Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:29]=[CH:28][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]([N+:25]([O-])=O)=[C:18]([N:20]([CH3:24])[C:21](=[O:23])[O-:22])[CH:19]=2)=[CH:11][C:10]=1[OH:30])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.O1CCCC1.[Pd]>[NH2:25][C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]2[CH:28]=[CH:29][C:9]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([OH:30])[CH:11]=2)=[CH:19][C:18]=1[N:20]([CH3:24])[C:21](=[O:23])[O:22][C:2]([CH3:7])([CH3:3])[CH3:1]
Reactant: CN(C(=O)[O-])c1cc(Oc2ccc(C(=O)c3ccccc3)c(O)c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Cc3ccccc3)c(O)c2)ccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 166.1 %

Procedure:
A mixture of a solution of N-[5-(4-benzoyl-3-hydroxyphenoxy)-2-nitrophenyl]-N-methylcarbamate (2.1 g) in methanol/tetrahydrofuran=5/3 (80 ml) and palladium on carbon (20%, 0.5 g) was stirred at ambient temperature under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated to give the title compound (1.8 g).
Reaction SMILES: [Li+].[OH-].[CH2:3]([O:10][P:11]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31]C)=[O:30])=[CH:24][CH:23]=1)([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>C1COCC1.CO>[CH2:14]([O:13][P:11]([O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:26][CH:27]=1)([O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1ccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1ccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.3 %

Procedure:
LiOH (1N, 9 mL, 5 mmol) was added into a mixture of methyl 2-(4-(bis(benzyloxy)phosphoryloxy)phenyl)acetate (1.53 g, 3.59 mmol) in THF (15 mL) and methanol (5 mL) at 0° C. The reaction was stirred at 0° C. for 3.5 h, than 0.5 h at rt. The reaction was monitored by LC-MS until the hydrolysis was completed. The mixture was cooled to 0° C. and acidified by 1N HCl to pH=2. The mixture was concentrated and extracted by ethyl acetate (50 mL×3). The extraction was dried over Na2SO4 and concentrated to dryness to give the acid (1.5 g, 67.6% yield) as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]C(C)(C)C.Br[C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17](N(C)C)=[O:18].O>C1COCC1.CCCCC>[Br:1][C:2]1[CH:7]=[C:6]([C:17]([C:16]2[CH:22]=[CH:23][CH:24]=[CH:14][CH:15]=2)=[O:18])[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: CN(C)C(=O)c1cccc(Br)c1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCC
Product: O=C(c1ccccc1)c1cccc(Br)c1
Temperature: -80 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of 8.25 g (52.5 mmol) of bromobenzene in 100 mL of THF, 70 mL (105 mmol) of 2.5 M tBuLi in pentane was added dropwise with vigorous stirring for 2 h at −80° C. This mixture was slowly warmed to room temperature and then stirred for 30 min at this temperature. 11.4 g (50 mmol) of 3-bromo-N,N-dimethylbenzamide was added at 0° C., and the resulting mixture was stirred for 12 hr at room temperature. 150 mL of water was added, the organic solvent was evaporated using a rotary evaporator, and the product was extracted with 2×100 mL of dichloromethane. The combined extracts were dried over K2CO3 and then evaporated to dryness. This procedure gave 12.2 g (89%) of 16 which was further used without an additional purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[CH:20][N:21]=4)[CH:18]=3)[OH:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1.C([O-])([O-])=O.[K+].[K+].COCCOC>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.C(Cl)Cl>[N:21]1[CH:20]=[CH:19][N:17]2[CH:18]=[C:13]([CH:11]([C:8]3[N:6]4[N:7]=[C:2]([C:26]5[CH:25]=[N:24][N:23]([CH3:22])[CH:27]=5)[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)[OH:12])[CH:14]=[CH:15][C:16]=12
Reactant: OC(c1ccc2nccn2c1)c1cnc2ccc(Cl)nn12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: Cn1cc(-c2ccc3ncc(C(O)c4ccc5nccn5c4)n3n2)cn1
Temperature: 80 °C

