Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[OH:17][C@@H:18]1[CH2:22][NH:21][CH2:20][C@@H:19]1[CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)(Cl)Cl>[OH:17][C@@H:18]1[CH2:22][N:21]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:16])[CH2:20][C@@H:19]1[CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(NC[C@H]1CNC[C@H]1O)OCc1ccccc1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3C[C@H](CNC(=O)OCc4ccccc4)[C@H](O)C3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde (as the methyl hemiacetal) (0.654 g, 3.0 mmol) in 1:1 (MeOH/CHCl3) (50 mL) were added phenylmethyl {[(3R,4S)-4-hydroxy-3-pyrrolidinyl]methyl}carbamate (0.750 g, 3.0 mmol) and Na2SO4 (0.100 g) and the resulting solution stirred at ambient temperature for 18 hours. Na(OAc)3BH (1.91 g, 9.0 mmol) was added and the solution stirred an additional 2 hours. The reaction mixture was concentrated onto silica gel and chromatographed on a silica gel column [0-100% CHCl3/(90:10:1) CHCl3/MeOH/NH4OH)] to yield a colorless oil. (0.897 g, 66%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH3:11].[Br:12]NC(=O)CCC(N)=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][Br:12]
Reactant: COc1cc(C)c(Br)c(C)c1
Reactant: NC(=O)CCC(=O)NBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C)c(Br)c(CBr)c1
Temperature: 75 °C
Yield: 92 %

Procedure:
A solution of 2-bromo-5-methoxy-1,3-dimethyl-benzene ((Example 192: step a) 1.01 g, 4.70 mmol) in CCl4 (50 mL) was treated with N-bromosuccinamide and AIBN (catalytic amount) and heated to 75° C. 3.5 h. The reaction was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the product 2-bromo-1-bromomethyl-5-methoxy-3-methyl-benzene (1.27 g, 92%) as a pale orange solid. 1H NMR (CDCl3): δ 6.641 (s, 2H), 4.601 (s, 2H), 3.760 (s, 3H), 2.380 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH2:49][O:50][CH3:51])[CH2:46][N:45]3[C:52](OC(C)(C)C)=[O:53])=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].[CH3:59][O:60][C:61]([NH:63][C@@H:64]([CH:68]([CH3:70])[CH3:69])C(O)=O)=[O:62].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>Cl.CCO.CN(C=O)C>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@@H:6]([CH:7]([CH3:8])[CH3:9])[C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH2:49][O:50][CH3:51])[CH2:46][N:45]3[C:52](=[O:53])[C@@H:64]([NH:63][C:61]([O:60][CH3:59])=[O:62])[CH:68]([CH3:70])[CH3:69])=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11]
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c65)cc3-4)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Reaction time: 3 h
Yield: 82.5 %

Procedure:
Tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (100 mg, 0.13 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50° C. for 3 h and then concentrated under reduced pressure. The crude residue was treated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (34 mg, 0.20 mmol), HATU (54 mg, 0.14 mmol) and DMF (1.3 mL), then N-methylmorpholine (0.043 mL, 0.39 mmol) was added dropwise. After 3 h, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (91 mg, 82%).
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][O:15][CH2:16][C:17]#[C:18][C:19]1[S:23][CH:22]=[N:21][CH:20]=1)[C:6](=[O:12])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1.O>[C:1]([N:5]([CH2:13][CH2:14][O:15][CH2:16][C:17]#[C:18][C:19]1[S:23][CH:22]=[N:21][CH:20]=1)[C:6](=[O:12])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)N(CCOCC#Cc1cncs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)N(CCOCC#Cc1cncs1)C(=O)C(=O)O
Temperature: 55 °C
Reaction time: 1 h
Yield: 104.2 %

