Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=1)[CH2:18][O:19][C:20]1[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[N:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:21]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=1)[CH2:18][O:19][C:20]1[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[N:22]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:21]=1
Reactant: CCOC(=O)CCc1cc(OCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)nn1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(COc2cc(CCC(=O)O)n(-c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
A mixture of ethyl 3-[3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-5-yl]propionate (830 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give 3-[3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-5-yl]propionic acid (490 mg, yield 62%), which was then recrystallized from acetone-isopropyl ether. melting point: 137–138° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][C:25]1[O:24][CH2:23][CH:22]([N:31]3[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]3)[CH2:21][C:20]2=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][C:25]1[O:24][CH2:23][CH:22]([N:31]3[CH2:32][CH2:33][CH:34]([NH:37][C:12]([C:9]4[CH:10]=[CH:11][C:5]5[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)=[O:14])[CH2:35][CH2:36]3)[CH2:21][C:20]2=1
Reactant: COc1ccc2ncc3c(c2c1)CC(N1CCC(N)CC1)CO3
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2ncc3c(c2c1)CC(N1CCC(NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)CO3
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (31 mg, 0.14 mmol, 1.0 eq) is added at room temperature to a stirred solution of 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene-3-yl)-piperidin-4-ylamine (50 mg, 0.14 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL), followed by 1-hydroxybenzotriazole (21 mg, 0.15 mmol, 1.1 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (31 mg, 0.16 mmol, 1.15 eq) and N,N-diisopropylethylamine (53 μL, 0.31 mmol, 2.25 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid [1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene-3-yl)-piperidin-4-yl]-amide as an off-white lyophilizated powder (24 mg, 33% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[CH3:13][N:14](C)[CH2:15]CCN=C=NCC.CNC.CCO>ClCCCl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:14]([CH3:15])[CH3:13])=[O:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: CCO
Solvent: ClCCCl
Product: CN(C)C(=O)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.6 %

