Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:13]([C:10]1[CH:11]=[CH:12][C:7]2[O:6][CH2:5][CH2:4][CH:3]=[CH:2][C:8]=2[CH:9]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(O)CCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2c(c1)C=CCCO2

Procedure:
300 ml of toluene are poured over 25.1 g (0.12 mole) of 5-hydroxy-7-nitro-2,3,4,5-tetrahydro-1-benzoxepin and, with the addition of 1.5 g of p-toluenesulfonic acid, the mixture is refluxed with a water trap for 2 hours. The cold reaction solution is washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulfate and filtered, and the solvent is evaporated off in vacuo. The residue is a solid of melting point 94°-95.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[S:5][CH:6]=1.[CH2:16]([Mg]Br)[CH3:17].O1CCCC1.[Cl-].[NH4+]>CCOCC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:12]([Si:9]([O:8][CH2:7][C:4]1[S:5][CH:6]=[C:2]([CH2:16][CH3:17])[CH:3]=1)([CH3:11])[CH3:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)cs1
Reactant: CC[Mg]Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCc1csc(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution of [(4-bromo-2-thienyl)methoxy](t-butyl)dimethylsilane (0.61 g, 2.0 mmol) and [1,3-bis(diphenylphosphino)propane]dichloronickel (54 mg, 0.1 mmol) in ether (5 ml) was added slowly a 1.0 M solution of ethylmagnesium bromide in tetrahydrofuran (3.0 ml, 3.0 mmol) at 0° C. with stirring, and after raising the reaction temperature to room temperature, the resulting mixture was stirred for 1 hour. After stirring, a saturated aqueous solution of ammonium chloride (5 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was poured into water (20 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 5:95) as the eluent to afford the title compound (0.44 g) in a yield of 95% as a pale yellow oily product.
Reaction SMILES: [Br:1]Br.[C:3]1([NH:19][C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)O>>[Br:1][C:26]1[CH:27]=[CH:28][C:20]([NH:19][C:3]2[C:16]3[C:15](=[O:17])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8](=[O:18])[C:7]=3[CH:6]=[CH:5][CH:4]=2)=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23]
Reactant: BrBr
Reactant: O=C(O)c1ccccc1Nc1cccc2c1C(=O)c1ccccc1C2=O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(Br)ccc1Nc1cccc2c1C(=O)c1ccccc1C2=O

Procedure:
which comprises first adding 1-1.5 molar equivalents of bromine to a reaction medium consisting essentially of 2-(1-anthraquinonylamino)-benzoic acid of formula II ##STR14## and 96 to 100% sulfuric acid at a temperature of 0°-25° C. to form a 5-bromo-2-(1-anthraquinonylamino)benzoic acid of the formula I ##STR15## in at least 92% absolute yield and then removing excess bromine and product hydrogen bromide and then raising the temperature to 50°-100° C.
Reaction SMILES: C([O:8][C:9]1[C:13]2([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]2)[N:12]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:11](=[O:25])[C:10]=1[C:26]1[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=1[CH3:34])C1C=CC=CC=1>CO.[Pd]>[CH:22]1([CH2:21][N:12]2[C:13]3([CH2:14][CH2:15][N:16]([O:19][CH3:20])[CH2:17][CH2:18]3)[C:9]([OH:8])=[C:10]([C:26]3[C:27]([CH3:34])=[CH:28][C:29]([CH3:33])=[CH:30][C:31]=3[CH3:32])[C:11]2=[O:25])[CH2:24][CH2:23]1
Reactant: CON1CCC2(CC1)C(OCc1ccccc1)=C(c1c(C)cc(C)cc1C)C(=O)N2CC1CC1
Agent: [Pd]
Solvent: CO
Product: CON1CCC2(CC1)C(O)=C(c1c(C)cc(C)cc1C)C(=O)N2CC1CC1

