Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]2[C:7]([NH2:19])=[N:8][CH:9]=[C:10]([C:11]3[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:5]=2[S:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[NH:37][C:38]([C:40]1[N:41]([CH3:49])[C:42]2[C:47]([CH:48]=1)=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:19][C:7]1[C:6]2[C:2]([C:26]3[CH:25]=[CH:24][C:23]([NH:37][C:38]([C:40]4[N:41]([CH3:49])[C:42]5[C:47]([CH:48]=4)=[CH:46][CH:45]=[CH:44][CH:43]=5)=[O:39])=[C:22]([O:21][CH3:20])[CH:27]=3)=[CH:3][S:4][C:5]=2[C:10]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[CH:9][N:8]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: COc1ccc(-c2cnc(N)c3c(Br)csc23)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cnc(N)c3c(-c4ccc(NC(=O)c5cc6ccccc6n5C)c(OC)c4)csc23)cn1
Reaction time: 0.08 h

Procedure:
A mixture of Example 215 (1.0 eq) in 1,2-dimethoxyethane (10 mL) and water (5 mL) was reacted with N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-indole-2-carboxamide (1.2 eq), Na2CO3 (2.4 eq), and Pd(PPh3)4 (0.06 eq) at 95° C. for 18 hours. The organic solvent was removed in vacuo and the the mixture was extracted with dichloromethane. The extract was dried (MgSO4), filtered, and concentrated. The residue was purified by preparative reverse phase HPLC (Rainin C18, 8 mm, 300 Å, 25 cm; 40% acetonitrile/0.1M ammonium acetate isocratic for 5 minutes, then 40–100% acetonitrile/0.1M ammonium acetate over 30 minutes, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyophilized to provide the desired product. 1H NMR (DMSO-d6, 400 MHz) δ 9.52 (s, 1H), 8.45 (s, 1H), 8.02 (t, 1H), 7.91 (s, 1H), 7.71 (d, 1H), 7.55–7.63 (m, 2H), 7.28–7.38 (m, 2H), 7.23 (s, 1H), 7.08–7.18 (m, 2H), 7.03 (d, 1H), 5.57–5.69 (br s, 2H), 4.04 (s, 3H), 3.93 (s, 3H), 3.92 (s, 3H); reverse phase HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 50%-100% acetonitrile/0.1M ammonium acetate over 10 min, 1 mL/min) Rt=9.30 min.; MS m/e 536 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](Cl)=[O:13])=[CH:4][N:3]=1.[CH:15]1([CH2:21][NH2:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[CH:15]1([CH2:21][NH:22][C:12]([C:5]2[C:6]([C:8]([F:11])([F:10])[F:9])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=2)=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NCC1CCCCC1
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CCCCC1)c1cnc(Cl)nc1C(F)(F)F

Procedure:
To a solution of 2-chloro-4-trifluoromethyl-pyrimidin-5-carbonyl chloride (750 mg, ex Maybridge) in dichloromethane (15 ml) at −400 was added dropwise over 30 minutes a solution of cyclohexanemethanamine (0.35 ml, ex Lancaster) and triethylamine (0.41 ml) in dichloromethane (15 ml). Dichloromethane was removed under reduced pressure and ethyl acetate (20 ml) added. The solution was washed sequentially with water, 5% sodium bicarbonate solution and water, dried (MgSO4), evaporated and triturated with ether:hexane to afford 2-chloro-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (666 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:21])[N:4]=1.[N:22]1[C:30]([NH2:31])=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[N:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:31][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][N:26]2[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:21])[N:4]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=c1c2c(F)cccc2nc(CCl)n1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2cccc(F)c2c(=O)n1-c1ccccc1Cl
Yield: 64.3 %

