Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([NH2:12])[C:3]=1[NH2:13].[N:14]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[C:3]2[NH:13][N:14]=[N:12][C:4]=2[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Nc1cc(C(F)(F)F)cc(Br)c1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1cc(Br)c2[nH]nnc2c1
Reaction time: 0.25 h

Procedure:
To a cooled (15° C.) solution of 3-bromo-5-(trifluoromethyl)benzene-1,2-diamine (1.82 g, 7.14 mmol) in acetic acid (20 mL) was added a solution of sodium nitrite (0.517 g, 7.49 mmol) in water (10 mL). After 15 min, the product was collected by filtration and washed with 65% HOAc in water and air dried to give 1.5 g (79%) as a faint pink powder. 1H-NMR (4:1 CDCl3/CD3OD, 500 MHz) δ 8.08 (s, 1H), 7.71 (s, 1H), 4.23 (bs, 1H); 13C-NMR (4:1 CDCl3/CD3OD, 126 MHz) δ 139.9, 129.0 (q, J=33 Hz), 125.3, 123.3 (q, J=273 Hz), 113.4, 108.2. Mass spec.: 265.82 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Cl[CH:18]([OH:21])[CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>[I-].[K+].O>[OH:1][C:2]1[CH:15]=[C:14]([O:16][CH2:20][CH2:19][CH2:18][OH:21])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Reactant: CCC(O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(c1ccccc1)c1ccc(OCCCO)cc1O
Temperature: 125 °C
Yield: 76.2 %

Procedure:
To a 250 mL 3-necked round-bottom flask equipped with a magnetic stirrer was charged 20 g (93.5 mmol) of 2,4-dihydroxybenzophenone, 8.8 g (93.5 mmol) of chloropropanol, 100 mg (0.6 mmol) of potassium iodide, 12.92 g (93.5 mmol) of potassium carbonate, and 100 mL of dimethyl sulfoxide. The flask was immersed in an oil bath and the mixture heated at a bath temperature of 125° C. for 14 hours. The mixture was poured into 1.4 L of water and extracted with four 500 mL portions of methylene chloride. The combined organic extracts were washed with five 1200 in L portions of water, followed by two 2 L portions of 0.025% aqueous NaOH, and another 1.2 L portion of water. The organic layer was dried (MgSO4), filtered through Celite, and concentrated, leaving 19.4 g of product as a yellow solid. 1H NMR (CDCl3): δ12.58 (s, 1H, ArOH); 7.60-7.35 (m, 6H, Ar—H); 6.45-6.30 (m, 2H, Ar—H); 4.10 (t, 2H, Ar—O—CH2—); 3.79 (t, 2H, H—O—CH2—); 1.99 (m, 2H, —CH2—CH2—CH2—).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:11]=[CH:10][O:9][CH:8]=1.CON(C)[C:15](=[O:25])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].C([O-])(O)=O.[Na+]>CCOCC.C1COCC1>[O:9]1[CH:10]=[CH:11][C:7]([C:15](=[O:25])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:8]1
Reactant: Brc1ccoc1
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCC(=O)c1ccoc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 37.2 %

Procedure:
To a solution of n-BuLi (2.5 M in hexane, 7.68 mL) in anhydrous ether (10 mL) was added dropwise (over a 20-min period) a solution of 3-bromofuran (2.35 g, 16 mmol) in anhydrous THF (15 mL) under nitrogen atmosphere at −78° C. After stirring at −78° C. for 20 min, a solution of the Weinreb amide 45 (1.75 g, 8 mmol) in THF (15 mL) was added slowly to the mixture. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was poured into a saturated NaHCO3 solution and extracted with EtOAc. The organic phase was dried over anhydrous MgSO4, filtered and evaporated under vacuum. The residue was further purified by silica column chromatography to provide the titled compound (671 mg, 37%). MNa+248.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH3:27][NH2:28].C(O)C>O1CCOCC1>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17](=[O:19])(=[O:18])[NH:28][CH3:27])=[CH:13][CH:12]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)cc2)s1
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)cc1
Reaction time: 8 h

