Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([O:13][C:14]([CH3:17])(C)C)=[O:12].Cl.O1CCOCC1.ClC1C=C(C#N)C=CC=1CC(OCC)=O.C(O[CH:43](OCC)[N:44]([CH3:46])[CH3:45])C>C(O)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C:10](=[CH:43][N:44]([CH3:46])[CH3:45])[C:11]([O:13][CH2:14][CH3:17])=[O:12]
Reactant: CC(C)(C)OC(=O)Cc1ccc(C#N)cc1Cl
Reactant: CCOC(OCC)N(C)C
Agent: CCOC(=O)Cc1ccc(C#N)cc1Cl
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1Cl
Temperature: 60 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
Combined tert-butyl 2-(2-chloro-4-cyanophenyl)acetate (274 mg, 1.089 mmol) and 4N HCl in dioxane (0.136 mL, 0.544 mmol) in ethanol (2.51 mL). The mixture was stirred for 16 hours at 60° C., then concentrated by rotary evaporation and combined with ethyl 2-(2-chloro-4-cyanophenyl)acetate (0.243 g, 1.086 mmol) and 1,1-diethoxy-N,N-dimethylmethanamine (0.931 mL, 5.43 mmol) in DMF (2.173 mL) and stirred for 16 hours at 100° C. The reaction was concentrated in rotary evaporation and purified on a NH silica gel column eluting with hexanes and EtOAc to give the title compound (164 mg, 54%) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 1.04-1.29 (m, 1 H) 3.96-4.31 (m, 1H) 7.38 (d, J=7.8 Hz, 1 H) 7.49 (dd, J=7.8, 1.8 Hz, 1 H) 7.63-7.71 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:14]([OH:16])=O)[N:6]2[CH2:12][CH3:13].C(Cl)(=O)C(Cl)=O.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:14]([C:5]3[N:6]([CH2:12][CH3:13])[C:7]4[C:3]([CH:4]=3)=[C:2]([Cl:1])[C:10]([Cl:11])=[CH:9][CH:8]=4)=[O:16])=[CH:40][CH:41]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCn1c(C(=O)O)cc2c(Cl)c(Cl)ccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1c(C(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc2c(Cl)c(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4,5-dichloro-1-ethyl-1H-indole-2-carboxylic acid (440 mg, 1.71 mmol), CH2Cl2 (10 mL), and a catalytic amount of DMF was stirred under Ar, and oxalyl chloride (2M in methylene chloride, 2.0 mL, 4.0 mmol) was added into the mixture over 5 min. The mixture was stirred at room temperature for 1.0 hr and the reaction was concentrated to dryness. Benzene was added and the solution was evaporated to dryness again. The white-yellow solid was re-dissolved in 5 mL of methylene chloride and dripped, under Ar, into a solution of 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (475 mg, 1.71 mmol), and triethylamine (204 mg, 2.0 mmol) in 5 mL of methylene chloride. The mixture was first stirred at room temperature for 0.5 hr then concentrated and the residue was taken up in 50 mL of ethyl acetate and washed with 50 mL of saturated ammonium chloride, brine and dried with anhydrous sodium sulfate. The solvent was removed and the crude product was purified by flash chromatography (hexanes/EtOAc), to afford the desired 4-{4-[(4,5-dichloro-1-ethyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester, as an off white solid (750 mg, 85% yield). LCMS for C26H30Cl2N4O3 calcd. (m/e) 516, observed 517 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[N:64]1[CH2:68][CH2:67][CH:66]([C:69](O)=[O:70])[C:65]1=[O:72]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:69]([CH:66]1[CH2:67][CH2:68][N:64]([C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=2[F:57])[C:65]1=[O:72])=[O:70]
Reactant: O=C(O)C1CCN(c2ccccc2F)C1=O
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2ccccc2F)C1=O
