Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]([CH3:24])([CH3:23])[CH2:9][NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[F:22])=[O:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33](=[O:38])=[N:34][C:35](Cl)=[O:36]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]([CH3:24])([CH3:23])[CH2:9][N:10]1[C:35](=[O:36])[NH:34][C:33](=[O:38])[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=2[F:22])[C:11]1=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(NC(=O)NCC(C)(C)NC(=O)OC(C)(C)C)c1F
Reactant: O=C=NC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(-n2c(=O)[nH]c(=O)n(CC(C)(C)NC(=O)OC(C)(C)C)c2=O)c1F
Reaction time: 1 h

Procedure:
To 20 mL of anhydrous CH2Cl2 was added 0.93 g of {2-[3-(2-Fluoro-3-methoxy-phenyl)-ureido]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester and triethylamine (1.0 eq, 0.36 mL). N-(chlorocarbonyl) isocyanate (1.0 eq, 0.11 mL) was added to the solution in one portion. The reaction stalled after one hour, so additional triethylamine (1.0 eq, 0.36 mL) and N-(chlorocarbonyl) isocyanate was added. The reaction was determined to be complete by LC/MS after two hours. Excess isocyanate was quenched with the dropwise addition of H2O (1 mL). The reaction was then diluted with 20 mL H2O, and the organic layer was collected. The aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography and eluted with 60% EtOAc/hexanes to yield 0.65 g (59%). Rf=0.66 in 60% EtOAc/hexanes. 1H NMR (CDCl3) δ: 7.19 (dt,1H), 7.09 (dt,1H), 6.90 (dt,1H), 5.15 (ds,1H), 4.1 (q,2H), 3.92 (s,3H), 1.42 (s,9H), 1.38 (d,6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:12]=[C:11]([CH3:23])[N:10]=2)=[CH:5][CH:4]=1.[Br:24]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:24][CH2:23][C:11]1[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-c2cc(-c3ccc(OC)cc3)nc(C)n2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(-c2cc(-c3ccc(OC)cc3)nc(CBr)n2)cc1
Temperature: 75 °C

Procedure:
4,6-Bis-(4-methoxy-phenyl)-2-methyl-pyrimidine 23 (0.21 g, 0.7 mmol) is dissolved in 4 mL carbon tetrachloride. N-Bromo-succinimide (0.10 g, 0.56 mmol) is added and the mixture is heated to 75° C. with stirring. Solid 2,2′-azobisisobutyronitrile (AIBN) (0.01 g, 0.06 mmol) is added and the mixture is stirred at 75° C. for 24 hours. Cooling, diluting with dichloromethane, washing with water, saturated aqueous NaHCO3, and brine, followed by drying over solid Na2SO4 and concentration yielded 2-bromomethyl-4,6-bis-(4-methoxy-phenyl)-pyrimidine 24 as an oil. It is used without further purification in the next step. 1H-NMR (400 MHz, CDCl3) δ=8.02 (d, J=8.8 Hz, 2H), 7.69 (s, 1H), 6.94 (d, J=8.8 Hz, 2H), 3.82 (s, 2H).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([NH2:13])[CH3:12]>C1C=CC=CC=1>[CH2:11]([NH:13][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:12]
Reactant: CCN
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccccc1
Product: CCNC(=O)Cc1ccccc1

Procedure:
Dissolved 15 g (0.1 mol) of phenylacetyl chloride in 100 ml of benzene. While stirring on a magnetic stirrer, added 25 g of ethylamine (0.5 mol) into the benzene solution at 20°-30° C. After reaction, the solution was washed with water, dehydrated with anhydrous magnesium sulfate. The solvent was removed by rotary evaporator and the residue was purified by column chromatography as compound 3-1 to yield N-ethyl phenylacetamide as yellowish crystal. Yield, 14 g (85%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]([OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]=2[CH3:13])[S:4](=[O:20])(=[O:19])[CH2:3]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[CH3:21][C:2]1([CH3:1])[CH:11]([O:12][S:23]([CH3:22])(=[O:25])=[O:24])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]=2[CH3:13])[S:4](=[O:20])(=[O:19])[CH2:3]1
Reactant: CCOC(=O)c1ccc2c(c1C)C(O)C(C)(C)CS2(=O)=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc2c(c1C)C(OS(C)(=O)=O)C(C)(C)CS2(=O)=O
Reaction time: 8 h
Yield: 96.5 %

