Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH:23]([CH3:26])[CH2:24][Cl:25].O>CN(C)C=O>[CH3:1][N:2]([CH:24]([Cl:25])[CH:23]([CH3:26])[CH3:22])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: CC(CCl)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)C(Cl)C(C)C)cc1OC
Yield: 40 %

Procedure:
8.0 g of N-methyl-(2-(3,4-dimethoxyphenyl)ethyl)amine was dissolved in 120 ml of N,N-dimethylformamide, followed by the addition of 6.8 g of anhydrous potassium carbonate and 14.4 ml of 1-bromo-3-chloro-2-methylpropane. The obtained mixture was reacted at a room temperature for 12 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous potassium carbonate and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (50:1)] to obtain 4.67 g of the title compound as a pale yellow oil (yield : 40%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=2)[O:9][CH2:10][CH2:11][O:12][CH:13]([CH3:18])[C:14](OC)=[O:15])=[CH:2]1.[Li].[H-]>O1CCCC1>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=2)[O:9][CH2:10][CH2:11][O:12][CH:13]([CH3:18])[CH2:14][OH:15])=[CH:2]1
Reactant: COC(=O)C(C)OCCOc1cccc(-c2ccsc2)c1
Agent: [H-]
Agent: [Li]
Solvent: C1CCOC1
Product: CC(CO)OCCOc1cccc(-c2ccsc2)c1
Yield: 99.1 %

Procedure:
0.20 g of the resulting ester compound was dissolved in 5 ml of tetrahydrofuran, and reduced as in Referential Example 31 with 25 mg of lithium alminum hydride to give 0.18 g of the captioned compound as a colorless oil.
Reaction SMILES: [CH2:1]=[CH:2][C:3]([CH3:6])([CH3:5])[CH3:4].[CH3:7][SiH:8]([Cl:10])[Cl:9].[SiH4]>C1COCC1.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH2:1]([Si:8]([CH3:7])([Cl:10])[Cl:9])[CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: C[SiH](Cl)Cl
Reactant: C=CC(C)(C)C
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Agent: [SiH4]
Solvent: C1CCOC1
Product: CC(C)(C)CC[Si](C)(Cl)Cl
Temperature: 42 °C
Yield: 93 %

Procedure:
A 2 liter, 4-necked flask equipped as in Example 1 was charged with 500 g (5.94 mol) of neohexene and 1 ml of a 10% chloroplatinic acid in THF solution. The mixture was heated to reflux (about 42° C.). 805 g (5.94 mol) of methyldichlorosilane was then added dropwise. After the addition of about 70 ml of the silane, the reaction commenced and the temperature in the flask rose to 102° C. as the remainder of the silane was added. The reaction mixture was allowed to cool to room temperature (about 25° C.) after the addition of the silane. Upon completion of the reaction, the remaining volatile components were removed at reduced pressure and the residue was distilled to give 1100 g (84% of theory) of neohexylmethyldichlorosilane.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:11]([CH3:17])[C:10]=1[C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:23]([N:20]([CH2:21][CH3:22])[C:18]([C:10]1[N:11]([CH3:17])[C:12]([CH3:16])=[CH:13][C:14](=[O:15])[C:9]=1[OH:8])=[O:19])[CH3:24]
Reactant: CCN(CC)C(=O)c1c(OCc2ccccc2)c(=O)cc(C)n1C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC)C(=O)c1c(O)c(=O)cc(C)n1C

Procedure:
Pd(OH)2 on charcoal (0.1 g) was added to a solution of 3-(benzyloxy)-N,N-diethyl-1, 6-dimethyl-oxo-1,4-dihydropyridine-2-carboxamide(1.0 g, 3.05 mmol) in ethanol (100 ml) under nitrogen. The mixture was hydrogenated at 50 psi hydrogen for 4 hrs.
Reaction SMILES: [F:1][C:2]1([F:13])[CH2:7][CH2:6][C:5]([O:8][Si](C)(C)C)=[CH:4][CH2:3]1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1([F:13])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1
Reactant: C[Si](C)(C)OC1=CCC(F)(F)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: O=C1C=CC(F)(F)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 50.5 %