Yield: 43.5 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.104 g; 0.448 mmol), PyBOP (0.349 g; 0.672 mmol), N,N-diisopropylethylamine (0.232 mL; 1.34 mmol) and 1-(2-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.448 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.078 g (44%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:11]([C:23]#[N:24])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH2:20][O:21][CH3:22])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.O>C(O)(=O)C.[Fe]>[NH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([CH:11]([C:23]#[N:24])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH2:20][O:21][CH3:22])=[N:4][CH:5]=1
Reactant: COCOc1ccc(Cl)cc1C(C#N)c1ncc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COCOc1ccc(Cl)cc1C(C#N)c1ncc(N)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
In acetic acid (300 ml) was dissolved 3-chloro-2-(5-chloro-a-cyano-2-methoxymethoxybenzyl)-5-nitropyridine (15.0 g). To the solution were added water (10 ml) and powdery iron (11.4 g). The mixture was stirred for 2 hours at room temperature. The solvent was distilled off under reduced pressure. To the residue were added ethyl acetate and an aqueous solution of sodium carbonate. Insolubles were filtered off by using celite. The organic layer was washed with water and a saturated aqueous saline solution, successively, which was then dried (anhydrous magnesium sulfate), followed by concentration. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to afford 5-amino-3-chloro-2-(5-chloro-α-cyano-2-methoxymetho-xybenzyl)pyridine (12.4 g) (Compound D-13). Physico-chemical properties and spectrum data are shown in Table 13 and Table 15.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:9])[CH2:5][CH2:6][O:7][NH2:8].[C:10]([O-:13])(=[O:12])[CH3:11].[Na+].[O:15]=[C:16]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C@H:18]([CH2:19][CH2:20][C@@H:21]3[C@@H:30]2[CH2:29][CH2:28][C@@:26]2([CH3:27])[C@:22]3(O)[CH2:23][CH2:24][C@@H:25]2[CH:35]=O)[CH2:17]1>C(O)(=O)C.O1CCOCC1>[C:10]([O:13][C@@:22]12[C@H:21]3[C@@H:30]([C@:31]4([CH3:34])[C@H:18]([CH2:19][CH2:20]3)[CH2:17][C:16](=[O:15])[CH2:33][CH2:32]4)[CH2:29][CH2:28][C@:26]1([CH3:27])[C@@H:25](/[CH:35]=[N:8]/[O:7][CH2:6][CH2:5][N:4]([CH3:9])[CH3:3])[CH2:24][CH2:23]2)(=[O:12])[CH3:11]
Reactant: CN(C)CCON
Reactant: CC(=O)[O-]
Reactant: C[C@]12CCC(=O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@]12O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(=O)O[C@]12CC[C@H](/C=N/OCCN(C)C)[C@@]1(C)CC[C@H]1[C@H]2CC[C@@H]2CC(=O)CC[C@@]21C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a solution of 0.21 g of 2-dimethylaminoethoxyamine dihydrochloride, 2.00 g of sodium acetate in 25 ml of 0.2M acetic acid a solution of 0.30 g of 3-oxo-14β-hydroxy-5β-androstane-17β-carboxaldehyde (Prepn. 6) in 40 ml of dioxane was added dropwise. After 2 hrs at room temperature, the mixture was evaporated to dryness under reduced pressure and the crude product was extracted three times with iso-propanol. Evaporation of the solvent gave 0.33 g of (E)-3-oxo-17β-(2-dimethylaminoethoxyiminomethyl)-5β-androstane-14β-ol acetate as a white foam.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]2[C:16](=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1F)[NH:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]2=1.Cl>CS(C)=O.O>[Cl:5][C:6]1[CH:7]=[C:8]2[C:16](=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1[O:1][CH2:2][CH3:3])[NH:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]2=1
Reactant: CC[O-]
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Reaction time: 8 h
Yield: 40 %

Procedure:
Sodium ethoxide (232 mg, 3.4 mmol) was added to a solution of 6-chloro-7-fluoro-8-nitro-9H-β-carboline (200 mg, 0.76 mmol) in DMSO (4 ml) and the reaction mixture allowed to stir overnight. The reaction mixture was diluted with water and the pH of the solution was adjusted to about 4 by adding 1N HCl. The aqueous solution was extracted (3×) with EtOAc. The combined EtOAc layers were dried and evaporated. The crude product was purified by flash chromatography to give the desired product in 40-60% yield.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C@@H:24]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:25]Br)=[C:17]2[C:22]=1[NH:21][C:20](=[O:23])[CH:19]=[CH:18]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>CN(C=O)C>[N:1]([CH2:25][C@@H:24]([C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20](=[O:23])[NH:21]2)[O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[N+:2]=[N-:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 80 °C
Yield: 148.3 %

Procedure:
NaN3 (266 mg, 4.1 mmol) was added to a stirred solution of (R)-8-(benzyloxy)-5-[2-bromo-1-[(tert-butyldimethylsilyl)oxy]ethyl]quinolin-2(1H)-one (1 g, 2.05 mmol) in DMF (20 mL) at rt and warmed to 80° C. for 3 h. The resulting solution was poured into H2O (80 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with H2O (2×100 mL), brine (100 mL), dried over Na2SO4 (s), and concentrated to give the title compound (1.37 g) as a yellow solid. The compound was used with no further purification. ES/MS calcd. for C24H31N4O3Si+ 451.2, found m/z=451.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:15]=[CH:16][C:9]=23)[CH:7]=1.[CH2:28]([Li])CCC.[O:33]1[CH2:38][CH2:37][C:36](=[O:39])[CH2:35][CH2:34]1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:17]([C:20]4[CH:25]=[CH:24][C:23]([CH3:28])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[C:15]([C:36]4([OH:39])[CH2:37][CH2:38][O:33][CH2:34][CH2:35]4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: [Li]CCCC
Reactant: COc1ccc(F)cc1-c1ccnc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: O=C1CCOCC1
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1ccnc2c1cc(C1(O)CCOCC1)n2S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of Example 87A (200 mg, 0.504 mmol) in tetrahydrofuran (5 mL) at −78° C. was added 1.6M n-butyllithium in hexanes (0.473 mL, 0.757 mmol) under nitrogen. The mixture was stirred for 5 minutes and dihydro-2H-pyran-4(3H)-one (101 mg, 1.009 mmol) was added. Stirring was continued at −78° C. for 1 hour and the mixture was warmed to room temperature overnight. The mixture was quenched with water, extracted with ethyl acetate, dried over magnesium sulfate, filtered and purified by flash chromatography (silica gel, 20-100% ethyl acetate/heptanes to afford the title compound. MS (ESI+) m/z 497.0 (M+H)+.
Reaction SMILES: [Br:1][CH:2](Br)[CH3:3].[N+:5]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[OH:17])([O-:7])=[O:6].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:5]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[O:17][CH2:3][CH2:2][Br:1])([O-:7])=[O:6]
Reactant: CC(Br)Br
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCBr)c([N+](=O)[O-])c1
Temperature: 85 °C
Yield: 35.2 %

Procedure:
Dibromoethane (5.25 g, 0.049 mol) and 2,4-dinitrophenol (3 g, 0.016 mol) were added to dimethylformamide (20 ml) and, after adding a fine powder of potassium carbonate (2.24 g), the mixture was heated at 85° C. for 1.5 h. Thereafter, the solvent was evaporated and three extractions were conducted with ethyl acetate. The organic extracts were combined and dried with sodium sulfate, with the residue being subjected to column chromatography on silica gel using methylene chloride as an eluent. The fractions containing the end product were collected and the solvent was evaporated to yield the end compound 2,4-dinitrophenoxyethly bromide (1.64 g).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[Si]([O:13][CH2:14][C:15]#[C:16][C:17](=O)[C:18]([F:21])([F:20])[F:19])(C(C)(C)C)(C)C>CO>[F:19][C:18]([F:21])([F:20])[C:17]1[CH:16]=[C:15]([CH2:14][OH:13])[O:3][N:2]=1
