Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[C@H:2]1([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:23](=[NH:26])SC)[CH:18]=3)[N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)C>[CH2:27]([NH:34][C:23]([NH:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([NH:11][C@H:2]1[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]1)[CH:21]=[CH:20]2)=[NH:26])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: CSC(=N)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: I
Solvent: CCO
Product: N=C(NCc1ccccc1)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Yield: 56.9 %

Procedure:
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-2-methyl-isothiourea hydroiodide (345 mg, 0.72 mmol) was dissolved in 10 mL ethanol. Benzylamine (310 mg, 2.9 mmol) was added and the reaction mixture was refluxed overnight. The solvent was evaporated and the residue was purified by column chromatography (silica gel, dichloromethane/methanol 19:1). The title compound (167 mg, 56%) was obtained as a light yellow foam; MS: m/e=408.5 (M+H+).
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[C:4]1[CH:30]=[CH:29][C:7]2[C:8]3[NH:9][C:10](=[O:28])[N:11]([O:16]CC4C=CC(OC)=CC=4OC)[C:12](=[O:15])[C:13]=3[O:14][C:6]=2[CH:5]=1)[CH3:2].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([N:9]1[C:8]2[C:7]3[CH:29]=[CH:30][C:4]([N:3]([CH2:31][CH3:32])[CH2:1][CH3:2])=[CH:5][C:6]=3[O:14][C:13]=2[C:12](=[O:15])[N:11]([OH:16])[C:10]1=[O:28])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: CCN(CC)c1ccc2c(c1)oc1c(=O)n(OCc3ccc(OC)cc3OC)c(=O)[nH]c12
Product: CCN(CC)c1ccc2c(c1)oc1c(=O)n(O)c(=O)n(Cc3ccccc3)c12

Procedure:
Following general procedure B2 and D1, 7-Diethylamino-3-(2,4-dimethoxy-benzyloxy)-1H-benzo[4,5]furo[3,2-d]pyrimidine-2,4-dione was alkylated with benzyl bromide and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) 1.09 (t, J=7 Hz, 6H); 3.34-3.47 (m, 4H); 5.48 (s, 2H); 6.69-6.83 (m, 2H); 7.24-7.37 (m, 5H); 7.48 (d, J=9 Hz, 1H); 10.75 (br s, 1H); Ret. time=2.97 min., m/z=380.0.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:11]Br>C(Cl)Cl>[Br:11][C:2]1[C:1](=[O:10])[C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: BrBr
Reactant: O=C1C=Cc2ccccc21
Solvent: ClCCl
Product: O=C1C(Br)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The indenone of formula 23 prepared in Step 2 is dissolved in CH2Cl2, 1M Br2 solution (dissolved in CH2Cl2) is added thereto. The resulting mixture is stirred for 2 to 3 h at room temperature, to obtain the 2-bromoindenone of formula 17.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[CH:12][C:11]2[CH:20]=[CH:21][CH:22]=[CH:23][C:10]1=2)[C:4]([O:6]CC)=[O:5].[OH-].[K+].CCCCCC.CC(O)C>C(O)C.O>[ClH:1].[NH2:2][CH:3]([CH:9]1[C:10]2[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=2[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]1=2)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(N)C1c2ccccc2C=Cc2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCO
Solvent: CCCCCC
Product: NC(C(=O)O)C1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C

Procedure:
Ethyl α-amino-5H-dibenzo[a,d]cycloheptene-5-acetate, hydrochloride (0.21 g, 0.6 mmol) dissolved in 10 mL of absolute ethanol is stirred with 3 mL of 1.25M ethanolic potassium hydroxide solution until TLC (SiO2, hexane:2-propanol/3:1) shows no starting material (2 hours). The solvent is stripped and a residual solid is taken up in water and extracted with dichloromethane. The aqueous layer is acidified with 6N hydrochloric acid to pH 1 and stripped to dryness. The residue is treated with 5 mL of boiling water, cooled to room temperature, then refrigerated overnight. A solid is collected, washed with diethyl ether (0.05 g); mp 225° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([O:18][CH:19]3[CH2:37][CH:36]4[N:21]([C:22](=[O:57])[N:23](CC5C=CC(OC)=CC=5)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:41][S:42]([CH:45]6[CH2:47][CH2:46]6)(=[O:44])=[O:43])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:60])[C:12]([O:58][CH3:59])=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1>ClCCl.FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]([O:18][CH:19]3[CH2:37][CH:36]4[N:21]([C:22](=[O:57])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:41][S:42]([CH:45]6[CH2:47][CH2:46]6)(=[O:44])=[O:43])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:60])[C:12]([O:58][CH3:59])=[CH:13][CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)NS(=O)(=O)C3CC3)NC(=O)C3CC(Oc4nc(-c5ccc(F)cc5)nc5c(C)c(OC)ccc45)CN3C2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCNC(=O)N4C3)nc(-c3ccc(F)cc3)nc2c1C
Yield: 38.5 %

