Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[N:6]([CH3:28])[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8]/[C:9]/1=[N:10]\[C:11](=[O:23])[C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1F)[CH2:2][CH2:3][CH3:4].[SH:29][CH2:30][CH:31]([OH:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([N:5]1[N:6]([CH3:28])[C:7]([C:24]([CH3:26])([CH3:27])[CH3:25])=[CH:8]/[C:9]/1=[N:10]\[C:11](=[O:23])[C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[S:29][CH2:30][CH:31]([OH:33])[CH3:32])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)cc(C(C)(C)C)n1C
Reactant: CC(O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2SCC(C)O)cc(C(C)(C)C)n1C
Yield: 67.9 %

Procedure:
A mixture of Example 81C (400 mg, 1 mmol), 1-mercaptopropan-2-ol (277 mg, 3 mmol) and potassium carbonate (415 mg, 3 mmol) in DMF (10 mL) was heated at 50° C. for 16 hours. The mixture was then poured into water and extracted with ethyl acetate. The acetate layer was washed with brine, dried with MgSO4, filtered, and concentrated under reduced pressure. Purification by chromatography afforded 320 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (t, J=7.3 Hz, 3H), 1.15-1.24 (m, 3H), 1.27-1.44 (m, 11H), 1.54-1.79 (m, 2H), 2.68-3.07 (m, 2H), 3.76-3.94 (m, 4H), 4.27-4.45 (m, 2H), 4.94 (d, J=4.8 Hz, 1H), 6.83 (s, 1H), 7.42-7.52 (m, 1H), 7.54-7.66 (m, 1H), 8.24 (d, J=1.6 Hz, 1H). MS (DCI/NH3) m/z 472 (M+H)+. Anal. calculated for C23H32F3N3O2S: C, 58.58 H, 6.84 N, 8.91. Found: C, 58.57 H, 6.96 N, 8.77.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH3:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:16]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:17]
Reactant: CCBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (V-1) (3 g, 15 mmol) in DMF (6 mL) were added bromoethane (3.24 g, 30 mmol) and K2CO3 (4.26 g, 30 mmol). The reaction mixture was stirred at 60° C. overnight, then diluted with EtOAc, washed with water and then brine. The organic layer was separated, then dried over Na2SO4, and concentrated to afford the title compound (3.40 g). MS (m/z): 223 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][N:12]([CH2:14][CH2:15][NH:16][C:17](=O)[CH3:18])[C:13]=3[C:5]=2[CH:4]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)C>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[C:11]4[C:17]([CH3:18])=[N:16][CH2:15][CH2:14][N:12]4[C:13]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)-c1c(ccn1CCNC(C)=O)CC2
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)-c1c(cc3n1CCN=C3C)CC2
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
N-[2-(4,5-Dihydro-8-methoxy-1H-benzo[g]indol-1-yl)-ethyl]acetamide (4.7 g) was treated with 15 ml of phosphorus oxychloride under argon and the mixture was stirred at 50° C. for 30 minutes. The cooled mixture was added to 2000 g of ice-water and treated with 200 ml of 28% sodium hydroxide solution. The mixture was extracted once with 300 ml of methylene chloride and twice with 100 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. 4.2 g of residue were chromatographed on 250 g of aluminium oxide (neutral, III) with methylene chloride as the eluent. 3.8 g of crude product were dissolved in a 20-fold amount of hot ethanol and treated while hot with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 4.7 g (84%) of 5,6,10,11-tetrahydro-2-methoxy-8-methylbenzo[g]pyrazino[1,2-a]indole fumarate (1:1); m.pt.: 175°-177° C. (dec.).
