Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[S-:11][C:12]#[N:13].[NH4+].BrBr.O>C(O)(=O)C>[N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]#[N:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: N#CSc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a well-stirred mixture of 108 g of o-nitroaniline and 128 g of ammonium thiocyanate in 400 ml of acetic acid there is added dropwise a solution of 128 g of bromine in 160 ml of acetic acid below 20° C. The mixture is stirred for 4 hours at room temperature and then poured into 4 liters of water. The resulting solid is filtered off and crystallized from ethanol to yield 86.7 g, m.p. 111°-114° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:15])=[C:4]([CH2:12][CH2:13][CH3:14])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH2:16]([O:18][C:19](=[O:45])[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][CH2:40]Br)[C:25]=1[CH2:42][CH2:43][CH3:44])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:16]([O:18][C:19](=[O:45])[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][CH2:40][O:15][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8](=[O:10])[CH3:9])=[C:5]([OH:11])[C:4]=2[CH2:12][CH2:13][CH3:14])[C:25]=1[CH2:42][CH2:43][CH3:44])[CH3:17]
Reactant: CCCc1c(O)c(Cl)cc(C(C)=O)c1O
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCCOCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCCOCCCOc1c(C(C)=O)ccc(OCCCC(=O)OCC)c1CCC
Yield: 21.9 %

Procedure:
A mixture of 0.850 g of 1-(5-chloro-2,4-dihydroxy-3-propylphenyl)ethanone, 1.811 g of 4-[4-acetyl-3-[3-(3-bromopropoxy)propoxy]-2-propylphenoxy]butanoic acid ethyl ester and 1.0 g of anhydrous potassium carbonate in 65 ml of anhydrous acetone was stirred at reflux for 4 days. Additional 1.0 g portions of potassium carbonate were added after 21 and 30 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to a brown oil. Purification by high pressure liquid chromatography using 20% ethyl acetate-hexane gave 0.516 g (22% yield) of 4-[4-acetyl-3-[3-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]butanoic acid ethyl ester as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[Mn]([O-])(=O)(=O)=[O:22].[K+]>CC(C)=O>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:12]([C:13]([OH:22])=[O:14])=[CH:11][C:10]=1[F:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C=O)cc(F)c1OCc1ccccc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C(=O)O)cc(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 7.5 g of 4-benzyloxy-3-fluoro-5-methoxybenzaldehyde in 200 ml of acetone was added dropwise at 15 to 20° C. to a mixture of 200 ml of water and 6.8 g of potassium permanganate. The mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated to about a half amount under reduced pressure. Aqueous sodium hydrogen sulfite solution and dilute hydrochloric acid were added to the concentrate and extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 4-benzyloxy-3-fluoro-5-methoxybenzoic acid.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18]([CH3:26])=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:27].CO>>[ClH:27].[CH3:26][C:18]1[C:17]2[C:22](=[CH:23][CH:24]=[CH:25][C:16]=2[O:15][C@H:12]2[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]2)[CH:21]=[N:20][CH:19]=1
Reactant: Cc1cncc2cccc(O[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Solvent: CO
Product: Cc1cncc2cccc(O[C@H]3CC[C@H](N)CC3)c12

Procedure:
According to the method of Example 1, Step C, deprotection was performed (room temperature, 2 hours) by using Intermediate 129 (194 mg) and 10% hydrogen chloride/methanol solution (3.5 ml). The solvent was evaporated under reduced pressure, and the residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (172 mg).
Reaction SMILES: C(N(CC)CC)C.[N:8]([C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=1)=[C:9]=[S:10].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]2([C:37]#[N:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1.ClCCl.CC(C)=O>C1COCC1>[NH:38]=[C:37]1[C:31]2([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[N:30]([C:27]2[CH:26]=[CH:25][C:24]([CH3:23])=[CH:29][CH:28]=2)[C:9](=[S:10])[N:8]1[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:19]([F:20])([F:22])[F:21])[CH:12]=1
Reactant: Cc1ccc(NC2(C#N)CCCCC2)cc1
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=N)C23CCCCC3)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 8 %