Procedure:
Compound 103 (75 mg, 0.09 mmol) was stirred for 2 h in a mixture of dichloro-methane-trifluoroacetic acid; 2:1. Evaporation and purification by HPLC gave pure title compound (25 mg, 38%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][NH:21]1>>[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][N:21]1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCc4ccccc4C3)n2)c1

Procedure:
B40 was prepared following the general procedure reported for B10 using A1 and 1,2,3,4-tetrahydroisoquinoline; yield: 23.6 mg (6%), colorless amorphous solid. MS (ES) C19H20N6O2S requires: 396. found: 397 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([NH:17][NH:18]C(OC(C)(C)C)=O)=[O:16])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[N:12][C:11]([CH3:14])=[N:10]1.[ClH:26]>CO>[ClH:26].[ClH:26].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[N:12][C:11]([CH3:14])=[N:10]1)[C:15]([NH:17][NH2:18])=[O:16]
Reactant: COc1cc(C(=O)NNC(=O)OC(C)(C)C)ccc1-n1cnc(C)n1
Agent: Cl
Solvent: CO
Product: COc1cc(C(=O)NN)ccc1-n1cnc(C)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of tert-butyl 2-{[3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]carbonyl}hydrazinecarboxylate (0.22 g) in methanol (2 mL) was added hydrochloric acid (4M ethyl acetate solution, 1 mL) at room temperature, and the mixture was stirred at room temperature for 4 hr. The precipitated solid was collected by filtration, and washed with ethyl acetate to give the title compound (0.15 g).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:15](Cl)=[O:16])[CH:6]=1.[CH3:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27]1.[OH-].[Na+]>C(Cl)Cl>[CH3:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:15]([C:7]2[CH:6]=[N:5][C:14]3[C:9]([CH:8]=2)=[CH:10][CH:11]=[CH:12][CH:13]=3)=[O:16])=[CH:27]1
Reactant: CN1CCCCC1Cn1ccc2ccccc21
Reactant: O=C(Cl)c1cnc2ccccc2c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCCCC1Cn1cc(C(=O)c2cnc3ccccc3c2)c2ccccc21
Reaction time: 0.5 h

Procedure:
To the suspension of 200 mg (1.5 mmol) of anhydrous AlCl3 in 8 ml absolute methylene chloride was added 287.4 mg (1.5 mmol) 3-quinolinecarbonyl chloride in 5 ml methylene chloride and the reaction mixture was stirred 30 min at room 22–25° C. The (N-Methyl-2-piperidinyl)methyl-1H-indole 228.3 mg (1.0 mmol) in 5 ml of methylene chloride was added by dropwise during 1.5 h and the mixture stirred 36 h. The reaction was work-up by addition of 20 ml 2M solution of sodium hydroxide and extracted by ethyl acetate (3×20 ml). The combined extract dried by sodium sulfate. After removing of solvents the rest (0.365 g) was purified by chromatography (silica gel, toluene-triethylamine, 10:1).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]([CH3:22])([CH3:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].BrC1C(NC(C(C)C)CNC(=O)OC(C)(C)C)=NC(Cl)=NC=1>>[Br:1][C:2]1[C:3]([NH:10][C:11]([CH3:22])([CH3:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(N)CNC(=O)OC(C)(C)C
Agent: CC(C)C(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Product: CC(C)(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br

Procedure:
tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and tert-butyl N-(2-amino-2-methyl-propyl)carbamate using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate. LCMS (ESI) 379 (M+H).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:5](=[O:11])[NH:6][NH:7][C:8](=[O:10])[CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1COCC1>[N:6]1[NH:7][C:8](=[O:10])[CH:9]=[C:4]2[CH2:3][CH2:2][O:11][C:5]=12
Reactant: O=c1cc(CCO)c(=O)[nH][nH]1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1cc2c(n[nH]1)OCC2
Temperature: 40 °C
Yield: 16.3 %