Procedure:
4.1 Grams (13 mmol)of 3,3,5-trimethyl-4-hydroxy-6-ethoxycarbonylthiochroman-1,1-dioxide was dissolved in 15 ml of pyridine, and the mixture was cooled in an ice bath. 1.8 Grams (16 mmol, 1.2 eq.) of methanesulfonyl chloride was gradually added thereto. After the addition, the ice bath was removed, and the mixture was allowed to stand overnight. The reaction mixture was diluted with 200 ml of ethyl acetate, and washed with 200 ml of water, with 150 ml of a 1 wt % hydrochloric acid aqueous solution twice, with 150 ml of a saturated sodium hydrogencarbonate aqueous solution and with 50 ml of water in this order. An organic layer was dried over sodium sulfate, the solvent was distilled off, and the residue was dried under reduced pressure to give 4.9 g (yield 97%) of a brownish oil. The brownish oil solidified after allowed to stand overnight.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH:2]=[CH2:3].C1COCC1.[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][CH2:3][CH:2]=[CH2:1])=[CH:14][CH:13]=1
Reactant: C=CC[Mg]Cl
Reactant: BrCc1ccc(Br)cc1
Solvent: C1CCOC1
Product: C=CCCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a 2M solution of allylmagnesium chloride in THF (24 mL, 48.00 mmol, 1.5 equiv) at 0° C. was added, under an atmosphere of N2, 4-bromobenzyl bromide (8.00 g, 32.01 mmol, 1.0 equiv) neat in 10 portions over a period of 5 min. The mixture was stirred for 1 h at 0° C. and then at rt for 28 h. The mixture was carefully quenched with water (100 mL) and then extracted with ethyl acetate (3×150 mL). The combined extracts were washed with brine (2×50 mL), dried over anhydrous Na2SO4, and concentrated. High-vacuum drying gave 11a (6.51 g, 30.84 mmol, 96%) as a clear oil: Rf=0.94 (ethyl acetate); 1H NMR (400 MHz, CDCl3): δ 2.32-2.38 (m, 2H), 2.67 (t, J=7.8 Hz, 2H), 4.98-5.06 (m, 2H), 5.78-5.86 (m, 1H), 7.06 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 34.9, 35.4, 115.4, 119.7, 130.4, 131.5, 137.7, 140.9; HRMS (EI) Calcd. for C10H11Br: 210.0044 (M+). Found: 210.0053.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[N:13]=3)=[CH:10][N:9](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[C:1]1([C:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=4)[N:13]=3)=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1c[nH]nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
A mixture of 3-(3-phenyl-1-trityl-1H-pyrazol-4-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (1.50 g, 2.4 mmol), TFA (5 mL), and CH2Cl2 (15 mL) was stirred overnight at room temperature. The reaction mixture was alkalinized with 1 M NaOH aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from MeOH to give the title compound (751 mg, 82% yield) as a white solid: mp 206-208° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 6.58 (1H, d, J=7.9 Hz), 7.37-7.67 (9H, m), 8.33 (0.35H, brs), 8.65 (0.65H, brs), 8.91 (1H, d, J=7.9 Hz), 13.17-13.46 (1H, m). LC-MS (ESI) m/z 383 [M+H]+. Anal. Calcd for C20H13F3N4O.0.35H2O: C, 61.81; H, 3.55; N, 14.42. Found: C, 61.83; H, 3.61; N, 14.49.
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:58][C:59]1([CH3:62])[CH2:61][O:60]1>CN(C=O)C.CCOCC>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:58][C:59]([OH:60])([CH3:62])[CH3:61])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: CC1(C)CO1
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCC(C)(C)O)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]-amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.1 M) was added cesium carbonate (2.5 eq.) and 2,2-dimethyloxirane (15 eq.). The reaction was stirred for 18 h at 50° C., then added more 2,2-dimethyloxirane (10 eq.). The reaction was heated to 80° C. and stirred for 4.5 h. After cooling to rt, the reaction was diluted with ether. The organic extract was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 45%→55% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: B.[CH:2]1([C:5]([N:7]2[CH2:11][CH2:10][C:9]([OH:25])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:8]2)=O)[CH2:4][CH2:3]1.[ClH:26].Cl.CCOCC>C1COCC1>[ClH:26].[CH:2]1([CH2:5][N:7]2[CH2:11][CH2:10][C:9]([OH:25])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:8]2)[CH2:4][CH2:3]1
Reactant: O=C(C1CC1)N1CCC(O)(c2ccccc2Cc2ccccc2)C1
Agent: B
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(c2ccccc2Cc2ccccc2)CCN(CC2CC2)C1
Temperature: 25 °C

