Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[N:18][CH:19]=1>>[F:13][C:14]1[CH:15]=[C:16]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=3)[CH:7]=2)[CH:17]=[N:18][CH:19]=1
Reactant: O=Cc1cnc2ccc(Br)cn12
Reactant: OB(O)c1cncc(F)c1
Product: O=Cc1cnc2ccc(-c3cncc(F)c3)cn12
Yield: 52 %

Procedure:
The title compound was prepared by following the procedure as described for Intermediate 1 using 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde and 5-fluoropyridin-3-ylboronic acid. Yield: 52%; 1H NMR (DMSO-d6; 300 MHz): δ 10.01 (s, 1H), 9.66 (s, 1H), 8.84 (s, 1H), 8.66-8.67 (d, 1H, J=2.1 Hz), 8.59 (s, 1H), 8.18-8.21 (d, 1H, J=9 Hz), 8.08-8.11 (d, 1H, J=9.6 Hz), 8.03 (s, 1H); MS: m/z 241.6 (M+1)+.
Reaction SMILES: [C:1]1([Se:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[CH2:13](Cl)[Cl:14]>>[C:1]1([Se:7][CH2:8][CH2:9][O:10][CH2:13][Cl:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC[Se]c1ccccc1
Reactant: ClCCl
Agent: C=O
Product: ClCOCC[Se]c1ccccc1

Procedure:
To a solution of 2-(phenylselenyl)ethanol (4.0 g, 20 mmol) [prepared according to the literature procedure: P. Rollin, V. V. Bencomo, P. Sinay, Synthesis, 13 (1984)] in CH2Cl2 (15 mL) was added paraformaldehyde (620 mg, 20 mmol). HCl gas was then bubbled into the solution at 5° C. for 2 hr. The solution was dried (MgSO4), and the solvent was removed under reduced pressure to give the title compound as a colorless oil in a quantitative yield.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Br:31][C:32]1[CH:37]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:35]=[CH:34][C:33]=1[CH2:42]Br.Cl>CN(C)C=O>[Br:31][C:32]1[CH:37]=[C:36]([C:38]([CH3:40])([CH3:39])[CH3:41])[CH:35]=[CH:34][C:33]=1[CH2:42][N:9]1[C:10](=[O:23])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:12]([OH:13])[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]1=[O:24]
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Reactant: CC(C)(C)c1ccc(CBr)c(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(Cn2c(=O)c(C(=O)NCC(=O)O)c(O)n(C3CCCCC3)c2=O)c(Br)c1
Reaction time: 8 h
Yield: 7.5 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (740 mg, 5.35 mmoles) and 2-bromo-1-(bromomethyl)-4-(1,1-dimethylethyl)benzene (612 mg, 2.0 mmoles) in dimethylformamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide (1.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Preparative HPLC (50-90% acetonitrile-water-0.1% TFA) gave the title compound (40 mg, 7.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br. s., 1 H), 10.14 (br. s., 1 H), 7.59 (d, J=1.52 Hz, 1H), 7.33 (dd, J=8.08, 1.52 Hz, 1 H), 6.92 (d, J=8.08 Hz, 1 H), 4.96 (s, 2 H), 4.65 (t, J=11.75 Hz, 1H), 4.13 (d, J=5.56 Hz, 2 H), 2.25 (q, J=11.54 Hz, 2 H), 1.79 (d, J=12.13 Hz, 2 H), 1.53-1.73 (m, 3 H), 1.20-1.38 (m, 11 H), 1.11 (q, 1 H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=3)[CH:19]=2)[CH:3]=1.[H][H]>C1COCC1.CO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[C:26]([NH2:30])[CH:27]=[CH:28][CH:29]=3)[CH:19]=2)[CH:3]=1
Reactant: [H][H]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3cccc([N+](=O)[O-])c3)c2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3cccc(N)c3)c2)c1
Yield: 75.1 %

