Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S-:2].[Na+].[Br:4][C:5]1[CH:6]=[C:7]([S:11]([C:14]2[CH:15]=[C:16]([C:22]#[N:23])[S:17][C:18]=2[N+]([O-])=O)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1.C(O)(=O)C>CCO.C1COCC1.C(OCC)C>[Br:4][C:5]1[CH:6]=[C:7]([S:11]([C:14]2[CH:15]=[C:16]([C:22]#[N:23])[S:17][C:18]=2[S:2][CH3:1])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1
Reactant: C[S-]
Reactant: N#Cc1cc(S(=O)(=O)c2cccc(Br)c2)c([N+](=O)[O-])s1
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSc1sc(C#N)cc1S(=O)(=O)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
A solution of sodium thiomethoxide (1.87 g, 26.8 mmol) in EtOH (26.8 mL, anhydrous) was added to a suspension of 4-(3-bromo-benzenesulfonyl)-5-nitro-thiophene-2-carbonitrile (10 g, 26.8 mmol, Example 286: step e) in THF (67 mL, anhydrous) portionwise at −78° C. The temperature of the reaction was maintained at −78° C. with stirring for 1 hour. The reaction was quenched with acetic acid (2 mL, 34.9 mmol) at −78° C. followed by warming the reaction mixture to rt and then filtered. The yellow solids were washed with diethyl ether and saved. The filtrate was concentrated in vacuo resulting in a residue that was suspended in diethyl ether and stirred at rt overnight. The solids were filtered from the suspension. The combined yellow solids were dried under high vacuum to afford the title compound (8.77 g, 87.4%). 1H-NMR (DMSO-d6): δ 8.45 (s, 1H), 7.97–8.16 (m, 3H), 7.62–7.67 (m, 1H), 2.71 (s, 3H).
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:16][NH:15][C@H:14]([CH2:17][NH:18][CH2:19][C:20]([O:22]C)=O)[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C>CO>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:16][N:15]4[C:20](=[O:22])[CH2:19][NH:18][CH2:17][C@@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:3][CH2:4]1
Reactant: COC(=O)CNC[C@@H]1C[C@@H](Oc2cnc(C3CC3)cn2)CN1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C1CNC[C@@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN12
Reaction time: 18 h

Procedure:
To a solution of the product from Example 174F (0.958 g, 2.79 mmol) in methanol (10 mL) was added triethylamine (2.337 mL, 16.77 mmol). The mixture was heated to reflux and stirred for 18 hours. The cooled mixture was concentrated in vacuo, and the crude product was purified by flash chromatography on a 12 g silica gel column, eluting with 2.5% methanol (containing 2 N ammonia) in dichloromethane for 3 minutes and then a gradient to 10% methanol (2 N ammonia) in dichloromethane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.15 (dd, J=9.2, 1.4 Hz, 2H), 5.47 (t, J=5.0 Hz, 1H), 4.05-3.88 (m, 1H), 3.87-3.69 (m, 1H), 3.26-3.01 (m, 4H), 2.67 (s, 1H), 2.34 (dd, J=12.7, 10.2 Hz, 1H), 2.24-2.03 (m, 2H), 1.73 (ddd, J=13.3, 11.9, 4.8 Hz, 1H), 1.03-0.88 (m, 2H), 0.82 (ddd, J=6.8, 4.7, 2.4 Hz, 2H); MS (ESI) m/z 449 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1(Br)[CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[Na+].CN(C=O)C>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: BrC1CCCC1
Reactant: Oc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OC2CCCC2)cc1
Temperature: 100 °C
Reaction time: 13.5 h
Yield: 83.3 %

Procedure:
A mixture of 4-bromophenol (40 g, 231 mmol), cyclopentylbromide (50 ml, 462 mmol), NaOH (18.5 g, 462 mmol) and DMF (150 mL) was stirred at 100° C. for 13.5 h, poured into water (300 mL) and extracted with t-BuOMe (4×100 mL). The combined organic extracts were washed with water (2×100 mL), brine, dried (Na2SO4), concentrated and distilled in vacuo to yield the sub-title compound (46.4 g, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:2]([Br:1])=[C:3]([CH:6]=1)[CH:4]=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1cc(O)ccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1cc(OCc2ccccc2)ccc1Br
Temperature: 80 °C