Procedure:
To a solution of 45 ml of 1 M-borane in THF is added under dry nitrogen at 0° C., 6.36 g 1-cyclopropylcarbonyl-3-hydroxy-3-(α-phenyl-2-tolyl)pyrrolidine in 20 ml of dry THF. The solution is then brought to reflux and maintained there for 1 hour. The solution is permitted to cool to room temperature and 3.3 ml of 6 N-HCl is added slowly. The THF is removed by distillation at atmospheric pressure and the residue is crystallized with 50 ml of anhydrous ether and recrystallized from methanol/ether (30 ml/80 ml) to give colorless crystals. The mother liquid is made acid with a slight excess of HCl/ether and a second crop is obtained by suction filtration. The mother liquid is concentrated in vacuo to an oil and a third crop is obtained by crystallization with ether. Recrystallization from methanol/ether (20 ml/50 ml) yields 1-cyclopropylmethyl-3-hydroxy-3-(α-phenyl-2-tolyl)pyrrolidine hydrochloride, mp 168°-169° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH2:26][OH:27].[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(C(C)C)CC)(C)C>ClCCl>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH2:26][O:27][S:29]([CH3:28])(=[O:31])=[O:30]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(CO)cc(OC)c21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(COS(C)(=O)=O)cc(OC)c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
A mixture of 100 mg (0.23 mmol) [4-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-methanol, 26 μl (0.33 mmol) methanesulfonyl chloride and 60 μl (0.35 mmol) diisopropylethylamine in 4 ml dichloromethane is stirred at 0° C. for 2 h. The reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo to afford 120 mg of the title compound as an oil that is used directly in the next reaction.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:30][C:29]1[CH:28]=[CH:27][C:4]([C:5]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: Cc1ccc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc1Br
Reactant: C1COCCN1
Product: Cc1ccc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc1N1CCOCC1

Procedure:
Compound is formed by reacting 3-bromo-4-methyl-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide with morpholine under conditions described in general procedure B. 1H NMR (300 MHz, CDCl3) δ 8.32 (m, 1H), 7.98 (broad s, 1H), 7.86 (m, 1H), 7.74 (m, 2H), 7.53 (m, 3H), 7.32 (m, 1H), 6.87 (t, 1H, J=7.5), 4.34 (m, 2H), 3.88 (m, 4H), 3.77 (m, 4H), 2.97 (m, 6H), 2.68 (m, 4H), 2.42 (d, 3H, J=5.7). MS: 476.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[O:7])=[C:4](F)[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[O:7])=[C:4]([O:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][C:22]=2[CH3:27])[CH:3]=1
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1ccc(Cl)cc1F
Reactant: Cc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(F)ccc1Oc1cc(Cl)ccc1C(=O)Nc1cc[nH]c(=O)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a solution of 4-chloro-2-fluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (500 mg, 1.87 mmol) in NMP (5 mL) was added 4-fluoro-2-methyl-phenol (709.5 mg, 5.62 mmol) and Cs2CO3 (1.83 g, 5.62 mmol) and the reaction mixture was stirred at 90° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The organics were combined, washed with 3N NaOH (3×), water, brine, dried (Na2SO4) and evaporated to dryness. Purification by silica gel column chromatography gave 4-chloro-2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)benzamide (13a) (300 mg, 43%) as a tan solid. ESI-MS m/z calc. 372.07, found 373.1 (M+1)+; Retention time: 1.5 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.25 (s, 1H), 10.48 (s, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.30 (dd, J=7.9, 1.6 Hz, 2H), 7.21 (d, J=8.7 Hz, 1H), 7.09 (d, J=5.5 Hz, 2H), 6.75 (dd, J=5.1, 1.8 Hz, 2H), 6.38 (dd, J=7.2, 2.0 Hz, 1H), 2.16 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[CH:4][CH:5]=[C:6]([NH2:8])[CH:7]=1.[Br-:14].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>O1CCCC1.C(OCC)C>[Br:14][C:5]1[CH:4]=[C:3]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[C:2]([F:1])=[CH:7][C:6]=1[NH2:8]
Reactant: [Br-]
Reactant: Nc1ccc(-n2cccn2)c(F)c1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1cc(F)c(-n2cccn2)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-fluoro-4-(pyrazol-1-yl)phenylamine (2.56 g, 14.5 mmol) in tetrahydrofuran (50 ml) was added dropwise a solution of pyridinium tribromide (5.09 g, 15.9 mmol) in tetrahydrofuran (50 ml). The mixture was stirred for 1 h at room temperature then diluted with diethyl ether (250 ml). After stirring for a further 30 min the precipitate was filtered and washed with diethyl ether (50 ml×2). The white solid was dissolved in water (200 ml) and extracted with ethyl acetate (100 ml×3). The combined organic phases were dried over magnesium sulphate, filtered and the solvent removed to leave an orange oil. Purification by chromatography (silica gel, CH2Cl2) gave 2-bromo-5-fluoro-4(pyrazol-1-yl)phenylamine as a white solid: MS (ES+) m/z 256 and 258 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:15][CH:16]([CH2:18][CH3:19])[CH3:17])=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:9])=[N:6][C:7]=1[SH:8].[N:20]([O-])=O.[Na+]>C(O)(=O)C>[CH:16]([NH:15][C:3]1[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([CH3:9])[N:6]=[C:7]2[S:8][N:20]=[N:1][C:2]=12)([CH2:18][CH3:19])[CH3:17]
Reactant: CCOC(=O)c1c(C)nc(S)c(N)c1NC(C)CC
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nc2snnc2c1NC(C)CC
Yield: 72 %