Procedure:
Prepared according to Procedure C using Intermediate 2e (200 mg, 0.619 mmol), adenine (92 mg, 0.681 mmol), K2CO3 (94 mg, 0.680 mmol), and DMF (4 mL). The crude product was chromatographed in MeOH/CH2Cl2 to provide 168 mg of an off-white solid (64%), mp 159-172° C. (gradually decomposes). 1H NMR (DMSO-d6) δ: 8.10 (s, 1H); 8.08 (s, 1H); 7.73-7.89 (m, 3H); 7.57-7.71 (m, 2H); 7.37-7.48 (m, 2H); 7.34 (d, J=11 Hz, 1H); 7.30 (d, J=8.3 Hz, 1H); 5.14 (d, J=17 Hz, 1H); 4.94 (d, J=17 Hz, 1H). 13C NMR (DMSO-d6) ppm: 160.8 (d, J=264 Hz), 157.5 (d, J=4.2 Hz), 155.8, 152.4, 152.4, 150.0, 148.7, 142.1, 136.4 (d, J=11 Hz), 133.0, 132.2, 132.1, 131.2, 130.9, 129.4, 123.8 (d, J=3.6 Hz), 118.4, 114.5 (d, J=20 Hz), 110.2 (d, J=6.0 Hz), 44.9. MS (ES): m/z 422.0 (M+). Anal. calcd. for C20H13ClFN7O: C, 56.95; H, 3.11; Cl, 8.40; N, 23.24. Found: C, 54.62; H, 3.32; Cl, 9.40; N, 21.29.
Reaction SMILES: [S:1]1[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=[C:2]1[C:9](OCC)=O.[CH3:14][NH2:15]>CO>[CH3:14][NH:15][CH2:9][C:2]1[S:1][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cc2ccsc2s1
Reactant: CN
Solvent: CO
Product: CNCc1cc2ccsc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
A suspension of ethyl thieno[2,3-b]thiophene-2-carboxylate (3.84 g, 18.1 mmole) in 40% aqueous CH3NH2 (100 mL) and MeOH (10 mL) was stirred at RT for 18 hr. During that time the suspension became a solution. The mixture was concentrated to approximately ⅓ volume at which time the product precipitated. The solid was collected by filtration, washed with H2O, and dried in vacuo to give the title compound (3.01 g, 85%): 1H NMR (400 MHz, d6-DMSO) δ 8.60 (bs,1H), 7.92 (s,1H), 7.67 (d, J=5.2 Hz, 1H), 7.38 (d, J=5.2 Hz,1H), 2.78 (d, J=4.6 Hz. 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15](=[O:17])[CH3:16])[C:10]([CH2:18]Br)=[C:9]2[CH3:20])=[O:5])[CH3:2].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15](=[O:17])[CH3:16])[C:10]([CH2:18][C:22]1[NH:21][CH:25]=[CH:24][N:23]=1)=[C:9]2[CH3:20])=[O:5])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1ccc2c(c1)c(C)c(CBr)n2C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc2c(c1)c(C)c(Cc1ncc[nH]1)n2C(C)=O
Reaction time: 18 h
Yield: 86.9 %

Procedure:
A mixture of 1-acetyl-2-bromomethyl-3-methylindole-5-carboxylic acid ethyl ester (5.74 g), imidazole (11.56 g), sodium bicarbonate (2.9 g) and acetone was stirred for 18 hours and then evaporated. The residue was partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed with water and dried (Na2SO4). The solvent was evaporated and the residue was chromatograhed on silica gel. Elution with chloroform first gave some impurity followed by pure product. Evaporation of the product-containing fractions gave 1-acetyl-2-[1-imidazolylmethyl]-3-methylindole-5-carboxylic acid ethyl ester (4.80 g) which was used without further characterisation.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[C:21](=[O:30])[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1Br)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>COCCOC.[Cu]I>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[C:21]1[O:30][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)O[C@@H]1C[C@@H](C(=O)Nc2ccccc2Br)N(C(=O)OCc2ccccc2)C1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)O[C@@H]1C[C@@H](c2nc3ccccc3o2)N(C(=O)OCc2ccccc2)C1
Yield: 57.7 %