Procedure:
Debenzylation was conducted using an H-Cube® continuous-flow hydrogenator: 4-benzyloxy-1-cyclopropylmethyl-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (546 mg, 1.34 mmol) was dissolved in methanol (47 ml) and this substrate solution (0.029 M) pumped twice through a 5% Pd/C filled cartridge at a flow-rate of 1 mL/min, a temperature of 35° C. and a pressure of 2-3 bars. The collected product solution was concentrated, and the residue purified by chromatography on silica gel (ethyl acetate/heptane 1:1). Yield: 215 mg of 1-cyclopropylmethyl-4-hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (title compound P2.8) as a white solid, mp 223-225° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:40][S:41]([C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1)(=[O:43])=[O:42].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:47]2[CH:48]=[CH:49][C:44]([S:41]([CH3:40])(=[O:43])=[O:42])=[CH:45][CH:46]=2)=[CH:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COc1cnc2c(c1)cc(C(=CC1CCOCC1)OS(=O)(=O)c1ccc(C)cc1)n2S(=O)(=O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cnc2c(c1)cc(C(=CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Yield: 50.4 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl ester (1.1 g, 1.94 mmol), 4-(methanesulfonyl)phenylboronic acid (775 mg, 3.88 mmol), dichlorobis(triphenylphosphine)palladium (II) (136 mg, 0.194 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 2.5 mL, 5 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The resulting mixture was diluted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (540 mg, 54%) as a light yellow solid: LC/MS m/e calcd for C28H28N2O6S2 [M+H]+ 553.67, observed 553.2.
Reaction SMILES: CC(C)([O-])C.[K+].CO[C:9](=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]([CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>C1(C)C=CC=CC=1>[CH2:33]([O:32][C:30]([CH:29]1[CH2:28][CH2:27][N:16]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]1=[O:35])=[O:31])[CH3:34]
Reactant: CCOC(=O)CCCN(c1ccccc1C(=O)OC)S(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc2C1=O
Temperature: 25 °C
Yield: 64.9 %

Procedure:
To a heated mixture of potassium t-butoxide (371 g, 3.58 mol) in toluene (4 l) at 70° C. was added 2-[(3-Ethoxycarbonyl-propyl)-(toluene-4-sulfonyl)-amino]-benzoic acid methyl ester (750 g, 1.79 mol). After the addition was completed, the mixture was cooled to room temperature then poured into ice water. The extraction with CH2Cl2 was successively done, and organic layer was dried over MgSO4 and concentrated under reduced pressure to afford crude compound 5-Oxo-1-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester (450 g) as a mixture of Me and Et esters.
Reaction SMILES: [OH:1][C:2]1[C:3]2[S:23][CH:22]=[C:21]([CH3:24])[C:4]=2[N:5]([CH3:20])[C:6](=[O:19])[C:7]=1[C:8]([NH:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[O:9].OC1C2SC=C(C)C=2N(C)C(=O)C=1C(OCC)=O.NC1C(C)=CSC=1C(OC)=O.Cl.NCC(OC(C)(C)C)=O>O1CCOCC1.CCN(C(C)C)C(C)C.C(Cl)(Cl)Cl>[OH:1][C:2]1[C:3]2[S:23][CH:22]=[C:21]([CH3:24])[C:4]=2[N:5]([CH3:20])[C:6](=[O:19])[C:7]=1[C:8]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[O:9]
Reactant: Cc1csc2c(O)c(C(=O)NCC(=O)OC(C)(C)C)c(=O)n(C)c12
Agent: CC(C)(C)OC(=O)CN
Agent: CCOC(=O)c1c(O)c2scc(C)c2n(C)c1=O
Agent: COC(=O)c1scc(C)c1N
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc2c(O)c(C(=O)NCC(=O)O)c(=O)n(C)c12
Temperature: 90 °C
Reaction time: 12 h