Procedure:
4-(2-Acetylamino-4-methyl-thiazol-5-yl)-benzenesulfonyl chloride (Example 3a) (0.05 g, 0.15 mmol) is dissolved in dioxane (1 ml). The solution is treated with 2M aqueous sodium carbonate (0.15 ml, 0.24 mmol) followed by the addition of a 33% solution of methylamine in ethanol (0.08 ml, 0.6 mmol). The reaction mixture is stirred overnight. The solvent is removed in vacuo and the residue is purified by prep LC-MS i.e. liquid chromatography mass spectrometry to give N-[4-Methyl-5-(4-methylsulfamoyl-phenyl)-thiazol-2-yl]-acetamide. MH+ (ESMS): 326.1
Reaction SMILES: [OH:1][CH:2]1[CH2:23][NH:22][CH2:21][CH2:20][C:3]21[C:7](=[O:8])[N:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)[CH2:5][CH2:4]2.[CH3:24][C:25]([CH3:32])([CH3:31])[CH2:26][S:27](Cl)(=[O:29])=[O:28]>>[CH3:24][C:25]([CH3:32])([CH3:31])[CH2:26][S:27]([N:22]1[CH2:21][CH2:20][C:3]2([C:7](=[O:8])[N:6]([C:9]3[CH:14]=[CH:13][C:12]([CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:11][CH:10]=3)[CH2:5][CH2:4]2)[CH:2]([OH:1])[CH2:23]1)(=[O:29])=[O:28]
Reactant: O=C1N(c2ccc(CC(F)(F)F)cc2)CCC12CCNCC2O
Reactant: CC(C)(C)CS(=O)(=O)Cl
Product: CC(C)(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(CC(F)(F)F)cc3)C2=O)C(O)C1

Procedure:
The title compound was prepared in analogy to example 2 step B from a mixture of (5SR,6RS)-6-hydroxy-2-[4-(2,2,2-trifluoro-ethyl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (described in example 7 step B) and 2,2-dimethyl-propane-1-sulfonyl chloride. Light yellow solid. MS (ESI): 463.2 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[C:10]([NH:17]N)[CH:9]=1.[C:19]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[C:10]2[C:9]=1[C:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=1[NH:17]2
Reactant: O=C1CCCCC1
Reactant: NNc1cc(-c2ccccc2F)ccc1C(=O)O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2ccccc2F)c2c3c([nH]c12)CCCC3
Temperature: 25 °C
Yield: 34.4 %

Procedure:
Step 4 A solution of 2′-fluoro-3-hydrazinylbiphenyl-4-carboxylic acid (0.306 g, 1.24 mmol) and cyclohexanone (0.183 g, 1.86 mmol) in acetic acid (6.2 mL) was heated at reflux under nitrogen for 2 h. The mixture was cooled to rt and concentrated. The residue was partitioned between EtOAc and 1 M hydrochloric acid. The organic layer was washed with brine, dried and concentrated. The residue was triturated with EtOAc and DCM to give 5-(2-fluorophenyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid (0.132 g) as a white solid. The filtrate was purified by column chromatography (eluting with a gradient from hexane to 50:50 EtOAc-hexane) to give additional product (0.029 g, 41% total). 1H NMR (400 MHz, DMSO-d6) δ 12.95 (br s, 1H), 10.79 (s, 1H), 7.68 (d, J=7.15, 1H), 7.42-7.51 (m, 1H), 7.24-7.34 (m, 3H), 6.87 (d, J=7.15, 1H), 2.67-2.82 (m, 2H), 1.89-2.10 (m, 2H), 1.65-1.81 (m, 2H), 1.44-1.63 (m, 2H). Mass spectrum m/z 310.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1)#[CH:2].C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>C(Cl)Cl>[CH3:21][S:18]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[CH:2])=[CH:4][CH:5]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: C#Cc1ccc(CO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#Cc1ccc(COS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a solution of 4-ethynylbenzyl alcohol (5.0 g, 37.8 mmol) in CH2Cl2 (50 mL) and triethylamine (Et3N) (14.4 mL, 104.0 mmol) was added mesyl chloride (8.04 mL, 104.0 mmol) at 0° C. and the reaction was allowed to warm to room temperature. Stirring continued for 2 h under argon during which TLC revealed a quantitative conversion into a higher Rf product. Ice cold water was added into the reaction mixture and extracted with Et2O (200 ml). The organic layer was washed with 1N HCL (70 ml), H2O (100 ml), aqueous NaHCO3 (70 ml), and finally H2O (100 ml); and then dried over Na2SO4. Solvent was evaporated off and dried in vacuo to give 7.0 g of compound 3 as brownish oil which was used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)#[N:33]>>[CH:18]1([N:13]2[C:12]([C:37]3[CH:38]=[CH:39][C:34]([C:32]#[N:33])=[CH:35][CH:36]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: N#Cc1ccc(-c2c3c(nn2C2CCCCC2)CCNCC3)cc1
Yield: 96.9 %