Procedure:
A microwave tube was charged under argon atm. with (rac)-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-imidazo[1,2-a]pyridin-6-yl-methanol (Stage 9.1, 89.9 mg, 0.3 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (62.4 mg, 0.3 mmol), Pd(PPh3)2Cl2 (6.3 mg) and 2 M K2CO3 (0.405 mL) and DME (1 mL). The mixture was heated at 80° C. for 3 h. The RM was taken up with DCM and washed with NaCl solution. After filtration of both layers, the solid part was dissolved in MeOH and evaporated to dryness. The residue was stirred in EtOAc and filtered to give the pure title compound. The organic layer of the first filtrate was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, DCM/MeOH=95:5—>80:20) to afford a second batch of the title compound (tR 2.57 min (conditions 3), MH+=346.2)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH2:32]([NH2:34])[CH3:33]>C1COCC1>[CH2:32]([NH:34][C:16]1[N:17]=[C:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[CH3:26])[C:13]2[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1)[CH3:33]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CCN
Solvent: C1CCOC1
Product: CCNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1

Procedure:
The product of Example 48 (200 mg, 0.45 mmol) was combined and stirred with 5 mL of a 2M solution of ethylamine in THF. After 5 min the solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography with 0-2% EtOAc/CH2Cl2 followed by recrystallization from CH2Cl2/hexane gave the product as a white-crystalline solid. mp 195-196°, LC MS m/z=411 (MH+) Retention time=2.4 min.
Reaction SMILES: [Cl-].C[SiH](C)C.[CH2:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.O>O1CCCC1.BrC(Br)C.[Zn]>[Cl:14][C:15]1[CH:20]=[C:19]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:18]=[CH:17][N:16]=1
Reactant: BrCc1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: CC(Br)Br
Agent: C[SiH](C)C
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Clc1cc(Cc2ccccc2)ncn1
Reaction time: 0.33 h
Yield: 40.8 %

Procedure:
In 10 ml of tetrahydrofuran was suspended 1.3 g of zinc (powder), to which dibromoethane (2 drops) was added. The mixture was heated under reflux for 5 minutes, to which trimethylsilane chloride was added. The mixture was further heated under reflux for 5 minutes, to which a solution of 1.7 g of benzyl bromide dissolved in 20 ml of tetrahydrofuran was slowly added with heating under reflux, followed by stirring for 20 minutes. (The solution thus obtained is referred to as solution A). In 10 ml of tetrahydrofuran were suspended 1.5 g of 4,6-dichloropyrimidine and 0.1 g of dichlorobistriphenylphosphine palladium, to which the above solution A was added, followed by heating under reflux for 3 hours and further stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.83 g of 4-chloro-6-benzylpyrimidine.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28](O)=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[N:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][CH2:35][NH:34][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[C:25]([CH2:24][C@@H:19]2[CH2:20][CH2:21][CH2:22][CH:23]=[C:18]2[C:9]2[O:10][C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH:26]=1
Reactant: O=C(O)c1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: NCCc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCCc1ccccn1)c1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a mixture of (S)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoic acid (120 mg, 0.276 mmol) and 2-(2-aminoethyl)pyridine (0.040 ml, 0.331 mmol) in DMF (5 ml) was added 1-hydroxybenzotriazole (56 mg, 0.414 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (106 mg, 0.552 mmol). After stirring the resulting mixture at room temperature for 2 hours, the reaction mixture was diluted with EtOAc (30 ml), washed with water, saturated sodium hydrogencarbonate solution, water and brine successively, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (methylene chloride:MeOH, 20:1 elution) to give (S)-N-[2-(2-pyridyl)ethyl]-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzamide (138.8 mg, 93%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][NH2:12])[CH:5]=1.COC(=O)C1C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][NH:12][S:25]([CH3:24])(=[O:27])=[O:26])[CH:5]=1
Reactant: COC(=O)c1cccc(CCN)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: COC(=O)c1ccccc1
Product: COC(=O)c1cccc(CCNS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.6 %

