Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3](=[NH:21])[N:4]([CH3:20])[C:5](=[O:19])[N:6](S(C2C=CC(OC)=CC=2)(=O)=O)[CH:7]=1.FC(F)(F)C(O)=O.CSC>>[F:1][C:2]1[C:3](=[NH:21])[N:4]([CH3:20])[C:5](=[O:19])[NH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)n2cc(F)c(=N)n(C)c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Product: Cn1c(=O)[nH]cc(F)c1=N
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A 25-mL screw capped vial was charged with 5-fluoro-4-imino-1-(4-methoxyphenylsulfonyl)-3-methyl-3,4-dihydropyrimidin-2(1H)-one (80.4 mg, 0.257 mmol), trifluoroacetic acid (TFA; 16.0 mL, 215 mmol), and dimethylsulfide (94.0 μL, 1.28 mmol). The resulting solution was allowed to stir at room temperature for 5.5 h and was then concentrated to dryness by rotary evaporation at 30° C. The crude material was then dissolved in a minimal amount of methanol (CH3OH; −2 mL) and loaded onto a 5-g normal phase solid load Isco cartridge, rinsing the source vial with CH3OH (3×1 mL). The solid cartridge was then dried under vacuum at room temperature. After drying, the product was purified by chromatography (4 g SiO2 column; 0 to 30% CH3OH in dichloromethane (CH2Cl2) gradient). The material thus obtained was determined to be the 4-methoxysulfonic acid salt of the desired product. The free base was obtained by dissolving the material in CH3OH (4 mL), adding MP-carbonate resin (345 mg, 3.03 mmol/g, 4.0 equiv), and allowing to stir at room temperature. After stirring for 20 h, the solid resin was filtered off and rinsed with CH3OH (3×1 mL). After concentration under high vacuum, the title compound was obtained as a white solid (35.2 mg, 96%): mp 181-184° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J=4.1 Hz, 1H), 3.22 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 152.19 (s), 151.86 (d, J=27.3 Hz), 136.73 (d, J=221.0 Hz), 129.45 (d, J=26.0 Hz), 28.91 (s).
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.C1C(=O)NC(=O)N([C@@H:19]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[C@@H:20]2[OH:27])C=1>P([O-])([O-])([O-])=O.O>[CH:2]1[N:3]=[C:4]2[N:5]([C@@H:19]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[C@@H:20]3[OH:27])[CH:6]=[N:7][C:8]2=[C:9]([NH2:10])[N:1]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 60 °C
Yield: 51.3 %

Procedure:
50 kg of wet cell paste obtained by fermenting E. aerogenes were resuspended in approximately 200 liters of 30 mM phosphate buffer at pH 7 and mixed with 800 liters of phosphate buffer in which had been dissolved at elevated temperature 5.4 kg of adenine (final concentration 40 mM) and 8.9 kg of Ara-U (final concentration 40 mM). The mixture was maintained at 60° C., with agitation, for 20 hours, diluted to approximately 3000 liters with hot H2O and subjected to diafiltration on a membrane, collecting approximately 5000 liters of ultrafiltrate. The bioconversion yield determined by RP-HPLC was approximately 55%. The residue containing the cell paste is used for a subsequent reaction. The ultrafiltrate was concentrated to approximately 1000 liters and cooled to collect the precipitate constituted by Ara-A contaminated with non-reacted adenine (approximately 30 g of adenine per 100 g of Ara-A). 5 kg of Ara-A (total yield approximately 46%) with a degree of purity higher than 99.5% were finally obtained after crystallisation with H2O.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11][CH2:12][C:13]2[N:14](CC)[N:15]=[CH:16][N:17]=2)=[N:9][N:8]2[C:20]([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=3[F:31])=[N:21][N:22]=[C:7]2[CH:6]=1)([CH3:4])[CH3:3].[CH3:32]N1C=NC(CO)=N1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:3][C:2]([C:5]1[C:10]([O:11][CH2:12][C:13]2[N:17]=[CH:16][N:15]([CH3:32])[N:14]=2)=[N:9][N:8]2[C:20]([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=3[F:31])=[N:21][N:22]=[C:7]2[CH:6]=1)([CH3:1])[CH3:4]
