Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[C:8]([O:18]C3CCCCO3)=[CH:9][C:10]([F:17])=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH2:4][CH2:3]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[C:8]([OH:18])=[CH:9][C:10]([F:17])=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1cc(C2=CCCC2(C)C)c(OC2CCCCO2)cc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC(=O)c1cc(C2=CCCC2(C)C)c(O)cc1F
Temperature: 50 °C
Reaction time: 19 h
Yield: 81 %

Procedure:
To a stirred mixture of T31.4 (5.65 g, 16.2 mmol) in MeOH (60 mL) was added PPTS (0.42 g, 1.69 mmol). The mixture was heated to 50° C. and monitored with TLC and LCMS. After 19 hours, the organic solvent was removed under reduced pressure, and the residue was then purified on silica gel (0-15% EtOAc in hexanes) to yield T31.5 as a white solid (3.47 g, 81% yield). 1H NMR (500 MHz, CDCl3) δ ppm 7.69 (1H, d, J=8.3 Hz), 6.71 (1H, d, J=12.0 Hz), 5.93 (1H, d, J=1.7 Hz), 5.80 (1H, t, J=2.4 Hz), 3.90 (3H, s), 2.54 (2H, m), 1.93 (2H, t, J=7.1 Hz), 1.11 (6H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH:9]1[CH2:11][O:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][NH2:14].C1COCC1>C(O)C>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH:9]([OH:10])[CH2:11][NH:14][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)NCC1CO1
Solvent: CCO
Solvent: C1CCOC1
Product: CNCC(O)CNC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 5 h

Procedure:
A solution of Oxiranylmethyl-carbamic acid tert-butyl ester (0.64 g, 3.7 mmol) in Ethanol (6 mL) was treated at room temperature with a 2.0M solution of methylamine in THF (5 mL, 10 mmol). The reaction mixture was stirred for 5 hours at 40° C. The solvent was evaporated in vacuo to yield a gum which was used directly into the next step (0.75 g, 98%)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[S:20].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH3:4][C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:24]2[NH:18][C:19](=[S:20])[NH:21][C:22]2=[O:23])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:2])[CH3:3]
Reactant: O=C1CNC(=S)N1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C=C2NC(=S)NC2=O)cc(C(C)(C)C)c1O
Reaction time: 24 h
Yield: 57.8 %

Procedure:
A mixture of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (30.0 g, 128 mmols), 2-thiohydantoin (14.8 g, 128 mmols), and sodium acetate (36 g) in acetic acid (200 ml) is stirred under nitrogen and heated to reflux. After 24 hours the mixture is allowed to cool, and is stirred into water (2 L). After an hour the product is filtered off, washed three times with water, and dried. Recrystallization from acetonitrile gave the 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2-thioxo-4-imidazolidinone (24.6 g), mp 278°-279° C. (dec).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[F:20][C:19]1[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:15][CH:16]=[C:17]([F:21])[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(F)cc2F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1cnc(N2CCNCC2)c(F)c1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A mixture of 4-(3,5-difluoro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester from step (b) above (140 mg, 0.47 mmol) and 4 M solution of HCl in dioxane (1 mL, Aldrich) was stirred at room temperature for 30 h. The solvent was evaporated in vacuo and the residue was dissolved in EtOAc (30 mL). The solution was washed successively with 1 N NaOH (20 mL) and brine (20 mL), dried over MgSO4, filtered, and the solvent was removed in vacuo. The residue was purified by silica gel chromatography, eluting with 10% MeOH in CH2Cl2 to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 200 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1.[CH2:26]([OH:29])[CH:27]=[CH2:28]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:29][CH2:26][CH:27]=[CH2:28])=[C:3]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Reactant: C=CCO
Product: C=CCOc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 44a), from 2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.6 mmol) and allyl alcohol (4 ml) the subtitle compound was obtained (216 mg, 97%). 1H NMR (DMSO) δ 8.83(d, 1H), 8.38(dd, 1H), 8.06(d, 1H), 7.82(d, 1H), 7.69(m, 3H), 7.44(t, 3H), 7.33(t, 1H), 6.08(m, 1H), 5.60(dd, 1H), 5.30(dd, 1H), 4.90(m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[Cl-].[C:19]([C:23]1[CH:32]=[CH:31][C:26]([CH:27]=[N+:28]([CH3:30])[CH3:29])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(C1C=CC(C=O)=CC=1)(C)(C)C.CNC>>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([CH:27]([N:28]([CH3:30])[CH3:29])[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:31][CH:32]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CCn1c(-c2ccccc2)cc2ccccc21
Reactant: C[N+](C)=Cc1ccc(C(C)(C)C)cc1
Agent: CC(C)(C)c1ccc(C=O)cc1
Agent: CNC
Agent: [Cl-]
Product: CCn1c(-c2ccccc2)c(C(c2ccc(C(C)(C)C)cc2)N(C)C)c2ccccc21

