Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7](Cl)=[N:8][S:9](=[O:11])(=[O:10])[C:4]2=[CH:3][CH:2]=1.[NH:13]1[CH2:18][CH2:17]O[CH2:15][CH2:14]1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:14]([N:13]([CH2:18][CH3:17])[C:7]1[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1)[CH3:15]
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCN(CC)C1=NS(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.4 %

Procedure:
10.0 g of pseudosaccharine chloride are initially introduced in 150 ml of toluene. 4.4 g of morpholine diluted with 25 ml of toluene are added dropwise at room temperature over the course of 30 minutes. Since the reaction is exothermic, the mixture is cooled with an ice bath. After a further 30 minues, 50 ml of pyridine in 25 ml of toluene are added and the mixture is subsequently stirred at room temperature for 2.5 hours. The solvent is then removed in vacuo and the residue is stirred up with 350 ml of water. The colorless precipitate is filtered off to give 10.8 g (86%) of 3-diethylaminobenzoisothiazole 1,1-dioxide.
Reaction SMILES: O[C@@H:2]([CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[Si:19]([O:26][CH2:27][C@@H:28]1[C@@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[CH2:31][NH:30][CH2:29]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[Si:19]([O:26][CH2:27][C@@H:28]1[C@@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[CH2:31][N:30]([C@H:2]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH2:29]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: O=C(OCc1ccccc1)[C@@H](O)CC1CCCC1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1cccc(F)c1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CN([C@H](CC2CCCC2)C(=O)OCc2ccccc2)C[C@@H]1c1cccc(F)c1
Yield: 87.5 %

Procedure:
The title compound was prepared from 100 mg (0.40 mmol) of 2-(S)-hydroxy-3-(cyclopentyl)propanoic acid, benzyl ester (from EXAMPLE 20, Step G) and 154 mg (0.49 mmol) of 3-(R)-(t-butyldimethylsilyloxy-methyl)-4-(S)-(3-fluorophenyl)pyrrolidine (from EXAMPLE 20, Step H) using a procedure analogous to that described in EXAMPLE 1, Step G to provide 189 mg (87%) of the title compound: RF: 0.59 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ 0.0 (s, 6H), 0.84 (s, 9H), 1.05-1.09 (m, 2H), 1.45-1.84 (m, 9H), 2.32 (m, 1H), 2.64 (br t, 1H), 2.74 (br t, 1H), 2.94 (br q, 1H), 3.04-3.15 (m, 2H), 3.37-3.57 (m, 3H), 5.16 (s, 2H), 6.83-6.98 (m, 3H), 7.16-7.39 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[C:15]([S:24]([CH3:27])(=[O:26])=[O:25])=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][N:37]=[C:36](Cl)[N:35]=3)=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.[O:41]([C:43]1[CH:50]=[CH:49][C:46]([CH2:47][NH2:48])=[CH:45][CH:44]=1)[CH3:42]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[C:15]([S:24]([CH3:27])(=[O:26])=[O:25])=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][N:37]=[C:36]([NH:48][CH2:47][C:46]4[CH:49]=[CH:50][C:43]([O:41][CH3:42])=[CH:44][CH:45]=4)[N:35]=3)=[CH:30][CH:29]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1nn(-c2ccccc2)c2nc(-c3ccc(-c4ccnc(Cl)n4)cc3)n(-c3ccc(Cl)cc3)c(=O)c12
Reactant: COc1ccc(CN)cc1
Solvent: CCO
Product: COc1ccc(CNc2nccc(-c3ccc(-c4nc5c(c(S(C)(=O)=O)nn5-c5ccccc5)c(=O)n4-c4ccc(Cl)cc4)cc3)n2)cc1
Temperature: 100 °C
Yield: 80 %

