Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:28]=[CH:27][C:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:20]=4[CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11].[C:29]([O:33]C(C)(C)C)(=[O:32])[CH:30]=[CH2:31].C(N(C(C)C)CC)(C)C>CO>[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:28]=[CH:27][C:21]4[CH2:22][CH2:23][N:24]([CH2:31][CH2:30][C:29]([OH:33])=[O:32])[CH2:25][CH2:26][C:20]=4[CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCNCC4)no2)cc1Cl
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCN(CCC(=O)O)CC4)no2)cc1Cl
Temperature: 90 °C
Reaction time: 5 h
Yield: 46.2 %

Procedure:
A mixture of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (Example 17) (200 mg, 0.52 mmol), 1,1-dimethylethyl 2-propenoate (151 μL, 1.04 mmol) and diisopropylethylamine (453 μL, 2.60 mmol) in methanol (5 ml) was heated in the microwave at 90° C. for 30 minutes before the solvent was removed in vacuo. The residue was dissolved in 4M HCl (2 ml) in dioxane and the mixture stirred at room temperature for 5 h. The solvent was removed in vacuo and the residue purified by MDAP. To the product containing fractions was added 2M HCl and the solution concentrated in vacuo to give the title compound as a white solid (116 mg, 0.24 mmol). δH (d6DMSO, 400 MHz): 12.73 (1H, br.s), 10.76 (1H, br.s), 8.19 (1H, d), 8.11 (1H, dd), 7.98 (1H, d), 7.93 (1H, dd), 7.46 (1H, d), 7.45 (1H, d), 4.89 (1H, septet), 3.76-3.64 (2H, m), 3.44-3.31 (4H, hidden under H2O peak), 3.25-3.03 (4H, m), 2.89 (2H, t), 1.37 (6H, d). MS (ES): C24H2635ClN3O4 requires 455; found 456 [M+H]+.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][N:8]=1.[F:9][C:10]1[CH:11]=[C:12]([C:17]2[O:18][C:19](=[O:22])[CH2:20][N:21]=2)[CH:13]=[CH:14][C:15]=1[F:16].O.[OH-].[Li+]>C1COCC1.O>[F:9][C:10]1[CH:11]=[C:12]([C:17]2[N:8]3[CH2:7][CH2:6][CH2:5][CH2:4][C:3]3=[C:20]([C:19]([OH:22])=[O:18])[N:21]=2)[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: COC1=NCCCC1
Reactant: O=C1CN=C(c2ccc(F)c(F)c2)O1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(-c2ccc(F)c(F)c2)n2c1CCCC2
Temperature: 90 °C
Yield: 70.2 %

Procedure:
6-methoxy-2,3,4,5-tetrahydropyridine (0.431 g, 3.80 mmol) was dissolved in THF (5 mL) in a 40 mL screw-cap vial and 2-(3,4-difluorophenyl)oxazol-5(4H)-one (0.75 g, 3.80 mmol) in THF (5 mL) was added, producing an orange solution. The vial was capped and heated to 90° C. for 3 hours. THF was removed under reduced pressure and the residue was dissolved in MeOH (10 ml) and lithium hydroxide monohydrate (0.479 g, 11.41 mmol) in water (1 mL) was added. The reaction was heated to 90° C. for 3 hours. MeOH was removed by evaporation under reduced pressure. The remaining aqueous solution was diluted with water (5 mL) and acidified to pH 2 with 5M HCl. The solution was extracted with EtOAc (3×5 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated to yield the desired product as a brown oil (742 mg, 71%) that was used without further purification. LCMS (+ESI) m/z: 279.3 [M+H]+.
Reaction SMILES: [Li+].[Cl-].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.C(N(CC)C(C)C)(C)C.[CH3:26][C:27]([S@:30]([NH:32][C@:33]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[F:48])([C:37]([F:41])([F:40])[CH:38]=O)[CH:34]([F:36])[F:35])=[O:31])([CH3:29])[CH3:28]>C(#N)C>[C:27]([S@:30]([NH:32][C@@:33]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[F:48])([CH:34]([F:35])[F:36])[C:37]([F:40])([F:41])[CH:38]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:31])([CH3:26])([CH3:28])[CH3:29]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)[S@@](=O)N[C@@](c1ccccc1F)(C(F)F)C(F)(F)C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C=CC(F)(F)[C@](N[S@](=O)C(C)(C)C)(c1ccccc1F)C(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
To a stirred suspension of LiCl (405 mg, 9.56 mmol) in acetonitrile (30 mL) under N2 were added ethyl 2-diethoxyphosphorylacetate (2.14 g, 9.56 mmol) and DIPEA (N,N-diisopropylethylamine) (2.06 g, 15.94 mmol) at 0° C. After 20 min, (R)-2-methyl-N—((S)-1,1,3,3-tetrafluoro-2-(2-fluorophenyl)-4-oxo-butan-2-yl)propane-2-sulfinamide (2.85 g, 7.97 mmol) in acetonitrile (10 mL) was added dropwise to the mixture at 0° C. and the mixture was stirred at 25° C. for 17.5 hours. The reaction mixture was concentrated to remove acetonitrile, water (50 ml) was added and extracted with ethyl acetate (200 ml). The organic layer was dried and evaporated. The crude product was purified by column chromatography (petrolium ether: ethyl acetate=5:1 to 4:1) to afford ethyl (S)-5-(((R)-tert-butylsulfinyl)amino)-4,4,6,6-tetrafluoro-5-(2-fluorophenyl)hex-2-enoate (1.77 g, 46.8% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]=[O:12])[CH2:7][CH2:6]1.[C-:13]#[N:14].[Na+]>C(O)C>[C:13]([CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]=[O:12])[CH2:7][CH2:6]1)#[N:14]
Reactant: [C-]#N
Reactant: O=CN1CCC(CCCBr)CC1
Agent: [Na+]
Solvent: CCO
Product: N#CCCCC1CCN(C=O)CC1
Yield: 61.5 %