Procedure:
To a stirred solution of (2S,4R)-2-(2-bromo-phenylcarbamoyl)-4-tert-butoxy-pyrrolidine-1-carboxylic acid benzyl ester (900 mg, 1.89 mmol) in DME (20 mL) at 25° C. in a sealed tube were added CuI (36 mg, 0.19 mmol), 1,10-phenanthraline (68 mg, 0.38 mmol), and Cs2CO3 (1.847 g, 5.68 mmol). The reaction mixture was refluxed for 14 h. After completion of reaction, water was added, and the mixture was then extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was then purified by column chromatography to give (2S,4R)-2-benzooxazol-2-yl-4-tert-butoxy-pyrrolidine-1-carboxylic acid benzyl ester (430 mg, 57.5% yield) as a yellowish liquid. MS calcd. for C23H27N2O4 [(M+H)+] 395, obsd. 395.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]#[N:17])[C:9](=[O:15])[C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][CH:20]=1.[O-]CC.[Na+].[Na]>O.C(O)(=O)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:10](=[O:12])[C:9](=[O:15])[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:16]#[N:17])[C:26]#[N:27])=[CH:21][CH:20]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)C(C#N)c1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: N#CC(C(=O)C(=O)C(C#N)c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
Ethyl 3-(p-chlorophenyl)-3-cyanopyruvate (40 g., 0.16 mol.) and 49.8 g. (0.33 mol.) of p-chlorophenylacetonitrile were added to an alcoholic solution of sodium ethoxide [prepared from 7.36 g. (0.32 g.-atom) of sodium and 190 ml. of absolute ethanol] and the resulting soltuion was refluxed for two hours. The reaction mixture was diluted with water, acidified with acetic acid and cooled (ice bath) to yield 2,5-di-(p-chlorophenyl)-3,4-dioxoadiponitrile, m.p. 280°.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([C:9]2[N:10]=[C:11]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])[C:12]3[CH2:17][N:16]([CH3:18])[CH2:15][C:13]=3[N:14]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>C1COCC1>[CH2:26]([NH:28][C:29]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([C:9]2[N:10]=[C:11]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])[C:12]3[CH2:17][N:16]([CH3:18])[CH2:15][C:13]=3[N:14]=2)=[CH:8][C:2]=1[F:1])=[O:30])[CH3:27]
Reactant: CCN=C=O
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)c(F)c2)nc2c1CN(C)C2
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C)C3)cc1F
Temperature: 40 °C
Reaction time: 48 h
Yield: 14.1 %