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-ethyl-2-phenylindole and (4-tert-butyl-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 4-tert-butyl-benzaldehyde and dimethylamine.
Reaction SMILES: [CH2:1]([CH:10]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)[N:11]1[CH:14]([CH2:15][C:16]([O:18]CC2C=CC(OC)=CC=2)=[O:17])[CH:13]([CH:28]([O:30][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[O:32])[CH3:29])[C:12]1=[O:44])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.COC1C=CC=C(OC)C=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:45]([CH:10]([CH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1)[N:11]1[CH:14]([CH2:15][C:16]([OH:18])=[O:17])[CH:13]([CH:28]([O:30][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[O:32])[CH3:29])[C:12]1=[O:44])[C:46]1[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=1
Reactant: COc1ccc(COC(=O)CC2C(C(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)N2C(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)cc1
Agent: COc1cccc(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)C(C(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C2CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
2.2 g of 1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-p-methoxybenzyloxycarbonylmethyl-2-azetidinone was dissolved in 20 ml of dried methylene chloride, and 0.88 g of m-dimethoxybenzene and 2.5 ml of trifluoroacetic acid were added to the solution, followed by stirring at room temperature for 4 hours. The solvent was removed by distillation, and the resulting oily residue was subjected to silica gel chromatography to obtain 1.75 g of 1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-carboxymethyl-2-azetidinone.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:7][C:8]1[S:12][N:11]=[C:10]([C:13](=[N:17][O:18][CH:19]2[CH2:23][CH2:22][CH:21]=[CH:20]2)[C:14]([OH:16])=O)[N:9]=1.[NH2:24][CH:25]1[C:57](=[O:58])[N:27]2[C:28]([C:41]([O:43][CH:44]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])=[C:29]([S:32]/[CH:33]=[CH:34]\[C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[CH2:30][S:31][C@H:26]12.C[Si](NC(=O)N[Si](C)(C)C)(C)C>C(Cl)Cl>[NH2:7][C:8]1[S:12][N:11]=[C:10]([C:13](=[N:17][O:18][CH:19]2[CH2:23][CH2:22][CH:21]=[CH:20]2)[C:14]([NH:24][CH:25]2[C:57](=[O:58])[N:27]3[C:28]([C:41]([O:43][CH:44]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[O:42])=[C:29]([S:32]/[CH:33]=[CH:34]\[C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)[CH2:30][S:31][C@H:26]23)=[O:16])[N:9]=1
Reactant: Nc1nc(C(=NOC2C=CCC2)C(=O)O)ns1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S/C=C\c3cccnc3)CS[C@H]12
Agent: C[Si](C)(C)NC(=O)N[Si](C)(C)C
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: Nc1nc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(S/C=C\c4cccnc4)CS[C@H]23)ns1
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
To a solution of phosphorus pentachloride (455 mg) in methylene chloride (15 ml) was added 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-cyclopenten-1-yl)oxyiminoacetic acid (syn isomer) (557 mg) at -20° C. The mixture was stirred at -20~-10° C. for 30 minutes. The resultant mixture was added to a solution of benzhydryl 7-amino-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (1 g) and bis(trimethylsilyl)urea (2 g) in methylene chloride (20 ml) at -20° C. The mixture was stirred at -20~-10° C. for 30 minutes. The mixture was concentrated in vacuo and the residue was dissolved in a mixture of water (100 ml), sodium bicarbonate (920 mg), ethyl acetate and tetrahydrofuran. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate, concentrated in vacuo, and the residue was triturated with diethyl ether to give benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-cyclopenten-1-yl)oxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (syn isomer) (1.12 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](=[O:32])[CH3:31])=[N:28][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.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:30]([C:27]1[N:28]=[CH:29][C:24]([NH:23][C:2]2[N:7]=[C:6]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]3([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]3)[C:5]([Cl:22])=[CH:4][N:3]=2)=[CH:25][CH:26]=1)(=[O:32])[CH3:31]
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: CC(=O)c1ccc(N)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(=O)c1ccc(Nc2ncc(Cl)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cn1
Temperature: 120 °C
Yield: 70 %