Procedure:
Triethylamine (0.05 g, 0.5 mmol) was added to a solution of 1a (0.228 g, 1 mmol) and 9a (0.214 g, 1 mmol) in dry THF (2 ml). The reaction mixture was stirred at room temperature for 2 days and then concentrated to yield a dark residue which was subjected to flash chromatography (dichloromethane/acetone, 95:5) to afford 4-(4-imino-2-thioxo-1-(4-methylphenyl)-1,3-diazaspiro[4.5]dec-3-yl)-2-trifluoromethylbenzonitrile, 9b (0.035 g, 0.08 mmol, 8%).
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH2:16][CH2:17][CH2:18][CH3:19])([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:20].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH2:33])(=[O:32])=[O:31]>C1(C)C=CC=CC=1>[CH2:16]([C:12]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:20])=[C:4]([C:3]2[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30](=[O:31])(=[O:32])[N:33]=2)[C:13]1=[O:14])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCC1(C)C(=O)C(=C(SC)SC)C(=O)c2ccccc21
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: Cc1ccccc1
Product: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 85.5 %

Procedure:
A solution of Example 27F (0.064 g, 0.191 mmol) and 2-amino-benzenesulfonamide (0.035 g, 0.201 mmol) in toluene (7 mL) was refluxed for 6 hours. The solution was cooled to 25° C. and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane followed by 20% and 30% ethyl acetate in hexane to give the desired product (0.067 g, 86%).
Reaction SMILES: [Br:1][C:2]1[N:6]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=O)[C:5]([C:18]([O:20]C)=O)=[CH:4][CH:3]=1.[CH2:22]([NH2:25])[CH2:23][NH2:24]>O1CCOCC1>[Br:1][C:2]1[N:6]2[CH2:7][C:8]3([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=4)[NH:25][CH2:22][CH2:23][N:24]3[C:18](=[O:20])[C:5]2=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: COC(=O)c1ccc(Br)n1CC(=O)c1ccc(OC)cc1
Solvent: C1COCCO1
Product: COc1ccc(C23Cn4c(Br)ccc4C(=O)N2CCN3)cc1
Yield: 52.5 %

Procedure:
To a solution of methyl 5-bromo-1-[2-(4-methoxyphenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (250 mg, 0.71 mmol) in 1,4-dioxane (50 mL) was added ethane-1,2-diamine (1.0 mL, 15 mmol). The solution was heated at reflux one week. During that time a batch of ethane-1,2-diamine (1.5 mL, 22 mmol) was added. The mixture was concentrated in vacuo to give a oil that was partitioned between water (30 mL) and CH2Cl2 (30 mL). The aqueous layer was further extracted with CH2Cl2 (2×30 mL). The organic layers were dried (MgSO4), filtered and concentrated in vacuo to give a oil that was purified by flash chromatography (Biotage SP4, 12 g cartridge, gradient 0-10% methanol in CH2Cl2) to give 8-bromo-10a-(4-methoxyphenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one as a pale yellow solid (135 mg, yield 52%). ESI-MI m/z calculated [M+H]+ 364.0.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17])[C:4]([OH:6])=[O:5].[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:2][CH:3]([CH2:7][CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])[C:4]([OH:6])=[O:5])=[O:24])=[CH:21][CH:20]=1
Reactant: NC(CC1C(=O)Nc2ccccc21)C(=O)O
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC(CC1C(=O)Nc2ccccc21)C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.25 Grams of 2-amino-3-(oxindol-3-yl)propionic acid hydrochloride prepared in reference example 1, and 1.3 g of N-hydroxysuccinimide ester of p-chlorobenzoic acid were dissolved in 50 ml of dimethylformamide. To this solution was added 1.2 g of triethylamine, and the whole mixture was stirred at a room temperature for 3 hours. Dimethylformamide was removed by evaporation, then water was added to the resultant residue, the crystals formed were collected by filtration to obtain 0.68 g of 2-(4-chlorobenzoylamino)-3-(oxindol-3-yl)propionic acid 1/4-hydrate. Melting point: 133°-135° C. (decomp.) [α]D25 -50.3° (C=1, methanol)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[OH:10].Br[CH:12]([CH:14]1[CH2:16][CH2:15]1)O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[O:10][CH2:12][CH:14]1[CH2:16][CH2:15]1
Reactant: OC(Br)C1CC1
Reactant: OCc1ccc(Cl)c(O)c1
Product: OCc1ccc(Cl)c(OCC2CC2)c1