Procedure:
To a solution of 3-(2-amino-ethyl)-benzoic acid methyl ester (500 mg) in CH2Cl2 (35 mL) at 0° C. was added amino-ethyl)-benzoic acid methyl ester (500 mg) in CH2Cl2 (35 mL) at 0° C. was added methanesulfonyl chloride (292 mg, 2.55 mmol) and triethylamine (1.6 mL, 11.5 mmol). The reaction was stirred at room temperature for 18 h and was washed consecutively with 5.5% HCl, water, saturated NaHCO3, and brine. The organic solution was dried over MgSO4, filtered, and concentrated to yield the title compound (522 mg) as a white solid. MS 275 (M+18).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[C:6]([Br:14])[C:5]=1[OH:15])(=[O:3])[CH3:2].[Na].[C:17](OCC)(=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[Br:14][C:6]1[C:5]2[O:15][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:2][C:1](=[O:3])[C:4]=2[CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11]2
Reactant: CC(=O)c1cc2c(c(Br)c1O)CCCC2
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Product: CCOC(=O)c1cc(=O)c2cc3c(c(Br)c2o1)CCCC3
Yield: 72.3 %

Procedure:
The product of step (a) (5.3 g) was treated with sodium (2.3 g) and diethyl oxalate (7.3 g) under the conditions of Example 1(d) to give the title ester (5.0 g; 72%), mp 130°-132°.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[C:4]([CH:19]=[O:20])[CH:3]=1.S(Cl)(Cl)=O.[CH3:25]O>>[CH3:25][O:15][C:14](=[O:16])[CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][C:4]=2[CH:19]=[O:20])[CH:8]=1
Reactant: O=Cc1cc(Br)ccc1Oc1cccc(CC(=O)O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Temperature: 65 °C

Procedure:
To [3-(4-bromo-2-formyl-phenoxy)-phenyl]-acetic acid (1 g, 3.0 mmol) in MeOH (10 mL) was added thionyl chloride (0.43 mL, 6.0 mmol), and the reaction was heated to 65° C. for 2 hours, and then at room temperature overnight. The mixture was quenched with 1N aqueous NaOH and extracted three times with EtOAc, and the combined organic layers were washed with H2O, dried, and concentrated. The residue was purified by silica gel chromatography (20-40% EtOAc in hexanes) to give the desired product (0.7 g); as well as the acetal by-product.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)=[C:5]([C:14](O)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].CC[N:27]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[OH-].[NH4+]>C(Cl)Cl>[C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)=[C:5]([C:14]([NH2:27])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1-c1ccc(Cl)c(Cl)c1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: N#Cc1c(N2CCOCC2)sc(C(N)=O)c1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To a suspension of 4-cyano-3-(3,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxylic acid (0.198 g, 0.517 mmol) in DCM (5 mL) was added EDCI (0.198 g, 1.03 mmol) and HOBT (0.140 g, 1.03 mmol). The reaction mixture was stirred at rt for 30 min then ammonium hydroxide (1 mL, 20 mmol) was added. The reaction mixture was stirred for 4 h and was concentrated. The residue was diluted with water and extracted with EtOAc. The organic solutions were combined, washed with sat NaHCO3, with brine, dried over MgSO4, filtered and concentrated to give 4-cyano-3-(3,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxamide (84) (0.195 g, 99%). LCMS: (FA) ES+ 382.2, ES− 380.1. 1H NMR (300 MHz, d6-DMSO) δ: 7.73 (d, 1H), 7.64 (d, 1H), 7.36 (dd, 1H), 3.73-3.79 (m, 4H) and 3.49-3.54 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:5]2[O:6][CH:7]=[C:8]([C:9]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)=[O:10])[C:4]=2[CH:3]=1.[N+]([O-])(O)=[O:30].O.C(Cl)(Cl)Cl.CO>C(O)(=O)C>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([CH:16]=[C:15]([O:17][CH3:18])[C:14]=1[O:19][CH3:20])[C:9]([C:8]1[C:4]2[C:3](=[O:30])[C:2](=[O:1])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:5]=2[O:6][CH:7]=1)=[O:10]
Reactant: COc1cc(C(=O)c2coc3c2cc(O)c2ccccc23)cc(OC)c1OC
Reactant: O=[N+]([O-])O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(C(=O)c2coc3c2C(=O)C(=O)c2ccccc2-3)cc(OC)c1OC
Temperature: 45 °C

