Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH:21][C:22](=[O:25])[CH2:23]Cl)[C:11](=[O:26])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:4].[F:27][C:28]([F:38])([F:37])[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33]>CN(C)C=O>[F:27][C:28]([F:37])([F:38])[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH:33][CH2:2][C:3]([NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH:21][C:22](=[O:25])[CH2:23][NH:33][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[C:29]([C:28]([F:27])([F:37])[F:38])[CH:30]=3)[C:11](=[O:26])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(CCl)Nc1cccc2c1C(=O)c1c(NC(=O)CCl)cccc1C2=O
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Product: O=C(CNCc1cccc(C(F)(F)F)c1)Nc1cccc2c1C(=O)c1c(NC(=O)CNCc3cccc(C(F)(F)F)c3)cccc1C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Add 0.4 g, 1.0 mmol 1,8-bis(chloroacetamido)anthraquinone (compound 3) with 0.5 ml TEA, and 0.8 ml, 6 mmole 3-(trifluoromethyl)benzylamine, dissolved in 20 ml dehydrated dimethylformamide (DMF). The mixture is reacted in a mini-reactor. The reaction temperature is 120° C. in the oil bath and the reaction time is 30 minutes. The reacted mixture is poured into 50 ml ice water and is filtered to collect precipitate. The precipitate is recrystallized from ethanol to get yellow compound 3q.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.7 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (2.5 g, 10.2 mmol) and dihydro-2H-pyran-4(3H)-one (1.3 g, 13.3 mmol) in methanol (20 mL), acetic acid (0.61 g, 10.2 mmol) was added and the solution stirred at room temperature for 18 h. Then sodium cyanoborohydride (1.2 g, 20.48 mmol) was added at 0° C. and stirring was continued overnight at room temperature. Then, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (2.2 g, 66%).
Reaction SMILES: C(C=P(CCCC)(CCCC)CCCC)#N.O[CH2:18][C@@H:19]([N:22]([CH2:35][CH2:36][OH:37])[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33])(=[O:25])=[O:24])[CH2:20][CH3:21]>C1(C)C=CC=CC=1>[CH2:20]([C@H:19]1[CH2:18][O:37][CH2:36][CH2:35][N:22]1[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33])(=[O:24])=[O:25])[CH3:21]
Reactant: CC[C@@H](CO)N(CCO)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC[C@H]1COCCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99.4 %

Procedure:
A 1 M solution of 0.558 ml (0.558 mmol) of (cyanomethylene)tributylphosphorane in toluene was added to a solution of 95 mg (0.298 mmol) of the title compound produced in step (ii) of Reference Example 9 in toluene (3 ml), and the mixture was stirred with heating under reflux for 1 hr 20 min. Thereafter, the reaction solution was cooled to room temperature, and the solvent was removed under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:4) to give 89 mg (yield 99%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:21]1[N:26]2[N:27]=[CH:28][CH:29]=[C:25]2[C:24]([C:30]#[N:31])=[C:23](O)[CH:22]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[NH2:73][C@H:74]1[CH2:79][CH2:78][C@H:77]([NH2:80])[CH2:76][CH2:75]1>O1CCOCC1.C(OCC)(=O)C>[NH2:73][C@H:74]1[CH2:79][CH2:78][C@H:77]([NH:80][C:23]2[CH:22]=[C:21]([N:8]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][CH:10]=3)[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[N:26]3[N:27]=[CH:28][CH:29]=[C:25]3[C:24]=2[C:30]#[N:31])[CH2:76][CH2:75]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CC(C)(C)OC(=O)N(c1ccc(-c2ccccc2)cc1)c1cc(O)c(C#N)c2ccnn12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(c1ccc(-c2ccccc2)cc1)c1cc(N[C@H]2CC[C@H](N)CC2)c(C#N)c2ccnn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(tert-Butoxy)-N-[4-cyano-5-hydroxy(pyrazolo[1,5-a]pyridin-7-yl)]7-N-(4-biphenylyl)carboxamide (40) (27 mg) was dissolved in 1,4-dioxane (600 μL)and to this solution were added triethylamine (22 μL) and benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (36 mg). This mixture was stirred at room temperature for 10 min. Trans-1,4-Diaminocyclohexane (145 mg) was added and the mixture was further stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with 1 mol/L aqueous sodium hydroxide solution, dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified with thin layer silica gel column chromatography (ethyl acetate/2 mol/L methanolic ammonia solution=5/1) to obtain the title compound (46).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[Na].[CH3:10][N:11]([C:13](=O)[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[NH2:12]>CO>[CH3:10][N:11]1[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:2][C:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[N:12]1
Reactant: N#Cc1ccncc1
Reactant: CN(N)C(=O)c1ccncc1
Agent: [Na]
Solvent: CO
Product: Cn1nc(-c2ccncc2)nc1-c1ccncc1
Reaction time: 0.5 h

