Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:17][N:16]=[C:15]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][NH2+:26][CH2:25][CH2:24]3)[S:21][CH:22]=2)[CH2:14]1)(=[O:5])=[O:4].[Si:29]([O:36][CH2:37][C:38](O)=[O:39])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].C(N(C(C)C)CC)(C)C.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C>CN(C)C=O>[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:17][N:16]=[C:15]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][N:26]([C:38](=[O:39])[CH2:37][O:36][Si:29]([C:32]([CH3:34])([CH3:33])[CH3:35])([CH3:30])[CH3:31])[CH2:25][CH2:24]3)[S:21][CH:22]=2)[CH2:14]1)(=[O:4])=[O:5]
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)O
Reactant: CS(=O)(=O)Oc1ccccc1C1CC(c2csc(C3CC[NH2+]CC3)n2)=NO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4OS(C)(=O)=O)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23 %

Procedure:
To 4-[4-(5-{2-[(methylsulphonyl)oxy]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidinium chloride (500 mg) in dimethylformamide (6 ml) under argon were added {[tert-butyl(dimethyl)silyl]oxy}acetic acid (225 mg), diisopropylethylamine (582 mg) and 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU, 542 mg). The reaction mixture was stirred at room temperature for 18 hours. Then ice-cold sodium hydrogencarbonate solution was added thereto, the mixture was filtered, and the aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Purification by column chromatography gave 2-(3-{2-[1-({[tert-butyl(dimethyl)silyl]oxy}acetyl)piperidin-4-yl]-1,3-thiazol-4-yl}-4,5-dihydro-1,2-oxazol-5-yl)phenyl methanesulphonate (150 mg, 22%).
Reaction SMILES: C(O[CH:9]([O:32]CC1C=CC=CC=1)[C:10]([N:12]([CH2:23][O:24]CC1C=CC=CC=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=[O:11])C1C=CC=CC=1.FC(F)(F)C(O)=O>[Pd].ClCCl>[OH:32][CH:9]1[O:24][CH2:23][N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)[C:10]1=[O:11]
Reactant: O=C(C(OCc1ccccc1)OCc1ccccc1)N(COCc1ccccc1)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(O)OCN1c1cccc(C(F)(F)F)c1
Reaction time: 5 h
Yield: 56.2 %

Procedure:
A mixture of 2,2-dibenzyloxy-N-benzyloxymethyl-N(3-trifluoromethylphenyl)-acetamide (0.27 g, prepared as described in Step 4), 10% palladium on carbon (50 mg), trifluoroacetic acid (1 ml) and dichloromethane (50 ml) was stirred under an atmosphere of hydrogen for five hours. It was filtered through Hyflo Supercel™, evaporated under reduced pressure and chromatographed on silica, using dichloromethane-ethanol (49:1) as eluant to give the title compound (0.07 g) as a waxy solid, m.p. 75°-76° C.
Reaction SMILES: C([Zn][CH2:4][CH3:5])C.[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([CH:6]([OH:13])[CH2:4][CH3:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: CC[Zn]CC
Product: CCC(O)c1ccccc1
Yield: 46 %

Procedure:
In an embodiment, the present disclosure relates to the use of the chiral ligands in asymmetric synthetic applications. Ligand 7a, derived from the more polar diastereomer 5a, was used as a chiral catalyst in the reaction between diethylzinc and benzaldehyde. The reaction provided 1-phenylpropan-1-ol in 46% yield and 60% ee (Scheme 8).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:15])([CH3:14])[CH:9]3[O:13][CH:10]32)=[CH:5][CH:4]=1)#[N:2].C(OCC)(=O)C.[OH-].[NH4+:23]>C(O)C>[NH2:23][C@@H:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:12]=2)[CH2:7][C:8]([CH3:15])([CH3:14])[C@H:9]1[OH:13]
Reactant: [NH4+]
Reactant: CC1(C)Cc2ccc(C#N)cc2C2OC21
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)Cc2ccc(C#N)cc2[C@@H](N)[C@@H]1O