Procedure:
To a solution of the [(4,4-difluorocyclohex-1-en-1-yl)oxy](trimethyl)silane (3.1 g, 15.0 mmol) prepared in Example 88a in acetonitrile (25 mL), palladium acetate (4.0 g, 17.8 mmol) was added, and the mixture was stirred at room temperature for 45 minutes. The reaction solution was filtered, the filtrate was vacuum concentrated, and the residue was purified with silica gel chromatography (hexane/ethyl acetate=9:1) to yield the title compound (1.0 g, 50%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([CH:33]=2)[C:30](O)=[O:31])[N:21]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:30](=[O:31])[C:29]3[CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=[N:27][CH:28]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1csc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: CC(C)(CNC(=O)c1cncc(-c2noc(C(F)(F)F)n2)c1)c1csc(-c2ccc(F)cc2)n1
Yield: 26 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropan-1-amine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (50 mg, yield 26%). 1H NMR (400 MHz, MeOD) δ 9.36 (d, J=2.0 Hz, 1H), 9.11 (d, J=2.3 Hz, 1H), 8.77-8.76 (t, J=2.1 Hz, 1H), 8.00-7.96 (m, 2H), 7.30 (s, 1H), 7.18-7.14 (t, J=8.8 Hz, 2H), 3.75 (s, 2H), 1.50 (s, 6H). MS (ESI) m/z: Calculated for C22H17F4N5O2S: 491.10. found: 492.0 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:6][CH2:5]2.C(N(CC)CC)C.[CH3:28][C:29]1([CH3:36])[C:33]([CH3:35])([CH3:34])[O:32][BH:31][O:30]1>O1CCOCC1.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]>[CH3:28][C:29]1([CH3:36])[C:33]([CH3:35])([CH3:34])[O:32][B:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[O:8][C@@H:7]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:6][CH2:5]3)[O:30]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCc2cc(I)ccc2O1
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC1(C)OB(c2ccc3c(c2)CC[C@H](CO[Si](C)(C)C(C)(C)C)O3)OC1(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Argon was bubbled through a solution of tert-butyl(dimethyl)silyl [(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl ether (Example 13, 11.1 mmol, 1.0 eq.) in dioxane (45 mL) for 10 minutes before Pd(dppf)Cl2 (0.306 mmol, 0.03 eq.), triethylamine (33.4 mmol, 3.0 eq.), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (17.8 mmol, 1.6 eq.) were added. The resulting reaction mixture was stirred at 80° C. overnight. The mixture was then filtered through a Celite® pad. The filtrate was concentrated and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes:EtOAc=10:1). The product was obtained as a pale brown waxy solid in 94% yield. MH+=405.3, retention time (LC-MS)=4.79 min.
Reaction SMILES: [N:1]1[N:2]=[C:3]([S:10][C:11]2[N:16]=[N:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Br[CH2:19][C:20]([NH:22][C:23]([CH:25]1[CH2:27][CH2:26]1)=[O:24])=O.P([O-])([O-])(O)=O.[K+].[K+].[I-].[K+]>CC(N(C)C)=O.CO>[N:1]1[N:2]=[C:3]([S:10][C:11]2[CH:12]=[CH:13][C:14]3[N:15]([CH:19]=[C:20]([NH:22][C:23]([CH:25]4[CH2:27][CH2:26]4)=[O:24])[N:17]=3)[N:16]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C(CBr)NC(=O)C1CC1
Reactant: Nc1ccc(Sc2nnc3ccccn23)nn1
Agent: O=P([O-])([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: O=C(Nc1cn2nc(Sc3nnc4ccccn34)ccc2n1)C1CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