Procedure:
By treating 5-amino-4-sec.butylamino-6-mercapto-2-methylpyridine-3-carboxylic acid, ethyl ester with sodium nitrite in acetic acid as described in Example 1 e, 7-(sec.-butylamino)-5-methyl[1,2,3]thiadiazolo[5,4-b]pyridine-6-carboxylic acid, ethyl ester is obtained, yield 72% m.p. 48°-50° (ether).
Reaction SMILES: [Na].[C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:15])[O:13][CH3:14])[O:8][N:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:16]O>>[CH3:16][N:11]([C:9]1[O:8][N:7]=[C:6]([C:2]([CH3:5])([CH3:3])[CH3:4])[CH:10]=1)[C:12](=[O:15])[O:13][CH3:14]
Reactant: COC(=O)Nc1cc(C(C)(C)C)no1
Reactant: CO
Agent: [Na]
Product: COC(=O)N(C)c1cc(C(C)(C)C)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a solution of metallic sodium (0.42 g) in methanol (12 ml), a solution of methyl 3-t-butyl-5-isoxazolylcarbamate (3.47 g) in methanol (5.5 ml) is added, and the resultant mixture is stirred at room temperature for 10 minutes. The reaction mixture is evaporated under reduced pressure to remove the methanol. The residue is combined with benzene, which is then evaporated. The residue is again combined with benzene (27 ml), and dimethyl sulfate (2.32 g) is added dropwise. The resultant mixture is stirred at room temperature for 1 hour and then refluxed for 1 hour. After cooling, the reaction mixture is filtered to remove the precipitate. The filtrate is washed with aqueous sodium bicarbonate solution and then water, dried over anhydrous sodium sulfate and evaporated to remove the solvent. The residue is recrystallized from cyclohexanone to give methyl N-methyl-3-t-butyl-5-isoxazolylcarbamate (3.41 g) as crystals melting at 70.5° to 71.5° C. The yield is 91.8%.
Reaction SMILES: C1(CC[CH2:9][CH2:10][P:11]([OH:13])[OH:12])C=CC=CC=1.C([CH:21](Br)[C:22]([O-:24])=[O:23])C1C=CC=CC=1>>[OH:13][P:11]([CH2:21][C:22]([OH:24])=[O:23])([CH2:10][CH3:9])=[O:12]
Reactant: O=C([O-])C(Br)Cc1ccccc1
Reactant: OP(O)CCCCc1ccccc1
Product: CCP(=O)(O)CC(=O)O

Procedure:
Following the procedure as set out in Example 1, except substituting ethylphosphonous acid for 4-phenylbutylphosphonous acid, and substituting chloroacetic acid for benzylbromoacetate, the title compound is obtained.
Reaction SMILES: Cl[C:2]1[C:3]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:2]2[C:3]([N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[C:4]([CH:7]=[CH:8][N:9]=2)[C:5]#[N:6])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1ccnc(Cl)c1N1CCCC1
Product: N#Cc1ccnc(-c2ccccc2)c1N1CCCC1
Yield: 66 %

