Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24]Cl)[CH:16]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.[Cl-].[Na+].O>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:16]=1
Reactant: Nc1c(C(=O)c2cccc(NCCCCl)c2)cnn1-c1ccc(F)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: Nc1c(C(=O)c2cccc(NCCCN3CCOCC3)c2)cnn1-c1ccc(F)cc1
Reaction time: 48 h

Procedure:
A mixture of 5-amino-4-[3-(3-chloropropylamino)benzoyl]-1-(4-fluorophenyl)-pyrazole (0.05 g, 0.13 mmol), morpholine (0.1 ml, 1.1 mmol), potassium carbonate (0.1 g) and potassium iodide (0.1 g) in acetonitrile (3 ml) was heated at reflux. After 2 days, the reaction mixture was poured into brine and the product was extracted into ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: 3% MeOH/CH2Cl2) to give 5-amino-1-(4-fluorophenyl)-4-[3-{3-(morpholin-4-yl)propylamino}-benzoyl]pyrazole as a solid.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=2[O:34][CH3:35])[CH2:6]1)=[N+]=[N-].CP(C)C.O>C1COCC1.C(Cl)Cl>[NH2:1][CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:13])([CH3:14])[O:12][C@H:8]2[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=2[O:34][CH3:35])[CH2:6]1
Reactant: COc1ccc(CNc2ncnc3c2ncn3[C@@H]2C[C@H](CN=[N+]=[N-])[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CP(C)C
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNc2ncnc3c2ncn3[C@@H]2C[C@H](CN)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
A solution of 9-((3aS,4R,6R,6aR)-6-(azidomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-9H-purin-6-amine (1.72 g, 3.58 mmol) in THF (16 mL) was cooled to 0° C. (ice/brine bath) and treated dropwise with a 1.0 M solution of trimethylphosphine in THF (6.30 mL, 6.30 mmol). The cold bath was removed after 30 min and the reaction mixture was stirred for 1.5 h; HPLC/LC MS indicated complete consumption of the starting azide. Water (2.84 mL, 157 mmol) was added to the orange solution (gas evolution noted) and the reaction mixture was stirred for 2.75 h at rt; HPLC indicated complete conversion to the desired amine. The reaction mixture was concentrated in vacuo to afford an orange oil. The residue was taken up in CH2Cl2 (150 mL) and washed with water (2×50 mL) and brine (1×75 mL). The separated organic layer was dried (Na2SO4) and concentrated in vacuo to afford the title compound (1.6 g, 98%) as a pale yellow foam: MS (ESI+) for C23H30N6O4 m/z 455.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]2[C:8](=[O:17])[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH:11]=[CH:12][C:6]=2[CH:5]=1)(O)=[O:2].C(Cl)(Cl)[Cl:21].S(Cl)(Cl)=O>CN(C)C=O>[Cl:21][C:1]([C:4]1[CH:19]=[CH:18][C:7]2[C:8](=[O:17])[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH:11]=[CH:12][C:6]=2[CH:5]=1)=[O:2]
Reactant: ClC(Cl)Cl
Reactant: O=C(O)c1ccc2c(=O)c3ccccc3ccc2c1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
A solution of 2.50 g. of 2-carboxy-5-oxo-5H-dibenzo[a,d]cycloheptene in 50 ml. of chloroform, 10 ml. of thionyl chloride and 0.3 ml. of dimethylformamide is stirred for 8 hours, then evaporated to dryness and the residue recrystallized from acetonitrile to yield 2-chloroformyl-5-oxo-5H-dibenzo[a,d]cycloheptene. This is dissolved in 50 ml. of chloroform and added to a 3-fold excess of ethereal diazomethane at 0° C. After 12 hours, the solution is evaporated to dryness and the residue recrystallized from acetonitrile to yield 2-diazoacetyl-5-oxo-5H-dibenzo[a,d]cycloheptene. A