Procedure:
A solution of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.200 g, 0.595 mmol) in 1,4-dioxane (2.0 mL) containing 1-(5-aminopyridin-2-yl)ethanone (0.121 g, 0.892 mmol), Cs2CO3 (0.581 g, 1.78 mmol), Xantphos (0.014 g, 0.024 mmol) and palladium (II) acetate (2.67 mg, 0.012 mmol) was heated under microwave irradiation for 30 minutes at 120° C. The reaction mixture was adsorbed onto silica gel and purified by silica column chromatography (Combiflash Rf, 4 g SiO2 Cartridge, 0-10% MeOH in DCM) to give title compound 32 as a light cream solid (0.183 g, 70%). LCMS-B: rt 6.98 min; m/z 437 [M+H]+.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].C(Cl)Cl.[CH:8]([CH:10]1[CH2:14][S:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]1[C:21]([O:23][CH3:24])=[O:22])=[O:9].[Cl-].[NH4+]>CO>[OH:9][CH:8]([CH:10]1[CH2:14][S:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]1[C:21]([O:23][CH3:24])=[O:22])[CH:1]=[CH2:2]
Reactant: COC(=O)N1C(C=O)CSC1c1ccccc1
Reactant: C=C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: C=CC(O)C1CSC(c2ccccc2)N1C(=O)OC
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a mixture of 310 ml. (0.440 mole) of vinylmagnesium chloride (from Ventron Corp., 1.42 molar in tetrahydrofuran) and 250 ml. of methylene chloride, which had been previously prepared and kept at -74° C., a solution of 14.2 g. (0.0565 mol) of 4-formyl-3-carbomethoxy-2-phenylthiazolidine dissolved in 50 ml. of methylene chloride was added over a period of 7-10 minutes, while the temperature of the reaction was kept at -60° to -70° C. After addition, the reaction mixture was stirred for 30 minutes at the same temperature while 30 ml. of methanol were slowly added, followed by addition of 150 ml. of saturated ammonium chloride. When the addition was finished, the mixture was allowed to reach room temperature and extracted with 3 × 300 ml. of methylene chloride. The combined organic phases were washed with 2 × 200 ml. of water, dried with sodium sulfate, and evaporated to give 13.7 g. (87% yield) of crude 4-(1-hydroxyprop-2-en-1-yl)-3-carbomethoxy-2-phenylthiazolidine which was obtained as thick oil. This contains a small amount of starting material which, for future separation purposes, is convenient to convert into its corresponding alcohol. To this end, the crude product, dissolved in 100 ml. of tetrahydrofuran was slowly added to a solution of 0.9 g. (0.0503 mol) of sodium borohydride in 75 ml. of water and 75 ml. of tetrahydrofuran. After addition, the resulting yellow emulsion was stirred for 2 hours at room temperature. 55 ml. of 1N hydrochloric acid were then slowly added, the tetrahydrofuran removed in vacuo and the residue extracted with 3 × 100 ml. of ethyl acetate. The combined organic phases were washed with 100 ml. of 5% sodium bicarbonate solution and finally with 2 × 100 ml. of water. Drying with magnesium sulfate and evaporating the solvent gave 13.0 g. of the desired product, which can be used as such for the further transformations or it can be further purified by chromatography on silica gel, using benzene/ethyl acetate (1:1) as eluent. 4.1 g. (corresponding to a yield of 26% from a starting material) of very pure product was obtained as pale yellow thick oil.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.CO.[NH2:19][C:20]1[N:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CS(C)=O.ClCCl>[C:11]1([N:10]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[N:1]=[C:22]2[C:21]2[C:20]([NH2:19])=[N:27][CH:26]=[CH:25][CH:24]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1ccccc1
Reactant: Nc1ncccc1C=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CS(C)=O
Product: Nc1ncccc1-c1nc2cccnc2n1-c1ccccc1
Temperature: 100 °C

