Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[C:22]([C:29]3[NH:37][C:36]4[CH:35]([CH3:38])[CH2:34][NH:33][C:32](=[O:39])[C:31]=4[CH:30]=3)[CH:23]=[CH:24][CH:25]=2)[N:20]=1.C(O)(C(F)(F)F)=O>CS(C)=O>[CH3:38][CH:35]1[CH2:34][NH:33][C:32](=[O:39])[C:31]2[CH:30]=[C:29]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:21]=3[N:20]=[C:19]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:28]=[CH:27]4)[NH:37][C:36]1=2
Reactant: CC1CNC(=O)c2cc(-c3cccc4ccc(Cl)nc34)[nH]c21
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC1CNC(=O)c2cc(-c3cccc4ccc(Nc5ccccc5)nc34)[nH]c21
Reaction time: 8 h
Yield: 40.1 %

Procedure:
A solution of LHMDS (1.0 M in THF; 2.197 ml, 2.197 mmol), aniline (0.200 ml, 2.197 mmol), and 2-(2-chloroquinolin-8-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 27; 0.137 g, 0.439 mmol) was stirred at RT for 1.5 h. An additional 2 equiv LHMDS (1.0 M in THF) was added, and the reaction was stirred overnight. The reaction was concentrated under N2, treated with DMSO and TFA (0.474 ml, 6.15 mmol), filtered, and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 10-80% ACN/H2O with 0.1% TFA); product-containing fractions were treated with saturated aq. NaHCO3 and DCM. The organic layer was separated, and the aq. layer was extracted 3×DCM. The combined organic layers were then dried over Na2SO4, filtered, and concentrated in vacuo to give rac-7-methyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.065 g, 0.176 mmol, 40% yield, Example 238) as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.11 (1H, br. s), 9.53 (1H, s), 8.12 (1H, d, J=9.0 Hz), 7.93 (1H, dt, J=7.4, 0.8 Hz), 7.56-7.71 (3H, m), 7.34-7.45 (2H, m), 7.29 (1H, t, J=7.6 Hz), 6.99-7.14 (2H, m), 6.85-6.98 (2H, m), 3.38-3.52 (1H, m), 2.86-3.08 (2H, m), 0.84 (3H, d, J=6.7 Hz). m/z (ESI, +ve) 369.1 (M+H)+. A portion of this material was resolved by chiral SFC (ChiralPak AS-H (21×250, 5 μm); additive in supercritical fluid CO2 was 40% MeOH with 20 mM NH3; 60 mL/min; column temperature 40° C.; outlet pressure 100 bar) to give separated enantiomers 7-methyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 29, first eluting enantiomer) and 7-methyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 30, second eluting anantiomer).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8][CH2:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12])=[CH:6][C:5]([Br:15])=[CH:4][N:3]=1.CC(C)=[O:18].[OH2:20].S([O-])(O[O-])(=O)=O.[K+].[K+]>CO>[NH2:1][C:2]1[C:7]([S:8]([CH2:9][CH2:10][C:11]([CH3:12])([OH:13])[CH3:14])(=[O:18])=[O:20])=[CH:6][C:5]([Br:15])=[CH:4][N:3]=1
Reactant: CC(C)=O
Reactant: O
Reactant: CC(C)(O)CCSc1cc(Br)cnc1N
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(O)CCS(=O)(=O)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To a solution of 4-[(2-amino-5-bromopyridin-3-yl)thio]-2-methylbutan-2-ol (90 mg, 0.31 mmol) in a mixture of methanol (750 μL), acetone (750 μL) and water (450 μL) was added potassium peroxymonosulfate (285 mg, 0.46 mmol) and the reaction mixture was stirred for 15 minutes at room temperature. The reaction mixture was partitioned between water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography (35% to 80% ethyl acetate in hexane) gave 4-[(2-amino-5-bromopyridin-3-yl)sulfonyl]-2-methylbutan-2-ol (48 mg, 48%); MS (EI) for C10H15BrN2O3S: 323 (MH+).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:51])[N:20]([CH2:39][C:40]2[C:48]3[O:47][C:46]([CH3:50])([CH3:49])[CH2:45][C:44]=3[CH:43]=[CH:42][CH:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:51])[N:20]([CH2:39][C:40]2[C:48]3[O:47][C:46]([CH3:50])([CH3:49])[CH2:45][C:44]=3[CH:43]=[CH:42][CH:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(Cc2cccc3c2OC(C)(C)C3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2cccc3c2OC(C)(C)C3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
A mixture of hydroxylammonium chloride (1.35 g), sodium hydrogen carbonate (2.17 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-1-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.67 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.25 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.16 g, 21%).