Procedure:
A solution of 2-bromo-5-hydroxy-benzaldehyde (5.99 g, 29.8 mmol, Preparation 13 Step A) in DMF (50 mL) was treated with benzyl bromide (7.65 g, 44.7 mmol) and Cs2CO3 (15.1 g, 44.7 mmol). The resulting mixture was heated at 80° C. for 60 min and was quenched with water (200 mL). The mixture was extracted with EtOAc (2×100 mL), dried (Na2SO4), and concentrated to a residue, which was purified on silica gel chromatography (hexanes/EtOAc 9/1) to afford 5-benzyloxy-2-bromo-benzaldehyde as white solid in quantitative yield.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([O:19][CH2:20][CH:21]([OH:30])[CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH:13]=[CH:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([O:19][CH2:20][CH:21]([OH:30])[CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH:13]=[CH:12]2
Reactant: OC(CCc1cccnc1)COc1ccc2cc(OCc3ccccc3)ccc2c1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc2cc(OCC(O)CCc3cccnc3)ccc2c1
Yield: 78.9 %

Procedure:
Solid α-(6-(benzyloxy)-2-naphthyloxymethyl)-3-pyridinepropanol (0.90 g; from Example 29 above) was dissolved in dry ethanol (20 ml) and hydrogenated for 2 hours at 5 atmospheres pressure using palladium on carbon (10%, 1 spatula end) as catalyst. The reaction was filtered through Celite and the residue washed with ethanol. The combined filtrate and washings were concentrated under reduced pressure and the residue obtained purified by column chromatography over silica eluting with dichloromethane:methanol (95:5) to give a white solid (0.55 g).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[CH:16][C:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[N:28]=[CH:27][N:26](COCC[Si](C)(C)C)[N:25]=4)=[CH:20][CH:19]=3)=[C:11]2[N:10]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[NH:26]1[CH:27]=[N:28][C:24]([C:21]2[CH:20]=[CH:19][C:18]([C:17]3[CH:16]=[N:15][N:12]4[CH:13]=[CH:14][C:9]([N:4]5[C@@H:3]([CH2:1][CH3:2])[CH2:7][O:6][C:5]5=[O:8])=[N:10][C:11]=34)=[CH:23][CH:22]=2)=[N:25]1
Reactant: CC[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)cc3)c2n1
Reaction time: 18 h
Yield: 45.3 %

Procedure:
A mixture of (S)-4-ethyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (0.024 g, 0.047 mmol) in DCM (1 mL) was treated with trifluoroacetic acid (0.4 mL) at ambient temperature. The mixture was stirred for 18 hours. The solvent was concentrated and the residue partitioned between EtOAc and aqueous satd. NaHCO3. The aqueous layer was further extracted with EtOAc. The combined organic extracts were washed with brine, dried (phase separator silicone treated filter paper), concentrated and purified on silica gel (1-5% 7N ammonia in MeOH/dichloromethane) to give (S)-3-(3-(4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-ethyloxazolidin-2-one (0.008 g, 45%) as a beige solid. MS (APCI+) m/z 376 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][N:6]=1.C(Cl)(=O)C([Cl:19])=O>ClCCCl>[F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:19])=[O:10])=[CH:7][N:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OCC(F)(F)F)nc1
Solvent: ClCCCl
Product: O=C(Cl)c1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102 %

Procedure:
To 6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (100 mg, 0.45 mmol) was added DCE (5 mL) and oxalyl chloride (60 ul, 0.68 mmol) under an atmosphere of nitrogen. The mixture was stirred at rt for 1.5 h then heated at 80 C for 2 h and after cooling to room temperature, evaporated to give the title compound as a pale yellow oil (110 mg, 100%). Method C HPLC-MS (in MeOH, identifying the methyl ester): MH+ requires m/z=236. Found: m/z=236, Rt=1.41 min (95%).
Reaction SMILES: [CH2:1]([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2C=C)=[C:7]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:6]2[S:23][C:24]([C:26]([O:28][CH3:29])=[O:27])=[CH:25][C:5]1=2)[CH:2]=[CH2:3]>C(Cl)Cl.Cl[Ru](Cl)(=CC1C=C(Cl)C=CC=1OC(C)C)=C1N(C2C(C)=CC(C)=CC=2C)C=CN1C1C(C)=CC(C)=CC=1C>[CH:17]1([C:7]2[C:6]3[S:23][C:24]([C:26]([O:28][CH3:29])=[O:27])=[CH:25][C:5]=3[N:4]3[CH2:1][CH:2]=[CH:3][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8]=23)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: C=CCn1c(-c2ccccc2C=C)c(C2CCCCC2)c2sc(C(=O)OC)cc21
Agent: Cc1cc(C)c(-n2ccn(-c3c(C)cc(C)cc3C)c2=[Ru](Cl)(Cl)=Cc2cc(Cl)ccc2OC(C)C)c(C)c1
Solvent: ClCCl
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c1n2CC=Cc2ccccc2-1
Yield: 83 %

