Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].F[C:8]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:9]=1[CH:10]=O.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][NH2:24]>CN1CCCC1=O>[I:16][C:13]1[CH:12]=[C:9]2[C:8](=[CH:15][CH:14]=1)[N:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=1)[N:24]=[CH:10]2
Reactant: NNc1ccccn1
Reactant: O=Cc1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Ic1ccc2c(cnn2-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cesiumcarbonate (29.86 g, 91.6 mmol) is added to a suspension of 2-fluoro-5-iodobenzaldehyde (11.45 g, 45.8 mmol) and 2-pyridylhydrazine (5 g, 45.8 mmol) in 230 mL N-methylpyrrolidon. The reaction mixture is stirred two hours at room temperature. After checking that the hydrazone has been formed (1H-NMR) the reaction mixture is heated for three hours at 150° C. The reaction mixture is allowed to cool down and the dark brown suspension is poured into ice water. After vigorously stirring at room temperature for 15 minutes the mixture is extracted with ethyl acetate. The organic phase is washed with brine, dried over Na2SO4, the solvent is removed i.vac., and the product purified by chromatography on silica gel. Yield 4.8 g (33%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:33]=[CH:32][C:31](OB(O)O)=[CH:30][CH:29]=1.[OH2:38]>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:31]3[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=3)=[CH:21][N:20]=2)=[O:38])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(Br)cn2)cs1
Reactant: O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)Nc2ccc(-c3ccc(Cl)cc3)cn2)cs1

Procedure:
2-[(4-{2-[(5-Bromopyridin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (700 mg) obtained in Example 242-2 and 4-chlorophenylboric acid (358 mg) were dissolved in dioxane (8 mL) and 2 mol/L sodium carbonate (4 mL), tetrakis(triphenylphosphine)palladium (88 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:2 to 2:1) to give the title compound (450 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][NH:16][C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6].CC(C)([O-])C.[Li+].Cl[CH2:28][C:29]1[C:37]2[C:32](=[N:33][C:34]([NH:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)=[CH:35][CH:36]=2)[N:31]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[N:30]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][N:16]([CH2:28][C:29]4[C:37]5[C:32](=[N:33][C:34]([NH:38][CH2:39][C:40]6[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=6)=[CH:35][CH:36]=5)[N:31]([CH2:48][C:49]5[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=5)[N:30]=4)[C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Reactant: COc1ccc(CNc2ccc3c(CCl)nn(Cc4ccc(OC)cc4)c3n2)cc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ccc3c(Cn4nnc5c(Oc6cc(Cl)cc(C#N)c6)c(Cl)ccc54)nn(Cc4ccc(OC)cc4)c3n2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
3-chloro-5-[(5-chloro-1H-1,2,3-benzotriazol-4-yl)oxy]benzonitrile (140 mg, 0.459 mmol) and lithium tert-butoxide (37 mg, 0.459 mmol) were dissolved in DMF (1 mL) under N2 and allowed to stir for 20 minutes. After this time, the reaction was cooled to 0° C. and 3-(chloromethyl)-N,1-bis(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-6-amine as a solution in DMF (1 mL) was added dropwise. After 1 hour, the reaction was quenched with saturated aqueous ammonium chloride (3 mL), diluted with water (3 mL) and the mixture was extracted with ethyl acetate (2×25 mL). The combined organic fractions were washed with dilute brine (4×10 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by automated column chromatography on silica gel (12 g), eluting with 0-100% EtOAc/hexanes to give the title compound. LRMS (M+1)=690.5.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:26][C:27]1[C:28]([F:50])=[CH:29][C:30]([Cl:49])=[C:31]([CH:48]=1)[O:32][C:33]1[CH:34]=[CH:35][C:36]2[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]3[CH2:47][CH2:46]3)=[O:44])[N:41]=2)[N:38]=1>CN(C)C=O.CN1CCCC1=O>[Cl:49][C:30]1[C:31]([O:32][C:33]2[CH:34]=[CH:35][C:36]3[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]4[CH2:46][CH2:47]4)=[O:44])[N:41]=3)[N:38]=2)=[CH:48][C:27]([NH:26][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([C:3]([C:1]#[N:2])([CH3:4])[CH3:5])[CH:7]=2)=[C:28]([F:50])[CH:29]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c(Cl)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c(Cl)cc2F)c1
Yield: 69.3 %

Procedure:
Using 3-(1-cyano-1-methylethyl)benzoic acid (100 mg, 0.55 mmol), oxalyl chloride (59 μL, 0.69 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (2.0 mL), N-[6-(5-amino-2-chloro-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (170 mg, 0.46 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (170 mg, 70%) was obtained as a white powder.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11]2[S:15][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:17][C:10]=12)C1C=CC=CC=1.CC(C)=O.CCCCCC>C(O)C.[Pd]>[OH:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11]2[S:15][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:17][C:10]=12