Procedure:
A solution of 450 mg of 11e in 4 ml of dioxane was mixed with a solution of 250 mg of KOH in 2 ml of water and stirred at 55° C. for 1 h. The reaction mixture was then cooled and diluted with 20 ml of water and made acidic to pH3 by addition of 0.5N HCl. The product was extracted with ethyl acetate. The organic extract was washed once with water, dried and concentrated, to give 430 mg of 11f as a colorless oil, which solidified on standing; Mp: 104-105° C.; Rf 0.20 (CH2Cl2/methanol 8/2). MS-ESI:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:22]2[O:26][N:25]=[C:24]([Br:27])[N:23]=2)[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[O:11]COCCOC)([CH3:4])[CH3:3]>[Br-].[Zn+2].[Br-]>[Br:27][C:24]1[N:23]=[C:22]([C:7]2[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=2)[O:26][N:25]=1
Reactant: COCCOCOc1c(C(C)(C)C)cc(-c2nc(Br)no2)cc1C(C)(C)C
Agent: [Br-]
Agent: [Zn+2]
Product: CC(C)(C)c1cc(-c2nc(Br)no2)cc(C(C)(C)C)c1O
Yield: 56.6 %

Procedure:
In a manner analogous to Example 59, 0.8 g (0.002 mole) of 5-[3,5-bis(1,1-dimethylethyl)-4-[(2methoxyethoxy)methoxy]phenyl]-3-bromo-1,2,4-oxadiazole is reacted with 2.0 g (0.009 mole) of zinc bromide to give 0.4 g (65%) of 4-(3-bromo-1,2,4-oxadiazol-5-yl)-2,6-bis(1,1-dimethylethyl)phenol, mp 113°-115° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][C:2]1=2.[N:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[C:11]=S.C[Si](C)(C)[Si](C)(C)C.[Li].O.[NH2:31][NH2:32]>C1COCC1.O.C(O)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]3[NH:31][N:32]=[C:11]([NH:10][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[O:19][CH3:20])[C:7]=3[CH2:8][C:2]1=2
Reactant: NN
Reactant: O=C1CCc2sccc21
Reactant: COc1ccccc1N=C=S
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccccc1Nc1n[nH]c2c1Cc1sccc1-2
Reaction time: 8 h
Yield: 33 %

Procedure:
A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-Isothiocyanato-2-methoxy-benzene (1.5 g, 7.2 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give (4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(2-methoxy-phenyl)-amine as brown solid in 33% yield.
Reaction SMILES: O.[OH-].[Li+].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10](/[CH:13]=[CH:14]/[C:15]([O:17]C)=[O:16])[CH:11]=2)[CH:6]=[CH:5]1.Cl>CO.O1CCCC1.O>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[CH:11]=2)[CH:6]=[CH:5]1
Reactant: COC(=O)/C=C/c1ccc2cc[nH]c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1ccc2cc[nH]c2c1
Yield: 97.7 %

Procedure:
Lithium hydroxide monohydrate (4.6 g) was added to a stirred solution of methyl E-indole-6-acrylate (5.5 g) in methanol (100 ml), tetrahydrofuran (10 ml), and water (10 ml) under an atmosphere of nitrogen; and the mixture was heated at 50° for 5 hr. The cooled mixture was diluted with water (100 ml) and acidified to pH 4 with 6M hydrochloric acid. The precipitate which formed was isolated by filtration, washed twice with water, and dried to give E-indole-6-acrylic acid (5 g, 97%) as a yellow powder; mp 215°-217°; partial NMR (250 MHz, DMSO-d6): 6.42(d, J=15.9 Hz, 1H, olefinic H), 6.47(m, 1H, H3 -indole), 7.70(d, J=15.9 Hz, 1H, olefinic H), 11.35(br s, 1H, NH), 12.18(br s, 1H, COOH).
Reaction SMILES: CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.[C:59]([OH:63])(C)([CH3:61])[CH3:60].O.[Br:65][C:66]1[C:75](C=C)=[C:74](C)[CH:73]=[C:72]2[C:67]=1[CH:68]=[CH:69][C:70]([CH3:79])=[N:71]2>C(OCC)(=O)C>[Br:65][C:66]1[C:60]([C@H:59]([OH:63])[CH2:61][OH:22])=[C:74]([CH3:75])[CH:73]=[C:72]2[C:67]=1[CH:68]=[CH:69][C:70]([CH3:79])=[N:71]2
Reactant: C=Cc1c(C)cc2nc(C)ccc2c1Br
Reactant: CC(C)(C)O
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc2c(Br)c([C@H](O)CO)c(C)cc2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
AD-mix-α (8 g, excess) was added to a mixed solvent of t-butanol and water (35 mL/35 mL) and stirred at room temperature for 5 min, cooled to 0° C. 5-bromo-2,7-dimethyl-6-vinylquinoline (678 mg, 2.6 mmol) was added and the mixture was stirred at 0° C. for 16 hrs. The mixture was diluted with ethyl acetate, washed with NaHCO3 solution, water and brine, and dried over Na2SO4. Concentration and purification by flash column chromatography yielded (S)-1-(5-bromo-2,7-dimethylquinolin-6-yl)ethane-1,2-diol. LCMS-ESI+ (m/z): [M+H]+ calc'd for C13H15BrNO2: 296.0; Found: 296.1.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]2[CH2:15][NH:14][C:13]2=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19].C[Si](C)(C)[NH:26][C:27](=[O:30])[CH2:28][Cl:29]>C(OCC)(=O)C>[Cl:29][CH2:28][C:27]([NH:26][S:18]([NH:21][C:22]([N:14]1[CH2:15][CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]1=[O:16])=[O:23])(=[O:20])=[O:19])=[O:30]
Reactant: C[Si](C)(C)NC(=O)CCl
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(CCl)NS(=O)(=O)NC(=O)N1CC(NC(=O)OCc2ccccc2)C1=O
Temperature: -50 °C
Yield: 46.6 %