Reactant: CCn1ncnc1COc1nn2c(-c3c(F)ccc(F)c3F)nnc2cc1C(C)(C)C
Reactant: Cn1cnc(CO)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cn1cnc(COc2nn3c(-c4c(F)ccc(F)c4F)nnc3cc2C(C)(C)C)n1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To the product of Example 4 Step a) (0.559 g) and (1-methyl-1H-1,2,4-triazol-3-yl)methanol (prepared as described in EP-A-421210) (0.20 g) in dry dimethylsulfoxide (2 ml) was added caesium carbonate (0.67 g), and the mixture stirred at 60° C. under an atmosphere of dry nitrogen for 48 hours. On cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic phase was separated, washed with water, evaporated at reduced pressure, and the residue chromatographed on silica gel (eluent 2% methanol-dichloromethane). The product was crystallised from ethyl acetate/diethyl ether, to afford the title compound as a colourless solid. 1H NMR (400 MHz, DMSO-d6) δ1.39 (9H, s), 3.85 (3H, s), 5.30 (2H, s), 7.46 (1H, m), 7.86 (1H, m), 8.14 (1H, s) 8.46 (1H, s); MS (ES+) m/z 418 [MH]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:15])[CH3:14])=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[C:13]([NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:3](=[O:4])[CH2:2][NH:1][C:32]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=1)=[O:33])(=[O:15])[CH3:14]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(=O)Nc1ccccc1N(CC(=O)OC(C)(C)C)C(=O)CN
Product: CC(=O)Nc1ccccc1N(CC(=O)OC(C)(C)C)C(=O)CNC(=O)Nc1cccc(C)c1
Yield: 54.2 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with tert-butyl 2-{2-amino-N-[2-(acetylamino)phenyl]acetamido}acetate (4.7 g) and 3-methylphenyl isocyanate (2 g), and after recrystallisation in ethyl acetate, tert-butyl 2-{N-[2-(acetylamino)phenyl]-2-[3-(3-methylphenyl)ureido]acetamido}acetate (3.6 g), m.p. 185° C., is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[O:7])=[CH:4][CH:3]=1.[CH3:18][N:19]([CH:21](N(C)C)OC(C)(C)C)[CH3:20]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11](=[O:15])[NH:12][C:13]=2[CH:14]=[CH:18][N:19]([CH3:21])[CH3:20])=[O:7])=[CH:16][CH:17]=1
Reactant: Cc1[nH]c(=O)ccc1C(=O)c1ccc(Br)cc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: C1COCCO1
Product: CN(C)C=Cc1[nH]c(=O)ccc1C(=O)c1ccc(Br)cc1

Procedure:
m.p. 265°-268° C. with decomposition, 53.8 g, was prepared following the procedure described in Example B-2 using 44 g of 5-(4-bromobenzoyl)-6-methyl-2(1H)-pyridinone, 300 ml of p-dioxane and 35 ml of bis-(dimethylamino)-t-butoxymethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([O:18][C@H:19]([CH3:23])[C@H:20]([OH:22])[CH3:21])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][CH:4]=1.[C:30]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])[CH:31]=[CH2:32].O>C1COCC1>[C:35]([O:34][C:30](=[O:33])[CH2:31][CH2:32][O:22][C@H:20]([CH3:21])[C@H:19]([O:18][C:16]1[C:17]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[C:10]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:11][C:12]=2[N:13]=[CH:14][N:15]=1)[CH3:23])([CH3:38])([CH3:37])[CH3:36]
