Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:20][C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:22])[CH2:16][C:17]([OH:19])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([NH2:33])[C:31]#[CH:32].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:20][C:21](=[O:22])[NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:16][C:17](=[O:19])[NH:33][CH2:30][C:31]#[CH:32])=[CH:11][CH:10]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C#CCN
Reactant: CCOC(=O)CNC(=O)NC(CC(=O)O)c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CCNC(=O)CC(NC(=O)NCC(=O)OCC)c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66 %

Procedure:
3-(4-(tert-butoxycarbonylamino)phenyl)-3-(3-(2-ethoxy-2-oxoethyl)ureido)propanoic acid (1 equivalent, 150 mg, 0.37 mmol), propargylamin hydrocholoride (1 equivalent, 33 mg, 0.37 mmol), DIPEA (2.2 equivalent, 140 μl, 0.81 mmol), and HOBt (1.2 equivalent, 60 mg, 0.45 mmol) were dissolved in 2 ml of DMF. The reaction mixture was stirred at room temperature for 20 minutes. Then EDAP (1.2 equivalent, 84 mg, 0.45 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was washed by 30 ml of NaHCO3, and extracted by 3×20 ml of EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated. The crude was purified by flash chromatography (EDP/EtOAc) to afford the compound 200 (108 mg, 66%) as a white solid, Rf=0.25 (EtOAc). 1H NMR (200 MHz, DMSO) δ 9.28 (s, 1H), 8.29 (t, J=5.2 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.16 (d, J=8.5 Hz, 2H), 6.72 (d, J=8.5 Hz, 1H), 6.34 (t, J=6.1 Hz, 1H), 4.99 (q, J=7.0 Hz, 1H), 4.09 (q, J=7.2 Hz, 2H), 3.86-3.78 (m, 2H), 3.76 (d, J=5.9 Hz, 2H), 3.41-3.32 (m, 2H), 3.13-3.08 (m, 1H), 1.50 (s, 9H), 1.20 (t, J=7.1 Hz, 3H).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)(O)[O-].[Na+]>C1COCC1.O>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:4]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCc1cccnc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COCc1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
To a suspension of 4.4 g of sodium hydride (60% oil dispersion; 110 mmol) in 300 mL of THF were added dropwise 10.91 g of 3-pyridinemethanol (100 mmol) in 20 mL of THF at room temperature, and the mixture was stirred at room temperature for 2 hours. The resulting white suspension was ice-cooled, and 19.51 g of tert-butyl bromoacetate (100 mmol) in 20 mL of THF was added dropwise, maintaining the inner temperature within 10 to 12° C. The suspension was warmed to room temperature with stirring for 3 hours, and then left overnight. After adding water and saturated sodium bicarbonate aq., the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated. The residue was purified by column chromatography on silica gel (gradient elution with n-hexane:ethyl acetate=1:1 to ethyl acetate) to give 7.56 g of tert-butyl (pyridin-3-yl)methoxyacetate (33.8%) as a light brown oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[NH2:12][C:13]1[C:14]([C:20](O)=[O:21])=[N:15][C:16]([Br:19])=[CH:17][N:18]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:12][C:13]1[C:14]([C:20]([N:6]([C:4]([C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=2[F:1])=[O:5])[NH2:7])=[O:21])=[N:15][C:16]([Br:19])=[CH:17][N:18]=1
Reactant: NNC(=O)c1ccccc1F
Reactant: Nc1ncc(Br)nc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(Br)nc1C(=O)N(N)C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-fluorobenzohydrazide (2 g, 12.98 mmol), 3-amino-6-bromo-pyrazine-2-carboxylic acid (2.830 g, 12.98 mmol), and TBTU (5.002 g, 15.58 mmol) in DMF (20.00 mL) was added DIPEA (3.691 g, 4.974 mL, 28.56 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×20 mL), the combined organic extracts were washed with water (3×20 mL) and brine (1×20 mL), dried over MgSO4 and concentrated in vacuo. The residue was then triturated with acetonitrile and filtered and dried to give 3-amino-6-bromo-N-(2-fluorophenylcarbonyl)pyrazine-2-carbohydrazide as an orange solid. This was taken up in MeCN (20.00 mL) and added bromo(triphenyl)phosphonium (5.331 g, 15.58 mmol) was added followed by DIPEA (3.691 g, 4.974 mL, 28.56 mmol). The reaction mixture was stirred for 30 min, and then filtered. The solid was washed with acetonitrile to give the product as a yellow solid (1.46 g, 67%); 1H NMR (400 MHz, DMSO) d 7.48-7.54 (m, 2H), 7.75 (m, 3H), 8.12 (m, 1H) and 8.45 (m, 1H) ppm; MS (ES+) 338.03
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:12][C:13](=O)[C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23](C(=O)C(F)(F)F)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH:8]=[C:9]([F:11])[CH:10]=1)=O)C.C([O-])(=O)C.[NH4+:37].O>C(O)(=O)C>[F:11][C:9]1[CH:10]=[C:6]2[C:4](=[O:3])[NH:37][C:13]([C:14]3[CH:15]=[CH:16][C:17]([CH:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]4)=[CH:18][CH:19]=3)=[CH:12][N:7]2[CH:8]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1cc(F)cn1CC(=O)c1ccc(C2CCN(C(=O)C(F)(F)F)CC2)cc1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(C3CCNCC3)cc2)cn2cc(F)cc12
Temperature: 110 °C
Reaction time: 8 h