Procedure:
(S)-3-[[(Phenylmethoxy)carbonyl]amino]-2-azetidinone (4.4 g) was suspended in 150 ml of dry ethyl acetate. The mixture was cooled to -50° C. and 3.3 g of chlorosulfonyl isocyanate was added with stirring; stirring was continued without cooling until the temperature reached 0° C. N-(Trimethylsilyl)chloroacetamide (6.0 g) was added and the solution was stirred overnight. The insoluble material was filtered off and the filtrate washed with water. The organic layer was extracted twice with saturated aqueous sodium bicarbonate. The alkaline aqueous layer was acidified to pH 1 with 20% hydrochloric acid and extracted twice with 150 ml portions of ethyl acetate. The organic layers were combined, dried and evaporated to dryness. The oily residue was dissolved in 50 ml of acetone and the pH was adjusted to 6.5 by addition of lN potassium hydroxide. The solvent was removed in vacuo and the crystalline residue filtered with ether, yielding 3.9 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Br:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:6])=[C:2]([F:1])[CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(c1ccccc1)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 2-fluoro-4-bromobenzoic acid (1.0 g, 0.0046 mol), thionyl chloride (0.77 mL, 0.010 mol) and a drop of DMF and the reaction was refluxed for 2 h. The excess thionyl chloride was then distilled off and the residual thionyl chloride was removed on the high vacuum pump. Benzene (20 mL, 0.2 mol) and aluminum trichloride (0.676 g, 0.00507 mol) were added to the reaction mixture. The reaction mixture was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc. HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=7.32-7:41 (m, 1H), 7.42-7.53 (m, 4H), 7.56-7.67 (m, 1H), 7.77-7.88 (m, 2H). MS (ES+): m/z 280.78 (40) [MH+]. HPLC: tR=3.8 min(Open Lynx polar—5 min).
Reaction SMILES: BrCCCCCC(C)C(OCC)=[O:9].CC(CCCCI)CC(OC)=O.C([O:29][CH:30]([CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH2:31][CH2:32][CH2:33][N:34]([CH2:37][CH2:38][CH2:39][CH2:40][CH:41](C)[CH2:42][C:43]([O:45]C)=[O:44])[C:35]#[N:36])(=O)C>>[OH:29][C@H:30]([CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:31]#[C:32][CH2:33][N:34]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44])[C:35]#[N:36].[OH:29][C@H:30]([CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:31]#[C:32][CH2:33][N:34]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44])[C:35]([NH2:36])=[O:9]
Reactant: CCOC(=O)C(C)CCCCCBr
Reactant: CCCCCC(CCCN(C#N)CCCCC(C)CC(=O)OC)OC(C)=O
Agent: COC(=O)CC(C)CCCCI
Product: CCCCC[C@@H](O)C#CCN(C#N)CCCCCCC(=O)O
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)C(N)=O