Procedure:
A mixture of 4-(2-hydroxyethyl)-1,2-dihydro-3,6-pyridazinedione (2.7 g) in THF (200 ml) was treated with triphenylphosphine (6.6 g) and bis(1-methylethyl) (E)-1,2-diazenedicarboxylate (5.0 ml) was warmed to 40° C. After 3 hours the mixture was evaporated and chromatographed onto silica which was added to the top of a column. Chromatography eluting with 0-10% methanol in DCM afforded impure product (420 mg) which was further purified by chromatography in a similar manner affording the product (390 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(Cl)(Cl)Cl.[CH2:22]([OH:24])C>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([CH:14]=1)[CH:22]=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=Cc1cc(OCc2ccccc2)ccc1O
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
The starting material is prepared as follows: 4-Benzyloxyphenol (20 g, 0.1 mol) is dissolved in 24 ml of ethanol and 120 ml of 20% aqueous sodium hydroxide (24 g NaOH, 0.6 mol), and heated at 70° C. To this is added chloroform (23.9 g, 0.2 mol) dropwise and the mixture is stirred for 3.5 hours at 70° C. The mixture is cooled and evaporated. The residue is then treated with conc. HCl until the pH of the solution is 1 to 3. The mixture is extracted with ether three times, and the combined organic layer is dried (MgSO4), evaporated and purified by silica gel chromatography (5% ethyl acetate/hexane) to give 5-benzyloxy-2-hydroxybenzaldehyde as a pale yellow, crystalline solid, m.p. 94°-96° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1C=CC=CC=1>C1COCC1.O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[C:18]3[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccc2[nH]nc(-c3ccccc3)c2c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2ccc3[nH]nc(-c4ccccc4)c3c2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
3-Nitro-N-(3-phenyl-1H-indazol-5-yl)benzenesulfonamide can be obtained in the following way: 0.89 g of 3-nitrobenzenesulfonyl chloride is added to a solution, at a temperature in the region of 0° C. and under argon, of 0.7 g of 5-amino-3-phenyl-1H-indazole in 15 ml of THF. The reaction mixture is cooled to a temperature in the region of 0° C., and then a solution of 0.33 ml of pyridine in 4 ml of THF is added over 10 minutes. The reaction mixture is stirred at a temperature in the region of 0° C. for 0.5 hours then at a temperature in the region of 20° C. for 3 hours. It is then diluted with 70 ml of water and 30 ml of ethyl acetate. After settling out, the organic phase is washed with 3 times 50 ml of water, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue thus obtained is purified by chromatography on a silica column (particle size 63-200 μm), eluting with pure dichloromethane then with a dichloromethane/methanol (98/2 by volume) mixture. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in 20 ml isopropanol and filtered through sintered glass. The solid is washed with 10 ml of diisopropyl ether, partially dried and then dried. 0.41 g of 3-nitro-N-(3-phenyl-1H-indazol-5-yl)benzenesulfonamide is thus obtained in the form of a white powder melting at 228° C. (analysis: C19H14N4O4S (0.44 CH2Cl2), % calculated C, 57.85; H, 3.58; N, 14.21; O, 16.23; S, 8.13. % found C, 57.84; H, 3.19; N, 14.22; S, 7.81).
Reaction SMILES: [C@@H:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C(CC[O:25][P:26](=O)([OH:28])[OH:27])#N.C1(N=C=NC2CCCCC2)CCCCC1.[OH-].[Li+]>CC(C)=O.N1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH:11]1[N:10]([C@@H:1]2[O:9][C@H:6]([CH2:7][O:8][P:26]([OH:28])([OH:27])=[O:25])[C@@H:4]([OH:5])[C@H:2]2[OH:3])[C:20]2[NH:19][C:17]([NH2:18])=[N:16][C:14](=[O:15])[C:13]=2[N:12]=1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: N#CCCOP(=O)(O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: Nc1nc(=O)c2ncn([C@@H]3O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]3O)c2[nH]1

Procedure:
For example, the aforesaid guanosine is reacted with zinc chloride in acetone to introduce an isopropylidene group into the 2'- and 3'-hydroxyl groups of guanosine and reacting the product with 2-cyanoethylphosphoric acid in pyridine in the presence of dicyclohexyl carbodiimide (DCC) to cyanophosphorylate the 5'-position. The resulting compound is subjected to a deprotection reaction with lithium hydroxide and then a cation exchange resin (H+) to obtain 5'-GMP. This reaction can be carried out, for example, in the following manner. One mole of 2',3'-O-isopropylideneguanosine and 4 moles of 2-cyanoethylphosphoric acid are dissolved in 50% aqueous pyridine solution. The solvent is evaporated at 30° C. under reduced pressure. The residue is dissolved in pyridine and dicyclohexyl carbodiimide (DCC) is added, and the mixture is allowed to stand for 18 hours at room temperature. A small amount of water is added. The mixture is left to stand for 1 hour, and then concentrated under reduced pressure. A 0.4N aqueous solution of lithium hydroxide is added and the mixture is boiled under reflux for 1 hour.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]1[O:16][C@@H:15]1[CH2:17]Cl>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:17][C@H:15]3[CH2:14][O:16]3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ClC[C@@H]1CO1
Reactant: Oc1ccc(C2CCCCC2)cc1
Product: c1cc(C2CCCCC2)ccc1OC[C@H]1CO1

