Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:28]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]#[N:37])[C:20]3[C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:12]1)C1C=CC=CC=1>[Pd].CCO.C1COCC1>[NH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:28]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]#[N:37])[C:20]3[C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:12]1
Reactant: CCn1ccc2nc(C3CCCC(NC(=O)OCc4ccccc4)C3)n(Cc3ccccc3C#N)c2c1=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCn1ccc2nc(C3CCCC(N)C3)n(Cc3ccccc3C#N)c2c1=O
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A solution of {3-[3-(2-cyano-benzyl)-5-ethyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl]-cyclohexyl}-carbamic acid benzyl ester (66 mg, 0.13 mmol) in 1:3 EtOH/THF (8 mL) was hydrogenated over 10% Pd/C (70 mg, 0.065 mmol) at room temperature. After 2 h, the catalyst was removed by filtration, rinsing with MeOH, and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography, eluting with 90:10:0.5 CH2Cl2/MeOH/NH4OH to give 2-[2-(3-amino-cyclohexyl)-5-ethyl-4-oxo-4,5-dihydro-imidazo[4,5-c]pyridin-3-ylmethyl]-benzonitrile (40 mg, 82% yield). The HCl salt was prepared by treating the amine in EtOAc with ethereal HCl (0.2 mL). 1H-NMR (CDCl3): δ 7.72 (dd, 1H, J=7.6, 1.2 Hz), 7.50 (t, 1H, J=7.6 Hz), 7.39 (t, 1H, J=7.6 Hz), 7.14 (d, 1H, J=7.2 Hz), 6.93 (d, 1H, J=7.6 Hz), 6.72 (dd, 1H, J=7.6, 2.0 Hz), 6.07 (m, 2H), 4.07 (m, 2H), 2.70 (m, 2H), 1.92 (m, 1H), 1.83 (m, 2H), 1.60 (m, 4H), 1.40 (m, 2H), 1.37 (dt, 3H, J=7.2, 3.2 Hz). MS: calculated for C22H25N5O+H 376.2; found: 376.2.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[NH2:3].C(N(CC)CC)C.C[O:21][C:22](=O)[N:23]=[C:24](SC)[C:25]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=1)=[N:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]=[C:36]([CH3:38])[O:35][N:34]=2)=[CH:29][CH:28]=1.Cl>CN(C=O)C.O>[CH3:48][O:47][C:41]1[CH:40]=[C:39]([C:25](=[N:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[N:37]=[C:36]([CH3:38])[O:35][N:34]=3)=[CH:29][CH:28]=2)[C:24]2[NH:23][C:22](=[O:21])[N:2]([C:4]3[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=3[C:6]([OH:8])=[O:7])[N:3]=2)[CH:44]=[CH:43][C:42]=1[O:45][CH3:46]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1ccc(OC)c(OC)c1
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc1OC
Temperature: 90 °C
Reaction time: 20 h
Yield: 32.3 %

Procedure:
After adding 38 mg of 2-hydrazinobenzoic acid hydrochloride and 0.056 ml of triethylamine to a solution of 91 mg of [2-(3,4-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 5 ml of DMF, the mixture was stirred at 90° C. for 20 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, 30 ml of water was added, hydrochloric acid was added (for adjustment to pH 3-4), and extraction was performed with 50 ml of ethyl acetate. The organic layer was washed twice with 30 ml of water and once with 30 ml of saturated brine, and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-dichloromethane) to give the title compound (34 mg) as a light yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=[N:3][CH:2]=1.[ClH:10]>O>[ClH:10].[NH:3]1[CH2:4][CH:5]([C:7]([OH:9])=[O:8])[CH2:6][N:1]=[CH:2]1
Reactant: O=C(O)c1cncnc1
Agent: Cl
Solvent: O
Product: O=C(O)C1CN=CNC1
Yield: 92.8 %

Procedure:
Pyrimidine-5-carboxylic acid (5.0 g, 40 mmol) was suspended in a mixture of 150 ml water and concentrated hydrochloric acid (4.0 g, 40.5 mmol). The mixture was hydrogenated at 26 psig over 1.0 g Pd-on-carbon 10% in a Parr hydrogenator for 3h. The suspension was filtered and the filter rinsed twice with hot water (20 ml). The filtrate was evaporated in vacuo to give 6.11 g yellow oil (92%). The oil was crystallized from anhydrous methanol/tetrahydrofuran (THF) to give 5.77 g (87%) white crystals in two crops. 300 MHz nmr indicated product.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:33][OH:34])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:14]([S:13][C@H:11]1[CH2:12][NH:8][C@H:9]([CH2:33][OH:34])[CH2:10]1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1
Temperature: 25 °C
Yield: 111.4 %

Procedure:
To 25.0 g (52.56 mmol) (2S,4R)-2-Hydroxymethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester in 80 ml CH2Cl2 were added 40 ml TFA at 0° C., and the solution was stirred at RT over night. The solution was concentrated in vacuo, and the residue was redissolved in EtOAc, washed with sat. NaHCO3 solution, brine, and was dried over Na2SO4. 21.98 g (quant.) (2S,4R)-(4-Tritylsulfanyl-pyrrolidin-2-yl)-methanol were isolated as light brown foam.