A mixture of 6-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)pyridazin-3-amine (2.443 g, 10 mmol), N-(2-bromoacetyl)cyclopropanecarboxamide (3.09 g, 15.00 mmol), potassium hydrogenphosphate (5.23 g, 30.0 mmol) and potassium iodide (0.830 g, 5.00 mmol) in DMA (100 mL) was stirred at 120° C. for 2 hrs. Additional amounts of N-(2-bromoacetyl)cyclopropanecarboxamide (2.06 g, 10 mmol) and potassium hydrogenphosphate (1.74 g, 10 mmol) were added to the mixture and the reaction was stirred at 120° C. for another 2 hrs. The reaction was then stirred at room temperature overnight. The reaction mixture was again stirred at 140° C. for 3 hrs and then cooled to room temperature. The resulting solid was filtered off and rinsed with DMA. The filtrate was concentrated to 100 mL and then poured into water (300 mL). The resulting precipitate was collected by filtration and rinsed thoroughly with water. The solid material was re-suspended in 10% MeOH/CH2Cl2 (100 mL), sonicated, refluxed for 30 min and cooled to room temperature. The MeOH/CH2Cl2 solution was filtered through a silica plug, rinsed with 10% MeOH/CH2Cl2 (200 mL). To above organic solution, activated charcoal (0.5 g) was added, the solution was refluxed for 30 min, and then stirred at room temperature overnight. The charcoal was filtered through Celite, and the filtrate was concentrated to dryness to provide an off white solid. This solid was refluxed in MeOH (10 mL) for 30 min. and cooled to room temperature. The resulting off white solid was collected by filtration, rinsed with MeOH (2 mL) and dried in vacuum to provide the title compound, N-(6-([1,2,4]Triazolo[4,3-a]pyridin-3-ylthio)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (1.2 g). 1H NMR (400 MHz, DMSO-d6) δ=11.17 (s, 1 H), 8.57-8.44 (m, 1 H), 8.03-7.94 (m, 1 H), 7.96-7.88 (m, 2 H), 7.59 (ddd, J=1.0, 6.6, 9.3 Hz, 1 H), 7.22-7.11 (m, 1 H), 7.11-7.03 (m, 1 H), 1.97-1.84 (m, 1 H), 0.83-0.73 (m, 4 H) ESI-MS:m/z 352.3 (M+H)+. MP 193-195° C.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C@H:9]([NH:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[CH2:8][S:7][CH2:6]1)=[O:4].[OH-].[Na+].Cl>O1CCCC1>[C:13]1([C@H:11]([NH:10][C@@H:9]2[CH2:8][S:7][CH2:6][C@H:5]2[C:3]([OH:4])=[O:2])[CH3:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)[C@@H]1CSC[C@H]1N[C@H](C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](N[C@@H]1CSC[C@H]1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A solution of Preparation of (3R,4S)-4-[(R)-1-phenyl-ethylamino]-tetrahydrothiophene-3-carboxylic acid methyl ester (673 mg, 2.54 mmol) in tetrahydrofuran (5 mL) was treated with 1.0 M sodium hydroxide solution (5.0 mL, 5.0 mmol) and the heterogeneous mixture was stirred at room temperature. After 75 min, the now homogeneous solution was treated with 1.0 M hydrochloric acid (5.0 mL, 5.0 mmol) and concentrated in vacuo. The residue was dissolved in water and lyophilized to provide the product, along with sodium chloride, as a fluffy white solid (928 mg, quantitative), used without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:31])[O:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:20][CH2:19]2)[C:12]2[S:17][CH:16]=[CH:15][C:13]=2[N:14]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([N:18]2[CH2:19][CH2:20][CH:21]([NH:24][C:25](=[O:31])[O:26][CH2:27][CH:28]([CH3:29])[CH3:30])[CH2:22][CH2:23]2)[C:12]2[S:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: COc1ccccc1-c1nc(N2CCC(NC(=O)OCC(C)C)CC2)c2sccc2n1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)COC(=O)NC1CCN(c2nc(-c3ccccc3O)nc3ccsc23)CC1
Temperature: 25 °C