Procedure:
To a solution of 4-cyanopyridine (4.1 grams, 0.04 mole) in methanol (60 ml.) is added sodium (0.2 grams). The resulting solution is allowed to stand at room temperature for 1/2 hour and is then added to a solution of N-methylisonicotinic acid hydrazide (6 grams, 0.04 mole) in methanol (80 ml.). The solution is refluxed for 3 hours and is then concentrated until a solid separates out of solution. The solid is collected by filtration and, upon recrystallization from ethanol, 1-methyl-3,5-di(4-pyridyl)-1,2,4-triazole is obtained, m.p. 168°-170°C.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:22]=[CH:23][C:24]=1[C:25](=[O:36])[CH:26]=[CH:27][C:28]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:29])[O:8][CH2:9][C:10]([NH:12][C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)=[O:11])C=C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO.O1CCOCC1.[C].[Pd]>[OH:4][C:5]1[CH:6]=[C:7]([CH:22]=[CH:23][C:24]=1[C:25](=[O:36])[CH:26]=[CH:27][C:28]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:29])[O:8][CH2:9][C:10]([NH:12][C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)=[O:11]
Reactant: C=CCOc1cc(OCC(=O)Nc2nc3ccccc3s2)ccc1C(=O)C=CC(=O)N1CCCCC1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: O=C(COc1ccc(C(=O)C=CC(=O)N2CCCCC2)c(O)c1)Nc1nc2ccccc2s1
Yield: 23.7 %

Procedure:
2-{3-Allyloxy-4-[3-(1-piperidinyl)carbonylacryloyl]phenoxymethylcarbonylamino}benzothiazole (0.55 g) is dissolved in methanol (70 ml) and dioxane (40 ml), and thereto are added 10% palladium-carbon (0.15 g), p-toluenesulfonic acid monohydrate (70 mg) and water (3 ml). The mixture is subjected to deaeration, and the mixture is refluxed under nitrogen atmosphere overnight. The mixture is filtered through a cerite pad, and to the filtrate is added water-methylene chloride, and the mixture is separated, and dried over sodium sulfate. The residue is crystallized from ethanol-methylene chloride, and recrystallized from dimethylformamide-ethanol to give 2-{3-hydroxy-4-[3-(1-piperidinyl)carbonylacryloyl]phenoxymethylcarbonylamino}benzothiazole (120 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH2:17]([NH2:25])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[Cl:1][C:2]1[C:7]([NH:25][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Cl
Reactant: NCCc1ccccc1
Solvent: C1COCCO1
Product: Nc1nc(NCCc2ccccc2)c(Cl)c(-c2ccco2)n1