Procedure:
To a suspension of crude 5-(4-chloro-phenyl)-6-[4-(2-chloro-pyrimidin-4-yl)-phenyl]-3-methanesulfonyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (from example 356) in EtOH (6 mL) is added 4-methoxylbenzylamine (0.4 mL). The mixture is heated at 100° C. for 24 h and then cooled down to room temperature. The precipitate is collected by filtration and washed with EtOH (2×3 mL). The solid is air dried for 14 h to provide the desired 5-(4-chloro-phenyl)-3-methanesulfonyl-6-{4-[2-(4-methoxy-benzylamino)-pyrimidin-4-yl]-phenyl}-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one as white solid (230 mg, 80%). HPLC-MS calculated C36H28ClN7O4S (M−H′): 690.2. Found: 690.2.
Reaction SMILES: [Br:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1.Cl[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[Br:1][C:2]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1
Reactant: CN(C)CCCl
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CN(C)CCn1c(=O)c2c(nc(Br)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 80 °C
Yield: 84 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.2 g, 0.54 mmol, intermediate 8) in DMF (5 mL) was added 2-chloro-N,N-dimethylethanamine (0.87 mg, 0.83 mmol), potassium carbonate (0.15 g, 1.08 mmol), and TBAI (2 mg, 0.02 mmol). The reaction was heated at 80° C. overnight. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product (0.2 g, 84%) as yellow oil, which was used without purification. LCMS MH+ 442.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:11]([CH3:17])[C:10]=1[CH:18](OS(C)(=O)=O)[C:19]([F:22])([F:21])[F:20])C1C=CC=CC=1>CCO.CC(O)C.O.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:11]([CH3:17])[C:10]=1[CH2:18][C:19]([F:22])([F:20])[F:21]
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(OS(C)(=O)=O)C(F)(F)F)n1C
Agent: [Pd]
Solvent: CC(C)O
Solvent: O
Solvent: CCO
Product: Cc1cc(=O)c(O)c(CC(F)(F)F)n1C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution of the product obtained in step 2 above (1.46 g, 3.60 mmol) in 100 mL of EtOH was added 10% wet Pd—C (330 mg), and the mixture was hydrogenated under a hydrogen atmosphere at 50 psi pressure for 2 hrs. The reaction mixture was filtered through CELITE™, and the filtrate was concentrated to dryness. The residue was purified by flash column chromatography on silica gel using a mixture of i-PrOH and a 28-30% conc. NH4OH solution (80/20, v/v) as eluant. The solid obtained was stirred in a mixture of i-PrOH (4 mL) and H2O (1 mL), then collected by suction filtration. Then, the solid was thoroughly washed with 4 mL of a mixture of i-PrOH and H2O (9/1, v/v). The solid was then dried overnight in a vacuum oven at 40° C. to afford the title product, 3-hydroxy-1,6-dimethyl-2-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one (420 mg, 53% yield) as light orange powder. HPLC purity (peak area percent) of this compound is 97.2% at λ=254 nm using HPLC Method 2 as described above. 1H NMR (400 MHz, MeOD-D4) δ: 6.39 (s, 1H), 3.96 (q, J=10.1 Hz, 2H), 3.69 (s, 3H, NCH3), 2.42 (s, 3H); MS m/z 222.2 [M+1]+, 202.4, 182.3, 153.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([CH:12]3[CH2:17][CH2:16][N:15]=[C:14]([CH3:18])[CH2:13]3)[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(F)(F)F.[CH3:23]COCC.[Li]C>C1COCC1>[CH3:18][C:14]1([CH3:23])[CH2:13][CH:12]([C:9]2[S:8][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=3[CH:10]=2)[CH2:17][CH2:16][NH:15]1
Reactant: CCOCC
Reactant: COc1cccc2sc(C3CCN=C(C)C3)cc12
Agent: FB(F)F
Agent: [Li]C
Solvent: C1CCOC1
Product: COc1cccc2sc(C3CCNC(C)(C)C3)cc12
Yield: 30.7 %

Procedure:
To a solution of the crude 4-(4-methoxybenzo[b]thiophen-2-yl)-2-methyl-3,4,5,6-tetrahydropyridine (2.19 g, 8.44 mmol) in THF (38 mL) cooled to −78° C. in a dry ice/acetone bath, was added dropwise BF3.Et2O (48%) (3.34 mL, 12.6 mmol) via a syringe. After stirring ten minutes, the solution was treated with 24.1 mL (33.77 mmol) of 1.4 M MeLi. The mixture was stirred for 16 h, then quenched with 100 mL of saturated aqueous NH4Cl and 50 mL of H2O. The mixture was then extracted with CH2Cl2 (3×100 mL). The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography [2.5 to 7% (2.0 M NH3 in MeOH)/CH2Cl2] to give the title compound as an orange oil (0.713 g, 30%). IR (KBr) 2936, 1571, 1471, 1259, 1049 cm1. Ion Spray MS 276.2 (M+H)+. [α]D=0 (c 0.578, MeOH). C16H21NOS.0.1H2O.0.1 CH2Cl2
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.ClC(Cl)(Cl)[CH:21]=[O:22]>C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH2:10][CH2:9][N:8]2[CH:21]=[O:22])=[CH:17][CH:18]=1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: Oc1ccc(CC2NCCC3=C2CCCC3)cc1
Solvent: ClC(Cl)Cl
Product: O=CN1CCC2=C(CCCC2)C1Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.7 %