Reactant: COC(=O)c1cc2c(OCc3ccccc3)cncc2s1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: CCO
Product: COC(=O)c1cc2c(O)cncc2s1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a suspension of 10 wt % Pd on activated carbon (38 mg, 10% w/w) in absolute ethanol (3 mL) was added a cold solution of Example 236C (380 mg, 1.3 mmol) in ethanol (82 mL) under nitrogen atmosphere. Then the reaction mixture was degassed and stirred at room temperature under hydrogen atmosphere. After one over night reaction mixture was treated with additional 10 wt % Pd on activated carbon (190 mg, 50% w/w) and stirred under hydrogen atmosphere. Additional catalyst (100 mg, 26% w/w) was added to the reaction mixture after 48 hours. The reaction mixture was stirred under hydrogen atmosphere for further 24 hours and filtered through Celite®. The filtrate was evaporated to dryness under reduced pressure to obtain the crude product (320 mg). The title compound Example 236E was obtained in 75% yield (200 mg) by flash chromatography on silica gel eluting with 5% acetone-hexane followed by 40% acetone-hexane.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:8][C:9]1[C:10]([N:16]=[C:17](SC)[S:18][CH3:19])=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=1.C(N(CC)CC)C>O>[CH2:6]([O:5][C:3]([C:2]1[N:11]2[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([Br:8])[C:10]2=[N:16][C:17]=1[S:18][CH3:19])=[O:4])[CH3:7]
Reactant: CSC(=Nc1ncc(C)cc1Br)SC
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1c(SC)nc2c(Br)cc(C)cn12
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Ethyl bromoacetate (5.4 g) was added to methyl N-(3-bromo-5-methyl-2-pyridyl)-(methylsulfanyl)methaneimidothioate, and the mixture was stirred at 60° C. for 4 hours. After cooled to room temperature, triethylamine was added to treat the material, and water was further added thereto. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by column chromatography (ethyl acetate:n-hexane=1:9) to give 8-bromo-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-carboxylic acid ethyl ester (2.4 g) as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20](OC(C)(C)C)=[O:21])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH:41]([N:44]=C=O)([CH3:43])[CH3:42]>O>[CH:41]([NH:44][C:20]([N:17]1[CH2:18][CH2:19][N:14]([CH2:13][C:2]2([CH3:1])[O:6][C:5]3=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]3[CH2:3]2)[CH2:15][CH2:16]1)=[O:21])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: CC(C)N=C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)N1CCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
A mixture of tert-butyl 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate prepared in Example 306 (140 mg, 0.38 mmol) and trifluoroacetic acid (3 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (3 ml), then neutralized with triethylamine (2 ml, 14.35 mmol). To the solution, isopropylisocyanate (75 μl, 0.76 mmol) was added followed by stirring at room temperature for 1 hour, then diluted with water. The solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylic acid isopropylamide (90 mg, yield 67%) as a white powder.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[CH3:28]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[C:20]([CH3:28])[CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: Cc1cc(B(O)O)ccc1F
Product: Cc1cc(-c2cc(Cl)cc3c(C)c4n(c23)CCNC4=O)ccc1F

Procedure:
The title compound, off-white solid (73 mg, 85%), MS (ISP) m/z=343.5 [(M+H)+], mp 235.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-fluoro-3-methyl-phenylboronic acid (50.0 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:15]([C:19]1[CH:20]=[C:21]2[C:26](=O)[O:25][C:23](=[O:24])[C:22]2=[CH:28][CH:29]=1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([C:19]1[CH:20]=[C:21]2[C:22](=[CH:28][CH:29]=1)[C:23](=[O:24])[N:1]([CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:26]2=[O:25])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Product: CCOC(=O)C(CN1C(=O)c2ccc(C(C)(C)C)cc2C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(5-t-butyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.54 g, 35%) in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.80 g, 3.94 mmol) and 4-t-butylphthalic anhydride (0.88 g, 4.33 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:19])[C:15]([F:18])([F:17])[F:16])=[C:10]([F:20])[CH:9]=1.[NH2:21][C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C@H:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:36]([OH:38])=[O:37])=[CH:30][CH:29]=2)[CH:25]=[C:24](Cl)[N:23]=1.O>O1CCOCC1.C(OCC)(=O)C>[NH2:21][C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C@H:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:36]([OH:38])=[O:37])=[CH:30][CH:29]=2)[CH:25]=[C:24]([O:19][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([Br:7])=[CH:9][C:10]=2[F:20])[C:15]([F:18])([F:17])[F:16])[N:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(Cl)nc(N)n2)cc1)C(=O)O