Procedure:
To a suspension of compound 25 (250 mg, 0.66 mmol) in glacial acetic acid (1.5 mL) at room temperature was added nitric acid (0.4 mL, d 1.35) dropwise with vigorous stirring. The mixture was heated at 45° C. for 30 min, allowed to cool to room temperature, and poured into cold water. The resulting precipitate was filtered and recrystallized to furnish compound SKC-NF-03 (100 mg, 38%) as a yellow solid. TLC Rf=0.6 (CHCl3-MeOH, 9.5:0.5); 1H NMR (CDCl3) δ 8.15 (d, J=7.6 Hz, 1H), 7.84-7.80 (m, 2H), 7.73 (app t, 1H), 7.55 (app t, 1H), 7.18 (s, 2H), 3.95 (s, 3H), 3.87 (s, 6H); MS (ES) m/z 393 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:30])=[C:14]([N:19]4[C:27](=O)[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20]4=O)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:32])[CH3:31])=[CH:4][CH:3]=1>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:30])=[C:14]([N:19]4[CH2:20][C:21]5[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:27]4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:32])[CH3:31])=[CH:4][CH:3]=1
Reactant: Cc1c(C)c(N2C(=O)c3ccccc3C2=O)c(C)c2c1OC(C)(C)C2c1ccc(F)cc1
Solvent: CCOC(C)=O
Product: Cc1c(C)c(N2Cc3ccccc3C2)c(C)c2c1OC(C)(C)C2c1ccc(F)cc1
Yield: 55 %

Procedure:
By using 2-[3-(4-fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-1H-isoindole-1,3(2H)-dione, the title compound was synthesized according to Example 2a. Yield: 55%. Melting point: 204-205° C. (Ethyl acetate)
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][N:5]1[CH:10]=[C:9]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[C:8](=[O:16])[C:7]2[C:17]([CH3:26])=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:19][C:6]1=2.[Br:32]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(OCC)(=O)C>[Br:32][CH2:26][C:17]1[C:7]2[C:8](=[O:16])[C:9]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])=[CH:10][N:5]([CH2:4][C:3]3[C:2]([F:1])=[CH:30][CH:29]=[CH:28][C:27]=3[F:31])[C:6]=2[S:19][C:18]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1c(-c2ccccc2)sc2c1c(=O)c(C(=O)C(C)C)cn2Cc1c(F)cccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: CC(C)C(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccccc3)c(CBr)c2c1=O
Yield: 79.1 %

Procedure:
The compound obtained in Example 15 (1.8 g) was admixed with N-bromosuccinimide (0.88 g), azobisisobutyronitrile (70 mg) and ethyl acetate (18 ml) and the mixture was heated under reflux for 2 hours. At the time when about 1 hour and 30 minutes had elapsed during this procedure, the suspension turned into a solution. The suspension obtained after allowing to cool was cooled on ice, and the precipitated crystal was recovered by a filtration, washed with cool ethyl acetate and water to obtain the title compound (1.68 g, 79.1%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C@:12]2([CH3:23])[O:16][C:15]3=[N:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][N:14]3[CH2:13]2)[CH2:7][CH2:6]1)=[O:4].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][CH2:2][C:3]([N:5]2[CH2:10][CH2:9][N:8]([CH2:11][C@:12]3([CH3:23])[O:16][C:15]4=[N:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][N:14]4[CH2:13]3)[CH2:7][CH2:6]2)=[O:4])=[CH:27][CH:26]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: C[C@]1(CN2CCN(C(=O)CCl)CC2)Cn2cc([N+](=O)[O-])nc2O1
Product: C[C@]1(CN2CCN(C(=O)CSc3ccc(Cl)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Yield: 20.3 %