Procedure:
From 5-chloro-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine and phenethylamine in dioxane. ES-MS m/e (%): 317 (M{37Cl}+H+, 30), 315 (M{35Cl}+H+, 100).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([C:14]#[N:15])[C:8]=1[F:16])(=O)=O.[CH2:19](O)[CH3:20]>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].C(Cl)Cl>[CH:19]([C:7]1[C:8]([F:16])=[C:9]([C:10]([F:13])=[CH:11][CH:12]=1)[C:14]#[N:15])=[CH2:20]
Reactant: N#Cc1c(F)ccc(OS(=O)(=O)C(F)(F)F)c1F
Reactant: CCO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: C=Cc1ccc(F)c(C#N)c1F

Procedure:
3-Cyano-2,4-difluorophenyl trifluoromethanesulfonate (5.20 g, 18.1 mmol), potassium vinyl trifluoroborate (4.85 g, 36.2 mmol), PdCl2(dppf)-CH2Cl2 Adduct (0.662 g, 0.905 mmol), and TEA (5.05 mL, 36.2 mmol) were added to 75 mL of ethanol. The reaction mixture was degassed then heated at reflux for 4 h. LC-MS analysis confirmed product peak. The reaction mixture was diluted with ethyl acetate, washed twice with brine, dried, and evaporated to dryness. The crude material was then purified by MPLC chromatography through a 330 g Redi-sep column eluting with 10% EtOAc/Hexane solvent system to yield 3-ethenyl-2,6-difluorobenzonitrile.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][C:11]1([CH2:20][CH2:19][CH:18]([O:21][CH3:22])[CH2:17][CH2:16]1)[C:10]2=[N:23]S(C(C)(C)C)=O>O1CCOCC1.C([O-])(O)=O.[Na+]>[F:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13]([CH2:12][C:11]3([CH2:16][CH2:17][CH:18]([O:21][CH3:22])[CH2:19][CH2:20]3)[C:10]2=[NH:23])=[CH:14][CH:15]=1
Reactant: COC1CCC2(CC1)Cc1ccc(OCCCF)cc1C2=NS(=O)C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC1CCC2(CC1)Cc1ccc(OCCCF)cc1C2=N
Reaction time: 8 h
Yield: 111.3 %

Procedure:
HCl (4 M in 1,4-dioxane, 1.489 mL, 5.96 mmol) was added to a solution of N-(5′-(3-fluoro-propoxy)-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide (Example 20v, Step 1, 244 mg, 0.60 mmol) in anhydrous 1,4-dioxane (25 mL). A white precipitate was formed immediately and the resulting cloudy mixture was stirred under a nitrogen atmosphere overnight. The mixture was diluted with NaHCO3 (aq) and extracted with DCM, dried over MgSO4 and concentrated in vacuo to give 204 mg (quantitative yield) of the title compound that was used without any purification in the next step: MS (ES+) m/z 306 [M+H]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.[CH3:24][N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:26]4[N:25]([CH3:24])[CH:29]=[CH:28][N:27]=4)=[CH:3][C:4]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Reactant: Cn1ccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4nccn4C)cc3C)c(C)nc12
Yield: 51 %