Procedure:
The title compound (135.4 mg) was prepared as in Example 177, Steps C and D, using 203.8 mg of 2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 177, Step B) and 198 mg of 4-cyanophenylboronic acid. MS (ESI): exact mass calculated for C20H24N4, 320.43; found, m/z 321.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.93 (d, J=8.5 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 3.92-3.84 (m, 1H), 3.43-3.38 (m, 2H), 3.19-3.15 (m, 2H), 2.80-2.75 (m, 2H), 1.98-1.80 (m, 6H), 1.71-1.64 (m, 1H), 1.32-1.20 (m, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[C:9](Br)[CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1.[CH3:18][N:19](C)C=O.C(N)CN>O>[CH3:1][N:2]([CH3:17])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[C:9]([C:18]#[N:19])[CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1
Reactant: CN(C)C1CCc2[nH]c3c(Br)cccc3c2C1
Reactant: CN(C)C=O
Solvent: O
Solvent: NCCN
Product: CN(C)C1CCc2[nH]c3c(C#N)cccc3c2C1

Procedure:
3-(Dimethylamino)-8-bromo-1,2,3,4-tetrahydrocarbazole (18.8 g.)(Example 211) and 17.5 g. of cuprous cyanide in 150 ml. of dimethylformamide was heated under reflux for four hours. The warm reaction mixture was poured into a solution of 200 ml. of ethylenediamine in 400 ml. of water. This was mixed thoroughly and extracted several times with chloroform. The chloroform layer was separated and washed with a dilute solution of ethylenediamine, water, saturated salt solution, and evaporated to dryness to give, after recrystallization from benzene, 6.9 g. of 3-(dimethylamino)-8-cyano-1,2,3,4-tetrahydrocarbazole, m.p. 177°-179° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([O:14][CH3:15])[CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:30]([C:32]1[CH:45]=[CH:44][C:35]([CH2:36][N:37]2[C:41]([CH:42]=O)=[CH:40][N:39]=[CH:38]2)=[CH:34][CH:33]=1)#[N:31]>ClCCCl.C(O)(=O)C>[C:30]([C:32]1[CH:33]=[CH:34][C:35]([CH2:36][N:37]2[C:41]([CH2:42][NH:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)=[C:4]([O:14][CH3:15])[CH:3]=3)=[CH:40][N:39]=[CH:38]2)=[CH:44][CH:45]=1)#[N:31]
Reactant: COc1cc(N)ccc1-c1ccccc1
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(NCc2cncn2Cc2ccc(C#N)cc2)ccc1-c1ccccc1
Reaction time: 15 h