Procedure:
4-Fluoro-1-(2-oxo-2-{4-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-yl]-phenyl}-ethyl)-1H-pyrrole-2-carboxylic acid ethyl ester (1.57 g; 3.42 mmol) is dissolved in acetic acid (10 ml) and ammonium acetate (5.80 g; 75.25 mmol) is added. The reaction mixture is stirred at 110° C. overnight. The reaction mixture is allowed to cool to room temperature, poured into cold water (250 ml) and extracted with ethyl acetate. The organic layers are discarded. The aqueous layer is basified with 2N NaOH (pH11). A precipitate forms. The solid is filtered off by suction, washed with water and a small amount of ethyl acetate. Then the solid is dissolved in 150 ml ethyl acetate, dried over Na2SO4, filtered off by suction and evaporated to dryness. The residue is triturated with diethylether, filtered off and dried under vacuum at 50° C. (overnight). The aqueous filtrate is extracted 3 times with ethyl acetate/MeOH (5%). The combined organic layers are washed with brine, dried over Na2SO4, filtered off and evaporated to dryness. The residue is triturated with diethylether, filtered off by suction and dried under vacuum to afford 7-fluoro-3-(4-piperidin-4-yl-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one as beige solid; HPLC/MS 1.37 min (A), [M+H] 312;
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][C@H:12]([N:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH:23][CH2:24][CH:25]4[CH2:27][CH2:26]4)[C:17]=3[CH:16]=[CH:15]2)[CH2:11][C@H:10]1[CH2:28][OH:29])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[S:31]([NH2:34])(=[O:33])=[O:32]>C(C#N)(C)=O>[S:31](=[O:33])(=[O:32])([O:29][CH2:28][C@@H:10]1[CH2:11][C@@H:12]([N:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH:23][CH2:24][CH:25]4[CH2:27][CH2:26]4)[C:17]=3[CH:16]=[CH:15]2)[CH2:13][C@@H:9]1[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[NH2:34]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(NCC4CC4)ncnc32)C[C@H]1CO
Reactant: NS(=O)(=O)Cl
Agent: CC(=O)C#N
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(NCC4CC4)ncnc32)C[C@H]1COS(N)(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(cyclopropylmethyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methanol (74.0 mg, 0.178 mmol) was dissolved in AcCN (3.50 mL) and cooled to 0° C. TEA (0.0500 mL, 0.355 mmol) was added followed by a 2.00 M solution of chlorosulfonamide in AcCN (0.178 mL, 0.356 mmol, as prepared in 1j). The reaction was stirred for 2 h, quenched with MeOH and concentrated in vacuo. The material was taken on to the next step without further purification. LC/MS: Rt=1.51 min, ES+ 496 (FA standard).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:27])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Cl>C(OCC)C.[BH4-].[Zn+2].[BH4-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:27])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:25])([F:26])[F:24])[CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)F)c1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)F)c1)C(O)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
While stirring zinc chloride (4.65 g, 34.1 mmol) in diethyl ether (50 ml), sodium borohydride (2.58 g, 68.3 mmol) was added as it was and the mixture was stirred as it was for 2 hrs. The insoluble material of the mixture was removed by filtration and washed with diethyl ether to give a solution of zinc borohydride in diethyl ether. To the obtained solution was added a solution of ethyl 3-(4-fluorophenyl)-3-oxo-2-[3-(trifluoromethoxy)benzyl]propionate (6.559 g, 17.07 mmol) in diethyl ether (30 ml) at room temperature and the mixture was stirred as it was for 2 hrs. Dilute hydrochloric acid was added to the solution by small portions to decompose excess zinc borohydride. The mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to give the objective substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH3:27])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:32]([BH3-])#N.[Na+]>CO.CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:12]([C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH3:27])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH3:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: Cc1cc2c(cc1NC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc2c(cc1N(C)C1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.7 %