Procedure:
To a mixture of 30.0 g (0.12 mol) of (±)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline and 75 ml of chloroform was added dropwise to a solution of 19.2 g of trichloroacetaldehyde in 30 ml of chloroform. After the mixture had been stirred for 16 hrs at room temperature it was diluted with 150 ml of chloroform and washed with 4 N aqueous hydrochloric acid (50 ml) and water (50 ml). After drying, the solvent was removed under reduced pressure to give a residue, which after crystallization from ethyl acetate afforded 33.1 g (98%) of pure (±)-1-(p-hydroxybenzyl)-2-formyl-1,2,3,4,5,6,7,8-octahydroisoquinoline, mp 154°-156°. For analysis a sample of this compound was recrystallized from ethyl acetate, mp 161°-162°.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[CH:4]([CH3:9])[O:5][CH:6](O)[CH:7]=1.P(=O)(O)(O)[OH:12]>>[CH3:9][C:4]1[O:5][CH:6]=[CH:7][C:2](=[O:12])[C:3]=1[OH:10]
Reactant: CC1OC(O)C=C(Br)C1=O
Reactant: O=P(O)(O)O
Product: Cc1occc(=O)c1O
Yield: 34 %

Procedure:
A solution of 4-bromo-6-hydroxy-2-methyl-2H-pyran-3(6H)-one (0.0025 mole) in 20 ml of 35% phosphoric acid was refluxed for about 5 hours. Maltol (34%) was isolated by the method of Example 1.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[C:11](O)(=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[O:2]1[C:6]2[CH2:7][N:8]([C:11](=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1
Reactant: c1cc2c(o1)CNCC2
Reactant: CCCCCCCCCC(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)N1CCc2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.19 g (1.1 mmol) of n-decanoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel chromatography (hexane/ethyl acetate=10/1) to yield the desired product.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[F:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][NH:18][NH2:19])=[CH:15][CH:14]=1>C(O)C>[NH2:10][C:6]1[NH:19][N:18]([CH2:17][C:16]2[CH:20]=[CH:21][C:13]([F:12])=[CH:14][CH:15]=2)[C:4](=[O:3])[CH:5]=1
Reactant: NNCc1ccc(F)cc1
Reactant: CCOC(=O)C=C(N)OCC
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccc(F)cc2)[nH]1

Procedure:
17.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and 13 g of 4-fluorobenzylhydrazine, on stirring for 5 hours in ethanol at 60° and working up as described in Example 1, yield 13.2 g of the compound identified above as colorless crystals of melting point 148°, corresponding to 63% of theory.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([NH:11][C:12]([C:14]1[S:47][C:17]2[N:18]=[C:19]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29](OC4C=CC([N+]([O-])=O)=CC=4)=[O:30])[CH:23]=3)[C:16]=2[C:15]=1[NH2:48])=[O:13])([CH3:10])([CH3:9])[CH3:8]>ClCCl>[C:7]([NH:11][C:12]([C:14]1[S:47][C:17]2[N:18]=[C:19]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:30])[CH:23]=3)[C:16]=2[C:15]=1[NH2:48])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: C1COCCN1
Reactant: CC(C)(C)NC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc(NC(=O)Oc4ccc([N+](=O)[O-])cc4)c3)c2c1N
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc(NC(=O)N4CCOCC4)c3)c2c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Morpholine (250 mg) was added to a solution of tert-butyl 5-amino-2-phenyl-4-(3-(p-nitro-phenoxycarbonylamino)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 31(h), 150 mg) in dichloromethane (5 ml) and the reaction mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was diluted with CH2Cl2 and washed with H2O. The organic layer was concentrated under reduced pressure. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: H2O/CH3CN=80/20 to 0/100 (v/v) in 45 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([S:10][CH3:11])[CH:3]=1.S(C)C.CO.Cl>O1CCCC1.C(OCC)(=O)C.O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([S:10][CH3:11])[CH:3]=1
Reactant: CSc1cc(F)ccc1C#N
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: CSc1cc(F)ccc1CN
Temperature: 60 °C
Yield: 7.6 %