Procedure:
A mixture of the above prepared 4-methyl-2′-(3-nitro-phenyl)-6-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl (1.12 g, 3.0 mmol) in THF-MeOH 1:1 (100 mL) and 10% palladium on carbon (1 mol %) was hydrogenated (1 bar hydrogen) at 23° C. for 2 h. The catalyst was filtered off, washed with MeOH and the filtrate was completely evaporated totally to leave a crude product, which was purified by trituration with diethyl ether to give the title compound as a light brown solid (0.914 g, 88%). MS (ISP) 406.5 [(M+H)+]; mp 87° C. (dec.).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+].O>C1COCC1.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>[CH2:26]([O:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]([C:6]3[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=3)=[CH:14][CH:15]=2)=[CH:24][CH:23]=1)[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
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: C1CCOC1
Product: CCCCCOc1ccc(-c2ccc(-c3ccc(C=O)cc3)cc2)cc1
Yield: 58 %

Procedure:
Under an argon atmosphere, (4-formylphenyl)boronic acid (0.54 g, 3.6 mmol), 4-Bromo-4′-pentyloxy-biphenyl (0.958 g, 3 mmol) 1) (A1), sodium hydrogen carbonate (0.76 g, 9 mmol), and tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) (0.057 g, 0.030 mmol) were dissolved in THF (15 mL) and water (15 mL) and stirred under a reflux condition. After they reacted with each other, liquid separation and extraction were performed with water and chloroform. After an organic layer was dried with anhydrous sodium sulfate and filtered, the solvent was distilled off under a reduced pressure. After the obtained reaction mixture was separated and purified with a silica gel column chromatography using chloroform as a moving bed, the mixture was purified by a recrystallization method using chloroform and hexane. Thereby, a white solid of 4″-(pentyloxy)-[1,1′:4′,1″-terphenyl]-4-carbaldehyde (A2) was obtained (0.60 g, yield: 58%). The obtained product (A2) was identified by using a 1H-NMR method. 1H-NMR (CDCl3, 400 MHz) δ=10.06 (s, 1H, CHO), 7.95-7.97 (d, 2H, phenylene), 7.79-7.81 (d, 2H, phenylene), 7.71-7.66 (m, 4H, phenylene), 7.00-6.98 (s, 2H, phenylene), 4.03-3.99 (t, 2H, —O—CH2—), 1.84-1.81 (t, 2H, —CH2—), 1.47-1.40 (m, 4H, —CH2—), and 0.93-0.97 (t, 3H, —CH3). 13C NMR (CDCl3, 100 MHz) δ=191.7, 159.0, 146.7, 141.0, 137.8, 135.2, 132.4, 130.2, 128.0, 127.2, 114.9, 68.1, 29.0, 28.3, 22.7, and 14.1.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[N:22]=[CH:21][N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[CH3:23].[Br:24]C(Cl)(Cl)C(Cl)(Cl)Br>C1COCC1>[Br:24][C:17]1[N:18]([CH3:23])[C:19]2[C:15]([N:16]=1)=[C:14]([Cl:13])[N:22]=[CH:21][N:20]=2
Reactant: Cn1cnc2c(Cl)ncnc21
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cn1c(Br)nc2c(Cl)ncnc21
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a dry flask was added diisopropyl amine (1.6 mL, 11.42 mmol) and THF (15 mL). The solution was cooled to −78° C. and n-butyllithium (2.5M in hexanes, 4.5 mL, 11.25 mmol) was added dropwise. After stirring for 10 minutes at −78° C., the solution was warmed to 0° C. and allowed to stir for an additional 10 minutes. The solution was cooled back to −78° C. and 6-chloro-9-methyl-9H-purine (1.5 g, 8.9 mmol) was added as a suspension in THF (20 mL). After stirring for 20 minutes −78° C., 1,2-dibromotetrachloroethane was added (5.7 g, 17.5 mmol), and after an additional 20 minutes the reaction was quenched with the addition of sat. aq. NH4Cl (15 mL). Upon warming to room temperature, the solution was diluted with ethyl acetate (75 mL) and the aqueous layer was discarded. The organics were washed with brine and dried using magnesium sulfate. The solvent was removed in vacuo to provide a brown solid that was purified by column chromatography (25-50% ethyl acetate in hexanes) to yield 1.493 g tan solid product. 1H NMR (400 MHz, DMSO-d6): δ 8.84 (d, J=72.7 Hz, 1H), 3.76 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]([CH3:31])[C:16]([NH:18][C:19]2[C:24]([Cl:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=2[Cl:30])=[O:17])[CH:10]=1.C(N(CC)CC)C.[Cl:39]/[CH:40]=[CH:41]/[C:42](O)=[O:43].C(Cl)Cl.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>>[Cl:39]/[CH:40]=[CH:41]/[C:42]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:10]=[C:11]([N:15]([CH3:31])[C:16]([NH:18][C:19]2[C:20]([Cl:30])=[C:21]([O:28][CH3:29])[CH:22]=[C:23]([O:26][CH3:27])[C:24]=2[Cl:25])=[O:17])[N:12]=[CH:13][N:14]=1)=[O:43]
Reactant: O=C(O)/C=C/Cl
Reactant: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3N)ncn2)c1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3NC(=O)/C=C/Cl)ncn2)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.3 %