Procedure:
To a stirred solution of (S)-2-fluoro-4-(6-methyl-4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)aniline (intermediate 16) (139 mg, 0.40 mmol) in dry THF, was added ethyl isocyanate (70 μL, 0.89 mmol) dropwise. The reaction mixture was stirred at 40° C. for 48 hours, before removal of the solvent in vacuo. The crude material was then purified prep. HPLC (high pH), affording the title compound as a white solid (23.3 mg, 13.7%).
Reaction SMILES: CC(C)([O-])C.[K+].C(COC)OC.[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C:15](=O)[CH2:14]2.S([CH2:32][N:33]=C=O)(C1C=CC(C)=CC=1)(=O)=O>C(O)C>[C:32]([CH:15]1[CH:16]2[CH2:19][CH2:20][N:13]([CH2:18][CH2:17]2)[CH2:14]1)#[N:33]
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Reactant: O=C1CN2CCC1CC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: N#CC1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
A solution of potassium tert-butoxide (18.27 ml) in 1:1 (v/v) mixture of dimethoxyethane and ethanol (100 ml) was added slowly to a stirred mixture of 3-quinuclidinone (8.14 g), tosylmethylisocyanate (16.53 g) in dry ethanol (6.5 ml), and dry dimethoxyethane (228 ml) under an atmosphere of argon whilst maintaining the temperature below 10° C. The reaction mixture was allowed to warm to ambient temperature and stirred at this temperature for 30 minutes. The reaction mixture was then stirred at 40° C. for 3 hours. The reaction mixture was cooled, filtered and the filtrate evaporated. The residue was purified by flash column chromatography on alumina (Brockmann Grade I) using a 2:98 (v/v) mixture of methanol/ethyl acetate as eluant to give 3-cyanoquinuclidine (6.6 g), microanalysis, found: C, 67.6; H, 8.5; N, 18.7%; C8H12N2 requires: C, 70.6; H, 8.8; N, 20.6%; NMR (CDCl3): 1.4-1.7 (3H, m), 1.85-2.0 (1H, m) 2.0-2.1 (1H, m) and 2.6-3.4 (7H, m); m/z 137 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:10][NH2:11])=[N:3][CH:4]=1
Reactant: Fc1ccc(Cl)nc1
Reactant: NN
Solvent: O
Product: NNc1ccc(F)cn1
Temperature: 200 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
2-chloro-5-fluoropyridine (5.00 g, 38.01 mmol) was combined with hydrazine monohydrate (15 mL, 303.0 mmol) in a Teflon® lined reactor. The reaction was purged with argon gas and sealed, then heated to 200° C. overnight. Following overnight heating, the reaction mixture was evaporated to solids under reduced pressure, and then dissolved in water containing NaHCO3. The mixture was transferred to a separatory funnel, and extracted 4 times with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated to residue under reduced pressure, followed by purification by flash column chromatography eluting with 5% MeOH 0.5% NH4OH in DCM to give the desired 5-fluoro-2-hydrazinylpyridine (1.50 g, 31% yield). MS APCI (+) m/z 128.0 (M+1) detected.
Reaction SMILES: CN[C:3]([C:5]1[N:6]([CH2:20][CH3:21])[CH:7]=[C:8]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:9]=1)=[O:4].[CH3:22][CH2:23][Mg+].[Br-]>C1COCC1>[CH2:20]([N:6]1[CH:7]=[C:8]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:9]=[C:5]1[C:3](=[O:4])[CH2:22][CH3:23])[CH3:21]
Reactant: CCn1cc(C#Cc2cccc(OC)c2)cc1C(=O)NC
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(=O)c1cc(C#Cc2cccc(OC)c2)cn1CC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere to a cold (0° C.) solution of 1-ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrole-2-carboxylic acid methyl amide (2.48 g, 7.93 mmol) in THF (40 ml) was added EtMgBr solution (1 molar in THF, 16 mL) over 10 minutes. The mixture was allowed to warm to room temperature and stirred for 18 hours, then poured into ice/1 N HCl solution and extracted with ether. The combined ether extracts were washed with brine, dried over MgSO4 and evaporated to dryness. The resultant residue was purified by flash chromatography (hexane/ethyl acetate 9.5/0.5) to give the title compound as an off white solid (1.8 g, 80% yield), mp 64° C., 1H NMR (400 MHZ, CDCl3) δ 1.16 (t, 3H), 1.35 (t, 3H), 2.8 (q, 2H), 3.79 (s, 3H), 4.35 (q 2H), 6.85 (m, 1H), 6.99-7.03 (m, 2H), 7.05 (m, 2H), 7.08 (m, 1H), MS m/e (M+H)+ 282.1.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:22]2[CH:26]=[C:25]([C:27]3([CH2:32][CH3:33])OCC[O:28]3)[S:24][CH:23]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)[N:3]=1.[OH-].[Na+]>C(OCC)C.Cl.C(Cl)Cl>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)([C:22]2[CH:26]=[C:25]([C:27](=[O:28])[CH2:32][CH3:33])[S:24][CH:23]=2)[N:3]=1
Reactant: CCC1(c2cc(C3(c4cccc(-c5cccnc5F)c4)N=C(N)N(C)C3=O)cs2)OCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(=O)c1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cs1
Temperature: 25 °C
Yield: 71 %