Procedure:
A solution of 3-(4,7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.16 g, 0.40 mmol) and paraformaldehyde (neat, 0.024 g, 0.80 mmol) in MeOH (10 mL) and HOAc (1 mL) was heated at 70° C. for 14 h. The mixture was cooled to ambient temperature and sodium cyanoborohydride (0.050 g, 0.80 mmol) was added. The resulting dark solution was stirred at 70° C. for 3 h. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluting with 33-60% EtOAc in petroleum ether) to give 3-[(4,7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-methyl-amino]-azetidine-1-carboxylic acid tert-butyl ester as yellow solid (0.081 g, 49%). LC/MS (Table 1, Method 2) Rt=1.168 min.; MS m/z: 416 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]3[CH2:12][CH:7]([CH2:8][CH2:9]3)[C:6]=2[C:5]2=[N:13][N:14]=[C:15]([CH3:16])[N:4]2[N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH3:16][C:15]1[N:4]2[N:3]=[C:2]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:11]3[CH:10]4[CH2:12][CH:7]([C:6]=3[C:5]2=[N:13][N:14]=1)[CH2:8][CH2:9]4
Reactant: C1COCCN1
Reactant: Cc1nnc2c3c(c(Cl)nn12)C1CCC3C1
Product: Cc1nnc2c3c(c(N4CCOCC4)nn12)C1CCC3C1
Yield: 80.6 %

Procedure:
The 6-chloro-7,8,9,10-tetrahydro-3-methyl-7,10-methano(1,2,4)triazolo[3,4-a]phthalazine (4.5 grams, 0.019 mol) was mixed with 25 milliliters of morpholine and the mixture heated at boiling under reflux for eight hours. The reaction mixture was concentrated and partitioned between methylene chloride and water. The organic layer was collected, dried over sodium sulfate and evaporated to dryness to yield 4.4 grams (80.6% yield) of 7,8,9,10-tetrahydro-3-methyl-6-(4-morpholinyl)-7,10-methano(1,2,4)triazolo[3,4-a]phthalazine. After recrystallization from benzene-hexane the product was found to melt at 166°-168° C. Infrared analysis and nuclear magnetic resonance analysis confirmed the assigned structure, as did elemental analysis. Calculated for C15H19N5O: C, 63.14; H, 6.71; N, 24.55. Found: C, 63.20; H, 6.71; N, 24.32.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.[Mg].[C:11]([N:18]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>O1CCCC1>[Cl:9][C:4]1[CH:3]=[C:2]([C:20]2([OH:23])[CH2:21][CH2:22][N:18]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:19]2)[CH:7]=[CH:6][C:5]=1[Cl:8]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
Preparation according to Preparation 1: 4-bromo-1,2-dichlorobenzene (2.0 g, 8.85 mmol), dry tetrahydrofuran (35 mL), magnesium turnings (0.21 g, 8.85 mmol) and 1-N-boc-3-pyrrolidinone (1.63 g, 8.85 mmol). Refluxed for 1 h before addition of 1-N-boc-3-pyrrolidinone and 2 h after addition. Yield: 1.0 g. MS m/z (rel. intensity, 70 eV) 332 (M+, 1), 275 (41), 232 (37), 231 (28), 230 (52), 57 (bp).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:25])[CH:5]=[C:6]([NH:8][C:9]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]([C:22](O)=[O:23])([CH3:21])[CH3:20])=[CH:16][CH:17]=2)=[O:10])[CH:7]=1.Cl.C[O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:25][C:4]1[CH:5]=[C:6]([NH:8][C:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([CH3:20])([CH3:21])[C:22]([C:30]3([C:29]([OH:28])=[O:35])[CH2:34][CH2:33][CH2:32][NH:31]3)=[O:23])=[CH:14][CH:13]=2)=[O:10])[CH:7]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(C)cc(NC(=O)Cc2ccc(OC(C)(C)C(=O)O)cc2)c1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1cc(C)cc(NC(=O)Cc2ccc(OC(C)(C)C(=O)C3(C(=O)O)CCCN3)cc2)c1