Procedure:
A solution of isobutyl 1-(2-(2-methoxyphenyl)thieno[3,2-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (0.13 g, 0.30 mmol) in CH2Cl2 (2 mL) was cooled to −50° C., and a solution of BBr3 in CH2Cl2 (1 M, 1.8 mL, 1.8 mmol) was slowly added. The reaction was allowed to gradually warm to room temperature over 3 h, and saturated aqueous NaHCO3 was slowly added. The organic layer was separated, washed with water, dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give isobutyl 1-(2-(2-hydroxyphenyl)thieno[3,2-d]pyrimidin-4-yl)piperidin-4-ylcarbamate. LC/MS: m/z 427.3 (M+H)+ at 3.08 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: O[CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23]>C1C=CC=CC=1>[CH2:4]([NH:5][CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23])[C:3]#[CH:2]
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CO)C1C
Solvent: c1ccccc1
Product: C#CCNC=C1C(=O)c2cc(OC)c(OC)cc2N(C(=O)OCC)C1C
Reaction time: 8 h

Procedure:
To 1.6 g. of 3-hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester in 15 ml. of benzene is added 275 mg. of proparglyamine, and the resulting solution allowed to stir overnight at room temperture. The reaction mixture is concentrated in vacuo to about 2 g. and is then dissolved in 50 ml. of chloroform. The resulting solution is washed with 50 ml. of a 1N aqueous sodium hydroxide solution and subsequently dried over magnesium sulfate. Removal of the chloroform solvent leaves 1.9 g. of the desired product as a yellow foam.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[OH:18])[CH:2]=[CH2:3].[CH2:19](Br)[CH:20]=[CH2:21].C(=O)([O-])[O-].[Cs+].[Cs+]>C(C(C)=O)C>[CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[O:18][CH2:21][CH:20]=[CH2:19])[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: C=CCc1cc(OCc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(OCc2ccccc2)cc1CC=C
Reaction time: 23 h

Procedure:
A mixture of 2-allyl-4-benzyloxy-phenol (ER2-YYR-17) (35.56 g, 148 mmol), allyl bromide (21.5 g, 178 mmol), cesium carbonate (58 g, 178 mmol) and methyl ethyl ketone (400 mL) was refluxed with stirring in a 1 L round bottomed flask. After 23 h, the reaction was cooled and concentrated. The residue was partitioned between water (500 mL) and EtOAc (400 mL). The organic layer was dried (MgSO4) and concentrated to a tan oil, 39.37 (95%) ER0-LKW-190A: 1H NMR (CDCl3) δ 3.45 (dd, 2H), 4.54 (dd, 2H), 5.04 (s, 2H), 5.18 (m, 2H), 5.29 (dd, 1H), 5.46 (dd, 1H), 5.94-6.18 (m, 2H), 6.81 (s, 2H), 6.88 (s, 1H), 7.30-7.48 (m, 5H), MS (ES) m/e 281 [M+1].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[F:11][C:12]([F:25])([F:24])[C:13]1[CH:14]=[C:15](I)[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC([O-])=O.[Ag+]>[F:11][C:12]([F:24])([F:25])[C:13]1[CH:14]=[C:15]([C:8]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[C:5]([OH:7])=[O:6])[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=1
Reactant: FC(F)(F)c1cc(I)cc(C(F)(F)F)c1
Reactant: Cc1cccc(C(=O)O)c1
Agent: [Ag+]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: Cc1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(C(=O)O)c1