solution of 1.37 g. of the latter compound in 50 ml. of tetrahydrofuran is added to 10 ml. of 0.1 N sulfuric acid containing 0.5 g. of copper powder. The mixture is refluxed for 3 hours and then cooled, filtered and poured into water. The solution is extracted with ethyl acetate and the extract washed, dried and evaporated to yield 2-hydroxyacetyl-5-oxo-5H-dibenzo[a,d]cycloheptene which is recrystallized from chloroform/hexane. A solution of 0.05 g. of cupric acetate monohydrate in 5 ml. of acetic acid is heated to 100° C and 3.0 g. of granular zinc is added. The mixture is shaken for 3 minutes and the acetic acid is then decanted. The residual zinc-copper couple is washed three times with 5 ml. portions of acetic acid, then three times with 5 ml. portions of ether. It is then refluxed for four hours under nitrogen in 20 ml. of ether containing 2.5 ml. of methylene iodide, 1.32 g. of 2-hydroxyacetyl-5-oxo-5H-dibenzo[a,d]cycloheptene is added, and reflux is continued for a further 4 hours. The mixture is cooled and diluted with 50 ml. of benzene. The liquid phase is decanted and washed with water and aqueous sodium bisulfate, then dried and evaporated. The residue is chromatographed on 50 gm. of silica gel, eluting with ethyl acetate/hexane, to yield 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1-en-3-ol.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][C:17]4[C:24]([CH3:26])([CH3:25])[CH2:23][CH2:22][C:21]([CH3:28])([CH3:27])[C:18]=4[CH:19]=3)[O:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1.Cl>CO>[CH3:27][C:21]1([CH3:28])[C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][C:17]=2[C:24]([CH3:26])([CH3:25])[CH2:23][CH2:22]1)[O:14][CH2:13][CH:12]=[C:11]3[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:29])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(C=C2CCOc3cc4c(cc32)C(C)(C)CCC4(C)C)cc1
Agent: Cl
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)OCC=C3Cc1ccc(C(=O)O)cc1
Temperature: 85 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
To a mixture of 4-(6,6,9,9-tetramethyl-6,7,8,9-tetrahydro-2H-benzo[g]chromen-4-ylidenemethyl)-benzoic acid methyl ester (220 mg, 0.56 mmol) in methanol (10 mL) was added concentrated HCl (0.05 mL) and the solution was allowed to stir at 85° C. for 12 h. The solution was quenched with aqueous saturated NaHCO3 solution (100 mL), extracted with EtOAc, dried (Na2SO4), and concentrated. The acid was obtained by hydrolysis according to the standard conditions and was purified by silica gel preparative TLC (50% EtOAc/Hexane) to afford 4-(6,7,8,9-tetrahydro-6,6,9,9-tetramethyl2H-benzo[g]chromen-4-ylmethyl)-benzoic acid (133) (89%) as a white solid: m.p. 200-201° C.; IR (neat) 2969 s, 2958 s, 2922 s, 2361 m, 1689 s, 1608 m, 1419 s, 1408 s, 1286 m, 1174 s, 1018 s cm−1; 1H NMR (400 MHz, CDCl3) δ 8.04 (½ ABq, 2H, J=8.0 Hz, ArH), 7.37 (½ ABq, 2H, J=8.0 Hz, ArH), 6.98 (s, 1H, ArH), 6,74 (s, 1H, ArH), 5.43 (broad t, 1H, olefinic), 4.75 (m, 2H, ring CH2), 3.79 (s, 2H, benzylic CH2), 1.59 (s, 4H, 2CH2), 1.22 (s, 6H, 2CH3), 1.13 (s, 6H, 2CH3).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.Cl.[C:24](Cl)(=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>O.ClCCl>[OH:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@H:5]([NH:6][C:24](=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:4]([O:3][CH3:2])=[O:15])=[CH:13][CH:12]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Yield: 90.9 %