Procedure:
A suspension of 4-aminophenylacetic acid (5 g, 30 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (6.9 g, 36 mmol), and dimethylamine (6.5 mol of a 5.6M solution in EtOH 36 mmol) in 1,2, DCE was stirred at room temperature for 4 h. Silica was added, the suspension evaporated and residue loaded onto silica plug column, eluting with DCM:MeOH/98:2). The title compound (2.6 g, 45%) was isolated as an orange solid. 1H MNR (400 MHz, CDCl3) δ2.94 (3H, s), δ2.98 (3H, s), 3.60 (2H, s), 6.64 (2H, d, J=8.3 Hz), 7.03 (2H, d, 8.2 Hz). MS (CI)+179 (M+H)+.
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:7]([O:9]CC)=O.[CH2:16]([N:19]1[C:23]2[CH:24]=[C:25]([NH:29][C:30](OCC)=[O:31])[C:26]([F:28])=[CH:27][C:22]=2[N:21]=[C:20]1[C:35]([F:38])([F:37])[F:36])[C:17]#[CH:18].N12CCCN=C1CCCCC2.Cl>CN(C)C=O>[CH2:16]([N:19]1[C:23]2[CH:24]=[C:25]([N:29]3[C:7](=[O:9])[CH:6]=[C:5]([C:12]([F:13])([F:14])[F:15])[NH:4][C:30]3=[O:31])[C:26]([F:28])=[CH:27][C:22]=2[N:21]=[C:20]1[C:35]([F:37])([F:38])[F:36])[C:17]#[CH:18]
Reactant: CCOC(=O)C=C(N)C(F)(F)F
Reactant: C#CCn1c(C(F)(F)F)nc2cc(F)c(NC(=O)OCC)cc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: C#CCn1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 0.4 gram (0.005 mole) of sodium methoxide in 5 mL of N,N-dimethylformamide was cooled to about 0°-5° C., and 1.8 grams (0.005 mole) of ethyl 3-amino-4,4,4-trifluoro-2-butenoate in 15 mL of N,N-dimethylformamide was added dropwise. Upon completion of the addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for 30 minutes. After this time, the reaction mixture was again cooled, and a solution of 1.8 grams (0.005 mole) of 1-(2-propyn-1-yl)-2-trifluoromethyl-5-fluoro-6-ethoxycarbonylaminobenzimidazole in 20 mL of N,N-dimethylformamide was added dropwise. The reaction mixture was heated to 110° C., and 0.24 mL (catalyst) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added in one portion. Upon completion of the addition, the reaction mixture was heated to about 130° C., where it stirred for about 3.5 hours. The reaction mixture was then allowed to cool to ambient temperature as it stirred for about 72 hours, after which the reaction mixture was poured into ice-cold aqueous 3N hydrochloric acid. The resultant precipitate was collected by filtration and dried, yielding 0.6 gram of 3-[1-(2-propyn-1-yl)-2-trifluoromethyl-5-fluorobenzimidazol-6-yl]-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:34])/[CH:20]=[C:21](/[C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)\[C:22]([F:25])([F:24])[F:23])=[CH:15][CH:14]=2)([F:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:35]([CH3:38])([O-:37])=[O:36].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:34])[CH2:20][C:21]([C:26]3[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=3)([CH2:38][N+:35]([O-:37])=[O:36])[C:22]([F:23])([F:25])[F:24])=[CH:15][CH:14]=2)([F:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C(=O)/C=C(/c3cc(Cl)cc(Cl)c3)C(F)(F)F)cc2)C1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C(=O)CC(C[N+](=O)[O-])(c3cc(Cl)cc(Cl)c3)C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
To the stirred solution of 3-{4-[(Z)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-phenyl}-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester (1.2 g, 2.315 mmol, 1 eq.) in acetonitrile (10 mL) was added nitro methane (1.24 mL, 23.152 mmol, 10 eq) and DBU (0.33 mL, 2.246 mmol, 0.97 eq) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. After complete consumption of starting material, the reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (2×25 mL). Combined organic layers were washed with brine (60 mL), dried over sodium sulphate and concentrated to get crude compound semi solid (1.37 g, crude). Crude compound was purified by column chromatography on silica gel using 230-400 mesh. Desired compound was eluted in 10% ethyl acetate in n-hexane to give product as light yellow sticky liquid (1.09 g, 81.34%). LC-MS (m/z): 576.8 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=2)[N:16]([CH2:26]/[CH:27]=[CH:28]/[C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][C:33]([Cl:39])=[CH:34][CH:35]=3)[N:30]=2)[CH:15]=1)[C:6]([O:8][CH3:9])=[O:7]>CCOC(C)=O.[Rh]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH2:23])[CH:21]=2)[N:16]([CH2:26][CH2:27][CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][C:33]([Cl:39])=[CH:34][CH:35]=3)[N:30]=2)[CH:15]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Cc2cn(C/C=C/c3ccc4ccc(Cl)cc4n3)c3ccc([N+](=O)[O-])cc23)c(OC)c1
Agent: [Rh]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cc2cn(CCCc3ccc4ccc(Cl)cc4n3)c3ccc(N)cc23)c(OC)c1
Reaction time: 48 h

Procedure:
The nitroindole from Step 4 (250 mg) was hydrogenated in the presence of 5% Rh/C at atmospheric pressure in EtOAc (25 ml). After 48 hrs, the catalyst was removed to afford the crude title compound which was immediately used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:16]=[CH:15][N:14]=1
Reactant: COc1ccccc1O
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: COc1ccccc1Oc1ccnc(Cl)c1
Yield: 97 %