Procedure:
A solution of 7-cyano-1,2-epoxy-3,3-dimethyl-1,2,3,4-tetrahydronaphthalene (3.5 g) in ethanol (50 ml) and ammonium hydroxide solution (100 ml) was stirred at room temperature for 10 days. Ethyl acetate (50 ml) was added and the mixture extracted with dilute hydrochloric acid. The acidic extracts were made basic with sodium hydroxide solution, and extracted with ethyl acetate. The organic extracts were washed with water, then brine, and dried over sodium sulphate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[NH2:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:13]1([CH2:12][NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:20][C:21]3[N:22]=[C:23]([O:29][CH3:30])[CH:24]=[C:25]([O:27][CH3:28])[N:26]=3)=[CH:3][C:4]=2[C:16]([F:19])([F:18])[F:17])(=[O:10])=[O:9])[CH2:15][CH2:14]1
Reactant: COc1cc(OC)nc(N)n1
Reactant: O=S(=O)(NCC1CC1)c1ccc(Br)cc1C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1cc(OC)nc(Nc2ccc(S(=O)(=O)NCC3CC3)c(C(F)(F)F)c2)n1
Yield: 41 %

Procedure:
Mixture of 4-bromo-N-cyclopropylmethyl-2-trifluoromethylbenzenesulfonamide (228 mg, 0.63 mmol), 2,-amino-4,6-dimethoxypyrimidine (156 mg, 1.0 mmol), Pd(OAc)2 (26 mg, 0.11 mmol), BINAP (78 mg, 0.12 mmol) and cesium carbonate (362 mg, 1.11 mmol) in 15 ml toluene was relaxed for 6 hours. Toluene was evaporated in vacuum and crude oil was purified by Combiflash (PE-THF). Yield 41%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:20][NH2:21])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH:8]([C:17]#[N:18])[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH2:30]([O:32][C:33](=[O:35])[CH3:34])[CH3:31]>>[CH2:30]([O:32][C:33](=[O:35])[CH3:34])[CH3:31].[Cl:1][C:2]1[CH:3]=[C:4]([NH:20][N:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:5]=[C:6]([Cl:19])[C:7]=1[CH:8]([C:17]#[N:18])[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1
Reactant: N#CC(c1ccc(Cl)c(Cl)c1)c1c(Cl)cc(NN)cc1Cl
Reactant: O=Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#CC(c1ccc(Cl)c(Cl)c1)c1c(Cl)cc(NN=Cc2ccccc2)cc1Cl
Yield: 68 %

Procedure:
In 50 ml of acetic acid ethyl ester was dissolved 3.0 g of 3,5-dichloro-4-(3,4-dichloro-α-cyanobenzyl)phenylhydrazine. To the solution was added equimol. of benzaldehyde, and the mixture was stirred for 3 hours at room temperature. The reaction mixture was dried over anhydrous magnesium sulfate, which was then concentrated to afford the titled compound in a yield of 68%, m.p.75-90° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29]([C:33]([OH:35])=[O:34])=[CH:28][CH:27]=[CH:26]2.[OH-].[K+].O>CS(C)=O>[CH2:15]([O:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([O:22][C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[C:29]([C:33]([OH:35])=[O:34])=[CH:28][CH:27]=[CH:26]4)=[CH:3][CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2c(Oc3ccc4c(C(=O)O)cccc4c3)ccnc2cc1OCc1ccccc1
Temperature: 130 °C
Yield: 62 %