Procedure:
Methyl 4-allyl-6-cyclohexyl-5-(2-vinylphenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate was dissolved in DCM (0.02M) and treated with Zhan catalyst (dichloro(5-chloro-2-isopropoxybenzylidene)(1,3-dimesityl-1,3-dihydro-2H-imidazol-2-ylidene)ruthenium; RC-301; 0.3 eq.) at 35° C. for 2 h. After removal of the solvent the residue was purified by chromatography (PE/EtOAc 14:1) to afford the title compound in 83% yield. 1H-NMR (400 MHz, CDCl3, 300 K, δ) 7.74 (s, 1H), 7.57-7.56 (m, 1H), 7.45-7.35 (m, 3H), 6.82 (d, 1H, J 10.4), 6.30-6.25 (m, 1H), 4.47 (bs, 2Hs), 3.93 (s, 3H), 2.83-2.76 (m, 1H), 1.85-1.29 (m, 10H); MS (ES+) m/z 378 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=O)=[CH:5][CH:4]=1.C(NC(C)C)(C)C.C(N=CC)(C)(C)C.ClP(=O)(OCC)[O:35][CH2:36][CH3:37]>CCCCCC.O1CCCC1>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:37][CH:36]=[O:35])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reactant: CCOP(=O)(Cl)OCC
Agent: CC=NC(C)(C)C
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(=CC=O)c2ccc(OC)cc2)cc1
Reaction time: 68 h

Procedure:
The compound was prepared according to the procedure described in Example 84 except that the reaction time was extended to 68 hours. The following reagents were used: 4,4'-dimethoxybenzophenone (24.2 g), diisopropylamine (32.2 mL) 1.55M n-butyl lithium in hexane (148 mL). acetaldehyde N-tert-butylimine (14.75 mL), diethyl chlorophosphonate (16.6 mL) and tetrahydrofurane (200 mL). The usual work up furnished 25.6 g of an orange oil which was crystallized from ether-hexane to give 22.7 g of 3,3-bis(4-dimethoxyphenyl)-2-propenal, as a yellow solid, mp 55°-57° C. The analytical specimen, mp 56°-57° C., crystallized from the same solvent system had been prepared in a previous experiment. Anal. Calculated for C17H16O3 : C, 76.10; H. 6.01 Found: C, 76.29: H, 6.29.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=O)(C)(C)C.Br[C:19]1[C:20]([C:30]#[N:31])=[N:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO.ClCCl.O>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]2[C:20](=[C:30]([NH2:31])[N:8]=[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]3=2)[N:21]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Reactant: CCCCOc1ccc(Br)c(C#N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCCCOc1ccc2c(n1)c(N)nc1ccccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and 3-bromo-6-butoxypicolinonitrile (from step 1) (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% ethyl acetate in methanol to give 3-butoxybenzo[f][1,7]naphthyridin-5-amine as a white solid. 1H NMR (acetone d-6): δ 8.91 (d, 1H), 8.34 (d, 1H), 7.61 (d, 1H), 7.48-7.52 (dd, 1H), 7.27-7.33 (m, 2H), 6.51 (br, 2H), 6.55 (t, 2H), 1.81-1.88 (m, 2H), 1.50-1.59 (m, 2H), 1.00 (t, 3H). LRMS [M+H]=268.1
Reaction SMILES: CS(O)(=O)=O.CO[CH:8]([O:20]C)[CH2:9][NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+].CS(OC)(=O)=O.Cl>O1CCCC1.O>[I:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]2[O:20][CH:8]=[CH:9][N:10]=2)=[CH:17][CH:16]=1
Reactant: COC(CNC(=O)c1ccc(I)cc1)OC
Agent: COS(C)(=O)=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Ic1ccc(-c2ncco2)cc1
Temperature: 140 °C