Reaction SMILES: C1COCC1.[BH4-].[Na+].[C:8]([NH:27][C@H:28]([C@H:34]([OH:50])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:29](OCC)=[O:30])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(OCC)(=O)C>O>[C:8]([NH:27][C@H:28]([C@H:34]([OH:50])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:29][OH:30])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](C(=O)OCC)[C@H](O)CCCCCCCCCCCCCCC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)CCCCCCCCCCCCCCC
Temperature: 60 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
A THF suspension (2 mL) containing sodium borohydride (39.2 mg, 0.96 mmol) was heated to 60° C., and ethyl (2R,3R)-2-octadecanoylamino-3-hydroxyoctadecanoate (300.0 mg, 0.49 mmol) synthesized in the same manner as Example 17 was added for 2.5 hours. After completion of the dropwise addition, the mixture was further stirred at 60° C. for 24 hours. After ethyl acetate and water were added thereto, the reaction mixture was stirred at 60° C. for 1 hour. After the organic layer was separated, the obtained organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was removed in reduced pressure. It was confirmed that 219.4 mg of the title compound was contained (yield: 78%). HPLC analysis was carried out to find that anti-form:syn-form was 81:19 and the optical purity of the anti-form was 99% ee.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])=[CH:5]2.[C:18]1([NH:24][CH2:25][CH2:26][OH:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH2:14][C:15]([N:24]([CH2:25][CH2:26][OH:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17])=[O:12])=[CH:5]2
Reactant: OCCNc1ccccc1
Reactant: O=C(O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCC(=O)N(CCO)c1ccccc1)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of N-[(5-chloro-1H-indol-2-yl)carbonyl]glycine (Cas Reg No 186429-62-9; Hulin, Bernard, et al, PCT International Patent Application (1996) WO 9639384; 374 mg, 1.5 mmol) and 2-(phenylamino)ethanol (228 mg, 1.6 mmol) in THF (20 ml) was stirred at ambient temperature for 30 minutes. 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)4-methylmorpholinium chloride (DMTMM) (480 mg, 1.6 mmol) was added and the reaction mixture stirred at ambient temperature overnight, poured into water (15 ml) and extracted with ethyl acetate (3×15 ml). The organic extracts were combined and washed with 1N citric acid solution (15 ml), sodium bicarbonate solution (15 ml), dried over magnesium sulphate, filtered and concentrated to give the title product (471 mg, 86%).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=1.[C:13]1(B2OC(C)(C)C(C)(C)O2)[CH2:17][CH2:16][CH2:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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].O>[C:13]1([C:2]2[CH:3]=[N:4][N:5]([CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][O:8]3)[CH:6]=2)[CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Reactant: Ic1cnn(C2CCCCO2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C1=C(c2cnn(C3CCCCO3)c2)CCC1
Yield: 84.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 39a by using 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (J. Org. Chem., 2007, 72 (9), 3589-3591; 1.51 g, 5.42 mmol), 2-cyclopent-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.37 g, 7.05 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (317 mg, 0.434 mmol), cesium carbonate (6.01 g, 18.4 mmol), dioxane (27 mL) and water (5.0 mL), to yield the title compound (1.00 g, 85%) as a colorless oil.