Procedure:
Using the method of Example 3, Step A, 2-methoxyphenol (2.35 g, 18.9 mmol), 60% sodium hydride in mineral oil (0.757 g, 18.9 mmol), and 2-chloro-4-nitropyridine (3.00 g, 18.9 mmol) were reacted to provide 2-chloro-4-(2-methoxyphenoxy)pyridine (4.32 g, 96.9% yield) as a white powder. 1H NMR (CDCl3) δ 8.20 (d, 1H), 7.27 (m, 1H), 7.10 (d, 1H), 6.99-7.06 (m, 2H), 6.72-6.75 (m, 2H), 3.79 (s, 3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:41])([C:37]([CH3:40])([CH3:39])[CH3:38])[O:3][C@@H:4]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:6]([C@@H:7]([O:29][Si:30]([CH3:36])([CH3:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:8][C@@H:9]3[C@@H:23]2[CH2:22]C[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)C=CC=O)[CH2:5]1.O1[CH2:46][CH2:45][CH2:44][CH2:43]1>>[CH3:36][Si:30]([CH3:35])([C:31]([CH3:33])([CH3:34])[CH3:32])[O:29][C@@H:7]1[CH2:8][CH2:9][C@@:23]2([CH3:22])[C@H:5]([C@@H:4]([O:3][Si:2]([CH3:41])([CH3:1])[C:37]([CH3:38])([CH3:40])[CH3:39])[CH2:26][C@@H:25]3[C@@H:24]2[CH2:27][CH2:25][C@@:26]2([CH3:4])[C@H:43]3[CH2:44][CH2:45][C@@H:46]2[C@H:23]([CH3:22])[CH2:9][CH2:8][CH:7]=[C:6]([CH3:24])[CH3:5])[CH2:6]1
Reactant: C1CCOC1
Reactant: C[C@H](C=CC=O)[C@H]1CC[C@H]2[C@@H]3C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]4C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C)=CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]4C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
1.4 g of 3α,6α-bis(dimethyl-t-butylsilyloxy)-5β-cholen-24-al (prepared as described in my U.S. patent application Ser. No. 236,160) was dissolved in 5 ml of tetrahydrofuran and added dropwise to the ylid solution (as described in Example I). The reaction mixture was stirred, refluxed and processed in the manner of Example I. The product remaining after the evaporation of the petroleum ether extract was identified by IR and NMR data as the 3α,6α-bis (dimethyl-t-butylsilyloxy)-5β-cholest-24-ene.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:30][CH2:31][N:32]4[CH2:35][CH2:34][CH2:33]4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([O:28][CH3:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[OH:36]O.[OH-].[Na+]>CS(C)=O>[NH2:1][C:2]1[C:7]([C:8]([NH2:9])=[O:36])=[C:6]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[N:17]([CH2:30][CH2:31][N:32]4[CH2:33][CH2:34][CH2:35]4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([O:28][CH3:29])[CH:22]=4)[N:20]=3)[CH2:14][CH2:15]2)[N:5]=[CH:4][N:3]=1
Reactant: OO
Reactant: COc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4C(N)=O)CC3)n2)ccc1F
Temperature: 25 °C

Procedure:
A reaction mixture of 4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-methoxy-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile (100.00 mg; 0.21 mmol; 1.00 eq.), DMSO 8 ml was stirred at RT added H2O2 (0.20 ml; 2.10 mmol; 10.00 eq.) and 2.0M NaOH.2.0MNaOH aq (1.05 ml; 2.10 mmol; 10.00 eq.), stirred at RT for 2 hr, got desired as major detected by lc-ms, purified the product by prep HPLC (basic), title compound 66 mg, 63%. LC-MS (M+1=495, obsd.=495).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](Cl)(Cl)=[S:12]>Cl>[N:1]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[C:11]=[S:12]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: S=C(Cl)Cl
Agent: Cl
Product: O=C(O)c1ccc(N=C=S)cc1

Procedure:
A sample of p-aminobenzoic acid is dissolved in 3N HCl (20% by weight). To this is added about one equivalent of thiophosgene in a single portion. The reaction mixture is stirred until a white precipitate appears, the crude product is filtered, washed with water, and crystallized from acetone-water to give crude p-isothiocyanatobenzoic acid.
Reaction SMILES: C[O-].[Na+].Cl.Cl[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[SH:13][C:14]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:22](=[O:30])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.O>CO>[C:24]1([N:23]2[C:22](=[O:30])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]2[S:13][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=c1c2ccccc2nc(S)n1-c1ccccc1
Reactant: ClCc1ccccn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=c1c2ccccc2nc(SCc2ccccn2)n1-c1ccccc1
Reaction time: 2.5 h
Yield: 49.8 %

Procedure:
6.1 ml Of 28% methanolic solution of sodium methoxide and 2.46 g of 2-chloromethylpyridine hydrochloride were added to a solution of 3.62 g of 2-mercapto-3-phenyl-4(3H)-quinazolinone in 100 ml of methanol, and the stirring was continued at room temperature for 2.5 hours. About 50 ml of water were added to the reaction solution and crystals precipitated were collected by filtration and recrystallized from ethyl acetate to give 2.45 g of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:16])C(=O)C1>C(#N)C>[Br:16][C:6]1[CH:7]=[C:2]([F:1])[C:3]([NH2:8])=[N:4][CH:5]=1
Reactant: Nc1ncccc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ncc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 140.9 %

