane layer was washed with water and saturated brine and was dried over magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give 2-phenyl-[1,8]naphthyridin-3-ol (23 mg, yield 13%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C[CH:13]=[CH:14][C:15](Cl)=[O:16].[CH2:18](Cl)Cl>>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][C:15](=[O:16])[C:14]([CH3:18])=[CH2:13])=[C:3]([CH:7]=1)[C:4]([NH2:6])=[O:5]
Reactant: CC=CC(=O)Cl
Reactant: NC(=O)c1cc(Cl)ccc1N
Reactant: ClCCl
Product: C=C(C)C(=O)Nc1ccc(Cl)cc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-5-chloro-benzamide (2.5 mmoL), a literature known compound, was treated with TEA (3.0 mmoL) followed by methylacryl chloride (2.5 mmoL) in DCM at 0° C. The reaction was slowly warmed to room temperature and kept for another 2 h. The reaction mixture was then partitioned between DCM and water. The organic layer was washed with sat. Na2CO3, brine, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel column chromatography to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:13].[Cl:14][CH2:15][C:16]([NH2:18])=[O:17]>O1CCOCC1>[Cl-:14].[C:16]([CH2:15][N+:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[C:6]([CH3:13])=[CH:7][CH:8]=1)(=[O:17])[NH2:18]
Reactant: COc1ccc2nccc(C)c2c1
Reactant: NC(=O)CCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1)c(C)cc[n+]2CC(N)=O
Product: [Cl-]

Procedure:
In 30 ml of dioxane 17.3 g of 6-methoxylepidine (0.1 mole) and 11.3 g of chloroacetamide (0.12 mole) were refluxed for 8 hours and the precipitated crystals were collected, washed with acetone and dried. Yield, 24.18 g (8.78%); M.p., 240°-241° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:14][CH:15]=2)[C:10]([CH:24]=[O:25])=[C:9]1[CH:26]([CH3:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][Mg+].[Br-]>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:14][CH:15]=2)[C:10]([CH:24]([OH:25])[CH3:29])=[C:9]1[CH:26]([CH3:28])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg+]
Reactant: CC(C)c1c(C=O)c2cc(OC3CCCCO3)ccc2n1Cc1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)c1c(C(C)O)c2cc(OC3CCCCO3)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
General Procedure C. To a −78° C. solution of (1-benzyl-2-isopropyl-5-(tetrahydropyran-2-yloxy)-1H-indole-3-carboxaldehyde (Compound 13, 200 mg, 0.55 mmol) in THF (5 mL) was added MeMgBr (3 M solution in THF, 1 mL, 3 mmol). The solution was stirred between −78° C. and −10° C. for 4 h, and then the reaction was quenched at −78° C. by adding EtOAc (2 mL) and water (5 mL). The mixture was warmed to room temperature and diluted with EtOAc (50 mL). The reaction was quickly washed with ice cold aqueous NH4Cl (5 mL), and brine (10 mL), and dried (Na2SO4), and the solvent was removed under vacuum to give 1-(1-benzyl-2-isopropyl-5-(tetrahydropyran-2-yloxy)-1H-indol-3-yl)ethanol as a mixture of two diastereomers that were used directly in the next step without further purification or characterization. Thus, crude 1-(1-benzyl-2-isopropyl-5-(tetrahydropyran-2-yloxy)-1H-indol-3-yl)ethanol (200 mg, 0.51 mmol) was oxidized to 1-(1-benzyl-2-isopropyl-5-(tetrahydropyran-2-yloxy)-1H-indol-3-yl)ethanone (Compound 14) by General Procedure B.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[N:6]=1.[C:27](Cl)([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:28]>O1CCCC1.N1C=CC=CC=1>[CH:14]([N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:28])[S:3][CH:4]=2)[CH2:9][CH2:10]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)Nc1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1
Yield: 30.5 %

Procedure:
To a solution of 2-amino-4-(4-benzhydrylpiperazin-1-ylmethyl)thiazole (1.8 g) in tetrahydrofuran (5 ml) and pyridine (10 ml) was added dropwise ethoxalyl chloride (1.1 g) under ice-cooling with stirring, and the stirring was continued at the same temperature for an hour. After concentration of the reaction mixture, the residue was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and then evaporated to dryness to give a residue, which was chromatographed on silica gel using ethyl acetate as an eluent. The eluates containing the desired compound were collected and evaporated, followed by recrystallization from a mixture of ethyl acetate and n-hexane to obtain pale yellow crystals (0.7 g) of 4-(4-benzhydrylpiperazin-1-ylmethyl)-2-ethoxalylaminothiazole, mp 125°-128° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:3][CH2:2]1.[CH3:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O.[CH:28]([C:30]1[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([OH:38])=[O:37])[CH:31]=1)=O>>[CH:1]1([CH2:4][N:5]2[C:10]3=[N:11][N:12]([CH2:26][C:20]4[C:19]5[C:23](=[CH:24][CH:25]=[C:17]([CH3:16])[CH:18]=5)[NH:22][CH:21]=4)[C:28]([C:30]4[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([OH:38])=[O:37])[CH:31]=4)=[C:9]3[C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:2][CH2:3]1
Reactant: Cc1ccc2[nH]cc(C=O)c2c1
Reactant: Cn1cc(C(=O)O)cc1C=O
Reactant: Cn1c(=O)cc(NN)n(CC2CC2)c1=O
Product: Cc1ccc2[nH]cc(Cn3nc4c(c3-c3cc(C(=O)O)cn3C)c(=O)n(C)c(=O)n4CC3CC3)c2c1

Procedure:
This compound was made following the procedure described above, staring with 1-(cyclopropylmethyl)-6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-methyl-1H-indole-3-carbaldehyde, followed by 5-formyl-1-methyl-1H-pyrrole-3-carboxylic acid. Mass: 487.23 (M+H).