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH:2]12.Cl[C:11]1[N:12]=[CH:13][C:14]([C:17]([NH:19][C:20]2[NH:21][N:22]=[C:23]([CH2:25][CH2:26][C:27]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=3)[CH:24]=2)=[O:18])=[N:15][CH:16]=1>CS(C)=O>[CH2:1]1[CH:2]2[CH2:9][CH2:8][CH2:7][N:3]2[CH2:4][CH2:5][N:6]1[C:11]1[N:12]=[CH:13][C:14]([C:17]([NH:19][C:20]2[NH:21][N:22]=[C:23]([CH2:25][CH2:26][C:27]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=3)[CH:24]=2)=[O:18])=[N:15][CH:16]=1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Reactant: C1CC2CNCCN2C1
Solvent: CS(C)=O
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN5CCCC5C4)cn3)[nH]n2)cc(OC)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
1,2,3,4,6,7,8,8a-Octahydropyrrolo[1,2-a]pyrazine (429 mg, 3.40 mmol) was added in one portion to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (659 mg, 1.70 mmol) in anhydrous dimethylsulfoxide (1.70 ml) at 25° C. The resulting solution was stirred at 100° C. for 18 h. The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% TFA) and MeCN as eluents. The material was then put through basic HPLC to obtain the free base. Fractions containing the desired compound were evaporated to dryness to afford the title compound (438 mg, 54%) as a cream solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH2:19]([NH:26][CH2:27][CH2:28][OH:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>O1CCCC1.CN(C)C=O>[CH2:19]([N:26]([CH2:27][CH2:28][OH:29])[C:5](=[O:7])[C:4]1[C:8]([F:11])=[CH:9][CH:10]=[C:2]([Br:1])[C:3]=1[F:12])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1c(F)ccc(Br)c1F
Reactant: OCCNCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(c1c(F)ccc(Br)c1F)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
To a solution of 3-bromo-2,6-difluorobenzoic acid (2.00 g, 8.44 mmol) and N,N-dimethylformamide (0.1 ml) in tetrahydrofuran (40 ml) was added dropwise oxalyl chloride (1.47 ml, 16.9 mmol) in a water bath, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure. The residue was added under ice-cooling to a solution of N-benzylethanolamine (1.28 ml, 8.44 mmol) and triethylamine (1.77 ml, 12.7 mmol) in tetrahydrofuran (50 ml), and the mixture was stirred at 0° C. for 15 min and at room temperature for 1 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solution of diethyl ether and diisopropyl ether to give the desired product (2.10 g, 67.3%) as a solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[C:32]1([CH3:41])[CH:37]=[CH:36][C:35]([C:38](Cl)=[O:39])=[CH:34][CH:33]=1>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:38](=[O:39])[C:35]3[CH:36]=[CH:37][C:32]([CH3:41])=[CH:33][CH:34]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and p-toluoyl chloride (0.43 g, 2.8 mmol). The mixture was then stirred at room temperature overnight and a suspension was obtained. The reaction mixture was quenched with MeOH (1 mL) and washed with H2O (40 mL), 1N HCl (40 mL) and brine (40 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The resulting mixture was purified by ISCO silica gel flash chromatography (eluent: 3% MeOH in CH2Cl2) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-4-methyl-benzamide as a white solid (0.5 g, 61%): mp, 218-220° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.3 (97%); 1H NMR (DMSO-d6): δ 2.06-2.11 (m, 1H), 2.36 (s, 3H), 2.54-2.64 (m, 2H), 2.85-2.93 (m, 1H), 4.94 (d, J=5.7 Hz, 2H), 5.15-5.21 (dd, J=5, 12 Hz, 1H), 7.31 (d, J=8.0 Hz, 2H), 9.07 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 20.93, 31.97, 30.92, 38.26, 48.85, 121.81, 127.08, 127.30, 128.87, 131.11, 131.51, 132.98, 134.77, 139.47, 141.35, 166.47, 166.97, 167.54, 169.83, 172.74. Anal Calcd for C22H19N3O5: C, 65.18; H, 4.72; N, 10.36. Found: C, 64.78; H, 4.72; N, 10.07.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.[F:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](O)=[O:33].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCCl>[C:25]([C:9]1[CH:8]=[N:7][N:6]2[CH:27]=[C:3]([NH:2][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[F:29])[C:4]([CH3:28])=[C:5]2[C:10]=1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)#[N:26]
Reactant: O=C(O)c1ccccc1F
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(NC(=O)c2ccccc2F)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Yield: 41.9 %

Procedure:
6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (8 mg, 0.02 mmol), 2-fluorobenzoic acid (4.2 mg, 0.03 mmol), PyBOP (16 mg, 0.03 mmol) and DIEA (6.5 mg, 0.05 mmol) in 1,2-dichloroethane (0.5 ml) were stirred at RT for 16 hrs. The reaction mixture was concentrated and purified by silica gel flash chromatography to isolate 374 as a white solid (4 mg, 42%). [M+H]+=478.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)Cc1cccc(Cl)c1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)C(Br)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
3-Chlorophenylacetic acid (20.90 g, 122.51 mmol) and NBS (23.50 g, 132.03 mmol) were dissolved in carbon tetrachloride (300 mL), then BPO (300 mg) was added, the resulting reaction was heated to reflux under a sunlamp for 5 hours, then cooled to room temperature, filtered and concentrated to give the desired α-bromo-3-chlorophenylacetic acid. 1.40 g of this α-bromo-3-chlorophenylacetic acid was reacted with 3,4-dimethylphenol (686 mg) according to the General procedure C to give 1.47 g of the desired title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 2.17 (s, 3 H) 2.21 (s, 3 H) 5.58 (s, 1 H) 6.65 (dd, J=8.20, 2.64 Hz, 1 H) 6.78 (d, J=2.64 Hz, 1 H) 7.01 (d, J=8.20 Hz, 1 H) 7.29-7.40 (m, 2 H) 7.42-7.52 (m, 1 H) 7.59 (s, 1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[CH:6][N+:5]([O-:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: [O-][n+]1ccc(Cl)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: COCCOC
Product: [O-][n+]1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 85.2 %

Procedure:
To a mixture of 4-chloropyridine-N-oxide (5.32 g, 41 mmol) and 4-trifluoromethylphenylboronic acid (9.36 g, 49.3 mmol) in anhydrous 1,2-dimethoxyethane (100 ml) was added tetrakis(triphenylphosphine)palladium (0) (1.5 g, 1.3 mmol) and saturated aqueous sodium carbonate solution (50 ml). Nitrogen was bubbled through the mixture for 5 minutes and the reaction was then heated with stirring at 100° C. for 15 hours under an atmosphere of nitrogen. The mixture was allowed to cool to room temperature and the solid was filtered off and washed with 1,2-dimethoxyethane (2×30 ml). The combined organic layers were evaporated under reduced pressure and triturated with diethyl ether (100 ml). The obtained solid was filtered off and dried on the sinter to give 4-(4-trifluoromethylphenyl)pyridine-N-oxide (8.36 g). This compound was suspended in phosphorous oxychloride (50 ml, 536 mmol) and the mixture was heated at 100° C. for 3 hours. After cooling to room temperature the homogeneous dark solution was evaporated under reduced pressure and repartitioned between chloroform and water (200 ml each). The pH was adjusted to 8 by portionwise addition of saturated aqueous sodium carbonate solution and the phases were separated. After two further extractions the combined organic extracts were washed with water and brine and dried over sodium sulfate. After filtration the compound was adsorbed onto silica gel and purified by flash chromatography (10% ethyl acetate-iso-hexane) to yield the title compound (5.5 g, 52%).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[Br-].[CH3:12][C:13]1[C:14]([Zn+])=[N:15][CH:16]=[CH:17][CH:18]=1.CCOC(C)=O.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>[Cl:1][C:2]1[C:3]([C:14]2[C:13]([CH3:12])=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: Cc1cccnc1[Zn+]
Reactant: CSc1ncc(Cl)c(I)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ncc(Cl)c(-c2ncccc2C)n1
Temperature: 25 °C
Yield: 64 %

Procedure:
A solution of 5-chloro-4-iodo-2-(methylthio)pyrimidine (5 g, 17.4 mmol) and Pd(PPh3)4 (1 g, 0.87 mmol) in dry THF (120 mL) was degassed under N2 three times. Then a solution of (3-methylpyridin-2-yl)zinc(II) bromide in THF (0.5 M, 53 mL, 26.3 mmol) was added. The resulting mixture was heated at reflux overnight. The mixture was then cooled to room temperature and was treated with EtOAc (80 mL) and H2O (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated and filtered. The filtrate was concentrated and the residue was purified via column chromatography (petroleum ether: EtOAc=9:1) to give the title compound (2.8 g, 64%) as a yellow syrup.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]1([N:18]=[C:19]=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(O)(C)C>[Br:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[NH:1][C:19](=[S:20])[N:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]2=[O:6]