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@H](C)[C@@H](C)O)c23)cc1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@H](C)[C@@H](C)OCCC(=O)OC(C)(C)C)c23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Add 157 mg (1.37 mmol) potassium tert.-butylate to a solution of 535 mg (1.37 mmol) (2R,3R)-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}butan-2-ol in 5 ml THF. After stirring for 15 min at RT, add 1.0 ml (878 mg, 6.65 mmol) tert.-butyl acrylate. After three hours, add 10 ml water, and concentrate the reaction mixture by vacuum evaporation. Purify the residue by preparative RP-HPLC (gradient: water/acetonitrile). 346 mg (47% of theor.) of the desired product is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:19][CH2:20][C:21](Cl)=O>C(O)(=O)C>[Cl:19][CH2:20][C:21]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:4](=[O:5])[C:3]2[C:2](=[CH:17][C:16]([F:18])=[CH:15][CH:14]=2)[N:1]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(F)ccc1C(=O)Nc1ccccc1Cl
Solvent: CC(=O)O
Product: O=c1c2ccc(F)cc2nc(CCl)n1-c1ccccc1Cl
Yield: 82 %

Procedure:
Prepared according to Procedure B with 1c (500 mg, 1.89 mmol) and chloroacetyl chloride (0.45 mL, 5.67 mmol) in acetic acid (10 mL). Purified by extraction from aqueous K2CO3, followed by recrystallization from isopropanol to afford 501 mg of a yellow crystalline solid (82%). 1H NMR (CDCl3) δ: 8.32 (dd, J=6.0, 8.9 Hz, 1H); 7.59-7.66 (m, 1H); 7.50-7.55 (m, 3H); 7.44 (dd, J=2.4, 9.4 Hz, 1H); 7.27 (dt, J=2.5, 8.5 Hz, 1H); 4.37 (d, J=12 Hz, 1H), 4.07 (d, J=12 Hz, 1H). MS (ES): m/z 323.0 (M+).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:8]=2[CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[C:17](Cl)(=[O:19])[CH3:18]>O1CCCC1>[C:17]([N:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:8]=1[CH3:14])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: Cc1cc(I)ccc1NC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(I)cc1C)C1CCCC1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
0.5 g (1.7 mmol) of 4-cyclopentylamino-3-methyl-iodobenzene are dissolved in 20 ml tetrahydrofuran and after the addition of 81.3 mg (1.7 mmol) of sodium hydride (50% in oil) stirred for 1 hour at 40 ° C. After cooling to ambient temperature 0.1 ml (1.5 mmol) of acetyl chloride is added and the mixture is stirred overnight at ambient temperature. The solvent is distilled off and the residue distributed in water/ethyl acetate. The combined organic extracts are dried, concentrated by evaporation and chromatographed on silica gel, eluting with dichloromethane/ethanol 0 to 5%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[C:37]([CH:42]=[C:43]([F:46])[C:44]=1F)[C:38]([O:40][CH3:41])=[O:39].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:12][N:11]([C:44]2[C:43]([F:46])=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][C:35]=2[F:34])[CH2:10]1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(F)c(N2CCC(c3ccccc3)C(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)c(F)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
A mixture of 150 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(4-phenylpiperidin-3-yl)methyl]carbamate, 96.2 mg of methyl 3,4,5-trifluorobenzoate, 93.3 mg of potassium carbonate, and 1.0 mL of DMSO was stirred at 110° C. for 1 hour. After cooling to room temperature, to the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 127 mg of methyl 4-[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]-3,5-difluorobenzoate as a colorless foamy substance. ESI+: 615