Procedure:
To a solution of 1-amino-3-methoxy-4-phenylbenzene in 1,2-dichloroethane at 0° C. was added 4A powdered molecular sieves and sodium triacetoxyborohydride. 1-(4-Cyanobenzyl)-5-imidazole-carboxaldehyde was added, followed by 5 drops of acetic acid. The cooling bath was removed after 5 hours, and the reaction was stirred for another 15 hours. The reaction was poured into ethyl acetate and water. The organic layer was extracted with sat. aq. NaHCO3 solution and brine, then dried (Na2SO4) and concentrated in vacuo to provide the product.
Reaction SMILES: ClC(Cl)(Cl)COC(=O)[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:30])[NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:16][C:15]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:9][CH:8]=1.[OH-].[Na+].Cl>O1CCCC1.O>[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:21][CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:30])=[CH:16][C:15]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:11][CH:12]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)NCCc4ccccc4)ccc3Sc3ccc(NC(=O)OCC(Cl)(Cl)Cl)cc3)ncnc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NCCc4ccccc4)ccc3Sc3ccc(N)cc3)ncnc2n1
Temperature: 60 °C

Procedure:
To a solution of the product of Example 182 in tetrahydrofuran and water (1:1) was added 1 M NaOH (5 equiv). The solution was heated at 60° C. for 40 minutes, cooled, adjusted to pH 6 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product was purified by silica gel chromatography eluting with 4% methanol in dichloromethane to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=6.62 Hz, 6 H) 2.82 (t, J=7.17 Hz, 2 H) 3.16-3.28 (m, 1 H) 3.45 (dt, 2 H) 5.58 (s, 2 H) 6.62 (d, J=8.46 Hz, 2 H) 6.81 (d, J=8.46 Hz, 1 H) 7.12 (d, J=8.46 Hz, 2 H) 7.16-7.33 (m, 5 H) 7.58-7.68 (m, 2 H) 7.80 (d, J=1.47 Hz, 1 H) 8.51 (t, J=5.15 Hz, 1 H) 8.57 (s, 1 H) 8.86 (d, J=8.46 Hz, 1 H) 10.10 (s, 1 H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:11]([C:13]2[C:14]([CH3:20])=[N:15][CH:16]=[CH:17][C:18]=2[CH3:19])=[O:12])=[N:6][CH:7]=[C:8]([Cl:10])[CH:9]=1)([O-])=O>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:1][C:4]1[C:5]([C:11]([C:13]2[C:14]([CH3:20])=[N:15][CH:16]=[CH:17][C:18]=2[CH3:19])=[O:12])=[N:6][CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: Cc1ccnc(C)c1C(=O)c1ncc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccnc(C)c1C(=O)c1ncc(Cl)cc1N
Temperature: 80 °C
Yield: 60.1 %

Procedure:
To a mixture of iron powder (220 mg, 4.0 mmol) in 4 ml of acetic acid at 80° C. was slowly added a solution of (3-Nitro-5-chloro-pyridin-2-yl)-(2,4-dimethyl-pyridin-3-yl)-methanone (260 mg, 0.89 mmol) in 2 ml of acetic acid. After the completion of addition the mixture was stirred at 80° C. for half an hour and then cooled. The mixture was diluted with ethyl acetate, filtered through celite and the filtrate was concentrated. The residue was purified by flash column (50% ethyl acetate in hexane) to afford 140 mg of title compound as off-white solid. MS: (M+H)/z=262.0.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH2:16].C(N(CC)CC)C>C(O)CCC>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH:16][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2
Reactant: NCc1cccc(Cl)c1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Clc1cccc(CNc2ncnc3nc[nH]c23)c1
Temperature: 90 °C
Yield: 95 %

Procedure:
3 mmol of 6-chloropurine were dissolved in 15 ml of butanol. Subsequently, 4 mmol of 3-chlorobenzylamine and 5 mmol triethylamine were added and the mixture was heated at 90° C. for 4 hours. After cooling, the precipitated product was filtered off, washed with cold water and n-butanol and crystallised from ethanol or dimethylformamide. M.p.=252° C., TLC(CHCl3:MeOH:conc. NH4OH (8:2:0.2, v/v/v)): single spot; HPLC: purity>98%. Yield 95%.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][C:16](=N)N)[CH:9]=1)[CH3:6].ClC[CH2:21][CH2:22][C:23]#[N:24].[OH-].[Na+]>O.C(O)C>[CH3:6][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][CH2:16][CH2:21][CH2:22][C:23]#[N:24])[CH:9]=1)[CH3:4]
Reactant: CN(C)Cc1ccnc(CSC(=N)N)c1
Reactant: N#CCCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)Cc1ccnc(CSCCCC#N)c1
Reaction time: 5 h
Yield: 80.7 %