Procedure:
tert-Butyl 2-(7-hydroxy-3,4-dimethyl-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-6-carboxamido)acetate. A mixture of ethyl 7-hydroxy-3,4-dimethyl-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-6-carboxylate (0.477 g, 1.78 mmol, prepared analogously to Method 3 utilizing commercially available methyl 3-amino-4-methylthiophene-2-carboxylate (Aldrich, Milwaukee, Wis.)) and tert-butyl 2-aminoacetate hydrochloride (0.598 g, 3.57 mmol) in dioxane and DIEA was stirred at 90° C. for 12 hours. The mixture was cooled to room temperature, diluted with CHCl3, washed with water (1×) and brine (1×), dried over MgSO4, and evaporated. Purification by flash chromatography (hexanes to hexanes/EtOAc=1:1) UV gave the title compound as a white solid (27 mg). MS (ESI) m/z: Calculated; 352.4: Observed; 353.1. 1H NMR (300 MHz, CDCl3) δ ppm 10.73 (1H, br. s), 7.36 (1H, s), 4.12 (2H, d, J=5.4 Hz), 3.88 (3H, s), 2.62 (3H, s), 1.50 (9H, s).
Reaction SMILES: Cl.CC1(C)[O:7][CH:6]([CH2:8][N:9]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[C:16]3[C:11]([N:12]([CH3:28])[C:13](=[O:27])[N:14]([CH3:26])[C:15]3=[O:25])=[CH:10]2)[CH2:5][O:4]1.O>C(#N)C>[OH:7][CH:6]([CH2:5][OH:4])[CH2:8][N:9]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[C:16]2[C:11]([N:12]([CH3:28])[C:13](=[O:27])[N:14]([CH3:26])[C:15]2=[O:25])=[CH:10]1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC3COC(C)(C)O3)cc2n(C)c1=O
Agent: Cl
Solvent: O
Solvent: CC#N
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC(O)CO)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
HCl (2 M in diethyl ether) (92 ml, 185 mmol) was added dropwise to a solution of 6-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (7.15 g, 18.46 mmol) and water (6.65 g, 369 mmol) in acetonitrile (35.1 mL). The mixture was stirred at room temperature for 30 minutes. Evaporation of the reaction mixture under vacuum afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[C:13]([O:16][CH2:17][CH3:18])(=[O:15])C>>[CH2:17]([O:16][C:13]([NH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5])=[O:15])[CH3:18]
Reactant: CCOC(C)=O
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Product: CCOC(=O)Nc1ccc([N+](=O)[O-])cc1C#N

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 (Method A) from 2-amino-5-nitrobenzonitrile. tlc: Rf=0.4 (33% ethyl acetate in hexanes)
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[C@@H:13]([C:17]2[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C(O)C.C(Cl)Cl>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[C@@H:13]([C:17]2[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(OC)cc1)c1ccc(F)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(OC)cc1)c1ccc(F)c2ccccc12
Reaction time: 1 h

Procedure:
To a solution of ethyl N-(4-{(1S)-1-[(4-fluoro-1-naphthyl)(4-methoxyphenyl)methyl]butyl}benzoyl)-β-alaninate (slower-eluting diastereomer, 10 mg, 0.018 mmol) in ethanol (2 mL) was added LiOH (2.0 N in water, 0.5 mL, 1.0 mmol), then the reaction mixture was stirred for one hour. The mixture was diluted with DCM (20 mL) acidified with 2.0 N HCl (aq). The organic layer was dried over MgSO4, concentrated, then the residue was purified by silica gel chromatography eluting with 10% MeOH/DCM to afford the title compound. 1H NMR (499 MHz, CDCl3): δ 8.27 (d, J=8.5 Hz, 1H); 8.13 (d, J=8.2 Hz, 1H); 7.67-7.49 (m, 5H); 7.20 (m, 3H); 6.95 (dd, J=8.3, 2.5 Hz, 2H); 6.76 (m, 1H); 6.51 (d, J=8.3 Hz, 2H); 4.86 (d, J=11.3 Hz, 1H); 3.76 (m, 2H); 3.60 (s, 3H); 3.58 (m, 1H); 2.65 (t, J=5.8 Hz, 2H); 1.70 (m, 2H); 1.07 (m, 2H); 0.76 (t, J=7.2 Hz, 3H). LC1 1.19 min. [M+]+ 514.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([C:19]3[C:23]([C:24]([F:27])([F:26])[F:25])=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:21][N:20]=3)[O:16][N:15]=2)=[CH:10][CH:9]=1)[C:3]([O:5]CC)=[O:4].[Li+].[OH-].Cl>C1COCC1.CO>[OH:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([C:19]3[C:23]([C:24]([F:25])([F:26])[F:27])=[C:22]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:21][N:20]=3)[O:16][N:15]=2)=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 0.33 h
Yield: 94.6 %