Procedure:
300 ml of dichloro methane (DCM) was added to (L)-tyrosine methyl ester HCl salt (23.16 g, 0.1 mol), and 28 ml of triethyl amine (TEA, 0.2 mol) was added thereto, thereby dissolving HCl salt. The reactor was temperature-lowered to 0° C. by using an ice bath, and 27.49 g of palmitoyl chloride (0.1 mol) was slowly added, following by stirring for 3˜4 hours. 200 ml of water was added to the reacted material, followed by extraction with 500 ml of ethyl acetate. Drying over sodium sulfate followed by filtering was carried out. The solvent was removed from the filtrate by rotary evaporation, followed by solidification with hexane and ethyl acetate, thereby obtaining a white solid (39.4 g, 90.8% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([C:26]#[CH:27])=[CH:25][C:19]=2[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24](/[CH:26]=[CH:27]/[C:27]#[C:26][C:24]3[CH:23]=[CH:22][C:20]4[NH:21][C:17]([C@@H:12]5[CH2:13][CH2:14][CH2:15][CH2:16][N:11]5[C:9]([O:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[O:10])=[N:18][C:19]=4[CH:25]=3)=[CH:25][C:19]=2[N:18]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1ccc2[nH]c([C@@H]3CCCCN3C(=O)OCc3ccccc3)nc2c1
Agent: Cl[Ru]Cl
Solvent: Cc1ccc(C(C)C)cc1
Product: O=C(OCc1ccccc1)N1CCCC[C@H]1c1nc2cc(C#C/C=C/c3ccc4[nH]c([C@@H]5CCCCN5C(=O)OCc5ccccc5)nc4c3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.3 %

Procedure:
A mixture of (S)-2-(5-ethynyl-1H-benzoimidazol-2-yl)-piperidine-1-carboxylic acid benzyl ester (41 mg, 0.115 mmol) and dichloro(p-cymene) ruthenium (II) dimer (5 mg) is purged with N2. AcOH (1 mL) is added and the mixture is stirred at room temperature overnight and concentrated in vacuum to dryness. The residue is purified by flash column chromatography on silica gel (EtOAc/hexanes 5% to 100%) and repurified by reverse phase HPLC using a gradient of CH3CN/water to afford the title compound (5.9 mg, 7%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].Cl.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][Cl:22]>C(O)C>[ClH:22].[F:11][C:2]([F:1])([F:10])[C:3]1[CH:4]=[C:5]([S:9][CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(S)c1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: FC(F)(F)c1cccc(SCc2ccccn2)c1
Reaction time: 5 h
Yield: 56 %

Procedure:
m-Trifluoromethylbenzenethiol (5 g) was added to a solution of NaOH (2.25 g) in ethanol (50 ml) and the resulting solution was treated with a solution of 2-picolyl chloride, hydrochloride (4.6 g) in ethanol (25 ml) and the mixture was stirred for 5 hours. The resulting suspension was filtered through kieselghur and the solvent was removed by evaporation. The residue was converted into the hydrochloride in ether with ethereal HCl and recrystallised from acetone-ether to give 2-(((3-trifluoromethylphenyl)thio)methyl)pyridine hydrochloride (4.8 g) mp 145°-6° C. (Found: C,51.1; H,4.0; N,4.7 C13H10F3NS.HCl requires C,51.0; H,3.6; N,4.6%).
Reaction SMILES: Cl[C:2]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][C:13]=2[F:21])[CH2:8][CH2:7]1)=[O:5].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[F:21][C:13]1[CH:14]=[C:15]([C:18](=[O:20])[CH3:19])[CH:16]=[CH:17][C:12]=1[N:9]1[CH2:10][CH2:11][N:6]([C:4](=[O:5])[C:3]2[CH:22]=[C:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=[CH:25][C:2]=2[N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH2:7][CH2:8]1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3Cl)CC2)c(F)c1
Reactant: C1COCCN1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3N3CCOCC3)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described for example 1 from 1-{4-[4-(2-Chloro-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-phenyl}-ethanone (example K) and morpholine (57%, white solid), MS (m/e): 490.2 (M+H, 100%)
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:46])[C@@H:15]([CH3:45])[CH2:16][CH2:17][CH2:18][N:19]([C:24]1[N:29]=[C:28]2[O:30][C:31]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)=[C:32]([C:33]([NH:35][CH3:36])=[O:34])[C:27]2=[CH:26][C:25]=1I)[S:20]([CH3:23])(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:49]1C=CC=C(OC)[C:54]=1[C:55]1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C(=O)([O-])[O-].[Na+].[Na+].C1(B(O)O)CC1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:46])[C@@H:15]([CH3:45])[CH2:16][CH2:17][CH2:18][N:19]([C:24]1[N:29]=[C:28]2[O:30][C:31]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)=[C:32]([C:33]([NH:35][CH3:36])=[O:34])[C:27]2=[CH:26][C:25]=1[CH:55]1[CH2:54][CH2:49]1)[S:20]([CH3:23])(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCC[C@H](C)C(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)S(C)(=O)=O)c(I)cc12
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCC[C@H](C)C(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)S(C)(=O)=O)c(C3CC3)cc12