Procedure:
A mixture of 2-amino-5-[5-(2-ethyl-[1,3]dioxolan-2-yl)-thiophen-3-yl]-5-[3-(2-fluoro-pyridin-3-yl)-phenyl]-3-methyl-3,5-dihydro-imidazol-4-one (0.11 g, 0.23 mmol) in diethyl ether and 1 N HCl was heated at reflux temperature for 1 h, cooled to room temperature, diluted with methylene chloride and basified to pH 9 using 2 N sodium hydroxide. The phases were separated. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. The resultant concentrate was freeze dried from 1:1 acetonitrile/water (4 mL) to afford the title compound as a white solid, 0.069 g (71% yield), mp 98-112° C.; 1H NMR (500 MHz, CDCl3) δ 8.19 (dt, J=4.7, 1.4 Hz, 1H), 7.85-7.81 (m, 1H), 7.78-7.69 (m, 3H), 7.61-7.55 (m, 1H), 7.52-7.48 (m, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.29-7.23 (m, 1H), 3.12 (s, 3H), 2.88 (q, J=7.3 Hz, 2H), 1.17 (t, J=7.3 Hz, 3H); ESI MS m/z 423 [C22H19FN4O2S+H].
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][C@@H:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.CCN(CC)CC.[CH2:23]([O:30][C:31](ON1C(=O)CCC1=O)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[OH:8][C@H:7]1[C@@H:3]([CH2:2][NH:1][C:31]([O:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:32])[CH2:4][C@H:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@H](CN)[C@H](O)C1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@H]1C[C@H](CNC(=O)OCc2ccccc2)[C@H](O)C1
Reaction time: 18 h
Yield: 89.7 %

Procedure:
To a solution of (±)-1,1-dimethylethyl (1S,3R,4R)-3-(aminomethyl)-4-hydroxycyclopentanecarboxylate (7.9 g, 37.0 mmole) in DCM (100 mL) at RT was added Et3N (6.7 mL, 48.4 mmole) and N-(benzyloxycarbonyloxy)succinimide (12.1 g, 48.4 mmole). After 18 h, the DCM was removed under vacuum and the residue purified on silica (1:1, hexanes/EtOAc) to give the title compound (11.6 g, 89%) as a white solid: LC-MS (ES) m/e 350 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4](O)[CH:5]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:9][CH:8]=1.CCN(S(F)(F)[F:36])CC>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:29])[C@H:4]([F:36])[CH:5]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](O)C(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Reactant: CCN(CC)S(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](F)C(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.5 %

Procedure:
To a solution of (R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-2-hydroxy-butyric acid methyl ester (220 mg, 0.524 mmol) is added DAST (0.083 mL, 0.629 mmol) at 0° C. The reaction mixture is gradually warmed to room temperature and stirred for 1 h. Additional DAST (0.083 mL, 0.629 mmol) is added and stirred at room temperature for 2 h. The reaction mixture is diluted with EtOAc and washed with saturated NaHCO3 aqueous solution and brine. The organic layer is dried over Na2SO4 and concentrated. The residue is purified by flash column chromatography (silica gel, eluent; heptane/EtOAc=100:0 to 0:100) to give (R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-2-fluoro-butyric acid methyl ester (63 mg). HPLC retention time=1.36 minutes (condition B): MS (m+1-Boc)=322. 1H-NMR (400 MHz, CDCl3) δ ppm 1.39 (s, 9 H), 2.84-2.95 (m, 2 H), 3.06 (bs, 0.5 H), 3.69 (s, 3 H), 4.43-4.61 (m, 1 H), 4.72-4.80 (m, 0.5 H), 5.00 (s, 0.5 H), 5.12 (s, 0.5 H), 7.28-7.34 (m, 3 H), 7.37 (t, 1 H, J=7.58 Hz), 7.42-7.47 (m, 1 H), 7.48-7.53 (m, 1 H), 7.55 (t, 1 H, J=2.02 Hz). 19F-NMR (377 MHz, CDCl3) δ ppm −204.18.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH2:13])=[NH:12].[N+:14]([C:17]1[CH:28]=[CH:27][C:20]([CH:21]=[CH:22][S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([CH:21]=[CH:22][S:23]([NH:12][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[NH:13])(=[O:25])=[O:24])=[CH:27][CH:28]=1)([O-:16])=[O:15]
Reactant: N=C(N)c1ccc2ccccc2c1
Reactant: O=[N+]([O-])c1ccc(C=CS(=O)(=O)Cl)cc1
Product: N=C(NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1)c1ccc2ccccc2c1