Procedure:
To a solution of S-(4-dimethylaminomethyl-2-pyridylmethyl)isothiourea trihydrochloride (11.88 g) and 4-chlorobutyronitrile (5.21 g) in water (50 ml) and ethanol (35 ml) at 0° C. (ice-salt bath) under nitrogen, was added dropwise over 20 minutes a solution of sodium hydroxide (6.4 g) in water (65 ml), keeping the temperature below 5° C. After having been stirred for 5 hours and allowed to stand for 20 hours, the solution was extracted with 3:1 chloroform:ethanol (3×100 ml) and the combined extracts washed with water and dried (MgSO4). Solvent was evaporated at reduced pressure and the residue vacuum-distilled to give 4-(4-dimethylaminomethyl-2-pyridylmethylthio)butyronitrile (7.16 g) as a pale yellow liquid, b.p.0.01 mm 170° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:27]([O:30][C:31]1[CH:32]=[C:33]([CH3:41])[CH:34]=[CH:35][C:36]=1[C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:29])[CH3:28]>C(Cl)(Cl)(Cl)Cl>[C:27]([O:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][C:36]=1[C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:41][Br:1])(=[O:29])[CH3:28]
Reactant: CC(=O)Oc1cc(C)ccc1C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1cc(CBr)ccc1C(C)(C)C

Procedure:
16.4 g of N-bromosuccinimide, 1 g of α,α'-azoisobutyronitrile and 1 g of dibenzoyl peroxide are added in succession to a solution, stirred at 70° C. of 19 g of 3-acetoxy-4-tert-butyltoluene in 900 ml of CCl4. The reaction mixture is stirred under reflux for 31/2 hours under UV irradiation and is filtered, and the filtrate is concentrated by evaporation. The title compound is obtained from the residue by means of FC (900 g of silica gel, hexane/ethyl acetate=95:5): Rf (hexane/ethyl acetate=95:5)=0.40.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][OH:8])=[N:4][CH:3]=1.N1C=CN=C1.CN(C)C=O.Cl[Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22]>C(OC(=O)C)C>[Br:1][C:2]1[S:6][C:5]([CH2:7][O:8][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[N:4][CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCc1ncc(Br)s1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[Si](OCc1ncc(Br)s1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 104 %

Procedure:
A 100 mL round bottom flask is charged with (5-bromothiazol-2-yl)methanol (2.5 g, 12.9 mmol), imidazole (1.75 g, 25.8 mmol), dimethylformamide (25 mL), and chlorotriisopropylsilane (3.4 mL, 15.5 mmol). The reaction is stirred at room temperature under nitrogen for 72 hours. Contents are diluted with ethylacetate (150 mL), washed with 0.5M hydrochloric acid (2×100 mL) and brine (100 mL), dried (Na2SO4), and concentrated under vacuum to afford the title compound (4.7 g): m/z (Cl) M+H 350+352.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[O:6][CH2:5]1.[NH:12]1[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]1=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:10][C:7]1([CH3:11])[O:8][CH2:9][CH:4]([CH2:3][CH2:2][N:12]2[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:5][O:6]1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: CC1(C)OCC(CCBr)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(CCn2ccc(=O)[nH]c2=O)CO1
Temperature: 25 °C
Reaction time: 120 h
Yield: 29.2 %