Procedure:
4-Chloro-7-benzyloxy-6-methoxy-quinoline (3 g) was mixed with 6-Hydroxy-1-naphthoic acid (2 g) and KOH (2.5 g) in DMSO (11 ml). The mixture was heated at 130° C. for 5 hours and cooled to RT. The reaction was then poured into a stirred water (60 ml) solution slowly to give a precipitate that was filtered to give 6-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-1-naphthoic acid (2.8 g). This product was mixed with MeNH2—HCl (2 g), EDC (3.3 g), HOBt (2 g) and DIPEA (4 ml) in DCM (80 ml). The reaction was stirred at RT overnight and washed with NaHCO3 solution, dried. The solution was evaporated and purified with silica gel column to give 6-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide. The title compound then was prepared according to the same procedures described in Method A.
Reaction SMILES: [C:1]([C:3]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]O)#[N:2].C(N(CC)CC)C.S(Cl)(C)(=O)=O.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[F:41][C:42]1[CH:56]=[CH:55][C:45]([O:46][CH2:47][CH2:48][N:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[CH:44][CH:43]=1>C(#N)C.[Cl-].[Na+].O.O.CN(C)C=O>[C:1]([C:3]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)([CH:8]([CH3:9])[CH3:10])[CH2:4][CH2:5][CH2:6][N:52]1[CH2:53][CH2:54][N:49]([CH2:48][CH2:47][O:46][C:45]2[CH:44]=[CH:43][C:42]([F:41])=[CH:56][CH:55]=2)[CH2:50][CH2:51]1)#[N:2]
Reactant: Fc1ccc(OCCN2CCNCC2)cc1
Reactant: CC(C)C(C#N)(CCCO)c1ccc2ccccc2c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2ccc(F)cc2)CC1)c1ccc2ccccc2c1
Temperature: 60 °C
Yield: 69.8 %

Procedure:
In acetonitrile (5 ml) was dissolved 310 mg (1.16 mmol) of 4-cyano-5-methyl-4-(2-naphthyl)hexanol, followed by adding 190 μL (1.36 mmol) of triethylamine and 105 μl (1.36 mmol) of mesyl chloride. After completion of mesylation, 1.11 g (7.38 mmol) of sodium iodide, 255 mg (1.85 mmol) of potassium carbonate, 414 mg (1.85 mmol) of 1-[2-(4-fluorophenoxy) ethyl]piperazine, 5 ml of dimethylformamide and 1 ml of water were added thereto, followed by heating to 60° C. After completion of the reaction, brine was added thereto and the objective product was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to give a crude product. The crude product was subjected to (NH) silica gel (eluted with ethyl acetate/hexane=2/3), to give 384 mg (0.81 mmol, 69.9%) of the title compound as a yellow syrup.
Reaction SMILES: O.[C:2](=[O:5])([O-:4])[O-:3].[Na+:6].[Na+].O.[OH:9][P:10]([O-:13])([OH:12])=[O:11].[Na+]>O>[C:2](=[O:3])([O-:5])[O-:4].[Na+:6].[Na+:6].[P:10]([O-:13])([O-:12])([O-:11])=[O:9].[Na+:6].[Na+:6].[Na+:6]
Reactant: O=P([O-])(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=P([O-])([O-])[O-]

Procedure:
Albumin (Human 25%, Plasbumin®-25 manufactured by Bayer Corporation) was buffered using differing amounts of Sodium Carbonate Monohydrate (Na2CO3H2O) (FW 124.00) (“Carbonate Buffer”) and Sodium Phosphate Monobasic Monohydrate (NaH2PO4H2O) (FW 137.99) (“Phosphate Buffer”). The buffered albumin formulations (2 cc) were mixed with 2 cc of the Shearwater PEG (0.45 g of PEG suspended in 2.2 cc of water), to provide 17% w/w PEG solids. The components were mixed by using the catheter device as generally shown in FIG. 2 (and as will be described in greater detail later). Upon mixing, the components were deposited in a test dish. The pH of the buffered albumin formulation (albumin plus buffer material) and the gelation time (as described above) and were recorded.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:16](=O)[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[NH2:25])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)N[C@H](C(=O)NC1C=C(I)C=CC=1N)CC1C=CC=CC=1)(C)(C)C>C(O)(=O)C>[C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:16]1[NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[N:25]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1ccc(I)cc1N
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1cc(I)ccc1N
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nc2cc(I)ccc2[nH]1
Temperature: 65 °C