Procedure:
To a solution of 3-fluoro-pyridin-2-ylamine (1.0 g, 8.92 mmol) in 300 mL of acetonitrile, NBS (794 mg, 4.46 mmol) was added at 0° C. The reaction mixture was stirred vigorously for 15 minutes (protected from light) at 0° C. and then at room temperature for 1 hour. The additional portion of NBS (794 mg, 4.46 mmol) was added at 0° C. and the solution was stirred at room temperature for 2 hours. The reaction mixture was quenched by addition Na2S2O3 (saturated aqueous solution, 40 mL) and the product was extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine (2×50 mL), dried over MgSO4 and concentrated in vacuo. The obtained crude yellowish solid was purified by Biotage using 3-20% EtOAc in hexane to afford 5-bromo-3-fluoro-pyridin-2-ylamine (1.2 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.93 (d, J=1.56 Hz, 1 H) 7.37 (dd, J=9.76, 1.95 Hz, 1 H) 4.63 (br. s., 2 H)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:30])[N:7]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21](=[O:29])[C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[N-:35]=[N+:36]=[N-].[Na+].[OH-].[Na+]>O.C(O)(=O)C>[N:1]([C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:30])[N:7]([CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][CH:18]([C:21](=[O:29])[C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH2:19][CH2:20]3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1)=[N+:35]=[N-:36]
Reactant: Nc1ccc2c(=O)n(CCN3CCC(C(=O)c4ccc(F)cc4)CC3)c(=O)[nH]c2c1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: [N-]=[N+]=Nc1ccc2c(=O)n(CCN3CCC(C(=O)c4ccc(F)cc4)CC3)c(=O)[nH]c2c1
Reaction time: 0.33 h
Yield: 55 %

Procedure:
To a stirred and cooled (5° C.) solution of 0.205 parts of 7-amino-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione in 50 parts of an acetic acid solution 1N was added a solution of 0.1725 parts of sodium nitrite in 2 parts of water. The whole was stirred for 20 minutes at 5° C. A solution of 0.1625 parts of sodium azide in 2 parts of water was added and stirring was continued for 20 minutes at 5° C. in vacuo. 5.5 Parts of a sodium hydroxide solution 10N were added whereupon the product solidified. The product was filtered off and crystallized from acetonitrile. The product was filtered off and dried, yielding 0.120 parts (55%) of 7-azido-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)quinazolinedione; mp. 193.7° C. (28).
Reaction SMILES: [Cl:1][C:2]([Cl:33])([Cl:32])[CH2:3][O:4][C:5](=[O:31])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][N:23]=3)=[CH:16][C:15]=2[NH2:30])=[CH:9][CH:8]=1.C([C:36]1[C:37]([N:45]=[CH:46][N:47]([CH3:49])C)=[N:38][C:39]([CH:42]([CH3:44])[CH3:43])=[CH:40][CH:41]=1)#N>C(O)(=O)C>[Cl:33][C:2]([Cl:1])([Cl:32])[CH2:3][O:4][C:5](=[O:31])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][N:23]=3)=[CH:16][C:15]=2[NH:30][C:49]2[C:36]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:43])[CH3:44])=[N:38][C:37]=3[N:45]=[CH:46][N:47]=2)=[CH:9][CH:8]=1
Reactant: CC(C)c1ccc(C#N)c(N=CN(C)C)n1
Reactant: Nc1cc(C(=O)Nc2ccc(Br)cn2)ccc1Sc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CC(=O)O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cn4)ccc3Sc3ccc(NC(=O)OCC(Cl)(Cl)Cl)cc3)ncnc2n1
Temperature: 140 °C
Yield: 79 %