Procedure:
3-Nitro-N-phenylpyridin-2-amine (structure 3 as shown in Scheme 1) was dissolved in dimethylsulfoxide (8 mL/mmol) and methanol (1.5 mL/mmol) in a round bottom flask. 2-aminonicotinaldehyde 4 (1.1 eq.) and Na2S2O4 (85%, 2.5 eq.) were added. The reaction mixture was heated at 100° C. for 15 to 36 hours. After cooling to room temperature the reaction mixture was diluted with dichloromethane (20 mL/mmol) and washed with water and brine. The organic phase was separated and dried over Na2SO4. After filtration the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane/methanol; 0-20% methanol over 60 min) to give a yellow to brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])([CH3:10])[CH3:9])=[N:6][CH:7]=1.C([Li])CCC.C(O[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1)(C)C>C1COCC1>[Si:12]([O:11][C:8]([C:5]1[CH:4]=[CH:3][C:2]([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)=[CH:7][N:6]=1)([CH3:10])[CH3:9])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O[Si](C)(C)C(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of 5-bromo-2-(1-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)pyridine (1.63 g, 4.93 mmol) in THF (30 mL) was cooled to −78° C. followed by the addition of n-butyllithium (2.5 M in hexanes, 2.17 mL, 5.43 mmol). After 5 min at −78° C., 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.31 mL, 6.41 mmol) in THF (5.0 mL) was added dropwise, and the reaction was maintained at −78° C. for 10 min. The reaction was allowed to warm to room temperature, quenched with saturated NH4Cl, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography of the crude residue (0-50% EtOAc/hexanes) afforded the title compound as a colorless solid.
Reaction SMILES: Br[C:2]1[C:3]([F:20])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1([CH3:16])[CH2:15][CH2:14]1)[N:8]([CH2:17][CH3:18])[C:7]2=[O:19].[CH3:21][C@@H:22]1[C:26]2[NH:27][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:29][C:25]=2[C:24](=[O:39])[NH:23]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[CH2:17]([N:8]1[C:7](=[O:19])[C:6]2[C:11](=[C:2]([C:28]3[NH:27][C:26]4[C@@H:22]([CH3:21])[NH:23][C:24](=[O:39])[C:25]=4[CH:29]=3)[C:3]([F:20])=[CH:4][CH:5]=2)[N:10]=[C:9]1[NH:12][C:13]1([CH3:16])[CH2:15][CH2:14]1)[CH3:18]
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: CCn1c(NC2(C)CC2)nc2c(Br)c(F)ccc2c1=O
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Solvent: O
Solvent: C1COCCO1
Product: CCn1c(NC2(C)CC2)nc2c(-c3cc4c([nH]3)[C@@H](C)NC4=O)c(F)ccc2c1=O
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 70.8 %

Procedure:
A solution of 8-bromo-3-ethyl-7-fluoro-2-(1-methylcyclopropyl)amino)quinazolin-4(3H)-one (513a, 181.1 mg, 0.53 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (Example 705; 174 mg, 0.665 mmol), potassium phosphate (339 mg, 1.597 mmol), and chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (XPhos precatalyst, 2nd generation; Aldrich; 20.97 mg, 0.027 mmol) in a mixture of 1,4-dioxane (2.2 mL) and water (0.55 mL) was stirred under argon at 45° C. for 1.5 h. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 50-100% EtOAc/hexanes, then 0-10% MeOH/DCM). The isolated product was suspended in MeOH (2 mL), collected by vacuum filtration, washed with ethyl ether (5 mL), and dried in vacuo to provide (R)-3-ethyl-7-fluoro-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one (148.2 mg, 0.375 mmol, 70% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 13.32 (1H, s), 7.90 (1H, s), 7.86 (1H, m, J=8.8, 6.3 Hz), 7.74 (1H, s), 7.11 (1H, dd, J=11.9, 8.8 Hz), 6.79 (1H, d, J=3.7 Hz), 4.66 (1H, q, J=6.3 Hz), 4.06 (2H, q, J=6.5 Hz), 1.54 (3H, s), 1.37 (3H, d, J=6.5 Hz), 1.15 (3H, t, J=6.9 Hz), 0.95-1.05 (2H, m), 0.86 (2H, d, J=2.0 Hz). 19F NMR (376 MHz, DMSO-d6) δ ppm −102.43 (1F, s). m/z (ESI, +ve) 395.9 (M+H)+.
Reaction SMILES: Cl[CH:2](P(=O)(OCC)OCC)[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[F:18][C:19]1[C:20]([CH:33]=O)=[CH:21][C:22]2[C:23]([CH3:32])([CH3:31])[CH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[C:27]=2[CH:28]=1>>[F:18][C:19]1[C:20]([C:33]#[C:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:9])=[CH:7][CH:8]=2)=[CH:21][C:22]2[C:23]([CH3:32])([CH3:31])[CH2:24][CH2:25][C:26]([CH3:29])([CH3:30])[C:27]=2[CH:28]=1
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc(C)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)c(F)cc21
Product: Cc1ccc(C#Cc2cc3c(cc2F)C(C)(C)CCC3(C)C)cc1