Procedure:
4-(3-Bromopropyl)-1-piperidinecarboxaldehyde (60 g, 0.256 M) and NaCN (25 g) in ethanol (600 ml) was refluxed for 7 hours, Solvent was removed, added water (300-400 ml) and extracted with CH2Cl2 (4×200 ml). The extracts, dried over Na2SO4 was stripped to dryness which was purified on silica gel columns, eluted with ethylacetate-hexane (8:2 parts by volume) to yield 4-(3-cyanopropyl)-1-piperidinecarboxaldehyde (28.4 g, 61% yield).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[O:12])[N:7]([C:27]2[CH:39]=[CH:38][C:30]([CH2:31][NH:32][C:33](=O)[CH2:34][O:35][CH3:36])=[CH:29][CH:28]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].B.CSC>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:18][CH:19]=2)=[O:12])[N:7]([C:27]2[CH:39]=[CH:38][C:30]([CH2:31][NH:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:29][CH:28]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC(=O)NCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: COCCNCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Temperature: 25 °C
Yield: 15.3 %

Procedure:
To a solution of N-[4-(3-tert-butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzyl]-2-methoxy-acetamide (200 mg, 0.38 mmol) in anhydrous THF (10 mL) was added borane-methyl sulfide complex (2.0 M solution in THF, 1 mL, 2 mmol), and the reaction was stirred at reflux for 7 h. The reaction mixture was cooled to room temperature, partitioned between EtOAc (50 mL) and water (50 mL), and then the organic layer was separated and washed with brine, dried over Na2SO4, and concentrated at reduced pressure. The residue was purified by MPLC (90:10 CH2Cl2/MeOH) to give 30 mg (15%) of the desired product. 1H-NMR (DMSO-d6) δ 8.79 (s, 1H), 8.42 (d, J=4.8 Hz, 2H), 7.61 to 7.46 (m, 7H), 7.06 (d, J=6.6 Hz, 2H), 6.84 (d, J=4.5 Hz, 2H), 6.44 (s, 1H), 3.85 (s, 2H), 3.49 (t, J=5.7 Hz, 2H), 3.29 (s, 3H), 2.81 (t, J=5.7 Hz, 2H), 1.31 (s, 9H); MS LC-MS [M+H]+=515, RT=2.02 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([C:13]([OH:15])=O)[N:12]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1.[NH2:21][CH2:22][CH2:23][CH2:24][OH:25].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([C:13]([NH:21][CH2:22][CH2:23][CH2:24][OH:25])=[O:15])[N:12]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: Cc1oc(-c2cnc(Cl)cc2NC(C)C)nc1C(=O)O
Reactant: NCCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(-c2cnc(Cl)cc2NC(C)C)nc1C(=O)NCCCO
Temperature: 25 °C