Procedure:
A mixture of the products of Example 364D (3.05 g, 5.16 mmol) and Example 8E (N′-(3-cyano-6-isopropyl-pyridin-2-yl)-N,N-dimethyl-formamidine) (1.34 g, 6.20 mmol, 1.2 equiv.) in 25 mL of glacial acetic acid was heated in a 140° C. preheated oil bath for 45 minutes. The reaction mixture was cooled, evaporated in vacuo and the residue partitioned between ethyl acetate (250 mL) and water (100 mL). The organic phase was then washed with saturated aqueous sodium bicarbonate and then brine, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was triturated with methanol, filtered, and dried in vacuo to provide the title compound (3.10 g, 79%) as a beige solid. MS (ESI+) m/z 762/764 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.33 (d, J=6.99 Hz, 6 H), 3.16-3.26 (m, 1 H), 4.97 (s, 2 H), 6.96 (s, 1 H), 7.43 (d, J=8.82 Hz, 2 H), 7.59 (s, 2 H), 7.86 (s, 1 H), 8.01-8.10 (m, 3 H), 8.15-8.20 (m, 1 H), 8.50 (d, J=2.57 Hz, 1 H), 8.57 (s, 1 H), 8.84 (s, 1 H), 10.23 (s, 1 H), 10.40 (s, 1 H), 10.94 (s, 1 H).
Reaction SMILES: [I:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=3)=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.Br[CH2:23][CH2:24][CH2:25][NH:26][C:27]([CH:29]1[CH2:31][CH2:30]1)=[O:28].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:21][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[C:19]=1[N:20]=[C:12]([S:11][C:3]1[C:2]([I:1])=[CH:10][C:6]3[CH2:7][CH2:8][O:9][C:5]=3[CH:4]=1)[N:13]2[CH2:23][CH2:24][CH2:25][NH:26][C:27]([CH:29]1[CH2:31][CH2:30]1)=[O:28]
Reactant: O=C(NCCCBr)C1CC1
Reactant: Nc1ncnc2[nH]c(Sc3cc4c(cc3I)CCO4)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1nc(Sc1cc3c(cc1I)CCO3)n2CCCNC(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
To a solution of 8-((5-iodo-2,3-dihydrobenzofuran-6-yl)thio)-9H-purin-6-amine (26 mg, 0.06 mmol) in DMF (1.5 mL) was added N-(3-bromopropyl)cyclopropanecarboxamide (39 mg, 0.18 mmol) and Cs2CO3 (41 mg, 0.12 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed under vacuum and the residue was purified by Prep TLC (CH2Cl2:NH3-MeOH (7N), 20:1) to yield WS61 as a white solid (12 mg, 35%). 1H NMR (600 MHz, CDCl3): δ 8.30 (s, 1H), 7.57 (s, 1H), 7.16 (m, 1H), 6.55 (s, 1H), 5.67 (br s, 2H), 4.50 (t, J=8.8 Hz, 2H), 4.22 (t, J=6.3 Hz, 2H), 3.13 (t, J=8.6 Hz, 2H), 3.01-3.07 (m, 2H), 1.80-1.86 (m, 2H), 1.38-1.44 (m, 1H), 0.87-0.93 (m, 2H), 0.67-0.72 (m, 2H); HRMS (ESI) m/z [M+H]+ calcd. for C20H22IN6O2S, 537.0570. found 537.0567.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:32]1[CH:33]=[C:34]([CH:45]=[CH:46][CH:47]=1)[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][NH:21][C:22]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][N:26]3[C:32]2[CH:33]=[C:34]([CH:45]=[CH:46][CH:47]=2)[C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: Cc1cc(N)c2cnn(-c3cccc(C(=O)OCc4ccccc4)c3)c2c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)OCc2ccccc2)c1)C(F)(F)F
Temperature: 85 °C
Yield: 65.3 %

Procedure:
A solution of racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane (which may be prepared according to WO 04/063163, 350 mg, 1.2 mmol), in acetonitrile (2 mL) was added to a mixture of phenylmethyl 3-(4-amino-6-methyl-1H-indazol-1-yl)benzoate (357 mg, 1.0 mmol) and ytterbium(III) triflate (124 mg, 0.2 mmol). The mixture was stirred and heated to 85° C. under nitrogen in a greenhouse apparatus for 18 hours when the temperature was raised to 100° C. and the mixture heated under vigorous reflux for a further ˜21 hours. The mixture was cooled to room temperature and partitioned between dichloromethane (50 mL) and aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted again with dichloromethane (50 mL) and the combined organic extracts were dried over anhydrous sodium sulphate and evaporated. The residue was purified by silica gel chromatography using the Flashmaster II (50 g cartridge) eluting with a cyclohexane to 1:1 cyclohexane:ethyl acetate gradient over 40 minutes to give the title compound as a white solid (424 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][S:26](=[O:29])[CH2:25][CH2:24]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH:13]([CH3:22])[C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:22][CH:13]([S:12][C:8]1[C:6]2[N:7]=[C:2]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][S:26](=[O:29])[CH2:25][CH2:24]3)[C:5]=2[N:11]=[CH:10][N:9]=1)[C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1
Reactant: CSc1ccc(C(C)Sc2ncnc3c(N4CCS(=O)CC4)nc(Cl)nc23)cc1
Reactant: C1CNCCN1
Product: CSc1ccc(C(C)Sc2ncnc3c(N4CCS(=O)CC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(α-methyl-4-methylthiobenzyl-thio)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 200°-202° C.) and piperazine.