Procedure:
Under an inert atmosphere, methanesulfonic acid (141 g, 1.46 mol) was added to a mixture of amide acetal (25 g, 74.6 mmol) and phosphorus pentoxide (25 g, 176 mmol). The reaction mixture was heated at 140° C. for about 12 hours. The reaction mixture was cooled to 0° C. and 150 mL of water was added while maintaining the reaction temperature below 40° C. The pH of the reaction mixture was adjusted to 12.5-13 with 50% sodium hydroxide and the reaction mixture was heated at ca. 45° C. to hydrolyze the carcinogenic byproduct methyl methanesulfonate. The reaction mixture was cooled to ambient temperature and 100 mL of tetrahydrofuran was added. The pH was adjusted to 5 with concentrated hydrochloric acid and the layers were separated. The spent aqueous phase was extracted twice with 100 mL of acetone. The rich organic extracts were combined and 200 mL of water was added to effect crystallization. The crystal slurry was filtered, washed and dried in vacuo at <50° C., to give 17 g (84 M %, HPLC area % >99) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CO[CH:16]1[CH2:20][CH2:19][CH:18](OC)O1>C(O)(=O)C>[N+:11]([C:8]1[CH:9]=[CH:10][C:2]([N:1]2[CH:16]=[CH:20][CH:19]=[CH:18]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])([O-:13])=[O:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: O=C(O)c1cc([N+](=O)[O-])ccc1-n1cccc1
Yield: 73 %

Procedure:
A mixture of 2-amino-5-nitrobenzoic acid (475 mg), 2,5-dimethoxytetrahydrofuran (345 mg) and acetic acid (10 ml) was heated under reflux for 3 hours and then concentrated at reduced pressure. Brine was added to the resulting residue and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and then concentrated at reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:1) to give the titled compound (yield, 73%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][C:10]2[C:24]([CH:25]3[CH2:29][CH2:28][CH2:27][NH:26]3)=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(OC([NH:39][CH2:40][C:41]([OH:43])=O)=O)(C)(C)C>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:24]([CH:25]3[CH2:29][CH2:28][CH2:27][N:26]3[C:41](=[O:43])[CH2:40][NH:39][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:30][CH:31]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Product: CS(=O)(=O)NCC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1

Procedure:
The entitled compound was obtained in the same method as in Example 171 and 178 or in accordance with the method or by combining it with an ordinary method but using 5-(4-methanesulfonyl-phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole obtained in Example 162 (step 7) and N-t-butoxycarbonyl-glycine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)([CH2:13][CH2:14][O:15][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:9]1)=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)N2CC[C@](CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Product: COc1cc(C(=O)N2CC[C@](CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 2.5.2 using (S)-(+)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (1.351 mmol) and methanesulfonyl chloride (0.14 mL, 1.81 mmol) to give the title compound: Rf=0.27 (silica gel, ethyl acetate).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]([NH2:12])=[O:11])=[N:6][C:5]=12.CO[C:15](OC)([N:17]([CH3:19])[CH3:18])[CH3:16]>>[CH3:18][N:17]([C:15](=[N:12][C:10]([C:7]1[CH:8]=[CH:9][N:4]2[CH:3]=[CH:2][N:1]=[C:5]2[N:6]=1)=[O:11])[CH3:16])[CH3:19]
Reactant: NC(=O)c1ccn2ccnc2n1
Reactant: COC(C)(OC)N(C)C
Product: CC(=NC(=O)c1ccn2ccnc2n1)N(C)C
Temperature: 25 °C