Procedure:
2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylic acid (30a) (100 mg, 0.338 mmol) was dissolved in DMF (5 mL). 3-aminopropan-1-ol (1.691 mmol, 5 equiv.) and DIPEA (1.353 mmol, 4 equiv.) were added to the reaction mixture and stirred at room temperature. HATU (1.014 mmol, 3 equiv.) was added to the reaction mixture and stirred for 3 h. The reaction mixture was concentrated under reduced pressure to remove excess of DMF. The residue obtained was partitioned between water and EtOAc. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by flash column chromatography through silica gel and MeOH:CHCl3 as eluent to afford the title compound, 2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-N-(3-hydroxypropyl)-5-methyloxazole-4-carboxamide (31).
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]([CH3:7])=[O:6])=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[C@@H:20]([OH:21])[C@H](CO)[C@@H:18]([OH:24])[C@H:17]([OH:25])[C@H:16]2[OH:26])=[CH:11][C:10]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:5]([O:4][CH2:2][C@@H:1]1[C@@H:18]([OH:24])[C@H:17]([OH:25])[C@@H:16]([OH:26])[C@H:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[C:10]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([CH2:34][CH3:35])=[CH:32][CH:33]=3)[CH:11]=2)[C@H:20]1[OH:21])(=[O:6])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1ccc(Cc2cc([C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)[C@@H]3O)ccc2Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1ccc(Cc2cc([C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@@H](COC(C)=O)[C@@H]3O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
Ac2O (377 mg, 1.5 eq) was added dropwised into the solution of (1R,2R,3S,4R,5R,6S)-4-(4-chloro-3-(4-ethylbenzyl)phenyl)-6-(hydroxymethyl)cyclohexane-1,2,3,5-tetraol (5, R=Et, 1 g, 2.46 mmol) and DMAP (cat.) in CH2Cl2 (10 mL) at 0° C. followed by pyridine (292 mg, 1.5 eq), and the mixture was stirred overnight at rt. The reaction mixture was washed with 3N HCl, and the organic layer was combined, dried over Na2SO4, filtered, and the filtrate was evaporated to dryness. The residue was purified by preperative HPLC to give target compound (566 mg, white solid, yield of 50.4%). 1H-NMR (400 MHz, CD3OD): δ 7.32 (1H, d, J=8.4 Hz), 7.06-7.14 (6H, m), 4.37 (2H, ddd, J=2.0, 10.8, 16.8 Hz), 4.04 (2H, s), 3.57 (1H, t, J=10.8 Hz), 3.40-3.47 (1H, m), 2.49-2.60 (3H, m), 2.04 (3H, s), 1.60-1.66 (1H, m), 1.18 (3H, t, J=8.0 Hz); MS (ESI+): 449 [M+H]+, 466 [M+NH4]+, 897 [2M+H]+, (ESI−): 492 [M+HCOO]−, 941 [2M+HCOO]−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[CH3:15][CH:16]([CH3:25])[CH2:17][CH2:18][N:19]1[CH:23]=[N:22][NH:21][C:20]1=[O:24]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:21]1[C:20](=[O:24])[N:19]([CH2:18][CH2:17][CH:16]([CH3:25])[CH3:15])[CH:23]=[N:22]1)[CH3:13]
Reactant: CC(C)CCn1cn[nH]c1=O
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: CC(C)CCn1cnn([C@H](C)[C@@]2(c3ccc(F)cc3F)CO2)c1=O
Yield: 49.4 %

Procedure:
In the same menner as in Reference Example 5, starting from 1.38 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.21 g of 4-(3-methylbutyl)-3(2H,4H)-1,2,4-triazolone, 2-[(1R, 2S)-2-(2,4-Difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(3-methylbutyl)-3 (2H, 4H)-1,2,4-triazolone (1.15 g) was obtained as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[CH2:12]([O:14][C:15]([C:17]([C:34]1[CH:44]=[CH:43][C:37]([O:38][CH2:39][C:40](=O)[CH3:41])=[CH:36][CH:35]=1)([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16])[CH3:13].C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH2:32]([O:31][C:29]([C:17]([C:34]1[CH:44]=[CH:43][C:37]([O:38][CH2:39][CH:40]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])[CH3:41])=[CH:36][CH:35]=1)([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:30])[CH3:33]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CCOC(=O)C(C(=O)OCC)C(C(=O)OCC)(C(=O)OCC)c1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: CCOC(=O)C(C(=O)OCC)C(C(=O)OCC)(C(=O)OCC)c1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)cc1
Yield: 11 %