Procedure:
To a solution of 5-(2-bromoethyl)-2,2-dimethyl-1,3-dioxane (15) (M. R. Harnden et al, J. Med. Chem., 30, 1636, 1987) (12.0 gm, 53.81 mmol) in dry DMF (150 ml) were added uracil (7.0 gm, 62.4 mmol) and potassium carbonate (14.0 gm). The reaction mixture was stirred at 25° C. for 5 days. The resulting solution was filtered and the solvent removed. The residue obtained was purified by column chromatography on silica gel eluting with chloroform-methanol (90:10, v/v) to afford 17 (4.0 gm, 25.2%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21].C1CCC(N=NC2(C#N)CCCCC2)(C#N)CC1>C(Cl)(Cl)(Cl)Cl>[CH3:9][O:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH2:21][Br:1]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc([N+](=O)[O-])cc1CBr
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.1 %

Procedure:
N-Bromosuccinimide (2.18 g, 12.30 mmol) was added to a stirred solution of 2-methyl-4-nitro-benzoic acid methyl ester (2 g, 10.25 mmol) and ABCN (626 mg, 2.56 mmol) in carbon tetra-chloride (80 ml) at room temperature. The reaction was heated at reflux for 2 hrs and then allowed to cool to room temperature and stirred for 15 hrs. The solvent was evaporated in vacuo and the resulting residue filtered through a pad of silica (eluting with dichloromethane). The solvent was evaporated in vacuo to afford the title compound as a yellow solid (2.70 g, 96%). HPLC retention time 4.49 min. Mass spectrum (ES+) m/z 256 (M+H).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].C(N(CC)CC)C.[C:14]1([C:20]2[O:24][N:23]=[C:22]([C:25]3[C:26]([NH2:37])=[N:27][CH:28]=[C:29]([C:31]4[CH2:32][CH2:33][NH:34][CH2:35][CH:36]=4)[N:30]=3)[N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[CH2:1]([S:3]([N:34]1[CH2:35][CH:36]=[C:31]([C:29]2[N:30]=[C:25]([C:22]3[N:21]=[C:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:24][N:23]=3)[C:26]([NH2:37])=[N:27][CH:28]=2)[CH2:32][CH2:33]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ncc(C2=CCNCC2)nc1-c1noc(-c2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CC=C(c2cnc(N)c(-c3noc(-c4ccccc4)n3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
Ethanesulfonyl chloride (62.13 mg, 45.78 μL, 0.4832 mmol) and triethyl amine (122.2 mg, 168.3 μL, 1.208 mmol) were added to a solution of 3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine (129 mg, 0.4027 mmol) in dichloromethane (5 mL) at 0° C. and the resulting solution stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, and freeze-dried. The solid was taken up in dichloromethane (5 mL) and washed with saturated aqueous NaHCO3 solution (2×5 mL), dried over MgSO4 and concentrated in vacuo to leave the product (65 mg, 40% yield) 1H NMR (400 MHz, DMSO) d 1.24 (t, 3H), 2.68 (m, 2H), 3.13 (q, 2H), 3.48 (m, 2H), 3.99 (m, 2H), 6.63 (m, 1H), 7.29 (br s, 2H), 7.68 (m, 2H), 7.77 (m, 1H), 8.26 (m, 2H) and 8.52 (1H, s) ppm; MS (ES+) 412.97
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]CCC(OCC)=O)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C1COCC1.CC([O-])(C)C.[K+].Cl>O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]3[C:16]([SH:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)CCSc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cnc(-c2ccc(-c3ccccc3S)cc2F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a solution consisting of ethyl 3-(4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-ylthio)propanoate (7.7 g, 19.4 mmol) and THF (60 mL) was added t-BuOK (4.3 g, 38.8 mmol) and the mixture stirred for 1 hour at rt. The reaction mixture was poured into water (100 mL) and the system brought to a pH=5-6 with 1 M HCl. The mixture was, extracted with EtOAc (80 mL×3) and the combined extracts dried over Na2SO4, filtered and concentrated to dryness to give 4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-thiol (4.6 g, 80%). MS (ESI): mass calcd. for C16H12FN3S, 297.07; m/z found, 298.0 [M+H]+.