Procedure:
The title compound was synthesized following the approach outlined in Procedure 2A (Example 100), modifying step (i) to the following procedure: To a solution of 1-(6-((2-aminophenyl)amino)pyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylurea (10 mg, 0.022 mmol), triethylamine (10.9 g, 0.11 mmol), and (E)-3-chloroacrylic acid (2.76 g, 0.026 mmol) in DCM (0.4 ml, 6.22 mmol), cooled to 0° C., was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.023 ml, 0.039 mmol, 50% solution in EtOAc). The resulting mixture was stirred at room temperature for 4 h and concentrated. The remaining residue was purified by silica gel flash chromatography to obtain the title compound (7.2 mg, yield: 61%). 1H NMR (400 MHz, CDCl3) δ 3.30 (s, 3H) 3.90 (s, 6H) 6.02 (s, 1H) 6.36 (d, J=12.92 Hz, 1H) 6.49 (s, 1H) 7.21-7.33 (m, 2H) 7.36-7.50 (m, 2H) 7.75 (d, J=6.53 Hz, 1H) 7.93 (br. s., 1H) 8.41 (s, 1H) 12.50 (s, 1H); MS (ESI): 551.0 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[C:18]([CH3:28])=[N:19][N:20]4[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][C:21]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1.C(O)(=O)C.C(Cl)Cl.[CH3:38][O:39][C:40]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:41]=1[CH2:42][NH2:43].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[C:18]([CH3:28])=[N:19][N:20]4[CH:25]=[CH:24][C:23]([CH2:26][NH:43][CH2:42][C:41]5[CH:44]=[CH:45][C:46]([O:48][CH3:49])=[CH:47][C:40]=5[O:39][CH3:38])=[CH:22][C:21]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1nn2ccc(C=O)cc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2nnc[nH]2)s1
Reactant: COc1ccc(CN)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(CNCc2ccn3nc(C)c(-c4nc(Cc5ccc(Cl)cc5)c(-c5nnc[nH]5)s4)c3c2)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
To a suspension of 3-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridine-5-carbaldehyde (0.300 g, 0.690 mmol) in acetic acid (0.20 mL, 3.5 mmol) and dry methylene chloride (10 mL, 200 mmol) was added 2,4-dimethoxybenzylamine (0.207 mL, 1.38 mmol), followed by additional of sodium triacetoxyborohydride (0.363 g, 1.71 mmol). The mixture was stirred at rt. for 16 hours. The mixture was basified with NaHCO3 solution to =pH 8 then extracted with DCM. The DCM solution was washed with water. The crude product was purified by column chromatography (SiO2, elution with 0-100% MeOH in DCM) to afford a solid product (0.252 g, yield 62%). LCMS: (FA) ES+ 586, 588; ES− 584, 586. 