Procedure:
Palladium acetate (11.4 mg, 0.05 mmol), AgOAc (217 mg, 1.3 mmol), 3-methylbenzoic acid (136 mg, 1.0 mmol, 3,5-bis(trifluoromethyl)iodobenzene (1.02 g, 3.0 mmol and acetic acid (200 μL) were combined and heated at 120° C. for 4.5 h. After purification white solid was obtained, 207 mg (59%), mp 217-219° C. (isooctane). Rf-0.60 (1/9 ethyl acetate-dichloromethane). 1H NMR (300 MHz, acetone-d6): δ 2.46 (s, 3H), 7.38-7.51 (m, 2H), 7.87 (s, 1H), 7.94 (s, 2H), 8.00 (s, 1H), 11.3 (brs, 1H). 13C NMR (75 MHz, acetone-d6) 320.6, 120.9 (br s), 124.2 (q, J-271.1 Hz), 129.7 (br s), 130.8, 131.1 (q, J-33.3 Hz), 131.5, 131.7, 133.1, 137.6, 139.3, 144.9, 168.0. FT-IR (neat, cm1) υ 1689, 1290, 1121. Anal. calcd for C16H10F6O2 (348.2 g/mol) C, 55.18; H, 2.89. Found: C) 55.07; H, 2.81. The 1H NMR and 13C NMR spectra are shown in FIGS. 24A&B, respectively.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([O:7][C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:4]=[N:3][CH:2]=1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24](O)=[O:25])=[CH:16]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[N:3]1[CH:4]=[C:5]([O:7][C:8]2[N:13]=[CH:12][C:11]([NH:14][C:24]([C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[NH:15][CH:16]=3)=[O:25])=[CH:10][CH:9]=2)[CH:6]=[N:1][CH:2]=1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: Nc1ccc(Oc2cncnc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2cncnc2)nc1)c1c[nH]c2ccccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
The 6-(pyrimidine-5-yloxy)-pyridine-3-ylamine (53 mg, 0.28 mmol) and indole-3-carboxylic acid (45 mg, 0.28 mmol) were dissolved in DMF (5 ml), DCC (58 mg, 0.28 mmol) was added to the solution, and then the mixture was stirred at 80° C. for 8 hours. After the reaction was completed, the product was washed and filtered to yield a target compound as a white solid (55 mg, 59%) by chromatography (methanol:dichloromethane=2:30).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH2:11][CH:12]1[O:16][CH2:15][CH2:14][O:13]1>ClCCl>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[CH2:11][NH:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCC1OCCO1
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Product: c1ccc(NCC2OCCO2)cc1
Reaction time: 0.08 h
Yield: 28.6 %

Procedure:
A suspension of phenylboronic acid (0.5 g, 4.1 mmol), copper(II)-acetate-1-hydrate (0.041 g, 0.21 mmol) and molecular sieves (1.5 g, size 0.4 nm, powdered) in dichloromethane (12 ml) was stirred for 5 min. Then 2-(aminomethyl)-1,3-dioxolane (0.211 g, 2.05 mmol) was added and oxygen was bubbled through the mixture for 5 min. The vessel was closed and shaken overnight at room temperature. For workup ethyl acetate (50 ml) and 1 M sodium bicarbonate solution (30 ml) were added and the mixture was shaken. The organic layer was separated, dried over magnesium sulfate and evaporated. The residue was purified using flash chromatography (SiO2; eluent: heptane/ethyl acetate=90:10) to yield a light yellow oil (105 mg, 14%); MS (EI): 179.1 (M+.).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Li])CCC.CCCCCC.Br[C:21]1[O:25][C:24]([CH:26]=[O:27])=[CH:23][CH:22]=1.Cl>C1COCC1.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.[Cl-].[Zn+2].[Cl-]>[C:1]([C:21]1[O:25][C:24]([CH:26]=[O:27])=[CH:23][CH:22]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=Cc1ccc(Br)o1
Reactant: C#CCCCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCC#Cc1ccc(C=O)o1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
To a solution of 1-octyne (5.5 g, 50 mmole) in dry THF (40 ml) at -30° C. was added n-butyl lithium in hexane (1.05 eq). After warming to 0° C. over 1 hr a solution of zinc chloride (6.95 g, 50 mmole) in THF (50 ml) was added and temperature raised to room temperature over 1/2 hr. Sequentially, solutions of 5-bromofuran-2-carboxaldehyde (8.75 g, 50 mmole) in THF (20 ml) and tetrakis triphenylphosphinepalladium (0) (5.7 g, 10%) in THF (50 ml) were added. The mixture was heated to reflux for 2 hr after which it was cooled and added to dilute hydrochloric acid (50 ml). After extracting into diethyl ether (3×100 ml), drying the ethereal solution (MgSO4) and removing the solvent under reduced pressure, the resulting oil was chromatographed on silica (DCM: Hexane 1:2) to give the title compound 6.83 g (67 %) as an oil. νmax (film) 3150, 3125, 2225, 1680, 890, 770; δ(CDCl3)0.90(3H, distorted t), 1.42(8H, complex m), 2.45(2H, t, J=6.5 Hz), 6.60(1H, d, J=3.0 Hz), 9.65(1H, s).
Reaction SMILES: O.O[CH:3]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:8]([O:9][C@@H:10]2[O:18][C@H:17]([CH2:19][OH:20])[C@H:15]([OH:16])[C@H:13]([OH:14])[C@H:11]2[OH:12])[C@H:6]([OH:7])[C@H:4]1[OH:5].[NH2:25][C:26]([NH2:28])=[O:27].OS(O)(=O)=O>O>[CH2:19]([OH:20])[C@H:17]1[O:18][C@@H:10]([O:9][C@H:8]2[C@H:6]([OH:7])[C@@H:4]([OH:5])[CH:3]([NH:25][C:26]([NH2:28])=[O:27])[O:22][C@@H:21]2[CH2:23][OH:24])[C@H:11]([OH:12])[C@@H:13]([OH:14])[C@H:15]1[OH:16]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Reactant: NC(N)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: NC(=O)NC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Reaction time: 2.5 h