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][OH:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].ClC(Cl)(Cl)C(=N)O[C:29]([CH3:32])([CH3:31])[CH3:30]>CCOC(C)=O.C1CCCCC1>[CH:7]1[C:6]2[CH:5]([CH2:4][O:3][C:1]([NH:18][CH:19]([CH2:20][OH:21])[C:22]([O:24][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:23])=[O:2])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(N[C@@H](CO)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)C(CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.3 %

Procedure:
To a solution of commercial N-Fmoc-L-serine (1.5 g, 4.58 mmol) in EtOAc (40 ml), a solution of t-butyl 2,2,2-trichloroacetimidate (4.00 g, 18.32 mmol) in cyclohexane (18 ml) was added dropwise. After stirring at room temperature for 24 hrs, the solution was evaporated and the residue was purified by flash chromatography (n-Hexane/EtOAc 70:3), yielding the title compound (1.20 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]([CH3:25])[CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH:18]([CH3:25])[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1CNC(C)c2ccccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1CN(C(=O)c2cc3ncc(Cl)cn3n2)C(C)c2ccccc21

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,4-Dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[CH:8]=[CH:9][CH:10]=1.Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:16]([O:15][C:14]([NH:13][C@H:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[O:4][C:3]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:2]=1[NH:1][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:12])=[O:20])([CH3:19])([CH3:18])[CH3:17]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Oc2cc(Cl)ccc2N)c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCNc1ccc(Cl)cc1Oc1cccc([C@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 66.7 %

Procedure:
A mixture of tert-butyl(1S)-1-[3-(2-amino-5-chlorophenoxy)phenyl]ethylcarbamate (3.2 g, 8.8 mmols), ethyl 4-bromobutyrate (14 g, 70 mmols), potassium carbonate (3.6 g, 26 mmols) and N,N-dimethylformamide (50 ml) was stirred at 80° C. for 48 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 4-[N-[2-[3-[(1S)-1-tert-butoxycarbonylaminoethyl]phenoxy]-4-chlorophenyl]]aminobutyrate (2.8 g, 66%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.[CH2:16](Br)[CH:17]=[CH2:18]>CC(C)=O>[CH2:18]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:8]=1[OH:7])[CH:12]=[O:13])[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCc1cc(C=O)ccc1O
Temperature: 220 °C

Procedure:
Two equivalents of potassium carbonate are added slowly with stirring to a solution of 4-hydroxybenzaldehyde in acetone. A solution of allyl bromide (1.1 equivalent) in acetone is added and the mixture is refluxed for two hours, filtered to remove inorganic salts and volatiles stripped under reduced pressure. The resulting 4-allyloxybenzaldehyde is then heated for six hours at 220° C. to yield the rearrangement product, 3-allyl-4-hydroxybenzaldehyde. One equivalent of 3-allyl-4-hydroxybenzaldehyde is dissolved in acetone and two equivalents of potassium carbonate are added slowly with stirring followed by a solution of 1.1 equivalents of methyl iodide in acetone. This mixture is refluxed for several hours, filtered and stripped to yield 3-allyl-4-methoxybenzaldehyde.