Reactant: CC(C)(C)[Si](C)(C)OCC#CC(=O)C(F)(F)F
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCc1cc(C(F)(F)F)no1
Yield: 31.4 %

Procedure:
To a solution of hydroxylamine hydrochloride (0.694 g 0.010 mol, 1 equ) and 0.02 g sodium hydroxide in 25 mL methanol was added 5-(tert-butyldimethylsilyloxy)-1,1,1-trifluoropent-3-yn-2-one (2.66 g 0.010 mol, 1 equ) and the mixture was heated to reflux for 3 h. The reaction mixture was extracted with ethyl acetate and purified by chromatography on silica gel (50 g) using a gradient of heptane:ethyl acetate=9:1 to 1:1. to yield 0.524 g of the title compound as colorless oil, MS 167(M)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([OH:14])[CH:7]=1)[CH3:2].F[C:17]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:18]=1[CH:19]=[O:20]>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:17]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:18]=2[CH:19]=[O:20])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(O)c1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 2, using the following starting materials: (3-hydroxy-4-methoxy-phenyl)-acetic acid ethyl ester and 2-fluoro-5-(trifluoromethyl)benzaldehyde.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.[Br:16][C:17]1[CH:18]=[C:19]([OH:24])[CH:20]=[C:21](Br)[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.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>[Br:16][C:17]1[CH:18]=[C:19]([OH:24])[CH:20]=[C:21]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH:22]=1
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2cc(O)cc(Br)c2)cn1
Temperature: 800 °C
Yield: 37 %

Procedure:
1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (750 mg; 3.6 mmol; 1.0 eq.), 3,5-Dibromo-phenol (4.54 g; 18.0 mmol; 5.0 eq.), bis(triphenylphosphine)palladium(II) chloride (253 mg; 0.36 mmol; 0.1 eq.) and potassium carbonate (2.49 g; 18.02 mmol; 5 eq.) were suspended in DMF (80 mL) and water (1 mL). The reaction mixture was then heated at 800° C. for 16 h in a sealed tube. It was filtered through Celite and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica (n-heptane:EtOAc, gradient from 95:5 to 10:90) afforded the title compound as a clear oil (337 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ 10.01 (brs, 1H), 8.14 (s, 1H), 7.83 (d, J=0.7 Hz, 1H), 6.96 (d, J=1.7 Hz, 1H), 6.92 (dd, J=2.1, 1.5 Hz, 1H), 6.76 (t, J=2.0 Hz, 1H), 3.84 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([C:34]([O:36]C)=O)[C:17]([C:20]4[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=4)=[CH:18][CH:19]=3)=[O:13])[CH2:8]2)[CH:2]=1.O.[NH2:39][NH2:40].C1(C)C=CC=CC=1>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([C:34]([NH:39][NH2:40])=[O:36])[C:17]([C:20]4[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[C:22]([C:30]([F:33])([F:31])[F:32])[CH:21]=4)=[CH:18][CH:19]=3)=[O:13])[CH2:8]2)[CH:2]=1
Reactant: COC(=O)c1cc(C(=O)N2CCC(c3cccnc3)C2)ccc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NN
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: NNC(=O)c1cc(C(=O)N2CCC(c3cccnc3)C2)ccc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 135 °C

Procedure:
A solution of 7a (160 mg, 0.300 mmol) and hydrazine hydrate (286 μL, 9.18 mmol) in ethanol:toluene (2.70 mL of an 8:1 mixture, respectively) was heated to 100° C. in a sealed microwave vial for 10 min, An additional aliquot of hydrazine hydrate (200 μL, 6.42 mmol) was added, and the resulting mixture was heated to 135° C. in a sealed microwave vial for 15 min. The reaction mixture was cooled to rt and partitioned between EtOAc and water. The combined organics were washed with water and brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound 9a. m/z (ES) 523 (MH)+.