Reactant: OC(c1ccc(Br)cc1F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(OC(c3ccc(Br)cc3F)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 82.6 %

Procedure:
Cs2CO3 (8.45 g, 26 mmol) was added to the solution of 1-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethanol (1.4 g, 5.2 mmol) in 10 ml of anhydrous 1,4-dioxane, the mixture was stirred for 5 minutes, then (S)-3-[4-(2-amino-6-chloro-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (2.0 g, 5 mmol) was added, and the resulting mixture was heated at 110° C. overnight. After cooling, 5 ml of water was added and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to give 2.6 g of (S)-3-(4-{2-amino-6-[1-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl}phenyl)2tertbutoxycarbonylamino-propionic acid (yield: 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][O:17][CH2:18][CH2:19][OH:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:31]([O:20][CH2:19][CH2:18][O:17][CH2:16][C:13]1[N:14]([CH3:15])[C:10]([S:9][C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]=1)(=[O:33])[CH3:32]
Reactant: CC(C)c1nc(COCCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCOCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1C
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
To dry methylene chloride solution (5 ml) of 200 mg (0.5 mmol) of 2-{[5-(3,5-dichlorophenylthio)-4-isopropyl-1 methyl-1H-imidazol-2-yl]methoxy} ethanol (25a), 161 mg (1.60 mmol) of triethylamine was added. Under ice-cooling, 63 mg (0.8 mmol) of acetyl chloride was added, and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate was added, neutralized, and extracted with methylene chloride. The extract was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate:n-hexane=1:1) to obtain 200 mg of 2-[-5-(3,5-dichlorophenylthio)-4-isopropyl-1-methylimidazol-2-ylmethoxy]ethyl acetate (Compound I-60) as oil (yield 90%).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:14]1[CH:29]=[CH:28][C:17]2[C@:18]3([CH3:27])[C@@H:23]([CH2:24][CH2:25][C:16]=2[CH:15]=1)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3.[CH2:30](O)CCC.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:30][N:22]1[C@H:23]2[C@@:18]([CH3:27])([C:17]3[CH:28]=[CH:29][C:14]([C:2]4[CH:3]=[CH:4][C:5]5[C:6]6[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=6)[CH2:12][C:13]=5[CH:1]=4)=[CH:15][C:16]=3[CH2:25][CH2:24]2)[CH2:19][CH2:20][C:21]1=[O:26]
Reactant: CCCCO
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccc4c(c3)Cc3ccccc3-4)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5c(c4)Cc4ccccc4-5)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2-fluorenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (31 mg, 0.08 mmol), 0.2 mL of butanol, and potassium t-butoxide (27 mg, 0.24 mmol). Methyl iodide (0.015 mL, 0.24 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 26 mg (82%) of the title compound as an off-white solid. mp 175° (decomp). FDMS: m/e=393.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:30]=[CH:29][C:10]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3([CH2:27][C:26](=[O:28])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[O:19]3)[CH2:15][CH2:14]2)=[O:12])=[CH:9][C:8]=1[O:31][CH3:32])([CH3:6])([CH3:5])[CH3:4].[CH:33](OCC)=[O:34]>C1COCC1>[C:3]([C:7]1[CH:30]=[CH:29][C:10]([C:11]([N:13]2[CH2:14][CH2:15][C:16]3([C:27](=[CH:33][OH:34])[C:26](=[O:28])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[O:19]3)[CH2:17][CH2:18]2)=[O:12])=[CH:9][C:8]=1[O:31][CH3:32])([CH3:6])([CH3:4])[CH3:5]
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2ccccc2O3)ccc1C(C)(C)C
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2C(=O)C3=CO)ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.8 %

Procedure:
NaH (57 mg, 1.4 mmol) was added in small portions to a mixture of 1′-(4-tert-butyl-3-methoxy-benzoyl)spiro[chromane-2,4′-piperidine]-4-one (250 mg, 0.61 mmol) in THF (2.5 mL) at 25° C. A solution of ethyl formate (74 μL, 0.90 mmol) in THF (0.5 mL) was added and the mixture was allowed to stir at 25° C. for 3 h before it was quenched with 0.5M aqueous HCl. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo to provide 1′-(4-tert-butyl-3-methoxybenzoyl)-3-(hydroxymethylene)spiro[chroman-2,4′-piperidin]-4-one (50 mg, 19%) as an orange oil. ESI-MS m/z talc. 435.2, found 436.2 (M+1)+; Retention time: 1.87 minutes (3 min run).