Procedure:
A mixture of imidazo[1,2-α]pyrimidine-7-carboxylic acid amide (310 mg) and N,N-dimethylacetamide dimethylacetal (270 mg) was heated at reflux for 16 h then cooled to ambient temperature. The reaction was then partitioned between dichloromethane and water. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to give imidazo[1,2-α]pyrimidine-7-carboxylic acid [1-(N,N-dimethylamino)ethylidene]amide as a brown oil. This oil was dissolved in 70% aqueous acetic acid (120 ml) and 1,4-dioxane (60 ml). A solution of hydroxylamine in water (40 wt. %, 0.15 ml) was then added and the mixture heated at 100° C. for 2 h then cooled to ambient temperature. This reaction mixture was dissolved in 50% methanol in dichloromethane and pre-adsorbed onto silica. Purification on silica gel eluting with dichloromethane (+1% conc. ammonia) on a gradient of methanol (2-5%) gave 7-(3-methyl-[1,2,4]oxadiazol-5-yl)imidazo[1,2-α]pyrimidine as a yellow solid (110 mg, 29% over 2 steps): δH (360 MHz, DMSO) 2.43 (3H, s), 7.76 (1H, d, J 7), 8.02 (1H, d, J 1), 8.19 (1H, d, J 1), 9.22 (1H, d, J 7).
Reaction SMILES: S(Cl)(Cl)=O.[I:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([OH:11])=O.C(N(CC)CC)C.[CH2:27]([N:29]1[C:33]([OH:34])=[CH:32][CH:31]=[N:30]1)[CH3:28].CC(C)(O)C#N.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(#N)C.ClCCCl>[CH2:27]([N:29]1[C:33]([OH:34])=[C:32]([C:9](=[O:11])[C:8]2[CH:12]=[CH:13][C:14]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:6]([I:5])[C:7]=2[CH3:19])[CH:31]=[N:30]1)[CH3:28]
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1I
Reactant: CCn1nccc1O
Agent: CC(C)(O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(I)c2C)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (20 mL) was added to a mixture of 62.1 g (182 mmol) of 3-iodo-2-methyl-4-methylsulfonylbenzoic acid and 300 mL of 1,2-dichloroethane and the mixture was heated to reflux with stirring for 3 hours, absorbing the hydrogen chloride gas that evolved in an aqueous sodium hydroxide trap. The resulting solution was concentrated by evaporation under reduced pressure, diluted with 200 mL of toluene and reconcentrated by evaporation under reduced pressure. The resulting residue was dissolved in 100 mL of dichloromethane to obtain a first solution. A second solution was prepared by dissolving 22.3 g (270 mmol) of triethylamine and 24.7 g (270 mmol) of 1-ethyl-5-hydroxypyrazole in 200 mL of dichloromethane. This solution was cooled in an ice bath and the first solution was added to it dropwise with stirring and cooling. The resulting mixture was allowed to warm to ambient temperature and was then washed with cold 0.5N aqueous hydrochloric acid and then cold 5 percent aqueous potassium carbonate. It was then dried over magnesium sulfate and concentrated by evaporation under reduced pressure to obtain 84.2 g of a nearly colorless solid. This solid was slurried in 400 mL of dry acetonitrile and 1 mL (11 mmol) of acetone cyanohydrin and 37.7 g (270 mmol) of solid potassium carbonate were added. The mixture was allowed to stir overnight and was then concentrated by evaporation under reduced pressure. The residue was dissolved in water and the solution was extracted with ether and then acidified with 3N aqueous hydrochloric acid. The resulting mixture was extracted three times with dichloromethane and the combined extracts were dried over magnesium sulfate and concentrated by evaporation under reduced pressure. The gummy residue was crystallized by adding ethanol, heating to reflux, and allowing the solution to cool to obtain 63.3 g (68 percent of theory) of the title compound as yellow crystals. The compound melts at 149-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([NH2:10])=[CH:5][CH:4]=1.[C:11](Cl)(Cl)=[S:12]>O1CCCC1.C(=O)([O-])O.[Na+]>[N:10]([C:6]1[C:7]([CH3:9])=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[C:11]=[S:12]
Reactant: S=C(Cl)Cl
Reactant: COc1ccc(N)c(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(N=C=S)c(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A mixture of 6-methoxy-2-methylpyridin-3-amine (10.0 g, 0.0724 mol) in tetrahydrofuran (50 mL) and aqueous saturated sodium hydrogen carbonate (50 mL) was added thiophosgene (6.62 mL, 0.0868 mol) at 0° C. The reaction mixture was stirred at room temperature for 1 hr. The mixture was extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. To the residue was added n-hexane and the precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was washed with cold-n-hexane to give the title compound as a pale yellow solid (5.35 g, 0.0297 mol, 41%).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([CH2:21][CH2:22][CH3:23])=[C:18](O)[N:19]=2)=[N:6]1.P(Cl)(Cl)(Cl)=O.[NH3:33]>C(#N)C>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([CH2:21][CH2:22][CH3:23])=[C:18]([NH2:33])[N:19]=2)=[N:6]1
Reactant: N
Reactant: CCCc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCCc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.730 g (4.748 mmol) of 3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-propyl-1,2,4-triazin-5-ol were admixed with 23 ml of phosphoryl chloride and stirred overnight at RT. The reaction mixture was diluted with 100 ml of dry acetonitrile and, with ice-cooling, stirred into 330 ml of concentrated aqueous ammonia solution (25% strength). Stirring was carried out for 48 h at RT and for 24 h at 50° C. After cooling, the mixture was concentrated on a rotary evaporator, the residue was stirred with 200 ml of water and filtered off with suction and the filtercake was washed with a little water. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70→95:5). This gave 1.360 g (60% of theory) of the target compound.