Procedure:
Using a process similar to that described in Example 13, 27.7 g (0.1 mole) of diethyl 1-chloro-1-(4-tolyl)-methylphosphonate, 23.4 g (0.1 mole) of 3-fluoro-2-formyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene and 22.5 g (0.2 mole) of potassium tert.-butylate were reacted for 1 hour to give the title compound. Recrystallization from isopropanol gave 16.4 g (51%) of product of melting point 60°-61° C.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Br)[N:12]=1>O1CCCC1.O>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][S:3][CH2:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([Br:10])[N:12]=1)[CH3:9]
Reactant: CCOC(=O)CS
Reactant: BrCc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CSCc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.48 g, 11.96 mmol) was suspended in tetrahydrofuran (52.4 mL) and cooled to 0° C. Ethyl mercaptoacetate (0.48 mg, 3.99 mmol) was added and the solution was stirred for 30 minutes at 0° C. 2-Bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (1.0 g, 3.99 mmol) was added and the solution was allowed to stir until completion. The reaction mixture was then diluted with water and extracted with ethyl acetate (2×). The combined organics were dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography to yield the title compound.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.Cl[S:16]([OH:19])(=[O:18])=[O:17]>>[C:1]1([S:16]([OH:19])(=[O:18])=[O:17])[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(O)c1cccc2ncc3ccccc3c12
Temperature: 10 °C
Yield: 49.7 %

Procedure:
Add phenanthridine (5 g, 28 mmol) in portions to chlorosulfonic acid (5.6 mL, 84 mmol) cooled to 10° C. over 20 minutes Heat the reaction mixture to reflux for 20 hours. Cool the now black reaction mixture to 0° C. and add cautiously to crushed ice (500 mL). Filter the solid and dry in vacuo to give the sulfonic acid (3.61 g) as an ivory colored solid consisting of a partially resolved 7:3 mixture of regioisomers. Rf=0.35 (major), 0.19 (minor (15:85 methanol:methylene chloride, 0.2% acetic acid buffer).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@:5]1([OH:13])[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[N:26][C:25]([N:31]=[C:32]=S)=[CH:24]2.C(N=C=NC(C)C)(C)C>CN(C)C=O>[Br:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[N:26][C:25]([NH:31][C:32]1[O:13][C@:5]3([CH2:4][N:3]=1)[CH:10]1[CH2:9][CH2:8][N:7]([CH2:12][CH2:11]1)[CH2:6]3)=[CH:24]2
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: S=C=Nc1cc2cc(Br)ccc2cn1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Brc1ccc2cnc(NC3=NC[C@@]4(CN5CCC4CC5)O3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.086 g, 0.377 mmol) in N,N-dimethylformamide (15 mL) was added Cs2CO3 (0.307 g, 0.943 mmol) and 6-bromo-3-isothiocyanatoisoquinoline (0.1 g, 0.377 mmol). The suspension was stirred at room temperature for 30 minutes. N,N′-Diisopropylcarbodiimide (0.176 mL, 1. 132 mmol) was then added and the mixture was stirred for a further 18 hours. The mixture was concentrated and purified by silica gel chromatography (5-25% [9.5:0.5 methanol:ammonium hydroxide]-ethyl acetate) to afford (R)—N-(6-bromoisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.054 g, 0.135 mmol, 36% yield) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 9.04 (1H, s), 7.80-8.05 (2H, m), 7.55 (1H, dd, J=8.81, 1.76 Hz), 7.37 (1H, br. s.), 4.10 (1H, d, J=10.58 Hz), 3.87 (1H, d, J=10.83 Hz), 3.68-3.77 (1H, m), 3.56-3.67 (1H, m), 3.29-3.49 (4H, m), 2.45 (1H, br. s.), 2.28-2.41 (1H, m), 1.86-2.15 (3H, m). LCMS:R.T.=1.76; [M+]+=387.21.