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([OH:10])=[O:9])([CH3:5])([CH3:4])[CH3:3].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17].C(N(CC)C(C)C)(C)C.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:2]([N:6]([C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:12]([F:11])([F:22])[F:23])[CH:14]=1)[CH2:7][C:8]([OH:10])=[O:9])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NCC(=O)O
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)N(CC(=O)O)C(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
tert-Butyl glycine hydrochloride (6.6 g, 50 mmol) was suspended in methylene chloride and meta-trifluoromethyl benzoic acid (9.5 g, 50 mmol) was added, followed by N,N-diisopropylethylamine (17.5 mL, 100 mmol), EDC (10.2 g, 53 mmol), and DMAP (300 mg, 2.5 mmol). The reaction was stirred for 12 hrs at RT and partitioned between EtOAc and 1 N HCl. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The material was purified via flash chromatography to give tert-Butyl (3-trifluoromethylbenzoyl)glycine as a clear and colorless oil (12 g), which was dissolved in methylene chloride (40 mL), cooled to 0° C., and treated with trifluoroacetic acid (20 mL). The reaction was stirred for 3.5 hrs at RT and concentrated in vacuo. The material was redissolved in methylene chloride and concentrated again; this procedure was repeated three more times to give the desired carboxylic acid 1.2 (Z=—C(O)—, R2=3-trifluoromethylphenyl, all other R=H; 8.9 g). 1H-NMR (300 MHz): δ 8.03 (s, 1H), 7.94 (d, 1H, J=7.7 Hz), 7.66 (d, 1H, J=7.7 Hz), 7.48 (t, 1H, J=7.9 Hz), 4.08 (s, 2H).
Reaction SMILES: Br[C:2]1[C:3]([C:22]([F:25])([F:24])[F:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[N:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O.O1CCOCC1>[N:26]1[CH:31]=[C:30]([C:2]2[C:3]([C:22]([F:25])([F:24])[F:23])=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])[CH:29]=[N:28][CH:27]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(C(F)(F)F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(C(F)(F)F)c(-c2cncnc2)c1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
5-Bromo-N-(4-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)nicotinamide (Stage 57.1, 125.7 mg, 0.293 mmol), pyrimidin-5-ylboronic acid (43.6 mg, 0.352 mmol), Cs2CO3 (191 mg, 0.586 mmol), PdCl2(dppf)-(CH2Cl2) (23.92 mg, 0.029 mmol), water (2 mL) and dioxane (8 mL) were added to a vial, which was sealed, evacuated/purged with argon and the RM was stirred at 70° C. for 2.5 h. The solvent was evaporated off under reduced pressure to give a residue which was treated with water and extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 25 g, n-hexane/EtOAc) and recrystallized from n-hexane/EtOAc to give the title compound as a pink powder. UPLC-MS (Condition 2) tR=1.07 min, m/z=429 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:5]=1.[CH:15]1([C:19]2[N:20]=[C:21](/[CH:24]=[CH:25]/[C:26]3[CH:27]=[C:28]([NH2:32])[CH:29]=[CH:30][CH:31]=3)[S:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26](/[CH:25]=[CH:24]/[C:21]3[S:22][CH:23]=[C:19]([CH:15]4[CH2:18][CH2:17][CH2:16]4)[N:20]=3)[CH:27]=2)=[O:13])[CH:5]=1
Reactant: COC(=O)c1cccc(CC(=O)O)c1
Reactant: Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(CC(=O)Nc2cccc(/C=C/c3nc(C4CCC4)cs3)c2)c1
Reaction time: 16 h
Yield: 77.5 %

Procedure:
A solution composed of 1.0 g of 3-carboxymethyl benzoic acid methyl ester, 1.3 g of (E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine, 1.0 g of N-ethyl-N-(dimethylaminopropyl) carbodiimide, 2.4 g of 4-dimethylaminopyridine and 75 ml of methylene chloride was stored at 0° C. After 16 hr., the reaction mixture was washed with 75 ml of water, dried (MgSO4) and the solvents removed by rotary, evaporation. The residual materials were triturated with ethyl acetate/hexane to yield 1.7 g of (E)-3-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid methyl ester; m.p. 119°-120° C.