Reactant: S=C=Nc1ccccc1
Reactant: Nc1c(Br)cccc1C(=O)O
Solvent: CC(C)(C)O
Product: O=c1c2cccc(Br)c2[nH]c(=S)n1-c1ccccc1
Temperature: 100 °C
Yield: 97.2 %

Procedure:
TEA (1.93 mL, 13.89 mmol), 2-amino-3-bromo-benzoic acid (Aldrich, 2.00 g, 9.26 mmol), phenyl isothiocyanate (Aldrich; 1.66 mL, 13.89 mmol) were combined in 30 mL t-BuOH, flask sealed, and heated to 100° C. overnight. The heterogeneous reaction was cooled to 40° C. and filtered, rinsing 3× Et2O, and the solid was collected and dried in vacuo to give 8-bromo-3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (3.0 g, 9.00 mmol, 97% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.76 (1H, br. s.), 8.02 (1H, dd, J=7.8, 1.4 Hz), 7.94 (1H, dd, J=7.9, 1.3 Hz), 7.34-7.51 (3H, m), 7.14-7.26 (3H, m). m/z (ESI, +ve) 332.9/334.9 (M+H)+.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][C:12](=[O:25])[NH:13][C:14]1[O:18][N:17]=[C:16]([C:19]([CH3:24])([CH3:23])[CH2:20][NH:21][CH3:22])[CH:15]=1)([CH3:10])([CH3:9])[CH3:8].[C:26](Cl)(=[O:28])[CH3:27]>C1COCC1>[C:7]([O:11][C:12](=[O:25])[NH:13][C:14]1[O:18][N:17]=[C:16]([C:19]([CH3:24])([CH3:23])[CH2:20][N:21]([C:26](=[O:28])[CH3:27])[CH3:22])[CH:15]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(=O)Cl
Reactant: CNCC(C)(C)c1cc(NC(=O)OC(C)(C)C)on1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)N(C)CC(C)(C)c1cc(NC(=O)OC(C)(C)C)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.4 %

Procedure:
Pyridine (0.055 mL, 0.68 mmol) is added to a solution of [3-(1,1-dimethyl-2-methylamino-ethyl)-isoxazol-5-yl]-carbamic acid tert-butyl ester (150.0 mg, 0.59 mmol) in THF (2.0 mL) followed by the addition of acetyl chloride (0.048 mL, 0.68 mmol). The reaction mixture is stirred at room temperature for 3 h. After this time, more pyridine (0.028 mL, 0.34 mmol) and more acetyl chloride (0.024 mL, 0.34 mmol) are added to the reaction mixture and stirred for another 1 h. After this time, the reaction mixture is quenched with saturated aqueous NaHCO3 solution and extracted with ethyl acetate twice. The organic extracts are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using methanol/DCM provides 87.0 mg of the title compound. Yield: 47%. m/z 312 [M+H].
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=2Br)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH:29](/B(O)O)=[CH:30]/[CH3:31].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=2/[CH:29]=[CH:30]\[CH3:31])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(N2CCN(CCOCc3ccccc3)CC2)c(Br)c1
Reactant: C/C=C\B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C/C=C\c1cc(C(=O)OC)ccc1N1CCN(CCOCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Methyl 4-{4-[2-(benzyloxy)ethyl]piperazin-1-yl}-3-bromobenzoate (78 mg, 0.180 mmol) was dissolved in N,N-dimethylformamide: water=3:1 (1.8 mL). At room temperature, (Z)-propenylboronic acid (containing about 10% E-isomer; Hereinafter the same is used for all) (37 mg, 0.433 mmol), tetrakistriphenylphosphine palladium (10 mg, 0.00902 mmol) and sodium carbonate (76 mg, 0.722 mmol) were added sequentially, and the mixture was stirred at 80° C. for 1 hour under microwave irradiation. The reaction solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (61 mg (yield 86%)) was obtained as a yellow oil.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[O:20][CH:21]=[CH:22][C:16]=2[CH2:15]1)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][NH:27][CH3:28].[CH2:29]=O>C(O)(=O)C>[CH3:26][N:27]([CH2:29][C:21]1[O:20][C:17]2[CH2:18][CH2:19][N:14]([C:12](=[O:13])[C:11]3[CH:23]=[CH:24][CH:25]=[C:9]([C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:10]=3)[CH2:15][C:16]=2[CH:22]=1)[CH3:28]
Reactant: C=O
Reactant: O=C(c1ccccc1)c1cccc(C(=O)N2CCc3occc3C2)c1
Reactant: CNC
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(C(=O)c1cccc(C(=O)c3ccccc3)c1)C2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.200 g (0.604 mmol) of 5-(3-benzoylbenzoyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 20 ml of acetic acid, 0.082 ml (0.91 mmol) of 50% aqueous dimethylamine and 0.073 ml (0.73 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 60 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform to chloroform/methanol=50/1 to 25/1) to yield the desired product.