1H NMR (400 MHz, CDCl3 and d4-methanol) δ: 8.23-8.25 (d, J=7.03 Hz, 1H), 8.18 (s, 1H), 8.01 (s, 1H), 7.28-7.30 (d, J=8.53 Hz, 2H), 7.09-7.11 (d, J=8.53 Hz, 2H), 7.01-7.03 (d, J=8.28 Hz, 1H), 6.78-6.80 (d, J=7.03 Hz, 1H), 6.33-6.37 (m, 2H), 4.53 (s, 2H), 3.65 (s, 2H), 3.64 (s, 6H), 3.61 (s, 2H), 2.61 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[CH3:12][CH:13]1[CH2:18][NH:17][CH2:16][CH:15]([CH3:19])[NH:14]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:17]1[CH2:16][CH:15]([CH3:19])[NH:14][CH:13]([CH3:12])[CH2:18]1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CC1CNCC(C)N1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(S(=O)(=O)c2ccccc2Br)CC(C)N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
A solution of 2-bromobenzene-1-sulfonyl chloride (100 mg, 0.39 mmol), 2,6-dimethylpiperazine (56 mg, 0.49 mmol), and diisopropylethyl amine (0.202 mL, 1.17 mmol) in CH2Cl2 (2.5 mL) was allowed to stir for 15 min at rt. The reaction mixture was then directly subjected to FCC purification to give the title compound (0.105 g, 81%). 1H NMR (600 MHz, CDCl3) δ 8.09-8.07 (m, 1H), 7.76-7.73 (m, 1H), 7.47-7.44 (m, 1H), 7.43-7.37 (m, 1H), 3.70-3.66 (m, 2H), 2.97-2.91 (m, 2H), 2.38-2.33 (m, 2H), 1.06-1.04 (m, 6H).
Reaction SMILES: C1(O[C:8]([N:18]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([N:26]3[CH2:31][CH2:30][CH:29]([CH:32]4[C:38]5=[N:39][CH:40]=[C:41]([Br:43])[CH:42]=[C:37]5[CH2:36][CH2:35][C:34]5[CH:44]=[C:45]([Cl:49])[CH:46]=[C:47]([Cl:48])[C:33]4=5)[CH2:28][CH2:27]3)=[O:25])[CH2:19]2)=[N:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)C=CC=CC=1.[NH4+:50].[OH-]>CC(O)C>[Br:43][C:41]1[CH:42]=[C:37]2[CH2:36][CH2:35][C:34]3[CH:44]=[C:45]([Cl:49])[CH:46]=[C:47]([Cl:48])[C:33]=3[CH:32]([CH:29]3[CH2:30][CH2:31][N:26]([C:24](=[O:25])[CH2:23][CH:20]4[CH2:21][CH2:22][N:18]([C:8](=[NH:50])[NH:9][C:10](=[O:17])[C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[CH2:19]4)[CH2:27][CH2:28]3)[C:38]2=[N:39][CH:40]=1
Reactant: [NH4+]
Reactant: O=C(N=C(Oc1ccccc1)N1CCC(CC(=O)N2CCC(C3c4ncc(Br)cc4CCc4cc(Cl)cc(Cl)c43)CC2)C1)c1ccccc1
Agent: [OH-]
Solvent: CC(C)O
Product: N=C(NC(=O)c1ccccc1)N1CCC(CC(=O)N2CCC(C3c4ncc(Br)cc4CCc4cc(Cl)cc(Cl)c43)CC2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product of Example 28 is dissolved in 2-propanol and concentrated NH4OH is added. he mixture is stirred at 25° C. for 24 h and then evaporated to dryness. The residue is triturated with Et2O (2×250 ml) and the ether discarded. The resulting product is chromatographed on a silica gel column to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[Cl:18])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2sc1=O
Reactant: OB(O)c1ccccc1Cl
Product: COC(=O)c1c(O)c2cc(-c3ccccc3Cl)ccc2sc1=O