Procedure:
Prepared in 66% yield from the product of Example 181A and phenylboronic acid according to the procedure described for Example 153A. MS (ESI+) m/z 249.8 (M+H)+; 1H NMR (DMSO-d6) δ 1.72-1.77 (m, 4H), 3.17-3.21 (m, 4H), 7.38-7.52 (m, 6H), 8.14 (d, J=4.7 Hz, 1H).
Reaction SMILES: Cl.Cl.[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:11]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)[CH3:4].[CH3:37][C:38]1([CH3:41])[CH2:40][O:39]1.CCN(C(C)C)C(C)C>CC#N>[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([OH:26])[CH2:25][CH2:24][CH2:23][N:22]([CH2:37][C:38]([OH:39])([CH3:41])[CH3:40])[CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[N:11]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)[CH3:4]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCNC3)n(C)c2n1
Reactant: CC1(C)CO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCN(CC(C)(C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 23.4 %

Procedure:
A mixture of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-3-ol dihydrochloride (150 mg, 0.28 mmol), 2,2-dimethyloxirane (100 μL, 1.12 mmol) and DIPEA (192 μL, 1.12 mmol) in MeCN (4 mL) was stirred at r.t. for 20 h then heated at 70° C. for 24 h. The reaction mixture was concentrated in vacuo and the resulting residue purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient acetonitrile 5-30%) affording 746 (35 mg, 23%). LCMS (method I): RT 2.57 min, [M+H]+ 535.2. 1H NMR (DMSO, 400 MHz): δ 8.03-7.98 (1 H, m), 7.65-7.61 (1 H, m), 7.28-7.21 (2 H, m), 5.46 (1 H, s), 4.45-4.05 (5 H, m), 3.96 (3 H, s), 3.77-3.76 (4 H, m), 3.30-3.22 (2 H, m), 3.07-2.99 (1 H, m), 2.91-2.83 (1 H, m), 2.70-2.60 (1 H, m), 2.45-2.35 (1 H, m), 2.26 (2 H, s), 2.15-2.00 (1 H, m), 1.96-1.69 (3 H, m), 1.32 (3 H, t, J=7.43 Hz), 1.01 (6 H, d, J=15.78 Hz)
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:11])=[N:7][NH:8][C:9]=1[NH2:10])([CH3:4])([CH3:3])[CH3:2].CN(C)[CH:14]=[CH:15][CH:16]=O>C(O)C.C(O)(=O)C>[C:1]([C:5]1[C:6]([NH2:11])=[N:7][N:8]2[CH:16]=[CH:15][CH:14]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=CC=O
Reactant: CC(C)(C)c1c(N)n[nH]c1N
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)c1c(N)nn2cccnc12
Temperature: 25 °C
Yield: 72.8 %

Procedure:
A mixture from Example 105A (2.61 g, 16.9 mmol), 3-dimethylaminoacrylaldehyde (2.0 mL, 20.0 mmol) and acetic acid (25 μL, 0.44 mmol) in ethanol (18 mL) was heated by microwave to 150° C. for 30 minutes. The mixture was cooled to ambient temperature and concentrated. Purification by silica gel chromatography (EtOAc, Rf=0.39) afforded 2.34 g (43%) of the title compound. MS (DCI) m/z 191 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][OH:15])=[CH:17][CH:18]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.3 %

Procedure:
To a stirred solution of 4-[N-(t-butoxycarbonyl)-aminomethyl]benzoic acid (16.5 g, 65 mmol) and triethylamine (10 mL, 71 mmol) in dry THF (500 mL) at 0° C. was added ethyl chloroformate (7.5 mL, 78 mmol) dropwise. After stirring for 15 min, sodium borohydride (6 g, 159 mmol) was added in one portion and the reaction was allowed to warm to RT and stirred for 16 h. The reaction was cooled in an ice bath and carefully quenched with 1N hydrochloric acid, extracted with ethyl acetate, and the organic phase was washed with brine, dried (magnesium sulfate), and concentrated. The residue was purified by flash chromatography (silica gel, 20% ethyl acetate:chloroform) to give the title compound (10.07 g, 65%) as a white solid. TLC Rf 0.31 (20% ethyl acetate:chloroform); 1H NMR (CDCl3) δ1.46 (9H, s), 3.28 (1H, br s), 4.27 (2H, d, J=6 Hz), 4.65 (2H, s), 5.04 (1H, br s), 7.30 (4H, dd).