Procedure:
3-(5-Bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo-[1,2-b]pyridazine (0.98 g, 2.51 mmol) and 1-methyl-1H-imidazole (0.2 mL), Pd(OAc)2 (34 mg, 0.15 mmol), PPh3 (79 mg, 0.299 mmol), Cs2CO3 (1.95 g, 6.0 mmol) in DMF (50 mL) is stirred under N2 at 130-140° C. overnight. The reaction mixture is cooled, diluted with EtOAc (300 mL), washed with H2O (3×100 mL); dried (Na2SO4); filtered and concentrated. Purification of the resulting crude material by chromatography yields the title compound (0.51 g, 1.29 mmol, 51%). 1H NMR (CDCl3): δ 0.89 (t, J=7.5 Hz, 6H), 1.77-1.92 (m, 4H), 2.17 (s, 3H), 2.51 (s, 3H), 2.54 (s, 3H), 3.30-3.40 (m, 1H), 3.81 (s, 3H), 6.69 (s, 1H), 7.02 (s, 1H), 7.24 (s, 1H), 7.52 (s, 1H). ES-MS (m/z): calcd for C22H27N5S (M+H)+: 394.6; found: 394.3.
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]2[CH2:7][C@@H:8]([O:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:9](/[CH:10]=[CH:11]/[C:12](=[O:21])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C@H:4]2[CH2:3]1.CO>C1COCC1>[OH:21][C@@H:12]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[CH:11]=[CH:10]/[C@@H:9]1[C@@H:4]2[C@@H:5]([O:6][C:2](=[O:1])[CH2:3]2)[CH2:7][C@H:8]1[O:22][C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)CCc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: O=C1C[C@@H]2[C@@H](/C=C/[C@@H](O)CCc3ccccc3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
To a solution of 50 g of compound 20a (MW=406.8; 1.0 eq.; prepared as described in example 2) in 500 mL of dry THF was slowly added 190 mL of (−)-DIP-Cl solution (MW=320.76; 2.75 eq. 63% in heptane) at −30° C. After stirring for 6 h 180 mL of methanol were added and the mixture was warmed to room temperature. After removal of the solvent under reduced pressure, the residue was dissolved in methanol/water (10/1) and extracted twice with heptane. After concentration of the aqueous layer, ethyl acetate was added and the resulting mixture was consecutively extracted with an aqueous NaCl solution (9%) and with an aqueous NaHCO3 solution (8.6%). The organic solvents were removed under reduced pressure and the residue was recrystallized from ethyl acetate/n-heptane (1/7) to give 41 g of the title compound after drying (40° C., 10 mbar; yield=81.2%, de(S)=89.2%).
Reaction SMILES: [C:1](=[O:3])=[O:2].[OH-:4].[CH2:5]([N+:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])[CH3:6]>>[C:1](=[O:4])([O-:3])[O-:2].[CH2:5]([N+:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])[CH3:6].[CH2:5]([N+:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])[CH3:6]
Reactant: [OH-]
Reactant: O=C=O
Agent: CC[N+](CC)(CC)CC
Product: O=C([O-])[O-]

Procedure:
Process according to claim 4 wherein carbon dioxide is passed through aqueous tetraethylammonium hydroxide to a pH of 8.3 to form tetraethylammonium carbonate plus dissolved carbon dioxide; adding the said tetraethylammonium carbonate to an aqueous solution of nitrates of yttrium, barium, and copper in a Y:Ba:Cu atomic ratio of 1:2:3 at a pH of about 7.7-8.0, thereby to precipitate the said Y, Ba, and Cu as carbonates; recovering and drying the precipitate; calcining the dried precipitate at about 950° C. and cooling the calcined product to about 150° C. over 8 hours.
Reaction SMILES: [CH3:1]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C[C:24]1([C:34]([NH:36][C@H:37]([C:41]([NH:43][CH:44]([CH:53]([OH:65])[CH2:54][O:55][CH2:56][C:57]2[C:62]([Cl:63])=[CH:61][CH:60]=[CH:59][C:58]=2[Cl:64])[CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[O:42])[CH:38]([CH3:40])[CH3:39])=[O:35])[C:32]([CH3:33])=[C:31]2[C:26]([CH:27]=[CH:28][CH:29]=[CH:30]2)=[N:25]1>CS(C)=O>[CH3:1][N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]([CH3:33])=[C:24]1[C:34]([NH:36][C@H:37]([C:41]([NH:43][CH:44]([C:53](=[O:65])[CH2:54][O:55][CH2:56][C:57]1[C:62]([Cl:63])=[CH:61][CH:60]=[CH:59][C:58]=1[Cl:64])[CH2:45][C:46]([O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[O:47])=[O:42])[CH:38]([CH3:39])[CH3:40])=[O:35]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CC1=c2ccccc2=NC1(C)C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(O)COCc1c(Cl)cccc1Cl)C(C)C
Solvent: CS(C)=O
Product: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COCc2c(Cl)cccc2Cl)C(C)C)n(C)c2ccccc12
Temperature: 25 °C
Yield: 86.7 %