Procedure:
Following a procedure similar to that described in Example 6, but using 1 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 3 g of 4-[1,1,2,2-tetrakis(ethoxycarbonyl)ethyl]phenoxyacetone (prepared as described in Preparation 22), 100 ml of dry benzene, 50 ml of absolute methanol and 920 mg of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and hexane as the eluent, 0.4 g of the title compound was obtained having an Rf=0.35 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[C:12]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)#[CH:13].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[NH2:18][C:17]1[CH:19]=[CH:20][C:14]([C:12]#[C:13][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=3)[N:7]=2)=[CH:15][CH:16]=1
Reactant: Nc1cn2nc(I)ccc2n1
Reactant: C#Cc1ccc(N)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc(C#Cc2ccc3nc(N)cn3n2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To the mixture of 6-iodo-imidazo[1,2-b]pyridazin-2-ylamine (780 mg, 3.0 mmol, 1 eq) and 4-ethynylaniline (543 mg, 1.5 eq) in anhydrous DMF (10 mL) under nitrogen atmosphere was added triethylamine (1.67 mL, 4 eq), bis(triphenylphosphine)palladium(II) dichloride (210 mg, 0.1 eq) and copper(I) iodide (114 mg, 0.2 eq). After the reaction mixture was stirred at 50° C. for 30 minutes, it was partitioned between saturated aqueous sodium bicarbonate and chloroform (containing 3% v/v of MeOH). The organic layer was separated and washed with aqueous ammonium chloride, brine, and lastly dried with anhydrous sodium sulfate. The upper suspension mixture was decanted, concentrated, and the solid residue was subject to a gradient column chromatography (from CHCl3 to MeOH—CHCl3 1:30) to give 6-[(4-aminophenyl)ethynyl]imidazo[1,2-b]pyridazin-2-amine as a yellow solid in amount of 166 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=2.[CH3:16][C:17]([CH3:22])([CH2:20]O)[CH:18]=[O:19]>CO>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:14][CH3:15])[N:4]=[CH:3][C:2]([NH:1][CH2:16][C:17]([CH3:22])([CH3:20])[CH2:18][OH:19])=[CH:11]2
Reactant: COc1cc2cc(N)cnc2cc1OC
Reactant: CC(C)(C=O)CO
Solvent: CO
Product: COc1cc2cc(NCC(C)(C)CO)cnc2cc1OC
Yield: 21.5 %

Procedure:
The reaction is run similar to the preparation in Example 11. To a MeOH solution of 4 Å powdered molecular sieves (0.35 g) under argon is added 3-amino-6,7-dimethoxyquinoline (0.32 g, 1.6 mmol) and 2,2-dimethyl-3-hydroxypropionaldehyde (0.19 g, 1.9 mmol). The product mixture is chromatographed (3% MeOH/CHCl3) to afford 0.10 g of material which is partitioned between CH2Cl2/10% NaOH. The organic layer is washed with 10% NaOH, H2O, and brine, then dried (MgSO4), and recrystallized from EtOAc/hexanes to provide a light-orange solid (m.p. 170-173.5° C.). Anal. Calcd. for C16H22N2O3: C, 66.18; H, 7.64; N, 9.65; Found: C, 66.11; H, 7.49; N, 9.33.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([Br:12])[C:9]2[C:4](=[C:5]([Br:22])[CH:6]=[C:7]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:14])[CH:8]=2)[N:3]=1.C1(C)C=CC=CC=1.[O:30]([CH3:32])[Na]>O1CCCC1>[Br:12][C:10]1[C:9]2[C:4](=[C:5]([Br:22])[CH:6]=[C:7]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:14])[CH:8]=2)[N:3]=[C:2]([O:30][CH3:32])[CH:11]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cc(Br)c2nc(Br)cc(Br)c2c1
Reactant: CO[Na]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(Br)c2cc(C(=O)c3ccc(Cl)cc3)cc(Br)c2n1
Temperature: 66 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed 2,4,8-tribromo-6-[(4-chlorophenyl)carbonyl]quinoline (2 g, 3.97 mmol, 1.00 equip), toluene (20 mL), and tetrahydrofuran (2 mL). To the resulting mixture was then added NaOCH3 (642 mg, 11.89 mmol, 3.00 equip). The resulting solution was stirred for 2 h at 66° C. Then another batch of NaOCH3 (642 mg, 11.89 mmol, 3.00 equip) was added to the solution. The resulting solution was allowed to react, with stirring, for an additional 2 h at 66° C. And then a final batch of NaOCH3 (642 mg, 11.89 mmol, 3.00 equip) was added to the solution. The resulting solution was allowed to react, with stirring, for an additional 2 h at 66° C. The reaction was then quenched by the addition of saturated sodium bicarbonate (200 mL). The resulting solution was extracted with DCM (2×100 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 4,8-dibromo-6-[(4-chlorophenyl)carbonyl]-2-methoxyquinoline as a yellow solid. LCMS (ES, m/z) 456 [M+H]+
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:20][CH3:21])=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[F:22][C:23]1[CH:24]=[C:25]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:26]=[CH:27][C:28]=1[CH2:29][OH:30]>C(Cl)Cl.O>[Cl:2][C:3]1[C:4]([O:20][CH3:21])=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:32]([NH:31][C:25]3[CH:26]=[CH:27][C:28]([CH2:29][OH:30])=[C:23]([F:22])[CH:24]=3)=[O:33])=[CH:12][C:11]([C:16]([F:18])([F:19])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1c(Cl)cccc1-n1nc(C(F)(F)F)cc1CN
Reactant: O=C(Nc1ccc(CO)c(F)c1)Oc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COc1c(Cl)cccc1-n1nc(C(F)(F)F)cc1CNC(=O)Nc1ccc(CO)c(F)c1
Reaction time: 16 h
Yield: 61.2 %