Procedure:
The title compound was prepared from 4-cyclohexyl-phenol and S-epichlorohydrin employing the procedures as set forth in Step 1 of Example 1.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].C=O.O.[C:12]([OH:15])(=[O:14])[CH3:13].N(CC(O)=O)CC(O)=O>COCCOC>[C:1]([N:4]([CH2:13][C:12]([OH:15])=[O:14])[CH2:5][C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NCC(=O)O
Reactant: CC(=O)O
Agent: C=O
Agent: O=C(O)CNCC(=O)O
Solvent: O
Solvent: COCCOC
Product: CC(=O)N(CC(=O)O)CC(=O)O
Temperature: 110 °C
Yield: 87 %

Procedure:
A 300 mL autoclave was charged with N-acetylglycine (XVIII)(23.4 g, 0.20 mole), 95% paraformaldehyde (6.8 g, 0.22 mole), water (6.5 g, 0.36 mole), acetic acid (16.8 g, 0 28 mole), DME (90 mL), and Co2 (CO)8 (2.01 g, 0.006 mole) and pressurized to 1500 psi (10,345 kPa) CO:H2 (95:5) at 25° C. This mixture was heated to 110° C. for 30 min. HPLC analysis of this stream gave an 87% yield of (XVI), 1.0% (XIV), and 10% unreacted (XVIII).
Reaction SMILES: [S:1]1[C:5]([NH:6][S:7]([C:10]2[CH:11]=[CH:12][C:13]3[NH:18][CH2:17][CH2:16][O:15][C:14]=3[CH:19]=2)(=[O:9])=[O:8])=[N:4][CH:3]=[N:2]1.Br[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CCOC(C)=O.Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1.C1(C)C=CC=CC=1>[C:23]([C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[N:18]1[CH2:17][CH2:16][O:15][C:14]2[CH:19]=[C:10]([S:7]([NH:6][C:5]3[S:1][N:2]=[CH:3][N:4]=3)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]1=2)#[N:24]
Reactant: O=S(=O)(Nc1ncns1)c1ccc2c(c1)OCCN2
Reactant: N#Cc1ccccc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: N#Cc1ccccc1N1CCOc2cc(S(=O)(=O)Nc3ncns3)ccc21
Temperature: 120 °C
Yield: 20.7 %

Procedure:
A vial was charged with N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE Z, 36 mg, 0.121 mmol), 2-bromobenzonitrile (32.9 mg, 0.181 mmol, Sigma-Aldrich, St. Louis, Mo.), Xantphos (13.96 mg, 0.024 mmol), Pd2(dba)3 (11.05 mg, 0.012 mmol), cesium carbonate (118 mg, 0.362 mmol), and toluene (1207 n1). The vial was sealed and placed in a 100° C. heating bath for 20 min, then 1,4-dioxane (1 mL) and cesium carbonate (180 mg) were added. The vial was heated overnight at 120° C., then the mixture was diluted with THF, EtOAc, and 1N aq. HCl. The mixture was extracted with EtOAC (3×), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The product was purified by chromatography on silica gel (12 g column, 0 to 10% MeOH/DCM to give 4-(2-cyanophenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (9.98 mg, 0.025 mmol) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.43 (s, 1 H), 8.01-7.92 (m, 1 H), 7.80 (dt, J=1.6, 7.8 Hz, 1 H), 7.59 (d, J=7.6 Hz, 1 H), 7.50 (dt, J=1.0, 7.7 Hz, 1 H), 7.23-7.05 (m, 2 H), 6.47 (d, J=8.4 Hz, 1 H), 4.40-4.24 (m, 2 H), 3.83-3.73 (m, 2 H). m/z (ESI) 400.2 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12](=[O:20])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:21])[N:5]=1)[CH3:3].[NH2:22][C:23]1[C:28]([I:29])=[C:27](Cl)[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C.O>CC(O)C>[NH2:22][C:23]1[N:24]=[CH:25][N:26]=[C:27]([NH:1][C@H:2]([C:4]2[N:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:12](=[O:20])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[Cl:21])[N:5]=2)[CH3:3])[C:28]=1[I:29]
Reactant: C[C@H](N)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: Nc1ncnc(Cl)c1I
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1I)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To (S)-2-(1-aminoethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (400 mg, 1.33 mmol) (prepared according to the procedure in Example 2a.A above) and 4-amino-6-chloro-5-iodopyrimidine (338 mg, 1.32 mmol) in IPA (5 mL) was added Hunig's base (0.4 mL). After stirring at 90° C. for 2 hours in a microwave reactor, water was added and the mixture was extracted with EtOAc (3×50 mL), dried (MgSO4), and concentrated. The residue was purified on a reverse phase system run from 0 to 95% ACN in water (0.1% TFA) to give (S)-2-(1-(6-amino-5-iodopyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one. ES/MS m/z=519.0 (M+), 521.0 (M+2).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:4]=2[O:3]1.[Br:13][CH2:14][CH2:15][CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:13][CH2:14][CH2:15][CH2:16][N:6]1[C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:4]=2[O:3][C:2]1=[O:1]
Reactant: OCCCBr
Reactant: O=Cc1ccc2[nH]c(=O)oc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=Cc1ccc2c(c1)oc(=O)n2CCCBr
Reaction time: 8 h
Yield: 90.8 %