Procedure:
Dess-Martin periodinane (195 mg) was added as a solid to a solution of N-[(2,3-dimethylindole-2-carbonyl)valinyl]-3-amino-4-hydroxy-5-(2′,6′-dichlorobenzyloxy)pentanoic acid, t-butyl ester (96 mg) in DMSO (1.5 ml). The resulting solution was stirred under a nitrogen atmosphere at room temperature for thirty minutes, hen partitioned between EtOAc and water. The organic phase was washed with water 2×) and brine, dried (Na2SO4), and concentrated to give a white solid (83 mg). Flash chromatographic purification with EtOAc/hexanes (1:1) afforded the title product as a white solid (54 mg). TLC (EtOAc/hexanes; 1:1, silica gel): Rf=0.52.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[S:6][CH:7]=[C:8]([CH:9]([P:23]([CH3:26])(=[O:25])[OH:24])[C:10](=[O:22])[NH:11][CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)[C:4]=2[CH:3]=1.[CH2:29]([N:31]([CH2:36][CH3:37])[C:32](=[O:35])[CH2:33]O)[CH3:30].CC1C=C(C)C(S(N2N=C([N+]([O-])=O)N=C2)(=O)=O)=C(C)C=1>N1C=CC=CC=1>[CH2:29]([N:31]([CH2:36][CH3:37])[C:32]([CH2:33][O:25][P:23]([CH:9]([C:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:28]=[CH:27][C:5]=2[S:6][CH:7]=1)[C:10](=[O:22])[NH:11][CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)([CH3:26])=[O:24])=[O:35])[CH3:30]
Reactant: CP(=O)(O)C(C(=O)NC=Cc1ccc(F)c(F)c1)c1csc2ccc(Cl)cc12
Reactant: CCN(CC)C(=O)CO
Agent: Cc1cc(C)c(S(=O)(=O)n2cnc([N+](=O)[O-])n2)c(C)c1
Solvent: c1ccncc1
Product: CCN(CC)C(=O)COP(C)(=O)C(C(=O)NC=Cc1ccc(F)c(F)c1)c1csc2ccc(Cl)cc12
Yield: 44.3 %

Procedure:
Using the procedure described in Example 47, Compound 17 (0.25 g, 0.57 mmol), N,N-diethyl-2-hydroxyacetamide (0.37 g, 2.86 mmol), and MSNT (0.25 g, 0.86 mmol) in pyridine (5 ml) yielded 0.14 g of Compound 185, as a white powder (−3:1 mixture of diastereomers). HPLC: 4.03 min (24%), 4.11 min (76%); MS (ES) m/z 555 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=[CH:22][C:23](N(C)C)=O)[CH:19]=3)[N:14]=[C:13]([CH:28]=[CH:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:32][CH:31]=3)[N:12]=2)[CH2:4]1.C([Sn](CCCC)(CCCC)CCCC)C=C.C(C1C=C2C(=CC=1)N=CN=C2)C=C.C(O)(C(F)(F)F)=O>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.ClCCl.O.CN(C=O)C>[CH2:21]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:32][CH:31]=1)[N:12]=[C:11]2[NH:10][CH2:9][CH:5]1[CH2:6][CH2:7][CH2:8][CH:3]([CH2:2][NH2:1])[CH2:4]1)[CH:22]=[CH2:23]
Reactant: CN(C)C(=O)C=Cc1ccc2nc(C=Cc3ccc(OCc4ccccc4)cc3)nc(NCC3CCCC(CN)C3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: C=CCc1ccc2ncncc2c1
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1ccc2nc(C=Cc3ccc(OCc4ccccc4)cc3)nc(NCC3CCCC(CN)C3)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Solid supported 6-iodoquinazoline (2) [synthesized according to example 5] (0.054 mmol, 0.54 mmol/g), allyltributyltin (140 mg, 0.5 mmol), Pd(PPh3)4 (20 mg), and 2 ml DMF are placed in a fritted polypropylene tube. The mixture is agitated at 80° got 24 h. After cooling to rt, the mixture is customary worked up for solid phase reactions. The solid supported 6-allylquinazoline and 2 ml of a mixture of H2O, TFA and dichloromethane (1:49:50) is placed in a fritted polypropylene tube. The contents are shaken for 2 h at rt. The suspension is filtered and the resin is washed with dichloromethane (1 ml) and methanol (1 ml) respectively. Evaporation of the combined filtrates give {6-allyl-2-[2-(4-benzyloxy-phenyl)-vinyl]-quinazolin-4-yl}-(3-aminomethyl-cyclohexylmethyl)-amine;
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][NH2:12])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C(O[CH:16]=[C:17]([C:23]#[N:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>CCO>[CH2:21]([O:20][C:18]([C:17]1[CH:16]=[N:12][N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)[C:23]=1[NH2:24])=[O:19])[CH3:22]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CS(=O)(=O)c1cccc(NN)c1
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2cccc(S(C)(=O)=O)c2)c1N