Procedure:
Using RSR13 acid (3.08 g, 9.0 mmol), proline methyl ester hydrochloride (1.5 g, 9.0 mmol) and 1-hydroxybenzotriazole hydrate (1.34 g, 9.9 mmol), N-methylmorpholine (1.37 g, 13.6 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.08 g, 10.8 mmol) in dimethylformamide (40 mL), the product was prepared in 3.9 g yield (99%).
Reaction SMILES: Cl[CH2:2][CH:3]([CH:5]1[CH:10]=[CH:9][C:8]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:7]=2[O:6]1)[OH:4].[OH-].[Na+].C(O)(=O)C.O>CC(O)C.C1(C)C=CC=CC=1>[F:15][C:12]1[CH:13]=[CH:14][C:7]2[O:6][CH:5]([CH:3]3[CH2:2][O:4]3)[CH:10]=[CH:9][C:8]=2[CH:11]=1
Reactant: OC(CCl)C1C=Cc2cc(F)ccc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: CC(=O)O
Product: Fc1ccc2c(c1)C=CC(C1CO1)O2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
2-Chloro-1-(6-fluoro-1-benzopyran-2-yl)-ethanol (2.5 g, 9.20 mmol, 84.9% A) was dissolved in i-PrOH (25 ml) under nitrogen and the reaction mixture cooled to 0° C. A 2M aqueous solution of NaOH (12.5 ml) was added to the solution over 5 min and the reaction was stirred for 1 hour 30 min. The reaction mixture was then diluted with toluene (50 ml) and the pH corrected with acetic acid (0.92 g). Toluene (50 ml) and demineralized water (10 ml) were then added to the mixture and the phases separated after extraction. The collected organic phases were then washed with demineralized water (50 ml). The toluene phase was then anhydrified by azeotropic distillation and concentrated until dryness in a rotary evaporator to give 6-Fluoro-2-oxiranyl-1-benzopyran as a mixture of diastereoisomers 52:48 (2.0 g, 96% yield, 86.1% A).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([NH:22][CH3:23])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[N:11]=[C:10]([N:22]([C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)nc(Cl)c2c1
Reactant: CNc1ccc(OC)cc1
Product: COc1ccc(N(C)c2nc(Cl)nc3ccc([N+](=O)[O-])cc23)cc1

Procedure:
The title compound was prepared from 2,4-dichloro-6-nitro-quinazoline and 4-methoxy-N-methylaniline by a procedure similar to example 10. 1H NMR (CDCl3): 8.31 (dd, J=9.6, 3.6, 1H), 7.78 (d, J=9.3, 1H), 7.73 (d, J=2.4, 1H), 7.21 (m, 2H), 7.06 (m, 2H), 3.90 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1C(P(C)C)P(C)C.CC(C)([O-])C.[Na+].N#N.Cl[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[N:30]=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C@@H:43]([NH2:45])[CH3:44])=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:35][C:31]1[N:30]=[C:29]([NH:45][C@H:43]([C:40]2[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=2)[CH3:44])[CH:34]=[CH:33][CH:32]=1
Reactant: Clc1cccc(Cl)n1
Reactant: C[C@H](N)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: C[C@H](Nc1cccc(Cl)n1)c1ccc(F)cc1
Temperature: 85 °C
Yield: 67.6 %

Procedure:
To a 25 ml round bottom flask was added Pd(OAc)2 (45 mg, 0.2 mmol), (biphenyl-2-ylmethylene)bis(dimethylphosphine) (120 mg, 0.4 mmol) and sodium tert-butoxide (480 mg, 5.0 mmol). The flask was sealed and refilled with N2. To the mixture was added a solution of 2,6-dichloropyridine (300 mg, 2.0 mmol) and [(1S)-1-(4-fluorophenyl)ethyl]amine (306 mg, 2.2 mmol) in toluene (4 ml). The reaction mixture was heated at 85° C. overnight. The solvent was removed and EtOAc was added and the mixture was washed with brine and was concentrated. Flash chromatography (10-40% EtOAc in hexanes) gave the title compound (339 mg, 68%). 1H NMR (CDCl3) δ 1.55 (m, 3H), 4.66 (m, 1H), 5.07 (br s, 1H), 6.01 (m, 1H), 6.54 (m, 1H), 7.00 (m, 2H), 7.25 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1)([O-])=O>C1COCC1.[Pd]>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N:7]2[CH:8]=[C:4]([NH2:1])[CH:5]=[N:6]2)[CH:10]=1
Reactant: O=[N+]([O-])c1cnn(-c2cccnc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cnn(-c2cccnc2)c1
Yield: 122.1 %