Reaction SMILES: COC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C=C2OC(C)CC=12)=O.[CH3:26][N:27]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[CH:46]=[C:45]([OH:47])[C:38]3[CH2:39][CH:40]([CH2:42][O:43][CH3:44])[O:41][C:37]=3[CH:36]=2)=[O:34])=[N:28]1.[N:48]1([C:52]([C:54]2[CH:59]=[CH:58][C:57](F)=[CH:56][CH:55]=2)=[O:53])[CH2:51][CH2:50][CH2:49]1>>[CH3:26][N:27]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[CH:46]=[C:45]([O:47][C:57]3[CH:56]=[CH:55][C:54]([C:52]([N:48]4[CH2:49][CH2:50][CH2:51]4)=[O:53])=[CH:59][CH:58]=3)[C:38]3[CH2:39][CH:40]([CH2:42][O:43][CH3:44])[O:41][C:37]=3[CH:36]=2)=[O:34])=[N:28]1
Reactant: O=C(c1ccc(F)cc1)N1CCC1
Reactant: COCC1Cc2c(O)cc(C(=O)Nc3ccn(C)n3)cc2O1
Agent: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Product: COCC1Cc2c(Oc3ccc(C(=O)N4CCC4)cc3)cc(C(=O)Nc3ccn(C)n3)cc2O1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (204d) and azetidin-1-yl-(4-fluoro-phenyl)-methanone. 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1 H) 7.59-7.67 (m, 2 H) 7.28 (d, J=2.53 Hz, 1 H) 7.13 (d, J=1.26 Hz, 1 H) 7.06 (d, J=1.26 Hz, 1 H) 6.97-7.02 (m, 2 H) 6.79 (d, J=2.27 Hz, 1 H) 4.99-5.08 (m, 1 H) 4.29-4.39 (m, 2 H) 4.19-4.29 (m, 2 H) 3.80-3.82 (m, 3 H) 3.56-3.64 (m, 2 H) 3.44 (s, 3 H) 3.16 (dd, J=16.55, 9.47 Hz, 1 H) 2.92 (dd, J=16.42, 7.33 Hz, 1 H) 2.31-2.41 (m, 2 H); LCMS for C25H26N4O5 m/z 463.20 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH:12]([C:14]2[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Nc1cc(F)cc(Cl)c1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: CC(Nc1cc(F)cc(Cl)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 76.2 %

Procedure:
3-chloro-5-fluoroaniline (0.074 mL, 0.73 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (0.09 g, 0.18 mmol)) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(3-chloro-5-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (0.065 g, 75%) as a white solid. Mass Spectrum: M+H+ 474. NMR Spectrum (CDCl3): 1.61 (d, 3H), 2.90 (bs, 3H), 3.09 (bs, 3H), 3.46-3.55 (m, 4H), 3.80-3.88 (m, 4H), 4.35 (d, 1H), 4.88-4.96 (m, 1H), 5.56 (s, 1H), 6.03 (ddd, 1H), 6.27 (dd, 1H), 6.39 (ddd, 1H), 7.70 (d, 1H), 8.12 (d, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]2[N:9]([CH3:16])[C:10](=[O:15])[NH:11][S:12](=[O:14])(=[O:13])[C:7]=2[CH:6]=1)=[O:4]>CO.[OH-].[Na+]>[CH3:16][N:9]1[C:8]2[CH:17]=[CH:18][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[S:12](=[O:14])(=[O:13])[NH:11][C:10]1=[O:15]
Reactant: COC(=O)c1ccc2c(c1)S(=O)(=O)NC(=O)N2C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C(=O)NS(=O)(=O)c2cc(C(=O)O)ccc21
Reaction time: 4 h
Yield: 100.2 %

Procedure:
4-Methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[1,2,4]thiadiazine-7-carboxylic acid methyl ester (10.0 g, Example 1, Step 1) was dissolved in 200 ML of methanol with 75 mL of 1M NaOH. Stirred for 4 hours and concentrated in vacuo to remove the methanol. The residue was acidified with concentrated HCl, filtered, and washed with water. Air dried on the vacuum filter to give 9.5 g of the title compound as a tan solid. 1H-NMR (DMSO-d6); δ 8.04 (s, 1H), 7.94 (dd, 1H), and 7.17 (d, 1H) ppm. MS: M+−1=255.1 Da