Procedure:
(R/S)-Ethyl 2-hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetate (Int-VIII, 380 mg, 0.83 mmol) was dissolved in THF (5.00 mL) and MeOH (5 mL). Then, 1N LiOH (0.83 mL, 0.83 mmol) was added. It was stirred for 20 min and additional 1N LiOH (0.83 mL, 0.83 mmol) was added. After stirring for 15 min, the solution was neutralized by 1N HCl to pH=5. The reaction mixture was concentrated and then EtOAc was added. The EtOAc was washed with brine. The organic layer was dried, filtered and concentrated to give (R/S)-2-hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-IX, 376 mg, 0.785 mmol, 95% yield): LCMS=432.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.02-8.20 (2 H, m), 7.49-7.79 (7 H, m), 5.27 (1 H, s).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:5]2=[N:4][C:3]=1[CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1C(OC(C)(C)C)=O>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:5]2=[N:4][C:3]=1[CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]1
Reactant: Cc1ccn2c(Cl)c(C[C@@H]3CCCCN3C(=O)OC(C)(C)C)nc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccn2c(Cl)c(C[C@@H]3CCCCN3)nc2n1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1,1-dimethylethyl (2S)-2-[(3-chloro-7-methylimidazo[1,2-a]pyrimidin-2-yl)methyl]-1-piperidinecarboxylate (D4) (0.085 g, 0.23 mmol) in DCM (2 ml), TFA (0.5 ml) was added dropwise at 0° C. and the solution was stirred for 1 h. The solvent was removed and the residue charged into a SCX column and eluted with methanol and ammonia 2 M in methanol. Collected fractions gave the title compound (0.060 g, 0.23 mmol, 97% yield) as a colorless oil. UPLC: rt=0.39, peak observed: 265 (M+1, 100%) and 267 (M+1, 33%). C13H17ClN4 requires 265. 1H NMR (400 MHz, CDCl3) δ(ppm): 8.12-8.21 (d, 1H), 6.80-6.88 (d, 1H), 3.02-3.14 (m, 2H), 2.78 2.91 (m, 2H), 2.60-2.72 (m, 4H), 1.28-1.84 (m, 6H).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24].N1C=CC=CC=1>ClCCl>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:17][C:18]3[CH:22]=[CH:21][S:20][C:19]=3[C:23]([O:25][CH3:26])=[O:24])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1sccc1N
Reactant: O=S(=O)(Cl)c1ccc(C2CCCCC2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.6 %

Procedure:
To a solution of 4-cyclohexylbenzene-1-sulfonyl chloride (0.45 g; 1.74 mmol) in dichloromethane (4.0 mL) at room temperature, methyl 3-aminothiophene-2-carboxylate (0.25 g; 1.6 mmol) was added followed by pyridine (0.25 g; 3.2 mmol) and then stirred at room temperature under a nitrogen atmosphere for 24 hours. The reaction mixture was concentrated under reduced pressure and then taken up in ethyl acetate (50 mL) and extracted with water. The aqueous layer separated and extracted with ethyl acetate (2×50 mL). The combined organic phases were successively washed with water and aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 40% v/v over 900 mL gradient elution) to give the title product as an off-white solid (0.55 g).
Reaction SMILES: CC([O-])(C)C.[K+:6].C1OCCOCCOCCOCCOCCOC1.[C:25]([O:32][CH2:33][CH3:34])(=[O:31])[C:26]([O:28]CC)=O.[C:35](#[N:38])[CH2:36][CH3:37]>C1COCC1>[C:35](/[C:36](/[CH3:37])=[C:26](\[O-:28])/[C:25]([O:32][CH2:33][CH3:34])=[O:31])#[N:38].[K+:6]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C([O-])=C(\C)C#N
Temperature: 60 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
3.84 g potassium 2-methylpropan-2-olate (34.2 mmol, 1.0 eq.) and 723 mg 18-crown-6 (2.74 mmol, 0.08 eq.) were dissolved in THF and 5.00 g diethyl oxalate (34.2 mmol, 1.0 eq.) were added within 5 minutes. The reaction mixture was heated to 60° C. and 1.88 g propiononitrile (34.2 mm ol, 1.0 eq.) were added within 5 minutes. The reaction was stirred at 60° C. for 1 hour. The solid was filtered off, dried in vacuo at 50° C. to provide 5.11 g (26.4 mmol, 77%) of the crude product which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([O:15]C)=[O:14])[C:5]2[O:11][CH2:10][CH2:9][CH2:8][O:7][C:6]=2[CH:12]=1.[OH-].[K+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[C:5]2[O:11][CH2:10][CH2:9][CH2:8][O:7][C:6]=2[CH:12]=1
Reactant: COC(=O)c1cc(Cl)cc2c1OCCCO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(Cl)cc2c1OCCCO2
Yield: 84 %

Procedure:
A mixture of intermediate (10) (0.25 mol) and potassium hydroxide (1 mol) in water (650 ml) was stirred and refluxed for 2 hours. The reaction mixture was cooled, acidified with HCl and the resulting precipitate was filtered off, washed with water, and dried, yielding 48 g of 8-chloro-3,4-dihydro-2H-1.5-benzodioxepin-6-carboxylic acid (intermediate 11).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:12]1(O)[CH2:16][CH2:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:12]1([O:1][C:2]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1ccc(C#N)c(O)c1
Reactant: OC1CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C#N)c(OC2CCCC2)c1
Temperature: 25 °C
Yield: 100.4 %