Procedure:
To 6-(N—((S)-5-((S)-4-benzyl-2-oxooxazolidin-3-yl)-4-methyl-5-oxopentyl)methylsulfonamido)-5-iodo-N-methyl-2-p-tolylfuro[2,3-b]pyridine-3-carboxamide (964 mg, 1.271 mmol) was added a premixed solution of S-Phos (52.2 mg, 0.127 mmol) and Pd(OAc)2 (11.41 mg, 0.051 mmol) in toluene (2.139 mL) Added a premixed solution of 2N SODIUM CARBONATE (12.71 mL, 25.4 mmol) and cyclopropylboronic acid (1637 mg, 19.06 mmol) in toluene (6.42 mL).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[C:14]2[C:10]=1[C:11]1[CH:24]=[C:23]([CH3:25])[CH:22]=[N:21][C:12]=1[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(S(C1C=C(C2C=C([C:46]([N:48]3[CH2:53]C[N:51](C)[CH2:50][CH2:49]3)=O)C=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[CH2:1]([S:8][C:9]1[CH:17]=[C:16]([C:18]([NH:51][CH2:50][CH2:49][N:48]([CH3:53])[CH3:46])=[O:20])[CH:15]=[C:14]2[C:10]=1[C:11]1[CH:24]=[C:23]([CH3:25])[CH:22]=[N:21][C:12]=1[NH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C(=O)N3CCN(C)CC3)cc3[nH]c4ncc(C)cc4c23)c1
Reactant: Cc1cnc2[nH]c3cc(C(=O)O)cc(SCc4ccccc4)c3c2c1
Product: Cc1cnc2[nH]c3cc(C(=O)NCCN(C)C)cc(SCc4ccccc4)c3c2c1

Procedure:
The title compound was synthesized from Compound 150 using an analogous procedure to that described in the preparation of Compound 140. 1H NMR (400 MHz, MeOD) δ ppm 2.53 (s, 3 H) 3.02 (s, 6 H) 3.43 (t, J=5.81 Hz, 2 H) 3.82 (t, J=5.81 Hz, 2 H) 4.42 (s, 2 H) 7.16-7.26 (m, 3 H) 7.31 (d, J=7.83 Hz, 2 H) 7.82 (d, J=1.26 Hz, 1 H) 7.96 (s, 1 H) 8.30 (s, 1 H) 8.80 (s, 1 H) [M+H] calc'd for C24H26N4OS, 419; found, 419.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.CC(C)=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[O:6]=[C:2]([CH3:1])[CH2:3][C:4]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:5]
Reactant: C=C1CC(=O)O1
Reactant: C1CCNC1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)N1CCCC1
Yield: 97.9 %