Procedure:
Under N2, 4-fluoro-2-(methylthio)benzonitrile (1.67 g, 0.1 mol) was dissolved in 20 mL tetrahydrofuran and treated with 10 mL 2M BH3.Me2S. This was heated at 60° C. for 2 hrs. Heating was discontinued and 5 mL MeOH was cautiously added, followed by the cautious addition of 4 mL 6N HCl. Additional H2O (20 mL) was added followed by ethyl acetate. The layers were separated. The aqueous layer was made basic with 1N NaOH and extracted with CH2Cl2. The extracts were dried (MgSO4), filtered, concentrated and dried in vacuo to give 1.3 g of the title compound as a solid (Yield 76%). 1H NMR (500 MHz, CDCl3) δ ppm: 7.20-7.31 (1H, m) 6.90 (1H, dd, J=2.4 Hz) 6.75-6.86 (1H, m) 3.86 (2H, s) 2.47 (3H, s); LC/MS m/z 172.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([C:14]2[CH:15]=[N:16][N:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@@H:27]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=5)[CH2:26][O:25][C:24]4=[O:35])=[N:19][C:18]=23)[CH:11]=[CH:10][C:3]=1/[CH:4]=[N:5]/[NH:6][C:7]([NH2:9])=[O:8].C([O-])(=O)C.[Na+].BrBr>C(O)(=O)C>[NH2:9][C:7]1[O:8][C:4]([C:3]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]=[N:16][N:17]4[CH:22]=[CH:21][C:20]([N:23]5[C@@H:27]([C:28]6[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=6)[CH2:26][O:25][C:24]5=[O:35])=[N:19][C:18]=34)=[CH:13][C:2]=2[F:1])=[N:5][N:6]=1
Reactant: NC(=O)N/N=C/c1ccc(-c2cnn3ccc(N4C(=O)OC[C@@H]4c4ccc(F)cn4)nc23)cc1F
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5ccc(F)cn5)nc34)cc2F)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
To a solution of (S,E)-2-(2-fluoro-4-(5-(4-(5-fluoropyridin-2-yl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzylidene)hydrazinecarboxamide (26 mg, 0.054 mmol) in acetic acid (0.6 mL) was added sodium acetate (44 mg, 0.54 mmol). After complete dissolution of the salt, a dilute solution of Br2 (2.7 μL, 0.054 mmol) in acetic acid was slowly added dropwise in portions. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was applied directly on a preparative TLC plate. Acetic acid was removed under a stream of air, and the preparative TLC plate was developed with 10% MeOH in DCM to afford (S)-3-(3-(4-(5-amino-1,3,4-oxadiazol-2-yl)-3-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(5-fluoropyridin-2-yl)oxazolidin-2-one (7.9 mg, 31% yield) as a yellow solid. MS (APCI+) m/z 477 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH2:10].[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[CH:14][CH:13]=1.O>C(OCC)(=O)C>[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[NH:10][C:3]3[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=3[N:1]=2)=[CH:14][CH:13]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: O=C(O)c1ccc(Cl)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1cc2nc(-c3ccc(Cl)cc3)[nH]c2cc1F
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
The mixture of 50.7 g (0.35 mol) 1,2-diamino-4,5-difluorobenzene, 55.1 g (0.35 mol) 4-chlorobenzoic acid and 507 g polyphosphoric acid was heated to 160° C. and stirred at this temperature for 90 min. After cooling to 55° C., 1000 mL water and 500 mL ethyl acetate were added. Under ice cooling ca 1000 mL 32% aqueous sodium hydroxide solution was added (pH ca 9). The suspension was filtered over dicalite and the filter cake was washed with 1.5 L ethyl acetate. The phases were separated and the aqueous phase was washed with 0.5 L ethyl acetate. The organic phases were washed with 1M aqueous sodium hydroxide solution and brine, dried over magnesium sulfate and filtered. To the solution, silica gel was added and the solvent evaporated. The crude adsorbed product was purified by column chromatography over silica gel using a gradient of n-heptane:ethyl acetate (v/v, 4:1 to 1:1) as eluant. The fractions containing the product in pure form were pooled and evaporated. The remaining fractions were dissolved in ethyl acetate, washed twice with 1M aqueous sodium hydroxide solution and brine, the combined aqueous layers extracted once with ethyl acetate and the combined organic layers dried over magnesium sulfate and filtered. Chromatography over silica gel afforded a second batch of compound. Total yield: 75 g (80%) light yellow solid.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([NH:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)=[O:26])=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1>>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:18]=[CH:19][C:2]([C:22]2[CH:23]=[C:24]([C:25](=[O:26])[NH:27][C:28]3[S:29][CH:30]=[CH:31][N:32]=3)[CH:33]=[CH:34][C:21]=2[CH3:20])=[N:3][CH:4]=1
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Product: COc1cccc(CNC(=O)c2ccc(-c3cc(C(=O)Nc4nccs4)ccc3C)nc2)c1