Reaction SMILES: C([N:20]1[C:24]2[CH:25]=[CH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:28][C:23]=2[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:46](Br)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C1COCC1.O>[CH2:46]([N:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27]1[CH:26]=[CH:25][C:24]2[NH:20][CH:21]=[N:22][C:23]=2[CH:28]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc(Nc2ccc3c(c2)ncn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CN(c2ccccc2)c2ccc3[nH]cnc3c2)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
N1-Trityl-N-phenyl-benzimidazol-5-amine (1.13 g; 2.5 mmol; 1 eq.) was dissolved in THF (5 ml), cooled to 0° C. and treated with lithiumbis(trimethylsilyl)amide 1M in THF (3 ml; 3 mmol; 1.2 eq.). Benzylbromide (3 mmol; 1.2 eq.) was added and stirred at room temperature for 24 h. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was dissolved in MeOH (5 ml) and treated with TFA (1 ml). After heating to reflux overnight the mixture was poured into saturated NaHCO3-solution and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography on silica using a CHCl3/MeOH gradient. Yield: 0.046 g (6.2%); MS m/z: 300.1 [M+H]+; 1H-NMR, 500 MHz, 1H-NMR (500 MHz, DMSO d6): δ 5.00 (s, 2H); 6.70-6.73 (m, 1H); 6.78-6.79 (m, 2H); 7.06-7.08 (m, 1H); 7.10-7.13 (m, 2H); 7.18-7.21 (m, 1H); 7.29-7.31 (m, 2H); 7.36-7.37 (m, 3H); 7.54 (d, 1H, 3J=8.5 Hz); 8.30 (s, 1H); 12.32 (br s, 1H); HPLC (METHOD [A]): rt 15.47 min (95.1%)
Reaction SMILES: Cl.C(Cl)Cl.C(OC(=O)[NH:11][CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:22]3[CH:31]=[C:30]4[C:25]([C:26](=[O:39])[C:27]5[C:37](=[O:38])[NH:36][S:35][C:28]=5[N:29]4[CH:32]4[CH2:34][CH2:33]4)=[CH:24][C:23]=3[F:40])[CH:18]=2)[CH2:13]1)(C)(C)C>C(O)(=O)C>[NH2:11][CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([C:22]3[CH:31]=[C:30]4[C:25]([C:26](=[O:39])[C:27]5[C:37](=[O:38])[NH:36][S:35][C:28]=5[N:29]4[CH:32]4[CH2:34][CH2:33]4)=[CH:24][C:23]=3[F:40])[CH:16]=[CH:15][C:14]=2[CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(-c3cc4c(cc3F)c(=O)c3c(=O)[nH]sc3n4C3CC3)ccc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: NC1CCc2cc(-c3cc4c(cc3F)c(=O)c3c(=O)[nH]sc3n4C3CC3)ccc2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In air, a solution of hydrogen chloride in acetic acid (1 M, 1.8 mL) is added at room temperature to a solution of methylene chloride (0.6 mL) containing (rac)-tert-Butyl[6-(9-cyclopropyl-6-fluoro-3,4-dioxo-2,3,4,9-tetrahydro-isothiazolo[5,4-b]quinolin-7-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (11.4 mg, 0.022 mmol). A yellow precipitate begins to appear within minutes of addition of the solution of hydrogen chloride. After stirring the mixture at room temperature for 18 h, additional methylene chloride is added (2 mL). The precipitate is collected by filtration, washed with methylene chloride (4×5 mL), and dried in vacuo to give pure 31 (97% purity by HPLC analysis) as a yellow powder. mp >257-258° C. dec. 1H NMR (DMSO-d6, 60° C.): δ 1.21 (m, 2H, c-Pr CH2), 1.29 (m, 2H, c-Pr CH2), 1.80 (m, 1H, H-3), 2.12 (m, 1H, H-3), 2.83 (dd, J=17.0 Hz, 10.0 Hz, 1H, H-1), 2.90 (m, 2H, H-4), 3.13 (dd, J=17.0 Hz, 6.0 Hz, 1H, H-1), 3.46 (m, 1H, H-2), 3.57 (m, 1H, c-Pr CH), 7.25 (d, J=8.0 Hz, 1H, H-8), 7.37 (s, 1H, H-5), 7.39 (d, J=8.0 Hz, 1H, H-7), 7.93 (d, JH-F=10.5 Hz, 1H, ITQ H-5), 8.01 (d, JH-F=6.5 Hz, 1H, ITQ H-8). 19F{1H} NMR (DMSO-d6, 60° C.): δ −123.3 (s). NMR spectra collected at room temperature contained broad, unresolved signals. LCMS m/z calcd for C23H20FN3O2S ([M]+) 421. Found 422 ([M+H]+). HRMS m/z calcd for C23H20FN3NaO2S ([M+Na]+) 444.1158. Found 444.1152.