Procedure:
9 ml (0.05 mol) of diketene-acetone adduct and a solution of 4.2 ml (0.05 mol) of pyrrolidine in 20 ml of toluene were treated as described in preparation 7. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (EtOAc/MeOH 0%→1%) yielding 7.6 g of the title compound as a dark oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:16][CH:15]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:14][C:13]2=[O:22])[CH:5]=[CH:6][C:7]=1[Sn](C)(C)C.Br[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:16][CH:15]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:14][C:13]2=[O:22])[CH:5]=[CH:6][C:7]=1[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2
Reactant: CC(=O)NCC1CN(c2ccc([Sn](C)(C)C)c(F)c2)C(=O)O1
Reactant: Brc1ccc2ncccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)NCC1CN(c2ccc(-c3ccc4ncccc4c3)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
(±)-N-[[3-[3-fluoro-4-(trimethylstannyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (PREPARATION 19, 0.367 g, 0.88 mmol), 6-bromoquinoline (0.239 g, 1.15 mmol) and bis(triphenyl-phosphine)palladium(II) chloride (0.062 g, 0.088 mmol) are combined with DMF (10 ml). The reaction mixture is thoroughly purged with nitrogen and then heated to 80° under nitrogen. After 2 hr, little progress is noted by TLC and so the reaction mixture is heated to 95° for a further 2 hr. At this point, TLC revealed the reaction is complete. The mixture is cooled to 20°-25° and concentrated under reduced pressure to give a crude material which is purified by chromatography over silica gel (10 g of silica gel; eluted with methanol/chloroform, 1→4%) to give the racemic title compound, mp 216°-219° (dec); IR (internal reflectance) 3411, 3281, 1743, 1657, 1630, 1566, 1521, 1499, 1416, 1226, 1194 cm-1 ; NMR (CDCl3, 300 MHz) 8.95, 8.26-8.20, 8.00, 7.92, 7.61, 7.57, 7.47, 7.35, 6.08, 4.84, 4.13, 3.86, 3.80-3.62, 2.05 8; MS (m/z) 379 (100.0, M+), 335, 307, 276, 264, 251.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][C:12]([CH3:26])([CH3:25])[C:13]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=O)=[O:10])[CH:5]=[CH:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.Cl>C(Cl)Cl>[CH3:25][C:12]1([CH3:26])[O:11][C:9](=[O:10])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[C:13]1[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CC(C)(OC(=O)Cc1cccc(F)c1)C(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OC(=O)C(c2cccc(F)c2)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
A solution of the product from Step 2 (120 g) in CH2Cl2 (1 L) was treated with DBU (81.6 g) and stirred for 1 h at r.t. The reaction mixture was then treated with 1 M HCl (550 mL) and the organic phase was separated, washed with saturated NaHCO3 and dried over MgSO4. After concentration, the crude was swished from 20% EtOAc/hexanes (450 mL) to give the title compound as a white solid (108.4 g, m.p. 172.7° C.).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH:3]=1.[BH4-].[Na+].CCOCC>C(O)C>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH2:14][CH2:15][CH:16]([OH:18])[CH3:17])[CH:3]=1
Reactant: COc1ccc2cc(CCC(C)=O)cc(F)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc2cc(CCC(C)O)cc(F)c2c1

Procedure:
4-(4-Fluoro-6-methoxy-2-naphthyl)butan-2-one (14.1 g) was dissolved in ethanol (200 ml) and sodium borohydride (6.7 g) was added to the stirred solution. After 1 hour ether (600 ml) was added and the solution was washed twice with brine, then with dilute hydrochloric acid and sodium hydrogen carbonate solution. After drying over anhydrous sodium sulphate the solvent was removed under reduced pressure. The oil obtained was chromatographed on silica gel (700 g) using an elution gradient from benzene to ether. The desired product was obtained as an oil. This was triturated with 60-80 petroleum ether to give the title compound as pale yellow crystals (5.65 g., 40%; m.p. 58°-60°).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[C:16](=[O:22])[NH:17][N:18]=[CH:19][C:20]=1Cl.C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:20]2[CH:19]=[N:18][NH:17][C:16](=[O:22])[C:15]=2[Cl:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=c1[nH]ncc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=c1[nH]ncc(N2CCN(Cc3ccccc3)CC2)c1Cl
Temperature: 110 °C