Procedure:
The mixture of regioisomers from step 2 {[(S)-1-(2-amino-4-iodo-phenylcarbamoyl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester and [(S)-1-(2-amino-5-iodo-phenylcarbamoyl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester} (1.0 g, 2.08 mmol) were dissolved in glacial acetic acid (30 mL) and heated to 65° C. for 1 hour. The reaction was cooled, concentrated in vacuo, basified with 10% w/v aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (2×20 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel eluted with 20% v/v ethyl acetate/hexanes to give [(S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester as a mixture of tautomers (950 mg, 99%).
Reaction SMILES: I.CS[C:4](=[NH:18])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:19][S:20][CH2:21][CH2:22][NH2:23]>C(O)C>[CH3:19][S:20][CH2:21][CH2:22][NH:23][C:4]([NH2:18])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: CSCCN
Reactant: CSC(=N)Nc1ccccc1N1CCOCC1
Agent: I
Solvent: CCO
Product: CSCCNC(N)=Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (1.7 g) prepared as described in Example 166, 2-methylthioethylamine (1.8 g) and ethanol (25 ml) was heated at 90°-95° C. for 22 hours to give 1-(2-methylthioethyl)-2-(2-morpholinophenyl)guanidine (m.p. 115°-116° C.) which was recrystallised from hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)(=[O:10])=[O:9])=[C:4]([CH2:22][NH2:23])[CH:3]=1.C(N(CC)CC)C.[CH:31]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32]1>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)(=[O:9])=[O:10])=[C:4]([CH2:22][NH:23][S:34]([CH:31]2[CH2:33][CH2:32]2)(=[O:36])=[O:35])[CH:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CNS(=O)(=O)C2CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.9 %

Procedure:
To a stirred solution of 4-amino-2-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (708 mg, 2.1 mmol) and triethylamine (1 mL, 7 mmol) in 100 mL of DCM was added cyclopropanesulfonyl chloride (0.3 g, 2.2 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the majority of the solvent was removed under vacuum, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated, the crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the desired product as a yellow solid (45 mg, yield 5%). MS calcd for (C17H20BN3O6S2): 437.1. MS found (ESI negative): (M−H)−=336.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.04 (s, 1H), 9.17 (bs, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.50 (t, J=6.4 Hz, 1H), 7.44 (d, J=1.6 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.11 (dd, J=8, 1.6 Hz, 1H), 6.83 (d, J=2.4 Hz, 1H), 6.40 (dd, J=8.4, 2.4 Hz, 1H), 4.86 (s, 2H), 4.44 (d, J=6.4 Hz, 2H), 2.60 (m, 1H), 0.92 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.O.[CH2:17](OCC)C>C(O)=O.C=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH3:17])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOCC
Reactant: COC1(c2cc(F)cc(F)c2)CCNC1
Agent: C=O
Solvent: O=CO
Solvent: O
Product: COC1(c2cc(F)cc(F)c2)CCN(C)C1
Temperature: 85 °C

Procedure:
A mixture of (+)-3-(3,5-difluorophenyl)-3-methoxypyrrolidine (0.02 g, 0.094 mmol) in formic acid (1 ml) and formaldehyde (37% solution in water, 1 ml) was heated at 85° C. for 5 h. The mixture was allowed to reach ambient temperature, water (5 ml) and diethyl ether was added, the phases were separated and the aqueous phase was basified by the addition of aqueous sodium hydroxide (5 M). The aqueous phase was extracted twice with ethyl acetate, the combined organic phases was dried (Na2SO4) and evaporated to give the crude product which was diluted in methanol and analyzed by GCMS. MS m/z (relative intensity, 70 eV) 227 (M+, 5), 212 (29), 197 (25), 141 (42), 57 (bp).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C(O)(C(F)(F)F)=O.[N+:22]([O-])([OH:24])=[O:23]>>[N+:22]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH:2]([N:10]1[CH2:11][CH2:12][CH2:13][CH2:14]1)[CH2:3]2)([O-:24])=[O:23]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)CC(N1CCCC1)C2
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc2c(c1)CC(N1CCCC1)C2
Temperature: 7.5 °C
Reaction time: 5 h