Reaction SMILES: [CH3:1][C:2]1([C:6]#[C:7][C:8]2[CH:9]=[C:10]3[C@@:21]4([CH2:25][S:24][C:23]([NH:26]C(=O)OC(C)(C)C)=[N:22]4)[C:20]4[C:15](=[N:16][CH:17]=[C:18]([C:34]5[CH:35]=[N:36][C:37]([CH3:40])=[CH:38][CH:39]=5)[CH:19]=4)[O:14][C:11]3=[CH:12][CH:13]=2)[CH2:5][O:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1([C:6]#[C:7][C:8]2[CH:9]=[C:10]3[C@@:21]4([CH2:25][S:24][C:23]([NH2:26])=[N:22]4)[C:20]4[C:15](=[N:16][CH:17]=[C:18]([C:34]5[CH:35]=[N:36][C:37]([CH3:40])=[CH:38][CH:39]=5)[CH:19]=4)[O:14][C:11]3=[CH:12][CH:13]=2)[CH2:3][O:4][CH2:5]1
Reactant: Cc1ccc(-c2cnc3c(c2)[C@]2(CSC(NC(=O)OC(C)(C)C)=N2)c2cc(C#CC4(C)COC4)ccc2O3)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2cnc3c(c2)[C@]2(CSC(N)=N2)c2cc(C#CC4(C)COC4)ccc2O3)cn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
(S)-Tert-butyl 7-((3-methyloxetan-3-yl)ethynyl)-3-(6-methylpyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate (0.027 g, 0.049 mmol) was taken up in 1.5 mL of DCM and TFA (0.057 mL, 0.735 mmol) was added. The reaction was heated to 50° C. and stirred for 2 h. The reaction was diluted with DCM and washed with saturated sodium bicarbonate solution. The aqueous layer was extracted with DCM, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated to afford (S)-7-((3-methyloxetan-3-yl)ethynyl)-3-(6-methylpyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (0.017 g, 0.037 mmol, 37.6% yield) as a light yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[N:8]([CH3:9])[CH2:7][C:6]2[CH:10]=[CH:11][C:12]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[N:13][C:5]=2[O:4][CH2:3]1.[ClH:27].C(OCC)(=O)C>>[ClH:27].[ClH:27].[ClH:27].[CH3:1][CH:2]1[N:8]([CH3:9])[CH2:7][C:6]2[CH:10]=[CH:11][C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:13][C:5]=2[O:4][CH2:3]1
Reactant: CC1COc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2CN1C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1COc2nc(N3CCNCC3)ccc2CN1C
Yield: 71 %

Procedure:
The compound (0.086 g) obtained in Example 23 in 4N hydrogen chloride/ethyl acetate (3.0 mL) was stirred at room temperature for 2 hr. The precipitate was collected by filtration, and recrystallized from MeOH-ethyl acetate to give the title compound (0.063 g, 71%) as a white powder.
Reaction SMILES: [NH2:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].[CH:17](=O)[CH2:18][CH3:19].C([BH3-])#N.[Na+]>C(O)C>[CH2:17]([NH:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:18][CH3:19]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: CCC=O
Agent: CC[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCCNC(C(=O)OCC)C(=O)OCC
Yield: 115.5 %

Procedure:
Diethyl aminomalonate (21.1 g, 0.1 mol) was dissolved in ethanol and sodium ethoxide in ethanol (50 mL of 1 M) was added. Propionaldehyde (6.6 g, 0.11 mol) and sodium cyanoborohydride (3.6 g, 0.058 mol) were added to the stirred solution. After 30 minutes additional propionaldehyde (6.0 g) and sodium cyanoborohydride (2.6 g) were added to complete the reaction. The solution was evaporated, and the residue was partitioned between ethyl acetate and water. Evaporation of the ethyl acetate gave 25.1 g of diethyl (propylamino)malonate. This was mixed with di t-butyl dicarbonate (34 g, 0.156 mol) and the mixture was heated at 100° C. for 1 hour. The crude product was chromatographed on silica gel using ethyl acetate:hexane as the eluant to give 21.2 g of diethyl (N-(1,1-dimethylethoxycarbonyl)propylamino)malonate as an oil.