Procedure:
A mixture of 7 g of 1-benzylpiperazine, 6.55 g of 4,5-dichloro-3(2H)-pyridazinone and 11 g of K2CO3 in 150 ml of DMF is heated at 110° C. for 4 hours and then concentrated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH (95/5; v/v) mixture. The product obtained is taken up in iso ether and triturated and the precipitate formed is isolated with suction. This gives 7 g of the expected product, which is recrystallized from iso ether; m.p.=173-175° C.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3].O1CCOCC1>O1CCCC1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3]
Reactant: O=C(Cl)c1ccc2c(c1)COC2=O
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=Cc1ccc2c(c1)COC2=O
Temperature: 40 °C
Reaction time: 7 h
Yield: 48.5 %

Procedure:
In a hydrogenator, 8.2 g (0.042 mole) of 5-chlorocarbonylphthalide, 50 ml of dioxane and 0.77 g of 5% Pd/BaSO4 are charged and the mixture is hydrogenated at 4 bar and 70° C. for 7 hours. After this period of time, the reaction no longer proceeds because of the co-precipitation of the formed product; thus, the hydrogenation is stopped, the mixture is diluted with 120 ml of tetrahydrofuran and stirred at 40° C. for 20 minutes. The solid is filtered off and the solution is concentrated to a little volume. The crystalline product is recovered by filtration and dried to give 3.3 g of 5-formylphthalide with a purity (HPLC)=82% (yield 40%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Br.CS(C)=[O:17]>O>[O:17]=[CH:2][C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: CS(C)=O
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Agent: Br
Solvent: O
Product: COC(=O)c1ccc(C(=O)C=O)cc1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 4-acetylbenzoate (1.00 g, 5.61 mmol) in DMSO (5 mL) was slowly added 40% HBr (1.5 mL) at 20° C. under stiffing. The mixture was stirred at 60° C. for 12 hours. The mixture was diluted with water (10 mL) and the resulting mixture was extracted with DCM (10 mL×3), washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give methyl 4-(2-oxoacetyl)benzoate (150 mg), which was taken forward without further purification. To a solution of 4-methoxybenzene-1,2-diamine (107 mg, 0.78 mmol) in 5 mL of acetic acid was added the crude methyl 4-(2-oxoacetyl)benzoate (150 mg). The mixture was refluxed for 2.5 hours. The solvent was removed in vacuo. The crude product was purified by prep-TLC (PE/EA:1/1) to separate the desired methyl 4-(6-methoxyquinoxalin-2-yl)benzoate (more polar) from the undesired methyl 4-(7-methoxyquinoxalin-2-yl)benzoate. The two structures were confirmed by HMBC spectra.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[S:6][CH:7]=1)=O.[Br-].[C:13]([C:16]1[CH:17]=[C:18]([CH:39]=[CH:40][CH:41]=1)[CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:15])=[O:14]>>[C:9]([NH:8][C:5]1[S:6][CH:7]=[C:3]([CH:1]=[CH:19][C:18]2[CH:17]=[C:16]([CH:41]=[CH:40][CH:39]=2)[C:13]([OH:15])=[O:14])[N:4]=1)(=[O:11])[CH3:10]
Reactant: O=C(O)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CC(=O)Nc1nc(C=O)cs1
Agent: [Br-]
Product: CC(=O)Nc1nc(C=Cc2cccc(C(=O)O)c2)cs1
Yield: 99.3 %

Procedure:
N-(4-Formyl-1,3-thiazol-2-yl)acetamide (1.702 g, 10.00 mmol) and (3-carboxybenzyl)(triphenyl)phosphonium bromide (5.251 g, 11.00 mmol) were condensed by a method similar to that of Production Example 4, step 3, to give 3-{2-[2-(acetylamino)-1,3-thiazol-4-yl]vinyl}benzoic acid (2.862 g, 9.926 mmol, yield 99.3%) as a pale-yellow solid.