Procedure:
The title compound was prepared from 2-chloro-5-(hydroxymethyl)phenol and bromocyclopropylmethanol according to the procedure for the preparation of Example 111, part A. 1H NMR (400 MHz, CDCl3): δ 0.36-0.40 (2H, m), 0.62-0.67 (2H, m), 1.29-1.33 (1H, m), 1.76 (1H, s), 3.89 (2H, d, J=6.8 Hz), 4.64 (2H, s), 6.84-6.86 (1H, m), 6.94 (1H, d, J=2.0 Hz), 7.32 (1H, d, J=8.0 Hz).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[C:21]1([C:27]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:28][CH2:29][C@@H:30]([OH:36])[CH2:31][C:32](OC)=[O:33])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.O>[C:21]1([C:27]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[O:28][CH2:29][C@@H:30]([OH:36])[CH2:31][C:32](=[O:33])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)C[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)C[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
125 mL of THF and 24 g of diisopropylamine were charged and cooled to −15° C. 168 mL of 1.2 N n-BuLi was added at −15 to −5° C. and was stirred for 30 minutes. 21.56 g of tert-butyl acetate in 45 mL of THF, which was pre-cooled to −45° C., was added maintaining the temperature between −45 to −25° C. for 60 minutes. The reaction mixture was cooled to −45° C. and 30 g of methyl 4 -triphenylmethyloxy-3(S)-hydroxybutyrate in THF was added over a period of 20 minutes and the stirring was continued at −25° C. for 90 minutes. Water was added and the layers were separated. The aqueous layer was extracted using EtOAc and the combined organic layers were washed with brine, water, dried and concentrated to give the title compound which was used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:45])=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:41])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][O:27][Si](C(C)C)(C(C)C)C(C)C)[CH:24]=2)[C:19]([C:38](=[O:40])[CH3:39])=[CH:18]1)=[O:8].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:1][C:2]1[C:3]([F:45])=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:41])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][OH:27])[CH:24]=2)[C:19]([C:38](=[O:40])[CH3:39])=[CH:18]1)=[O:8]
Reactant: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(CO)ccc12
Reaction time: 3 h

Procedure:
To a solution of (2S,4R)-1-[2-(3-acetyl-6-triisopropylsilanyloxymethyl-indol-1-yl)-acetyl]-4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide (50.0 mg, 0.057 mmol) in THF (5 mL), cooled to at 0° C., was added TBAF (1M in THF, 0.057 mL, 0.057 mmol), and stirring was continued for 3 h. The reaction was quenched with saturated aqueous NaHCO3 followed by addition of EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organics were washed with water (1×) and brine, dried (phase separator) and concentrated in vacuo. Purification by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 20% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) afforded after lyophilization of the purified fractions the title compound as a white solid. MS (LC/MS): 504 [M+H]+; tR (HPLC conditions k): 3.10 min.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.Cl.C(O[CH:15](OCC)[CH2:16][CH:17](OCC)OCC)C>CCO>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:17]=[CH:16][CH:15]=[N:10]2)=[CH:5][CH:4]=1
Reactant: NNc1ccc(Br)cc1
Reactant: CCOC(CC(OCC)OCC)OCC
Agent: Cl
Solvent: CCO
Product: Brc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a stirring suspension of (4-bromophenyl)hydrazine hydrochloride (3.28 g, 14.7 mmol) in EtOH (25 mL) was added concentrated HCl (0.147 mL, 1.47 mmol) and 1,1,3,3-tetraethoxypropane (3.87 mL, 16.1 mmol). The reaction mixture was heated at reflux for 2 h then cooled to room temperature. The reaction mixture was poured onto water (150 mL) and hexanes (20 mL) and stirred for 1 h. A brown precipitate was collected by filtration and washed with water (2×10 mL) and hexanes (10 mL). The resultant solid was dried in air then washed with toluene (10 mL) to afford 2 g (61%) of 1-(4-bromophenyl)-1H-pyrazole INT-84 as a light brown powder. LCMS-ESI (m/z) calculated for C9H7BrN2: 223; found 223/225 [M+H]+, tR=2.14 min (Method 10).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[CH:10]=1.[Cl:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15](B(O)O)=[C:14]([F:23])[CH:13]=1>C(COC)OC.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>[Cl:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][N:5]3[CH:10]=2)=[C:14]([F:23])[CH:13]=1
Reactant: Brc1cn2ccccc2n1
Reactant: COc1cc(B(O)O)c(F)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: COCCOC
Product: COc1cc(-c2cn3ccccc3n2)c(F)cc1Cl
Yield: 61.7 %