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]([O:16]C)=[O:15])=[CH:8]2)=[N:4][CH:3]=1.[Li+].[OH-]>>[CH3:1][C:2]1[S:6][C:5]([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]([OH:16])=[O:15])=[CH:8]2)=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc(=O)n(-c2ncc(C)s2)c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cnc(-n2cc(C(=O)O)ccc2=O)s1

Procedure:
A target compound was obtained using methyl 1-(5-methyl-1,3-thiazole-2-yl)-1,6-dihydro-6-oxo-3-pyridinecarboxylate and LiOH in the same manner as in Example 1-3.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9](CC(C)(C)C)=[CH:10][CH:11]=2)[C:6]=1[OH:20])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:2][CH2:3][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:20]
Reactant: COC(=O)C1=C(O)c2cc(CC(C)(C)C)ccc2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1c2ccccc2CCC1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To an ice-cooled solution of 7-(2,2-Dimethyl-propyl)-1-hydroxy-3,4-dihydro-naphthalene-2-carboxylic acid methyl ester (2.49 g, 9.07 mmol) in tetrahydrofuran (20 mL) was added lithium aluminum hydride (1 M in tetrahydrofuran, 9 mL, 9 mmol). The reaction mixture was stirred at 0° C. for 2 h and then quenched with saturated ammonium chloride and ethyl acetate. The resulting emulsion was filtered through diatomaceous earth. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Flash column chromatography (silica gel, 10-20% ethyl acetate/hexanes) provided hydroxymethyl tetralone (1.55 g, 70%): 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J=1.4 Hz, 1H), 7.27 (dd, J=7.8, 1.4 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 4.00-3.90 (m, 1H), 3.85-3.75 (m, 1H), 3.20-3.10 (m, 1H), 3.08-2.90 (m, 2H), 2.75-2.60 (m, 1H), 2.52 (s, 2H), 2.15-2.05 (m, 1H), 2.00-1.85 (m, 1H), 0.90 (s, 9H).
Reaction SMILES: C(O[C:6](=[O:41])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:39])[NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)[CH2:23][CH2:22]2)[C:18]([Cl:40])=[CH:17][N:16]=1)(C)(C)C.[C:42](O)([C:44](F)(F)F)=O.NC1C=CC=CC=1NC1N=C(N2CCN(C(NC3C=CC=C(C(F)(F)F)C=3)=O)CC2)C(Cl)=CN=1.C(Cl)(=O)C=C.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:6]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][N:24]([C:27]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[CH:30]=3)=[O:39])[CH2:25][CH2:26]2)[C:18]([Cl:40])=[CH:17][N:16]=1)(=[O:41])[CH:42]=[CH2:44]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1Nc1ncc(Cl)c(N2CCN(C(=O)Nc3cccc(C(F)(F)F)c3)CC2)n1
Reactant: O=C(O)C(F)(F)F
Agent: C=CC(=O)Cl
Agent: Nc1ccccc1Nc1ncc(Cl)c(N2CCN(C(=O)Nc3cccc(C(F)(F)F)c3)CC2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccccc1Nc1ncc(Cl)c(N2CCN(C(=O)Nc3cccc(C(F)(F)F)c3)CC2)n1
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of tert-butyl(2-((5-chloro-4-(4-((3-(trifluoromethyl)phenyl)carbamoyl)piperazin-1-yl)pyrimidin-2-yl)amino)phenyl)carbamate (0.025 g, 0.043 mmol) in DCM (1.0 mL) was added TFA (1.0 mL) and the mixture was stirred for 1 h. An aliquot of the reaction mixture was analyzed by LCMS, which indicated that the reaction had proceeded to completion. The solvents were removed and the residue was dried on high vacuum. The crude product was used for the next step without further purification. To a solution of 4-(2-((2-aminophenyl)amino)-5-chloropyrimidin-4-yl)-N-(3-(trifluoromethyl)phenyl)piperazine-1-carboxamide (0.043 mmol) in DCM (0.5 mL) was added acryloyl chloride (0.004 mL, 0.052 mmol) and DIEA (0.018 mL, 0.11 mmol) and the mixture was stirred at 0° C. for 1 h. The crude reaction mixture was loaded onto silica gel and purified using 0-7% MeOH/DCM gradient to give the title compound (10 mg, 43%). MS (ES+) C25H23ClF3N7O2 requires: 545. found: 546 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[C:4]([N+:8]([O-])=O)[CH:5]=[CH:6][CH:7]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl.Cl.