Procedure:
N-(3-Methoxybenzyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS: retention time 3.20 min, MH+ 459. NMR: δH [2H6]-DMSO 12.71,(1H, b), 9.31,(1H, t), 9.17,(1H, d), 8.39,(1H, dd), 8.22,(1H, s), 8.07,(1H, d), 7.83,(1H, d), 7.57, (1H, d), 7.52,(1H, d), 7.29-7.25,(2H, m), 6.94,(2H, m), 6.84,(1H, d), 4.52,(2H, d), 3.75,(3H, s), 2.45,(3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2.[Cl:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH:23]=O.[OH-].[Na+]>C(O)C>[Cl:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1/[CH:23]=[C:8]1/[C:9](=[O:15])[C:10]2[C:5]([CH2:6][CH2:7]/1)=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Reactant: O=Cc1ccncc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2c(cc1OC)C(=O)/C(=C/c1ccncc1Cl)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.4 %

Procedure:
At room temperature, a mixture of 6,7-dimethoxy-1-tetralone (1.44 g, 7 mmol) and 3-chloro-4-pyridinecarboxaldehyde (1.0 g, 7 mmol) was added in one portion to a solution of sodium hydroxide (280 mg, 1 equiv) in ethanol (7 mL). After being stirred at room temperature for 4 h, the solid obtained was filtered and rinsed with ethanol then diethyl ether to give the title compound 85 (Yield 932 mg, 44%).
Reaction SMILES: [CH:1]1([C:6]2[C:15]([CH:16]([F:27])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[C:14]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:13]3[C:12](=[O:35])[CH2:11][C:10]([CH3:37])([CH3:36])[CH2:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Li].[Cl-].[NH4+].[C:42]1(C)C=CC=CC=1>CCOCC>[CH:1]1([C:6]2[C:15]([CH:16]([F:27])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][CH:18]=3)=[C:14]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[C:13]3[C:12]([CH3:42])([OH:35])[CH2:11][C:10]([CH3:37])([CH3:36])[CH2:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CC(=O)c2c(nc(C3CCCC3)c(C(F)c3ccc(C(F)(F)F)cc3)c2-c2ccc(F)cc2)C1
Reactant: Cc1ccccc1
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(C)Cc2nc(C3CCCC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)cc3)c2C(C)(O)C1
Temperature: -78 °C

Procedure:
514 mg (1 mmol) of the keto compound from Example XI are dissolved in 50 ml of ether p.a. (which had been dried over a molecular sieve), and the mixture is cooled under argon to −78° C. and admixed dropwise with 3.1 ml (5 mmol, 5 eq.) of methyllithium (1.6 molar solution in ether). The solution is subsequently stored at −30° C. (deep freezer) for 20 hours. The solution is then cooled to −78° C. and admixed with 20 ml of ammonium chloride solution and 40 ml of toluene p.a. The cooling bath is removed and the solution is allowed to warm to room temperature. The organic phase is separated off, the aqueous phase is extracted twice with toluene and the combined organic phases are dried over Na2SO4, filtered and concentrated. The residue—dissolved in toluene—is chromatographed over 500 ml of silica gel using cyclohexane with a little added ethyl acetate as eluent.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:25]([CH:36]([CH3:38])[CH3:37])=[CH:24][C:10]=1[C:11]([NH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[CH:18]=[CH:17]2)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:48])=CC=1.O.NN>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:27]=[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:25]([CH:36]([CH3:38])[CH3:37])=[CH:24][C:10]=1[C:11]([NH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[CH:18]=[CH:17]2)=[S:48])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(C(=O)Nc2ccc3c(ccn3C)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: NN
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1cc(C(=S)Nc2ccc3c(ccn3C)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 0 °C
Yield: 83 %

Procedure:
Benzamide (A) was treated with Lawesson's reagent (3.46 g, 8.58 mmol, 0.6 equiv.) in 80 mL toluene at 110° C. for three hours. The reaction mixture was cooled to 0° C., and treated with hydrazine hydrate (1.50 g, 30 mmol) at 0° C. for 10 minutes to decompose by-product and excess reagent. Normal EtOAc/water workup, followed by recrystallization in EtOAc/hexane yielded 2,4-dibenzyloxy-5-isopropyl-N-(1-methyl-1H-indol-5-yl)-thiobenzamide (B) as yellow solid (6.20 g, 12 mmol, 83%).