Procedure:
6-(2-Chloro-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 6-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 7(a) using 2-chloro-phenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.412 (s, 1H), 7.697 (d, 1H), 7.490-7.305 (m, 5H), 4.018 (s, 3H).
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)[C:3](=[O:5])[CH3:4].C(N(CC)CC)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1>C(O)C>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:27][CH:26]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(=O)C(Cl)=NNc1cccc([N+](=O)[O-])c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)C(=NNc1cccc([N+](=O)[O-])c1)Sc1ccc(Cl)cc1

Procedure:
1-chloro-1-[(3-nitrophenyl)hydrazono]-2-propanone is reacted with 4-chlorothiophenol triethyl amine in ethanol as Example 11 to yield 1-[(4-chlorophenyl)thio]-1-[(3-nitrophenyl)hydrazono]-2-propanone.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].Cl.[CH2:13]([N:15]([CH2:23][CH3:24])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)[CH3:14].C(=O)([O-])O.[Na+]>ClCCl>[CH2:5]([O:4][C:2]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([N:15]([CH2:23][CH3:24])[CH2:13][CH3:14])=[CH:21][CH:20]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)c1ccc(NC(=O)OCc2ccccc2)cc1
Reaction time: 16 h
Yield: 61.2 %

Procedure:
Benzyl chloroformate (15.7 mL, 0.11 mol) was added dropwise to a stirred mixture of N,N-diethyl-p-phenylenediamine hydrochloride (20 g, 0.1 mol) and sodium hydrogen carbonate (42.0 g) in dichloromethane at room temperature under nitrogen. After 16 hours at room temperature, the precipitate which had formed was removed by filtration. The solid residue was washed with dichloromethane and the combined dichloromethane extracts were concentrated to produce a brown oil. This material was purified by preparative high pressure liquid chromatography (hereinafter HPLC) on silica gel eluting with 10% hexanes/dichloromethane followed by dichloromethane alone. The resultant oil was triturated with hexanes to give N-benzyloxycarbonyl-4-diethylaminoaniline (18.25 g, 61% yield) as a crystalline solid. The structure of this compound was confirmed by mass spectroscopy and by 1H NMR spectroscopy.
Reaction SMILES: [C:1]1(=[O:14])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[C:2]1=[O:13].[I:15]Cl>C(O)(=O)C>[I:15][C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([C:1](=[O:14])[C:2](=[O:13])[N:3]3[CH2:4][CH2:5][CH2:6]2)[CH:10]=1
Reactant: O=C1C(=O)N2CCCc3cccc1c32
Reactant: ClI
Solvent: CC(=O)O
Product: O=C1C(=O)N2CCCc3cc(I)cc1c32
Temperature: 0 °C