Procedure:
A mixture of 0.8 g (4.1 mmol) of 2-bromoimidazo[1,2-a]pyridine, 0.8 g (4.2 mmol) of 4-chloro-2-fluoro-5-methoxyphenylboronic acid, and 0.2 g (0.28 mmol) of bis(triphenylphosphine)palladium(II) chloride were heated in 30 ml of glyme at reflux for 2 h. The reaction mixture was partitioned between 250 ml of ethyl acetate and 100 ml of water and the separated organic layer washed with brine and dried over magnesium sulfate. On evaporating in vacuo, the remaining residue was flash chromatographed on silice gel (1:1 hexane/ethyl acetate) to afford 0.7 g of the title compound (m.p. 139-141° C.). NMR (CDCl3, 400 MHz): δ 4.03 (s, 3H), 6.81 (t, 1H), 7.21 (m, 2H), 8.63 (d, 1H), 7.92 (d, 1H), 8.04 (s, 1H), 8.14 (d, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:13]1[CH:26]=[C:25]2[C:16]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:32]4[C:33]([F:38])=[N:34][CH:35]=[CH:36][CH:37]=4)=[CH:22][C:23]=3[C@:24]32[CH2:30][O:29][C:28]([NH2:31])=[N:27]3)=[C:15]([F:39])[CH:14]=1)(=O)=O.[O:42]1[CH2:47][CH2:46][CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH2:43]1>CN(C=O)C.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>[O:42]1[CH2:47][CH2:46][CH:45]=[C:44]([C:13]2[CH:14]=[C:15]([F:39])[C:16]3[O:17][C:18]4[C:23](=[CH:22][C:21]([C:32]5[C:33]([F:38])=[N:34][CH:35]=[CH:36][CH:37]=5)=[CH:20][CH:19]=4)[C@@:24]4([CH2:30][O:29][C:28]([NH2:31])=[N:27]4)[C:25]=3[CH:26]=2)[CH2:43]1
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(OS(=O)(=O)C(F)(F)F)cc12
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: CN(C)C=O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(C3=CCCOC3)cc12
Temperature: 85 °C

Procedure:
Sodium carbonate (saturated) (1 ml), Pd(PPh3)4 (53.5 mg, 0.046 mmol), (S)-2-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (475 mg, 0.925 mmol; prepared from the alcohol by steps analogous to those described in Method BB40 and Example 2), and 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (389 mg, 1.850 mmol) were combined in DMF (5 ml). The solution was heated at 85° C. for three hours before being cooled to rt. The solution was concentrated and the derived residue was purified via silica gel column chromatography (RediSep 40 g column) using 20-70% 90/10/1 (CH2Cl2/MeOH/ammonia) in CH2Cl2 to afford (S)-2′-(5,6-dihydro-2H-pyran-3-yl)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as a white solid. MS m/z=448.0 [M+H]+. Chemical Formula: C25H19F2N3O3. Exact Mass: 447.14. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.18-2.36 (m, 2 H) 3.75 (t, J=5.5 Hz, 2 H) 4.24 (m, 2 H) 4.30-4.48 (m, 2 H) 6.22-6.36 (m, 1 H) 6.52 (s, 2 H) 7.07-7.15 (m, 1 H) 7.38 (m, J=8.5 Hz, 2 H) 7.50 (ddd, J=7.4, 4.9, 1.9 Hz, 1 H) 7.53-7.66 (m, 2 H) 8.12 (ddd, J=10.4, 7.5, 1.9 Hz, 1 H) 8.20-8.30 (m, 1 H)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:40]1([CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:43]3[CH2:44][CH2:45][N:40]([CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50])[CH2:41][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)NCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNC(C)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 4) was reacted with N-(2-piperazin-1-yl-ethyl)-acetamide dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound. HR-MS (ES, m/z) calculated for C38H48N5O3Cl2 [(M+H)+] 692.3129, observed 692.3125.
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([I:13])[CH:8]=1.[O:14]1[CH2:17][C:16](=[O:18])[CH2:15]1.[NH4+].[Cl-]>C1COCC1>[I:13][C:9]1[CH:8]=[C:7]([C:16]2([OH:18])[CH2:17][O:14][CH2:15]2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1COC1
Reactant: Ic1cccc(I)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2cccc(I)c2)COC1
Temperature: 25 °C