Procedure:
To a solution of 2-hydroxy-4-methoxy-benzonitrile (90 mg, 0.573 mmol), cyclopentanol (55 mg, 0.630 mmol) and triphenylphosphine (167 mg, 0.630 mmol) in tetrahydrofuran (3 mL) cooled to −78° was added diethylazodicarboxalate (0.16 mL, 0.860 mmol). The cooling bath was removed and the reaction was allowed to warm up to room temperature over 1.5 h. The reaction mixture was concentrated in vacuo, and purification of the residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 0-8% diethyl ether in hexanes yielded 2-cyclopentyloxy-4-methoxy-benzonitrile as a clear liquid (125 mg, 96%).
Reaction SMILES: [CH3:1][CH:2]1[NH:6][CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[S:3]1.C(N(CC)CC)C.[C:20](Cl)(=[O:28])[CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24]>ClCCl>[CH3:1][CH:2]1[N:6]([C:20](=[O:28])[CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[S:3]1
Reactant: CC1NCC2(CCN(C)CC2)S1
Reactant: CCCC(CCC)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(CCC)C(=O)N1CC2(CCN(C)CC2)SC1C
Temperature: 0 °C

Procedure:
2,8-dimethyl-1-thia-3,8-diaza-spiro[4.5]decane (982 mg, 5.28 mmol) was dissolved in dry dichloromethane (5 ml) under argon atmosphere. Distilled triethylamine (1.10 ml, 7.92 mmol) was added and the resulting solution was cooled to 0° C. Valproyl chloride (910 mg, 5.60 mmol) was added dropwise with a syringe. The reaction flask was allowed to warm to room temperature with stirring, and white solid started to precipitate. After 4 h of stirring, dichloromethane (100 ml) was added and the resulting solution was washed with water (10 ml). The two phases were separated and the aqueous phase was extracted with dichloromethane (2×50 ml). The combined organic phase was dried with sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (silica, CH2Cl2/EtOH/NH4OH 150/10/1) to give AF717 (521 mg, 99.2% chemical purity) as an off-white powder. 1H NMR (CDCl3, 300 MHz) δ 5.53, 5.26 (2q, J=6.12 and J=6.3 Hz, 1H, CHCH3), 4.67, 3.90 (2d, J=12.0 and J=11.35 Hz, 1H, CHHNCO), 3.48, 3.09 (2d, J=11.35 and J=12.0 Hz, 1H, CHHNCO), 2.78-2.59 (m, 2H, CH2N), 2.53-2.47 (m, 1H, CHCO), 2.30, 2.19 (2s, 3H, NCH3), 2.15-2.05 (m, 2H, CH2N), 2.02-1.84 (m, 2H, CH2CS), 1.74-1.61 (m, 4H, CH2CHCO), 1.55, 1.50 (2d, J=6.3 and J=6.12 Hz, 3H, CH3CH), 1.44-1.36 (m, 2H, CH2CS), 1.34-1.21 (m, 4H, CH2CH3), 0.93-0.87 (m, 6 h, CH3CH2) ppm; 13C NMR (CDCl3, 300 MHz) δ 174.35, 174.04 (C), 59.13 (C), 57.35, 57.19 (CH), 54.52, 54.06 (CH2), 53.13, 52.77 (CH2), 46.09 (CH3), 43.77, 42.55 (CH), 38.37, 37.58 (CH2), 37.04, 36.20 (CH2), 35.76, 35.35 (CH2), 35.08, 34.77 (CH2), 26.01, 23.01 (CH3), 21.08, 20.98 (CH2), 20.73, 20.56 (CH2), 14.27, 14.22 (CH3) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][C:5]=1[OH:18])([O-])=O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][C:5]=1[OH:18]
Reactant: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(O)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(C(=O)c2ccccc2)cc1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A mixture of 4-nitro-3-hydroxybenzophenone (900 mg, 3.7 mmol) and tin (II) chloride (2.5 g, 11.1 mmol) in ethanol (50 mL) was heated at 80° C. under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2CH2) gave the desired product (685 mg, 87%). 1H NMR (CD3OD): d 7.65 (d, 2H), 7.55 (d, 1H), 7.49 (t, 2H), 7.26 (s, 1H), 7.16 (dd, 1H), 6.68 (d, 1H).