Reaction SMILES: [C:1](=[S:4])([S-:3])[NH2:2].[NH4+].Br[CH2:7][CH2:8][C:9]([F:13])=[C:10]([F:12])[F:11]>C(O)C>[C:1](=[S:3])([S:4][CH2:7][CH2:8][C:9]([F:13])=[C:10]([F:12])[F:11])[NH2:2]
Reactant: FC(F)=C(F)CCBr
Reactant: NC(=S)[S-]
Agent: [NH4+]
Solvent: CCO
Product: NC(=S)SCCC(F)=C(F)F
Temperature: 40 °C
Reaction time: 3 h

Procedure:
2.8 g (25 mmol) of ammonium dithiocarbamate in 40 ml of ethanol are admixed dropwise with 5.32 g (26.3 mmol; purity 93.2%) of 4-bromo-1,1,2-trifluoro-1-butene, stirred at 40° C. for 3 h, another 2.8 g of ammonium dithiocarbamate is added after 1 h, and everything is left to stand at room temperature for 8 h. The filtrate is filtered off with suction and concentrated by evaporation under reduced pressure, the residue taken up in dichloromethane and washed once with water, and the organic phase dried over sodium sulphate. After concentration by evaporation under reduced pressure, 4.3 g (63% of theory; purity by GC/MS: 74 area %) of a semicrystalline residue are obtained.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][C:25]([O:27]CC)=[O:26])=[C:16]([N+:30]([O-:32])=[O:31])[CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.CCO>[CH2:3]([O:10][C:11]([NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][C:25]([OH:27])=[O:26])=[C:16]([N+:30]([O-:32])=[O:31])[CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cc1c([N+](=O)[O-])cc(NC(=O)OCc2ccccc2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1c([N+](=O)[O-])cc(NC(=O)OCc2ccccc2)c2ccccc12
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A solution of NaOH (0.17 g, 4.31 mmol) in H2O (20 mL) was added to a suspension of ethyl [4-(N-benzyloxycarbonylamino)-2-nitronaphthalen-1-yl]acetate (0.8 g, 1.96 mmol) in EtOH (20 mL), and the mixture was heated to reflux for 2hr. EtOH was evaporated and washed with Et2O (10 mL). The aqueous layer was acidified (pH 1) with 6 M HCl. The resulting precipitate was filtered and left out overnight to provide [4-(N-benzyloxycarbonylamino)-2-nitronaphthalen-1-yl]acetic acid (0.66 g, 89%) as an orange solid. M.p. 170-172° C. (decomp.); 1H NMR (DMSO-d6, 500 MHz) δ 8.40 (d, 8.5, 1H), 8.13 (d, 9.0, 1H), 7.67 (m, 2H), 7.55 (m, 1H), 7.41 (d, 7.5, 2H), 7.32 (t, 7.0, 2H), 7.22 (t, 8.0, 1H), 6.71 (s, 1H), 4.55 (d, 5.5, 2H), 4.04 (s, 2H); ESMS m/z 337 (M−CO2+H+), 673 ((M−CO2)×2+H+); IR (nujol) 3405, 2652, 1696, 1590, 1515, 1461, 1439, 1377, 1333, 1249, 1120, 929, 832, 792, 752, 699 cm−1. FABMS (NBA) m/z 336 (M−CO2+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7](=O)[CH3:8].[OH-].[K+].Cl>>[CH3:8][C:7]1[C:10]2[CH:11]=[CH:12][C:2]([OH:1])=[CH:3][C:4]=2[O:5][CH:6]=1
Reactant: CC(=O)COc1cccc(O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1coc2cc(O)ccc12
Temperature: 5 °C
Yield: 60.4 %

Procedure:
3 g (18 mmol) of (3-hydroxyphenoxy)acetone and 400 ml of a 0.1M potassium hydroxide solution are introduced into a 1 l three-necked flask equipped with a reflux condenser. Heating is carried out at reflux for 6 hours. The reaction mixture is cooled to 5° C., a molar hydrochloric acid solution is added, in order to obtain a pH of approximately 5, and extraction is carried out with ethyl ether (3×150 ml). The organic phases are combined, dried over magnesium sulphate and concentrated. The residue is purified by silica column chromatography (elution solvent: 8/2 cyclohexane/ethyl acetate). 1.61 g of 3-methyl-6-hydroxybenzofuran are obtained--M.p.: 92° C.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.C1(C)C(C)=CC=CC=1.[CH2:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1C)[CH3:17]>>[CH2:16]([C:18]1[CH:19]=[CH:20][C:21]([CH3:1])=[CH:22][CH:23]=1)[CH3:17]
Reactant: Cc1ccccc1
Reactant: CCc1ccccc1C
Solvent: Cc1ccccc1C
Product: CCc1ccc(C)cc1
Yield: 90.1 %

Procedure:
STDP and ethylation of toluene were carried out in the same manner as Examples 5 and 6. STDP gave a toluene conversion rate of 5.7% with a xylene product having 65.9% of the para isomer. Ethylation of toluene yielded 90.1% para-ethyltoluene in the ethyltoluene product at a toluene conversion of 20.0%.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([C:14](=[O:16])C)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-:17].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC>ClCCl>[Br:17][C:8]1([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:13]=[CH:12][C:11]([CH:14]=[O:16])=[CH:10][NH:9]1