Procedure:
To a solution of Example 55A (8.38 g, 44.7 mmol) in TFA (320 ml, 4154 mmol) was added concentrated nitric acid (2.86 ml, 44.7 mmol) dropwise at 0° C. The mixture was stirred at 0-15° C. for 5 hours. The mixture was next concentrated then dissolved in 200 mL of ethyl acetate and the organic solution was poured into a separatory funnel and washed with saturated aqueous sodium bicarbonate (2×150 mL) and saturated aqueous brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The crude was recrystallized in ethyl acetate/hexane mixture to give the title compound. MS (ESI) m/z 233.1 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([CH2:19][OH:20])=[CH:14][CH:13]=2.O>CS(C)=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([CH:19]=[O:20])=[CH:14][CH:13]=2
Reactant: OCc1ccc2[nH]c(CCOC3CCCCO3)cc2c1
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc2[nH]c(CCOC3CCCCO3)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{2-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-1H-indol-5-yl}-methanol (11.5 g 41.7 mmol) in anhydrous DMSO (45 mL) was added IBX (12.3 g, 43.8 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (300 mL), the organic phase was washed with water, then brine, and was purified by column chromatography on silica gel, eluting with dichloromethane, to give 2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-indole-5-carbaldehyde as a white solid. Yield: 8.50 g (75%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[C:11]3[C:15]([CH:16]=[C:17](B4OC(C)(C)CC(C)(C)O4)[CH:18]=2)=[N:14][N:13](C2CCCCO2)[CH:12]=3)=[O:8])[N:6]=1.Br[C:36]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:37]=1[CH:38]=[C:39]([CH3:45])[NH:40]2.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17]([C:36]3[CH:44]=[CH:43][CH:42]=[C:41]4[C:37]=3[CH:38]=[C:39]([CH3:45])[NH:40]4)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][NH:14]3)=[O:8])[N:6]=1
Reactant: Cc1cc2c(Br)cccc2[nH]1
Reactant: Cc1nc(C(=O)Nc2cc(B3OC(C)(C)CC(C)(C)O3)cc3nn(C4CCCCO4)cc23)cs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc2c(-c3cc(NC(=O)c4csc(C)n4)c4cn[nH]c4c3)cccc2[nH]1
Temperature: 140 °C
Yield: 42.2 %

Procedure:
2-Methyl-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg, 0.104 mmol), 4-bromo-2-methyl-1H-indole (22 mg, 0.104 mmol), Pd(dppf)Cl2 (8 mg, 0.01 mmol) and sodium carbonate (44 mg, 0.415 mmol) were added to a 0.5-2 ml microwave vial and suspended in 1,4-dioxane (0.5 mL) and water (0.5 mL). The mixture was heated in the microwave at 140° C. for 20 min, then cooled and passed through a 1 g silica cartridge which was washed with DCM:methanol. The solvent was evaporated by blow down. The residue was dissolved in 1.6 ml DMSO:methanol (1:1, v/v), passed through a 1 g C18 cartridge washing with acetonitrile and evaporated by blow down. The residue was dissolved in 1.6 ml DMSO:methanol (1:1, v/v) and purified by Mass Directed Auto Preparative HPLC (Method G). Pure fractions were combined, evaporated to dryness, the residue suspended in 3 ml dioxane:water (1:1, v/v) and freeze dried to afford the title compound as an off-white solid (17 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[CH:11]=[N:10]1.P(Br)(Br)[Br:20]>C(Cl)Cl.O>[Br:20][CH2:14][C:13]1[N:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[N:10]=[CH:11][C:12]=1[CH:16]([CH3:18])[CH3:17]
Reactant: BrP(Br)Br
Reactant: CC(C)c1cnn(-c2c(Cl)cccc2Cl)c1CO
Solvent: ClCCl
Solvent: O
Product: CC(C)c1cnn(-c2c(Cl)cccc2Cl)c1CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.3 %