Procedure:
360 g of lactose monohydrate (1 mole) were mixed with 60 g of urea (1 mole) and 10.6 ml of a solution made up of 100 ml of H2O and 6 ml of 98% H2SO4. The mixture was melted and deposited as a thin layer on the moving belt of a tunnel oven. This oven was equipped with a system for controlling its temperature in a first third of its length (zone I) according to a temperature gradient and, in the second 2/3 of its length (zone II), at a constant temperature. Zone I was subjected to a temperature gradient ranging from ambient, at the entrance, to 100°-110° at the end of zone I; zone II was maintained at a constant temperature of 100°-110° C. The mixture coated on the belt thus penetrated into the tunnel and was gradually heated, in 11/2 hrs, to 110° after which it entered zone II where it stayed for 2-3 hrs at 110° C. At the exit of the tunnel, the mixture was cooled and had the aspect of a slightly foamy, crystalline, light brown material, easy to remove from the belt with a doctor-knife and which could be ground into a powder. This product was collected in a continuous manner and about 400 g were obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:17])=[C:5]([CH3:16])[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=O.C1(C(=[N:31][C@@:32]2([C:38](OCC)=[O:39])[CH2:34][C@H:33]2[CH2:35][O:36][CH3:37])C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].C(O)(=O)C>C1COCC1.C(O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[C:6]3[C:5]([CH3:16])=[C:4]([CH3:17])[S:3][C:2]=3[NH:1][C:38](=[O:39])[C@@:32]3([CH2:34][C@H:33]3[CH2:35][O:36][CH3:37])[N:31]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)[C@]1(N=C(c2ccccc2)c2ccccc2)C[C@H]1COC
Reactant: Cc1sc(N)c(C(=O)c2ccc(Cl)cc2)c1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(=O)O
Product: COC[C@@H]1C[C@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)NC2=O
Temperature: 25 °C

Procedure:
To a solution of (2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone (7.09 g, 26.7 mmol) and (1S,2R)-ethyl 1-((diphenylmethylene)amino)-2-(methoxymethyl)cyclopropanecarboxylate (6 g, 17.78 mmol) in anhydrous THF (100 mL) was slowly (over 5 min) added a solution of potassium tert-butoxide (1 M in THF) at rt. The reaction was heated to 60° C. for approximately 20 h before acetic acid (10.68 g, 178 mmol) and absolute ethanol (20 mL) were added at 60° C. THF was distilled off, and the reaction was heated to reflux for 3 h. The reaction was cooled to rt before silica gel was added, and the solvent was removed under vacuum. The dry silica gel was packed and the product was purified by flash chromatography (EtOAc/hexane 1:19 to 6:14) to give (1S,2R)-5′-(4-chlorophenyl)-2-(methoxymethyl)-6′,7′-dimethylspiro[cyclopropane-1,3′-thieno[2,3-e][1,4]diazepin]-2′(1′H)-one a solid (3.7 g). LRMS (M+H)+: 375 m/z.