Procedure:
A solution of the above crude (3-methanesulfonyl-phenyl)-hydrazine (0.86 g, 4.6 mmol) and ethyl (ethoxymethylene)cyanoacetate (0.78 g, 4.6 mmol) in EtOH (23 mL) is heated at 80° C. for 2 h before removal of the solvent. The residue is purified by silica gel chromatography to provide 5-amino-1-(3-methanesulfonyl-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester as a light yellow solid; HPLC-MS calculated for C13H15N3O4S (M+H+) 310.1, found 310.1.
Reaction SMILES: [CH2:1]([CH:3]1[CH:6]([CH2:7][CH3:8])[C:5](=[O:9])[N:4]1S(Cl)(=O)=O)[CH3:2].C1(S)C=CC=CC=1.N1C=CC=CC=1.O>CC(C)=O>[CH2:7]([CH:6]1[CH:3]([CH2:1][CH3:2])[NH:4][C:5]1=[O:9])[CH3:8]
Reactant: CCC1C(=O)N(S(=O)(=O)Cl)C1CC
Agent: Sc1ccccc1
Solvent: O
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CCC1NC(=O)C1CC
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
(2RS,3RS)-2,3-Diethyl-4-oxoazetidine-1-sulfonyl chloride (step 1) (3.2 g, 14.18 mmol) in acetone (7 ml) was treated with thiophenol (2.92 ml, 28.4 mmol) and cooled to −30° C. Pyridine (1.376 ml, 17.01 mmol) in acetone (2.55 ml) was added dropwise over 30 mins, maintaining the temperature around −30° C. After stirring for 30 minutes, water (10 ml) was added slowly and the mixture was filtered. The filtrate was extracted with diethyl ether (5×25 ml) and the combined organic layers were dried MgSO4, filtered and evaporated to dryness (colorless oil 2.3 g). Purification by chromatography on silica eluting with iso-hexane followed by diethyl ether afforded the title compound;
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.C(O)(=O)C.[CH3:23][NH2:24].[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH:24][CH3:23])=[CH:8][C:6]=2[N:7]=1
Reactant: CN
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.2 %

Procedure:
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (1.0 g) and molecular sieves in methanol (20 mL) at room temperature was added acetic acid (0.1 mL) and a solution of methylamine (219 mg) in methanol (1 ml). The reaction mixture was stirred at room temperature for 24 h. Then sodium borohydride (542 mg) was added portionwise and the reaction stirred at room temperature for a further 30 min. The reaction was then quenched with saturated aqueous sodium hydrogen carbonate solution (10 mL) and extracted into dichloromethane (2×10 mL). The combined organics were washed with brine (20 mL), dried (MgSO4) and reduced in vacuo to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amine as a white solid (0.95 g).