Procedure:
To a solution of (1-(2,6-dichlorophenyl)-4-isopropyl-1H-pyrazol-5-yl)methanol (4.0 g, 0.014 mol) in CH2Cl2 (50 ml) is added phosphorus tribromide (5.69 g, 0.021 mol) at 0° C. Stir the mixture for 3 h at room temperature. Dilute with water and extract with ethyl acetate. Concentrate under reduced pressure, to give crude product, which is purified by column chromatography over silica gel eluting with 7:3 hexane/ethyl acetate to give 0.50 g (10%) of the title compound. ES/MS m/e (81Br) 348.93 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12]1)[CH2:10][C:9]2=[O:28].Cl>CC(O)=O>[CH2:17]([N:13]1[CH2:14][CH2:15][CH2:16][C:11]2([CH2:10][C:9](=[O:28])[C:8]3[C:25](=[CH:26][CH:27]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:29])=[O:2])[CH:7]=3)[O:24]2)[CH2:12]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccccc3)C1)O2
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccccc3)C1)O2
Yield: 86.4 %

Procedure:
(±)-(E)-3-[1′-Benzyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (300 mg, 0.767 mmol) was hydrolyzed with aqueous 20% HCl solution and AcOH following the procedure described in Example 1, Step A, giving (±)-(E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid (250 mg) as a white solid (hydrochloride salt).
Reaction SMILES: CN(/[CH:4]=[C:5]1/[CH2:6][C:7](=[O:21])[NH:8][C:9]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:10]=2[C:11]/1=O)C.[C:22]([O:26][C:27](=[O:43])[NH:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[N:34][C:35]([CH3:42])=[C:36]([NH:38][C:39]([NH2:41])=[NH:40])[CH:37]=1)([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CCO.O.CCOC(C)=O>[C:22]([O:26][C:27](=[O:43])[NH:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[N:34][C:35]([CH3:42])=[C:36]([NH:38][C:39]2[N:41]=[CH:4][C:5]3[CH2:6][C:7](=[O:21])[NH:8][C:9]4[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[CH:13][C:10]=4[C:11]=3[N:40]=2)[CH:37]=1)([CH3:24])([CH3:25])[CH3:23]
Reactant: CN(C)/C=C1/CC(=O)Nc2cc(C(F)(F)F)ccc2C1=O
Reactant: Cc1ncc(CCCNC(=O)OC(C)(C)C)cc1NC(=N)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ncc(CCCNC(=O)OC(C)(C)C)cc1Nc1ncc2c(n1)-c1ccc(C(F)(F)F)cc1NC(=O)C2
Temperature: 80 °C
Reaction time: 8 h
Yield: 111.8 %

Procedure:
To a solution of (4Z)-4-[(dimethylamino)methylene]-8-(trifluoromethyl)-3,4-dihydro-1H-1-benzazepine-2,5-dione (1.05 g, 3.51 mmol) and tert-butyl[3-(5-{[amino(imino)methyl]amino}-6-methylpyridin-3-yl)propyl]carbamate (1.62 g, 5.27 mmol) in EtOH (50 mL) was added potassium carbonate (2.91 g, 21.1 mmol). The reaction mixture was allowed to stir at 80° C. overnight. The reaction mixture was diluted with water (100 mL) and EtOAc (50 mL). The organic solution was separated and the aqueous solution was extracted with EtOAc (2×50 mL). The organic solutions were combined, washed with brine (100 mL), dried over MgSO4, filtered and concentrated to give tert-butyl[3-(6-methyl-5-{[6-oxo-9-(trifluoromethyl)-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl]amino}pyridin-3-yl)propyl]carbamate (2.13 g, >99%) as a dark brown solid. LCMS (FA): Rt=1.79 min, m/z=543.0 (M+H).