Reactant: CC(=O)c1cnc(Oc2ccccc2)nc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CCCCCC
Product: O=CC1=CNC(Br)(Oc2ccccc2)N=C1
Temperature: 40 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To a solution consisting of 1-(2-phenoxypyrimidin-5-yl)ethanone (Step B, 400 mg, 1.87 mmol) in dichloromethane (14 mL) was added tetrabutylammonium tribromide (990 mg, 2.05 mmol). The reaction mixture was sealed with a screw top and warmed at 40° C. overnight and allowed to cool to room temperature. Hexane (4 mL) was subsequently added. After three hours and little precipitation, additional (150 mg) tetrabutylammonium tribromide was added and the reaction mixture was stirred overnight at room temperature. The pale yellow precipitate that formed was collected on a filter and washed with 1:1 dichloromethane-hexane to afford the title intermediate (375 mg, 68%); Rf 0.43 with 3:1 v/v hexanes-ethyl acetate; MS (ESI+) m/z 295, 293 (M+1, Br isotopes).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[C:18]([CH2:33][CH2:34][O:35][CH3:36])=[N:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)=[N:21][CH:22]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)C.[OH-].[Li+]>C1COCC1>[CH3:36][O:35][CH2:34][CH2:33][C:18]1[C:17]([CH2:16][O:15][C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[N:6]([CH2:5][C:4]([OH:37])=[O:3])[CH:7]=[CH:8]3)=[CH:22][N:21]=[C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=2)[N:19]=1
Reactant: CCOC(=O)Cn1ccc2cc(OCc3cnc(-c4ccc(C(F)(F)F)cc4)nc3CCOC)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1COc1ccc2c(ccn2CC(=O)O)c1
Yield: 83.8 %

Procedure:
A solution of 147 mg (0.29 mmol) {5-[4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester and 0.9 ml 1N lithium hydroxide solution in 1.5 ml THF were stirred over night at RT. The reaction mixture was partitioned between ether, 1N HCl and water. The residue was suspended in ether/heptane 1:9 and the resulting crystals were filtered off to give 118 mg of pure {5-[4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C(O)C>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:20][C:19]3[CH:21]=[CH:22][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: COc1ccc(N)cc1
Reactant: CSc1ncnc2cc(N)ncc12
Solvent: CCO
Product: COc1ccc(Nc2ncnc3cc(N)ncc23)cc1
Temperature: 40 °C
Yield: 25 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (129 mg, 0.62 mmol) and 4-methoxyaniline ((0.15 g, 1.2 mmol) was in ethanol (5 mL) was heated at 40° C. for 16 h, and then reflux for 3 h. The reaction mixture was cooled to 0° C. overnignt, and the solid was colected by vacuum filtration and recrystalized from isopropanol to give 7-amino-4-(4-methoxyanilino)pyrido[4,3-d]pyrimidine (42 mg, 25%) as a yellow solid. 1H NMR (DMSO) δ 10.00 (1H, brs), 9.31 (1H, s), 8.35 (1H, s), 7.62 (2H, d, J=9.2 Hz), 6.96 (2H, d, J=9.2 Hz), 6.70 (2H, slbrs), 6.41 (1H, s), 3.77 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.C1CCN2C(=NCCC2)CC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:59]([CH2:66][CH2:67][N:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([N:71]2[CH2:70][CH2:69][N:68]([CH2:67][CH2:66][O:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[CH2:73][CH2:72]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: c1ccc(OCCN2CCNCC2)cc1
Reactant: Nc1nc2sc(CCc3ccc(F)cc3)nc2c(=O)[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(N2CCN(CCOc3ccccc3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.4 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-6H-thiazolo[5,4-d]pyrimidin-7-one (133 mg, 0.46 mmol) in DMF (5 ml) was added DBU (0.69 mmol), BOP (0.59 mmol) and 1-(2-phenoxyethyl)piperazine (1.37 mmol). The reaction mixture was stirred at room temperature for 3 hours whereupon the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 2% CH3OH in CH2Cl2), yielding the pure title compound (56 mg) which was characterized by its mass spectrum: MS m/z (%): 479 ([M+H]+, 100).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[N:6]1.[C:16]([O-:19])(=[S:18])[CH3:17].[K+]>CC(C)=O>[C:16](=[O:19])([S:18][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[N:6]1)[CH3:17]