Procedure:
The synthesis of this compound is carried out as described in Example 7 except that, in Step A, the ethyl 7-bromo-2-methylheptanoate is replaced by an equimolar amount of methyl 3-methyl-7-iodoheptanoate. The product of Step A is thus methyl 7-[N-(4-acetoxynonyl)cyanamido]-3-methylheptanoate. The subsequent steps yield 7-[N-(4-hydroxynonyl)cyanamido]-3-methylheptanoic acid (B) and 7-[1-(4-hydroxynonyl)ureido]-2-methylheptanoic acid (C).
Reaction SMILES: C([N:8]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27](O)[C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)[CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[OH:11])C1C=CC=CC=1>Cl.O1CCOCC1>[Cl:18][C:14]1[CH:13]=[C:12]([C@@H:10]([OH:11])[CH2:9][NH:8][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=3)=[CH:25][CH:26]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccc(C(O)c2ccc(CCN(Cc3ccccc3)C[C@H](O)c3cccc(Cl)c3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Oc1ccc(Cc2ccc(CCNC[C@H](O)c3cccc(Cl)c3)cc2)cc1
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
A mixture of 4-[[4-[2-[N-benzyl-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl] (hydroxy)methyl]phenol (545 mg) in 4N hydrogen chloride in 1,4-dioxane (1.0 ml) was stirred for 5 minutes. The solvent was removed by evaporation. A suspension of the residue in ethanol (2.2 ml) and chlorobenzene (5.2 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 55 mg) under hydrogen atmosphere for 2 hours. The catalyst was filtered off, and the filtrate was evaporated. The residue was diluted with ethyl acetate and saturated sodium biscarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 4-[4-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]benzyl]phenol (395 mg)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:60][CH2:61][C:62]1[CH:67]=[CH:66][C:65]([S:68]([NH:71][CH3:72])(=[O:70])=[O:69])=[CH:64][CH:63]=1>CN(C=O)C>[CH3:72][NH:71][S:68]([C:65]1[CH:66]=[CH:67][C:62]([CH2:61][NH:60][C:17]([C:12]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:16]=3[CH:15]=[CH:14][CH:13]=2)=[O:19])=[CH:63][CH:64]=1)(=[O:69])=[O:70]
Reactant: O=C(O)c1cccc2c1cnn2-c1ccc(F)cc1
Reactant: CNS(=O)(=O)c1ccc(CN)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (0.05 g, 0.2 mmol) in DMF (10 mL) was added PyBOP (0.14 g, 0.30 mmol) and triethylamine (0.07 g, 0.6 mmol) at room temperature. After 15 minutes, 4-aminomethyl-N-methyl-benzenesulfonamide (0.04 g, 0.2 mmol) was added. After 5 hours, the mixture was quenched with water (30 mL) and diluted with ethyl acetate (30 mL). The organic layer was separated, washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-30% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C([N:16]([CH2:19]C)[CH2:17][CH3:18])C.[OH-].[Na+].Cl.[N:24]1C=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH:16]1[C:17]2[CH2:18][CH2:28][CH2:27][CH2:26][C:25]=2[N:24]=[C:19]1[C:7]([C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1)=[O:8]
Reactant: c1ccncc1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(c1ccc(C(F)(F)F)cc1)c1nc2c([nH]1)CCCC2
Temperature: 25 °C
Yield: 70 %

Procedure:
The compound of Reference example 44-1 (3.13 g, 25.6 mmol) and 4-(trifluoromethyl)benzoyl chloride (10.0 g, 47.9 mmol) were dissolve in pyridine (20 ml) and the solution was stirred at room temperature. Therein was dropped triethylamine (4.85 g, 47.9 mmol) and the mixture was stirred for 4 hours at 60° C. Thereto was added 4N aqueous sodium hydroxide solution (20 ml) and the mixture was stirred for 3 hours at room temperature. The reaction mixture was neutralized with 1N diluted hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the residue was recrystallized from toluene to give the subject compound (5.24 g, 70%).
Reaction SMILES: [CH2:1]=[O:2].[Mg+2].[Cl-].[Cl-].[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].Cl>C(#N)C.C(N(CC)CC)C>[Br:6][C:7]1[C:8]([OH:13])=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH:1]=[O:2]
Reactant: Oc1ccccc1Br
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=Cc1cccc(Br)c1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.8 %