Procedure:
Using a mixture of (S)-2-chloro-1-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]ethanone prepared in Example 420 (300 mg, 0.87 mmol) and 4-chlorothiophenol (190 mg, 1.32 mmol) gave (S)-2-(4-chlorophenylsulfanyl)-1-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]ethanone (80 mg, yield 20%) as a white powder in the same manner as in Example 421.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][NH:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:24](Cl)(=[O:26])[CH3:25].Cl>N1C=CC=CC=1>[C:24]([N:14]([CH2:13][CH2:12][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:15]1[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:22][CH:23]=1)(=[O:26])[CH3:25]
Reactant: O=C(O)c1ccc(NCCOc2cccc3ccccc23)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)N(CCOc1cccc2ccccc12)c1ccc(C(=O)O)cc1

Procedure:
A solution of 6.14 g. of 4-[2-(1-naphthyloxy)ethylamino]benzoic acid and 20 ml. of acetyl chloride in 50 ml. pyridine is warmed on a steam-bath for 8 hours. The dark solution is then poured into 370 ml. of 2 N hydrochloric acid. The resulting solution is then extracted several times with methylene chloride. The residue from evaporation of this extract is crystallized from acetonitrile giving a white solid, m.p. 182°-183° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:12])=[C:7](B(O)O)[CH:8]=1)#[N:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:22]1[C:23]([N:42]2[CH2:46][CH2:45][C@@H:44]([OH:47])[CH2:43]2)=[N:24][CH:25]=[C:26]([CH:41]=1)[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]([Cl:40])([F:39])[F:38])=[CH:32][CH:31]=1)=[O:28]>O1CCOCC1>[Cl:40][C:37]([F:38])([F:39])[O:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27](=[O:28])[C:26]2[CH:41]=[C:22]([C:7]3[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[F:12])[C:23]([N:42]3[CH2:46][CH2:45][C@@H:44]([OH:47])[CH2:43]3)=[N:24][CH:25]=2)=[CH:31][CH:32]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: N#Cc1ccc(F)c(B(O)O)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: N#Cc1ccc(F)c(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2CC[C@@H](O)C2)c1
Temperature: 130 °C
Reaction time: 2.5 h

Procedure:
5-Cyano-2-fluorophenylboronic acid (53.5 mg, 0.324 mmol), K3PO4 (138 mg, 0.648 mmol) and PdCl2(dppf)-(CH2Cl2) (17.65 mg, 0.022 mmol) were added to (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1,) in dioxane (1.5 mL) in a vial at RT. The vial was evacuated/purged with argon, sealed and stirred at 130° C. for 2.5 h. The RM was diluted with EtOAc (60 mL), washed with an aq. sat. solution of NaHCO3 (20 mL) and brine (2×20 mL). The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated off under reduced pressure. The residue was dissolved in MeOH (3 mL), filtered through a SPE PL-Thiol cartridge (StratoSpheres™, 500 mg, nominal:1.5 mmol), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column 2-EP, from 18% to 23% in 6 min) to afford the title product as a white solid. HPLC (Condition 10) tR=6.31 min, UPLC-MS (Condition 3) tR=1.12 min, m/z=503.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.64-2.01 (m, 2H) 2.93 (br. s, 1H) 3.19 (dd, J=11.14, 4.11 Hz, 1H) 3.23-3.43 (m, 2H) 4.21 (br. s, 1H) 4.84 (br. s, 1H) 7.34 (d, J=8.99 Hz, 3H) 7.57 (br. s, 1H) 7.80-7.91 (m, 3H) 7.94-8.24 (m, 4H) 8.79 (d, J=1.96 Hz, 1H) 10.16 (s, 1H).