Procedure:
2.55 mL (6.37 mmol) n-butyl lithium (2.5 M in THF) was added dropwise to a mixture of 2.00 g (6.06 mmol) 1,3-diiodobenzene in 40 mL THF under argon atmosphere at −70° C. The resulting mixture was stirred for 15 min 476 μL (7.28 mmol) 3-oxetanone was added and the mixture was stirred over night at RT. The mixture was worked up by adding saturated NH4Cl solution followed by extraction with EtOAc. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by HPLC.
Reaction SMILES: [Li+].[OH-].C1COCC1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:31](=[O:47])[NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=3[CH3:46])=[CH:35][CH:34]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1.Cl>CCOC(C)=O.O.CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:31](=[O:47])[NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=3[CH3:46])=[CH:35][CH:34]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C(=O)Nc2ccc(-c3ccc(Cl)cc3C)cc2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(Cl)ccc1-c1ccc(NC(=O)c2ccc(Cl)cc2-c2ccc(C(=O)NCCC(=O)O)nc2)cc1
Temperature: 25 °C

Procedure:
A 1M aqueous solution of LiOH (2.0 mL, 2.0 mmol) was added to a THF (4.0 mL) and MeOH (1.0 mL) solution of ethyl 3-(5-(5-chloro-2-((4′-chloro-2′-methyl-[1,1′-biphenyl]-4-yl)carbamoyl)phenyl)picolinamido)propanoate (100 mg, 0.17 mmol) and the resulting mixture was stirred at room temperature. After 1 h the resulting mixture was neutralized with 2M aqueous HCl, diluted with EtOAc and water and the layers were separated. The aqueous layer was extracted with EtOAc and the combined extracts were dried (Na2SO4), and concentrated. The title compound was re-solidified from CH2Cl2/heptane (ca. 1/9) and dried in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:24]=3[N:25]=2)=[C:15]([Cl:32])[CH:14]=1)(=[O:11])=[O:10].[OH-:33].[K+].Cl>C(O)(C)(C)C>[Cl:19][C:17]1[CH:18]=[C:13]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])(=[O:11])=[O:10])[CH:14]=[C:15]([Cl:32])[C:16]=1[S:20][C:21]1[S:22][C:23]2[CH:29]=[CH:28][C:27]([C:30]([NH2:31])=[O:33])=[CH:26][C:24]=2[N:25]=1
Reactant: N#Cc1ccc2sc(Sc3c(Cl)cc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3Cl)nc2c1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)c1ccc2sc(Sc3c(Cl)cc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3Cl)nc2c1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
To a solution of 2,4-dichloro-N-[3,5-dichloro-4-(5-cyano-benzothiazol-2-ylsulfanyl)-phenyl]-benzenesulfonamide (297) (250 mg, 0.45 mmol) in tert-butanol (10 mL), was added KOH (EM Science Product, 126 mg, 2.25 mmol). The resulting mixture was refluxed for 1 hour. After cooling to room temperature, a 1M aqueous solution of HCl (50 mL) was added and the crude reaction mixture was extracted 3× with EtOAc (50 mL). The organic layers were combined and washed twice with a brine solution (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude solid was chromatographed (20% EtOAc in CH2Cl2, then 10% MeOH in CH2Cl2) to yield 207 mg (80%) of compound 303 as a white solid.