Procedure:
To a stirred solution of (1-(3-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (100 mg, 0.38 mmol, 1.0 eq) in DCM (5 mL) was added TEA (0.16 mL, 1.14 mmol, 3.0 eq) followed by phenyl 3-fluoro-4-(hydroxymethyl)phenyl-carbamate (131 mg, 0.38 mmol, 1.0 eq) at RT and stirred for 16 h. The reaction mixture was diluted with water (15 mL), extracted with DCM (2×15 mL). The combined organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. Crude product was purified by CC to get 1-((1-(3-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(hydroxymethyl)phenyl)urea (110 mg; 61%) as off white solid (TLC system: MeOH/CHCl3 (1:9); Rf: 0.55).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[OH:27])=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[OH:27])=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(-c4ccccc4O)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(-c4ccccc4O)cc3)cc12
Temperature: 70 °C
Reaction time: 15 h
Yield: 17 %

Procedure:
A round bottomed flask was charged with methyl 6-chloro-5-(2′-hydroxybiphenyl-4-yl)-1H-indole-3-carboxylate (80 mg, 0.21 mmol), methanol (1.8 mL), and sodium hydroxide solution (1.0 M, 0.60 mL, 0.60 mmol) then heated to 70° C. with stirring for 15 h. The reaction was then cooled to room temperature and quenched with 1.0 M Hydrochloric acid and diluted with ethyl acetate. The layers were separated and the aqueous extracted with ethyl acetate (×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse phase HPLC was then used to provide the title compound (13 mg, 16% yield). MS (ES−) 362.0 (M−H)−. Retention time: 1.93 min Waters Xbridge dC18 5 μm 4.6×50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.03% NH4OH). Flow: 2.0 mL/min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22]>>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH:14]=[C:20]3[S:16][C:17](=[O:22])[NH:18][C:19]3=[O:21])=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2cccc(O)c2)cc1
Reactant: O=C1CSC(=O)N1
Product: O=C1NC(=O)C(=Cc2ccc(-c3cccc(O)c3)cc2)S1
Yield: 100 %

Procedure:
In a manner similar to that of Example 1(f), starting with 15 g (75.7 mmol) of 3′-hydroxybiphenyl-4-carbaldehyde and 8.85 g (75.7 mmol) of 2,4-thiazolidine dione, 22.5 g (100%) of the expected product are obtained.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][C@@H:6]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:45])[C@H:26]([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:27][C:28]([O:30][CH3:31])=[O:29])[O:5][CH2:4]1.[C:46]1([N:52]=[C:53]=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(Cl)Cl>[CH3:31][O:30][C:28]([NH:27][C@H:26]([C:25]([NH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][CH2:16][C@H:6]1[O:5][CH2:4][C@@H:3]([CH2:2][NH:1][C:53](=[O:54])[NH:52][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[N:8]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7]1)=[O:45])[CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CN)CO1)C(c1ccccc1)c1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CNC(=O)Nc2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (2R,5R)-5-(aminomethyl)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate (1 eq.) in DCM (0.1M) was added phenyl isocyanate (2.2 eq). The reaction mixture was stirred for 16 hrs at room temperature, diluted with CH2Cl2 and the organic layer was washed with aqueous saturated sodium bicarbonate. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by automated silica gel flash chromatography system eluted with a gradient 10% to 100% of EtOAc/Hex to afford title compound.