Procedure:
To a solution of 3-(4-nitro-pyrazol-1-yl)-pyridine (1.8 g, 0.009 mol) in dry THF (18 ml) was added 5% Pd/C (180 mg) under nitrogen atmosphere. The mixture was then stirred under hydrogen atmosphere until the reaction was complete. The reaction mixture was filtered through a pad of celite, and concentrated to dryness to give an impure dark brown solid (1.76 g): 1H NMR (400 MHz, DMSO-d6) δ 8.89 (dd, J=2.8. 0.4 Hz, 1H); 8.48 (dd, J=4.8, 1.2 Hz, 1H), 7.99-7.96 (m, 1H), 7.54 (d, J=1.2 Hz, 1H), 7.45 (d, J=0.4 Hz, 1H), 7.38-7.35 (m, 1H), 4.81 (bs 1H); ESIMS (m/z) 161 [M+1].
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].[CH3:20][O:21][C:22]1[C:27](B(O)O)=[CH:26][CH:25]=[CH:24][N:23]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:27]3[C:22]([O:21][CH3:20])=[N:23][CH:24]=[CH:25][CH:26]=3)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15]
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(I)c(F)ccc12
Reactant: COc1ncccc1B(O)O
Product: COc1ncccc1-c1c(F)ccc2c(N)c(C(=O)NC3CC3)nnc12
Yield: 62.3 %

Procedure:
Using Method A, 4-amino-7-fluoro-8-iodo-N-cyclopropyl-cinnoline-3-carboxamide (188 mg, 0.50 mmol) and 2-methoxypyridine-3-boronic acid (155 mg, 1.01 mmol) were reacted. After purification the title compound (110 mg, 62% yield) was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.48 (bm, 1H), 8.29 (ad, J=5.0 Hz, 1H), 7.91 (a dd, J=5.2, 9.2 Hz, 1H), 7.67 (a d, J=7.3 Hz, 1H), 7.56 (a t, J=8.9 Hz, 1H), 7.05 (a dd, J=5.0, 7.3 Hz, 1H), 3.88 (s, 3H), 2.96 (m, 1H), 0.88 (m, 2H), 0.65 (m, 2H). MS APCI, m/z=354, HPLC 2.23 min.
Reaction SMILES: [Cl-].[Na+].C([Al](CCCCCCCC)CCCCCCCC)CCCCCCC.[Cl:28][Si](Cl)(Cl)Cl.[CH2:33]([Si:41](CCCCCCCC)([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>>[CH2:33]([Si:41]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[Cl:28])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCC[Si](CCCCCCCC)(CCCCCCCC)CCCCCCCC
Reactant: Cl[Si](Cl)(Cl)Cl
Agent: CCCCCCCC[Al](CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Product: CCCCCCCC[Si](Cl)(CCCCCCCC)CCCCCCCC

Procedure:
Utilizing the apparatus of Examples 1-5, 50 millimoles of sodium chloride, 100 millimoles of tri-n-octylaluminum, and 73 millimoles of tetrachlorosilane were reacted for 4 hours at 180° C. The analysis utilized in Examples 1-5 revealed that 62.9 mole percent tetraoctylsilane and 6.8 mole percent trioctylchlorosilane were produced based on tetrachlorosilane as the limiting reagent.
Reaction SMILES: [CH:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9](/[CH:8]=[CH:7]/[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:14][N:13]=1
Reactant: N#Cc1ccc(/C=C/C2CCCCC2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(/C=C/C2CCCCC2)cn1
Reaction time: 3 h
Yield: 33.9 %

Procedure:
Cool a stirred solution of (E)-5-(2-cyclohexylvinyl)-pyridine-2-carbonitrile (1.76 g, 8.3 mmol) in THF (55 mL) to 0° C. under nitrogen. Carefully add lithium aluminum hydride (1.26 g, 33.2 mmol) and warm to room temperature overnight. Quench the reaction mixture with sequential addition of water (1.26 mL), 15% aqueous NaOH (1.26 mL) and water (3×1.26 mL), and stir for 3 h. Filter the mixture through Celite®, wash with EtOAc, and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (120 g, pre-packed cartridge) eluting stepwise with DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) (1:0 over 5 min, 49:1 over 5 min, 19:1 over 5 min, 93:7 over 5 min and 9:1 over 5 min; 50 mL/min) to obtain the title compound (608 mg, 34%). MS (APCI+) m/z: 217 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:12]=[C:13]([NH2:15])[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)(=[O:19])=[O:18]>>[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:3]3[N:4]([N:12]=[C:13]([NH2:15])[N:14]=3)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: Nc1nc2c(Br)cc(C(F)(F)F)cn2n1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)cn3nc(N)nc23)cc1

Procedure:
8-(4-Methanesulfonyl-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and (4-methylsulfonylphenyl)boronic acid in a manner analogous to Step 2c to afford a white solid (67%) MP=236-237° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.28 (s, 1H), 8.42 (d, J=7.8 Hz, 2H), 8.07 (s, 1H), 8.06 (d, J=7.8 Hz, 2H), 6.58 (bs, 2H), 3.29 (s, 3H). MS=356.33 (MH)+.