Reactant: ClCCCn1cc(-c2ccccc2)cn1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)SCCCn1cc(-c2ccccc2)cn1
Yield: 88.6 %

Procedure:
0.23 g (1.04 mmol) 1-(3-chloroprop-1-yl)-4-phenyl-1H-pyrazole were dissolved in 6 ml acetone, potassium thioacetate (0.15 g, 1.3 mmol) was added and the mixture was heated to reflux during 16 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (hexane/ethyl acetate, gradient 9:1 to 7:3) to give 240 mg of the desired product as a yellow oil. MS (EI): 260.1 (M+). 1H-NMR (CDCl3): 2.19 (quint, 2H), 2.35 (s, 3H), 2.87 (t, 2H), 4.21 (t, 2H), 7.23 (m, 1H), 7.36 (m, 1H), 7.47 (m, 1H), 7.64 (s, 1H), 7.78 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:10]=[C:11]([C:20]#[N:21])[N:12]3[C:17](Cl)=[CH:16][C:15]([CH3:19])=[N:14][C:13]=23)=[C:4]([CH3:22])[CH:3]=1.NC(N)=[S:25].[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:10]=[C:11]([C:20]#[N:21])[N:12]3[C:17]([SH:25])=[CH:16][C:15]([CH3:19])=[N:14][C:13]=23)=[C:4]([CH3:22])[CH:3]=1
Reactant: Cc1cc(Cl)n2c(C#N)cc(-c3c(C)cc(Br)cc3C)c2n1
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(S)n2c(C#N)cc(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
A mixture of 8-(4-bromo-2,6-dimethyl-phenyl)-4-chloro-2-methyl-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (7.50 g), thiourea (7.11 g) in ethanol (50 mL) was heated at reflux for 2 h. The reaction mixture was cooled to room temperature, poured into 0.5 M NaOH aqueous solution, stirred for 1 hour and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: chloroform/methanol=10:1) to give 8-(4-bromo-2,6-dimethyl-phenyl)-4-mercapto-2-methyl-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (7.52 g).
Reaction SMILES: O=[C:2]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][C:4]([OH:6])=[O:5].[CH3:11][NH2:12].Cl[CH2:14][C:15](=O)[CH3:16].Cl>O>[C:4]([C:3]1[C:15]([CH3:16])=[CH:14][N:12]([CH3:11])[C:2]=1[CH2:7][C:8]([OH:10])=[O:9])([OH:6])=[O:5]
Reactant: CN
Reactant: O=C(O)CC(=O)CC(=O)O
Reactant: CC(=O)CCl
Agent: Cl
Solvent: O
Product: Cc1cn(C)c(CC(=O)O)c1C(=O)O
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
To 1200 parts of cold water (about 5° C.) there are added 292 parts of 3-oxo-pentanedioic acid and the reaction mixture is further cooled to -5° C. 1770 Parts of methanamine 35% in water are then added slowly while stirring and cooling to a temperature between -5° C. and 5° C. The reaction mixture is further cooled to about -15° C. Then 370 parts of 1-chloro-2-propanone are added portionwise under vigorous cooling. An exothermic reaction takes place and the temperature of the mixture raises to about 15° C. It is again cooled to about 0° C. and further stirred at this temperature for about 16 hours. The reaction mixture is then poured onto a mixture of 4000 parts of ice and 2200 parts of concentrated hydrochloric acid solution (10.5 N) and stirring is continued for 20 minutes. The product is filtered off and dried in vacuo at 50° C. over CaCl2, yielding 335 parts (85%) of 3-carboxy-1,4-dimethyl-1H-pyrrole-2-acetic acid, mp. 192.8°-194.6° C. dec.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]3[CH2:10][CH2:11][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:7]=3[C:6]=2[CH:19]=1.[C:20]([Cu])#[N:21]>CN1CCCC1=O>[C:20]([C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]3[CH2:10][CH2:11][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:7]=3[C:6]=2[CH:19]=1)#[N:21]
Reactant: N#C[Cu]
Reactant: CCOC(=O)C1CCc2sc3ccc(Br)cc3c2C1
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CCc2sc3ccc(C#N)cc3c2C1
Temperature: 170 °C
Yield: 88.1 %

Procedure:
To a solution of ethyl 8-bromo-1,2,3,4-tetrahydrodibenzo[b,d]thiophene-2-carboxylate (0.62 g, 1.83 mmol) in 10 mL 1-methylpyrrolidin-2-one was added CuCN (0.328 g, 3.66 mmol). The reaction was heated at 170° C. overnight, then was cooled to room temperature and was partitioned between EtOAc and water. The organic layer was washed with water, then brine, then dried over MgSO4, filtered and concentrated. Purification by chromatography on silica gel (25% EtOAc in hexane) afforded 0.46 g (88%) of the title compound as a white solid: mp 121-122° C.; MS (ES) m/z=285 [M]+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:32][N:33]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:36]3[CH2:37][CH2:38][CH2:39][N:33]([CH3:32])[CH2:34][CH2:35]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CN1CCCNCC1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCCN(C)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of the product of step i) (0.45 g) in dichloromethane (50 mL) was treated with 1-methyl-1,4-diazepane (0.61 g) and sodium triacetoxyborohydride (0.68 g) and then stirred at room temperature overnight. Methanol (5 mL) was added and the solution purified directly by SiO2 chromatography (eluting with 0 to 20% methanol in dichloromethane) followed by HPLC to give the title compound as a solid (150 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]([C:10]1[S:11][C:12]([S:26][CH3:27])=[C:13]([S:15]([C:18]2[CH:23]=[C:22]([OH:24])[CH:21]=[C:20](Br)[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>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>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]([C:10]1[S:11][C:12]([S:26][CH3:27])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[Cl:29])[CH:21]=[C:22]([OH:24])[CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1Cl
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cc(O)cc(Br)c1
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+]
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cc(O)cc(-c2ccccc2Cl)c1
Yield: 23.5 %

Procedure:
Following the procedure outlined in Example 1: step c, {[4-(3-bromo-5-hydroxy-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (80 mg, 0.158 mmol) was reacted with 2-chlorophenylboronic acid (98.6 mg, 0.631 mmol), Na2CO3 (134 mg, 1.26 mmol), and Pd(PPh3)4 (45.5 mg, 0.039 mmol). Aqueous workup followed by SiO2 flash chromatography yielded the title compound (20 mg, 24%).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[C:15]([Li])([CH3:18])([CH3:17])[CH3:16].CCCCC.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.[OH-].[Na+]>O1CCCC1>[C:15]([CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[N:6]1[S:33]([C:30]1[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=1)(=[O:35])=[O:34])([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: [Li]C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
A stirred solution of phenanthridine (7.16 g, 40 mmol) in anhydrous tetrahydrofuran (20 mL) was cooled to −30° C., and treated drop-wise under nitrogen via syringe with a solution of 1.7 M tert-butyllithium in pentane (24 mL, 40.8 mmol). The yellow solution was warmed to room temperature and stirred for 15 minutes. The mixture was cooled to −78° C., and treated with 4-methoxybenzenesulfonyl chloride (8.27 g, 40 mmol) as a solid in a single aliquot. The reaction mixture was warmed slowly to room temperature over one hour, poured into 1 N aqueous sodium hydroxide, and extracted with ethyl acetate. The organic phase was washed sequentially with water, a 1 N hydrochloric acid solution, and a saturated, aqueous, sodium chloride solution. After drying over anhydrous sodium sulfate, the organic phase was filtered through a short column of silica gel, and the filtrate evaporated in vacuo to yield a crude yellow oil (16.2 g, 99%). The crude oil was purified by preparative chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with a mixture of methyl tert-butyl ether-hexane (15:85) at a flow rate of 40 mL/min to afford, after evaporation of the solvent, a colorless oil. Crystallization of the colorless oil from a mixture of diethyl ether-hexane yielded the title compound (3.7 g, 9.1 mmol, 23%) as a homogeneous, colorless, crystalline solid, m.p. 156-158° C.