Procedure:
A mixture of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1,2dione (5 g) and iodine monochloride (5 g) in acetic acid (30 ml) was refluxed for 5 hours. After cooling, the mixture was poured into ice water and extracted with chloroform. The extract was washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution successively and then dried over anhydrous sodium sulfate. Evaporation of chloroform afforded the title compound. The compound was recrystallized from ethanol to give 6.2 g (73.8%) as dark red needles.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:16]1([CH2:22][S:23][CH:24]([C:28]([OH:30])=O)[C:25]([OH:27])=[O:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:31]1[CH2:35]O[CH2:33][CH2:32]1>>[OH:30][C:28]1[CH:33]=[C:32]([CH2:31][CH2:35][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:27][C:25](=[O:26])[C:24]=1[S:23][CH2:22][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C1CCOC1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: O=c1oc(CCc2ccccc2)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4-phenethylacetophenone (0.786 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. 164-166° C.; 1H NMR (400 MHz, DMSO-d6) δ2.75 (t, 3 H), 2.85 (t, 2 H), 3.92 (s, 2 H), 5.92 (s, 1 H), 7.23 (m, 9H), 11.69 (bs, 1 H).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:4]=[CH:5][N:6]2[C:12](=[S:13])[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][C:7]=12.[N:18]#[C:19]Br>O1CCCC1>[S:13]([C:12]1[N:6]2[CH:5]=[CH:4][N:3]=[C:7]2[S:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[N:11]=1)[C:19]#[N:18]
Reactant: S=C1Nc2ccccc2Sc2nccn21
Reactant: N#CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CSC1=Nc2ccccc2Sc2nccn21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The starting material is prepared as follows: To the suspension of 1.44 g of 50% sodium hydride in mineral oil and 150 ml of dry tetrahydrofuran, 6.45 g of imidazo[2,1-b][1,3,5]benzothiadiazepin-5(6H)-thione are added in portions, and the mixture is stirred at room temperature under nitrogen for one hour. The resulting white suspension is cooled to 0° and the solution of 3.5 g of cyanogen bromide in 10 ml of tetrahydrofuran are added dropwise. The mixture is stirred at room temperature for 0.5 hour and evaporated. The residue is triturated with methylene chloride, the mixture washed with water, dried, concentrated to a small volume, washed with diethyl ether and filtered, to yield the 5-thiocyanatoimidazo[2,1-b][1,3,5]benzothiadiazepine melting at 111°-113°.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:9]=[C:8]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])OC3C=CC=CC=3)=[CH:20][CH:19]=2)[N:7]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:41][NH:42][CH2:43][CH2:44][OH:45]>CN1C(=O)CCC1>[OH:45][CH2:44][CH2:43][N:42]([CH3:41])[C:25]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([C:8]2[N:7]=[C:6]([CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:9]=2)=[CH:23][CH:22]=1)=[O:33]
Reactant: CS(=O)(=O)Cc1cc(N2CCOCC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Reactant: CNCCO
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CN(CCO)C(=O)Nc1ccc(-c2nc(CS(C)(=O)=O)cc(N3CCOCC3)n2)cc1
Temperature: 70 °C

Procedure:
A solution of phenyl N-[4-[4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]phenyl]carbamate (94 mg, 2 mmol) and triethylamine (0.09 mL, 9.2 mmol) in NMP (1 mL) was added to 2-methylaminoethanol (10 mmol). The mixture was heated at 70° C. for 2 hours and the reaction purified by prep HPLC, to give the desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:15])[C:7]=1[CH2:8][CH2:9][C:10]([O:12]CC)=O.[Li]CCCC>C1COCC1>[Br:15][C:6]1[C:7]2[CH2:8][CH2:9][C:10](=[O:12])[C:2]=2[CH:3]=[N:4][CH:5]=1
Reactant: CCOC(=O)CCc1c(Br)cncc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1CCc2c(Br)cncc21
Reaction time: 2 h
Yield: 47.6 %

Procedure:
To a solution of ethyl 3-(3,5-dibromopyridin-4-yl)propanoate (4 g, 11.9 mmol) in THF (60 mL) was slowly added n-BuLi (9.52 mL, 23.8 mmol, 2.5 M in hexane) while keeping the inner temperature below −70° C. After the addition, the reaction mixture was stirred below −65° C. for additional 2 hours. The reaction was quenched with water and then extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhy. Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by column chromatography to afford the title compound (1.2 g, 47.6%) as a solid. MS: MS: 213.7 (M+H+, 1Br).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20]1[N:21]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:22]=[C:23]([CH3:25])[CH:24]=1)=[O:4].[OH-].[Li+]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([C@H:8]1[CH2:7][N:6]([C:20]2[N:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[N:22]=[C:23]([CH3:25])[CH:24]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]1)(=[O:12])=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1Cc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)O)n(Cc2ccc(Cl)cc2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-[2-(4-chloro-benzyl)-5-methyl-2H-pyrazol-3-yl]-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as off-white solid which was used in the next step without further purification. MS (ESI): m/z=494.1 [M+H]+.