Procedure:
Reaction of β-naphthamidine with 4-nitrostyrylsulfonyl chloride according to the above procedure affords N-(4-NITROSTYRYLSULFONYL)-β-NAPHTHAMIDINE, m.p. 180°-182.5° C., by triturating with isopropanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:12])[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.Br[C:56]1[CH:57]=[C:58]([S:62]([NH2:65])(=[O:64])=[O:63])[CH:59]=[CH:60][CH:61]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:12])[S:9][C:10]=1[NH:11][C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([S:62](=[O:64])(=[O:63])[NH2:65])[CH:57]=1)=[O:5])[CH3:2]
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: CCOC(=O)c1nc(C)sc1N
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(C)sc1Nc1cccc(S(N)(=O)=O)c1
Yield: 23.7 %

Procedure:
A microwave vial was charged with 5-amino-2-methyl-thiazole-4-carboxylic acid ethyl ester (0.300 g, 1.61 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.28 g, 0.48 mmol) and palladium dibenzylideneacetone (Pd2dba3)-chloroform complex (0.17 g, 0.16 mmol). Degassed dioxane (15.00 ml) was added, followed by 3-bromobenzenesulfonamide (0.38 g, 1.61 mmol) and cesium carbonate (0.93 g, 2.87 mmol) The vial was then irradiated in a microwave oven at 150° C. for 15 min. The mixture was diluted with THF and the solids filtered, washing with THF. The filtrate was evaporated and the residue purified by flash chromatography (heptane ethyl acetate) to yield 2-methyl-5-(3-sulfamoyl-phenylamino)-thiazole-4-carboxylic acid ethyl ester (0.13 g, 24%) as an off-white solid, MS (ISP): m/e=342.1 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([N:14]=[C:15]=[S:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C1COCC1>[CH:11]1[CH:12]=[CH:13][C:8]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[S:16])=[CH:9][CH:10]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Reactant: S=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ccccc1)c1ccc(NC(=S)Nc2ccccc2)cc1

Procedure:
Triethylamine (0.07 mL, 0.5 mmol) and phenyl isothiocyanate (2.1 mL, 11 mmol) were added sequentially to a solution of 4 (2.48 g, 10 mmol) in dry THF (10 mL). After heating under reflux for 48 h, all volatiles were removed under vacuum, and the resulting crude material was purified by flash chromatography on silica gel (hexanes/acetone, 3:1) to afford N-phenyl-4-[[(phenylamino)thioxomethyl]amino]benzenesulfonamide (5, also called LED209) (1.34 g, 35%) as a white solid, mp 160-162° C. 1H NMR (CD3COCD3, 300 MHz) δ 9.35 (br s, 1H), 9.30 (br s, 1H), 8.98 (br s, 1H), 7.80-7.72 (m, 4H), 7.51-7.47 (m, 2H), 7.38-7.33 (m, 2H), 7.28-7.16 (m, 5H), 7.08-7.04 (m, 1H); 13C NMR (CD3COCD3, 75 MHz) δ 180.2, 143.9, 138.9, 138.2, 135.2, 129.3 (2C), 129.1 (2C), 127.9 (2C), 125.8, 124.6 (3C), 122.8 (2C), 120.8 (2C).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C)C=O.[I-].[K+]>[N:19]1[CH:20]=[CH:21][CH:22]=[N:23][C:18]=1[CH2:17][NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: ClCc1ncccn1
Reactant: Cc1cccc(C)c1N
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NCc1ncccn1
Temperature: 100 °C
Reaction time: 5 h
Yield: 70.3 %

Procedure:
48.4 g (0.4 mol) of 2,6-dimethylaniline, 55.3 g (0.4 mol) of potassium carbonate and 0.2 g of potassium iodide were heated to 100° C. in 60 ml of dimethylformamide, and 25.7 g (0.2 mol) of 2-chloromethyl-pyrimidine were then added dropwise. The reaction mixture was subsequently stirred at 100° C. for 5 hours and then poured onto 500 g of ice. It was then extracted three times with 150 ml of methylene chloride each time. The combined organic phases were dried over sodium sulphate and concentrated in vacuo. The residue was distilled under a high vacuum. 30 g (70% of theory) of N-(pyrimidin-2-yl-methyl)-2,6-dimethylaniline were obtained as a colorless oil of boiling point 150° C./0.2 mm Hg. ##STR13##