Procedure:
A mixture of 290 mg (1.64 mmol) of 2-oxo-2,3-dihydro-1,3-benzoxazole-6-carbaldehyde (Intermediate 7), 272.8 mg (1.96 mmol) of 3-bromo-propan-1-ol, 514 mg (1.96 mmol) of triphenylphospine and 0.855 ml (1.96 mmol) of 40% toluene solution of DEAD in 7 ml THF is stirred overnight. After concentration in vacuo the residue is chromatographically purified over silicagel eluting with hexane/ethyl ether (100/0 to 0/100), obtaining 423 mg of the title product (58% purity; 52% total yield) that is used per se in the next synthetic step.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[C:14]([C:19](O)=[O:20])[CH:13]=3)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:44]12([NH2:54])[CH2:53][CH:48]3[CH2:49][CH:50]([CH2:52][CH:46]([CH2:47]3)[CH2:45]1)[CH2:51]2>O.CCN(CC)CC.CN(C=O)C>[C:44]12([NH:54][C:19]([C:14]3[CH:13]=[C:12]4[C:17]([CH:18]=[C:10]([C:7]5[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=5)[NH:11]4)=[CH:16][CH:15]=3)=[O:20])[CH2:51][CH:50]3[CH2:49][CH:48]([CH2:47][CH:46]([CH2:52]3)[CH2:45]1)[CH2:53]2
Reactant: O=C(O)c1ccc2cc(-c3ccc([N+](=O)[O-])cc3)[nH]c2c1
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC12CC3CC(CC(C3)C1)C2)c1ccc2cc(-c3ccc([N+](=O)[O-])cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an oven dried Argon cooled 100 mL flask, 605 mg acid 6, 493 mg EDCI.HCl, 348 mg of HOBt were added. While under Argon atmosphere, 30 mL of dry DMF and 1.79 mL of Et3N were added and the mixture was stirred at room temperature for 15 min. After this, 389 mg of 1-adamantylamine was added and the resulting mixture was heated at 60° C. with continuous stirring for a period of 16 hrs when TLC indicated the reaction was complete. The mixture was cooled to 0° C. and poured into water. The resulting yellow solid was collected and filtered to give the crude amide that was further purified by chromatography over silica gel using 50–90% ethyl acetate in hexane as eluent. Evaporation of the solvent yielded 600 mg of pure 7.
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([I:14])=[CH:8][C:3]=1[O:4][CH2:5][C:6]#[N:7].[C:15](OC(N(C)C)N(C)C)(C)(C)[CH3:16]>>[I:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([I:14])=[CH:8][C:3]=1[O:4][C:5](=[CH:15][CH3:16])[C:6]#[N:7]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COc1cc(I)c(OCC#N)cc1I
Product: CC=C(C#N)Oc1cc(I)c(OC)cc1I
Temperature: 105 °C
Yield: 116.6 %

Procedure:
(2,5-Diiodo-4-methoxy-phenoxy)-acetonitrile (2.8 g, 6.75 mmol) and tert-butoxybis(dimethylamino)methane (Bredrick's reagent, 7 mL, 33.7 mmol) were combined and heated to 105° C. under nitrogen for 2 hours. The reaction mixture was cooled and concentrated under reduced pressure to yield 3.47 g of crude 2-(2,5-diiodo-4-methoxy-phenoxy)-but-2-enenitrile, which was used directly in the following step.