Procedure:
To a 500 mL 3-neck round flask, paraformaldehyde (5.96 g, 199 mmol), and 12.60 g of anhydrous MgCl2 (12.60 g, 132 mmol) was added in acetonitrile (300 mL). Then 13.40 g of triethylamine was introduced slowly at room temperature. The mixture was stirred at room temperature for 20 min. 2-bromophenol (11.45 g, 66.2 mmol) was added to the above mixture. Then the reaction mixture was refluxed overnight. Then the mixture was cooled to room temperature, HCl (3N, 150 mL) were added to dilute the mixture. The resulted mixture was filtered through celite, and washed with tertbutyl methyl ether (200 mL). The organic solution was washed with 1N HCl (100 mL×2). The combined acid phase was extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (100 mL×2), water (100 mL×2), dried over sodium sulphate and concentrated to give 3-bromo-2-hydroxybenzaldehyde (D98) (2.1 g) as yellow oil, which was directly used in next step. MS (ES): C7H5BrO2 requires 199.9. found 201.0 (M+H+).
Reaction SMILES: C([NH2:4])(=O)C.B(F)(F)F.CCOCC.C([O:18][C:19](=[O:72])[CH2:20][N:21]([CH2:46][C:47]1[CH:71]=[CH:70][C:50]([C:51]([O:53][CH2:54][C:55]([C:57]2[CH:62]=[CH:61][C:60]([C:63]3[CH:68]=[CH:67][C:66]([CH3:69])=[CH:65][CH:64]=3)=[CH:59][CH:58]=2)=O)=O)=[CH:49][CH:48]=1)[C:22](=[O:45])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:44])[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=2[C:40]([F:43])([F:42])[F:41])=[CH:25][CH:24]=1)(C)(C)C.N#N>C(Cl)Cl.C(#N)C>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([C:22]([N:21]([CH2:20][C:19]([OH:18])=[O:72])[CH2:46][C:47]3[CH:48]=[CH:49][C:50]([C:51]4[O:53][CH:54]=[C:55]([C:57]5[CH:58]=[CH:59][C:60]([C:63]6[CH:64]=[CH:65][C:66]([CH3:69])=[CH:67][CH:68]=6)=[CH:61][CH:62]=5)[N:4]=4)=[CH:70][CH:71]=3)=[O:45])=[CH:24][CH:25]=2)=[O:44])=[C:33]([C:40]([F:42])([F:43])[F:41])[CH:34]=1
Reactant: CC(N)=O
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=O)OCC(=O)c4ccc(-c5ccc(C)cc5)cc4)cc3)cc2)c(C(F)(F)F)c1
Agent: FB(F)F
Agent: N#N
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4nc(-c5ccc(-c6ccc(C)cc6)cc5)co4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To stirring acetamide (292 mg, 4.95 mmol) at 100° C. was added boron trifluoride etherate (16.0 μl, 0.130 mmol). The temperature was raised to 140° C. and a solution of 2-(4′-methyl-[1,1′-biphenyl]-4-yl)-2-oxoethyl 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoate INT-38 (100 mg, 0.124 mmol) in DCM (1 mL) was added drop wise under a stream of N2. After 1 h, the reaction mixture was allowed to cool to room temperature and acetonitrile (2 mL) was added. The reaction mixture was stirred at room temperature for 2 h and the precipitate was collected by filtration and washed with acetonitrile (0.5 mL) and isohexanes (2 mL). The isolated precipitate was further re-slurried from DCM (2 mL) to afford 39 mg (43%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(4-(4′-methyl-[1,1′-biphenyl]-4-yl)oxazol-2-yl)benzyl)benzamido)acetic acid 360 as a white solid. LCMS-ESI (m/z) calculated for C42H34F3N3O6: 733; found 734 [M+H]+, tR=9.18 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.84 (s, 1H), 10.34 (s, 1H), 8.78 (s, 1H), 8.10-8.03 (m, 2H), 7.98-7.92 (m, 2H), 7.80-7.73 (m, 2H), 7.68-7.53 (m, 5H), 7.50-7.35 (m, 4H), 7.33-7.27 (d, J=7.8 Hz, 2H), 7.26-7.16 (m, 2H), 4.75 (s, 1H), 4.67 (s, 1H), 4.03 (m, 1H), 3.95 (s, 1H), 3.89-3.79 (m, 5H), 2.37 (s, 3H).