Reaction SMILES: C1(C)C=CC=CC=1.N1CCCCC1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:23]=[C:24]([C:31]2[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=2)[CH:25]=[C:26]2[O:30][CH2:29][O:28][C:27]=12.[S:39]1[CH2:43][C:42](=[O:44])[NH:41][C:40]1=[O:45]>C(O)(=O)C>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:23]=[C:24]([C:31]2[CH:32]=[CH:33][C:34]([CH:35]=[C:43]3[S:39][C:40](=[O:45])[NH:41][C:42]3=[O:44])=[CH:37][CH:38]=2)[CH:25]=[C:26]2[O:30][CH2:29][O:28][C:27]=12
Reactant: COc1ccccc1-c1cc(-c2ccc(C=O)cc2)cc2c1OCO2
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1cc(-c2ccc(C=C3SC(=O)NC3=O)cc2)cc2c1OCO2
Temperature: 25 °C
Yield: 58.8 %

Procedure:
A solution of toluene (10 mL), piperidine (10 μL), acetic acid (10 μL), 4-[3-(2-methoxyphenyl)-4,5-methylenedioxyphenyl]benzaldehyde (0.164 g, 0.493 mmol) and 2,4-thiazolidinedione (0.0578 g, 0.493 mmol) was heated at reflux overnight under an argon atmosphere. The reaction mixture was cooled to room temperature, and the resulting crystalline compound was filtered, washed with ethanol. The yellow solid was dried under high vacuum to afford 0.125 g (59%) of 4-[3-(2-methoxyphenyl)-4,5-methylenedioxyphenyl]-benzylidene-2,4-thiazolidinedione, mp 227–228° C. (dec.). 1H NMR (300 MHz; DMSO-d6): 3.77 (s, 3H), 6.05 (s, 2H), 7.12 (t, J=7.5 Hz, 1H), 7.12 (d, J=8.7 Hz, 1H), 7.23 (s, 1H), 7.30 (s, 1H), 7.33–7.43 (m, 2H), 7.63 (d, J=7.8 Hz, 2H), 7.80 (d, J=7.8 Hz, 2H), 7.81 (s, 1H), 12.5–12.7 (brs, 1H). 13C NMR (75 MHz; DMSO-d6): 56.3, 56.4, 101.9, 106.6, 112.4, 120.8, 121.0, 123.0, 123.6, 124.7, 127.8, 130.2, 131.3, 131.4, 132.0, 132.2, 133.1, 142.2, 145.9, 148.7, 157.1, 168.0, 168.4.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:16]([CH2:17][C:18](O)=[O:19])[C:15]2[N:21]=[CH:22][CH:23]=[CH:24][C:14]=2[C:13](=[O:25])[N:12]=1.[CH3:26][C:27]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)=[CH:44][CH:43]=2)[CH2:36][CH2:35]1)([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:16]([CH2:17][C:18]([N:40]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:49]=[CH:50][C:51]([C:54]([F:56])([F:55])[F:57])=[CH:52][CH:53]=3)=[CH:44][CH:43]=2)[CH:37]2[CH2:36][CH2:35][N:34]([C:27]([CH3:26])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:39][CH2:38]2)=[O:19])[C:15]2[N:21]=[CH:22][CH:23]=[CH:24][C:14]=2[C:13](=[O:25])[N:12]=1
Reactant: CCOC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2cccnc21
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: CCOC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3cccnc32)CC1
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 68.6 %

Procedure:
A mixture of [2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetic acid (Int. D1) (116 mg, 1 equiv), ethyl 2-methyl-2-[4-({[4′-trifluoromethyl)-4-biphenyl]-methyl}amino)-1-piperidinyl]propanoate (Int. B2) (150 mg, 1 equiv), HATU (151 mg, 1.2 equiv), DMF (2.72 ml) and DIPEA (0.17 ml, 3 equiv) was shaken at room temperature for 3.25 h. The reaction mixture was partitioned between ethyl acetate/methanol and aqueous sodium bicarbonate, the organic layer was brine-washed, dried and treated with activated charcoal (250 mg). Flash chromatography (silica, 3-4% methanol in DCM) gave ethyl 2-[4-({[2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetyl}{[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methylpropanoate as a white solid (178 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:32])=[C:11]([C:28]([F:31])=[CH:29][CH:30]=1)[CH2:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:35]([Si:38](Cl)([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])[CH3:40])([CH3:37])[CH3:36].O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([F:32])=[C:11]([C:28]([F:31])=[CH:29][CH:30]=1)[CH2:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:20]=2)[N:15]([Si:38]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:35]([CH3:37])[CH3:36])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(OCc2ccccc2)c(F)c1Cc1c[nH]c2ncc(-c3cccnc3)cc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2c(F)ccc(OCc3ccccc3)c2F)c2cc(-c3cccnc3)cnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 3-(3-Benzyloxy-2,6-difluoro-benzyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (P-1455, 700.0 mg, 1.64 mmol, prepared as described in Example 24, Scheme 43a) in tetrahydrofuran (40.0 mL) was added sodium hydride (60% in mineral oil, 100.0 mg, 2.5 mmol). After 10 minutes, triisopropylsilyl chloride (0.60 mL, 0.0028 mol) was added to the reaction. The reaction was stirred at room temperature for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to eive the compound as colorless oil (548, 0.85 g, 89%).