[OH-].[Na+]>>[Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:14])([F:16])[F:15])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cccc(Cl)c1OCC(F)(F)F
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: Nc1cccc(Cl)c1OCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.9 %

Procedure:
3-Chloro-2-(2,2,2-trifluoroethoxy)nitrobenzene (47 g, 185 mmol) and tin chloride dihydrate (126.5 g, 555 mmol) were placed in a 3 neck flask equipped with an overhead stirrer. Concentrated HCl (231 mL) was added in one portion with rapid stirring, and the reaction heated rapidly until it was homogeneous. After stirring an additional 15 minutes, the mixture was cooled to 0° C. and 50% NaOH added to pH=13. The alkaline solution was extracted with Et2O (2×500 mL) and the combined Et2O layers were washed with brine (2×500 mL), dried (MgSO4), and concentrated to afford 35 g of 3-chloro-2-(2,2,2-trifluoroethoxy)aniline as a light yellow oil. This oil was dissolve in the minimum amount of ether (~100 mL), then saturated with HCl gas. The product was precipitated by the addition of hexane (250 mL), and the resulting solid removed by filtration to afford 31 g (65%) of 3-chloro-2-(2,2,2-trifluoroethoxy)aniline as the hydrochloride salt, m.p. 170°-180° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][C:10]1[O:14][C:13]([CH2:15][CH2:16][C:17](Cl)=[O:18])=[CH:12][CH:11]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:17](=[O:18])[CH2:16][CH2:15][C:13]2[O:14][C:10]([CH3:9])=[CH:11][CH:12]=2)=[N:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: Cc1ccc(CCC(=O)Cl)o1
Solvent: c1ccncc1
Product: Cc1ccc(CCC(=O)Nc2ccc(Br)cn2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-bromopyridin-2-amine (123a, 600 mg, 3.47 mmol) in pyridine (10 ml) was added 3-(5-Methyl-furan-2-yl)-propionyl chloride (718.3 mg, 4.16 mmol) and stirred at room temperature for 16 hours. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4(s) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give N-(5-Bromo-pyridin-2-yl)-3-(5-methyl-furan-2-yl)-propionamide (123): 1H NMR (500 MHz, DMSO) δ: 10.68 (s, 1H), 10.68 (s, 1H),8.42 (d, 1H), 8.07 (m, 1H), 5.94 (s, 1H), 5.92 (s, 1H), 2.85 (t, 2H), 2.70 (t, 2H), 2.19 (s, 3H). ESI-MS: 310.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[C:12]([C:14]#[N:15])[N:13]=1.[OH-:25].[K+]>O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[O:10][C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[C:12]([C:14]([NH2:15])=[O:25])[N:13]=1
Reactant: COc1ccccc1Nc1oc(-c2c(F)cccc2F)nc1C#N
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: COc1ccccc1Nc1oc(-c2c(F)cccc2F)nc1C(N)=O
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
To a suspension of 2-(2,6-difluorophenyl)-5-(2-methoxyphenylamino)oxazole-4-carbonitrile (0.018 g, 0.055 mmol, prepared according to the procedure described for Q-1 step a) in water (4.5 mL) was added 1M aqueous potassium hydroxide (0.27 mL, 0.27 mmol) and the resulting mixture stirred at 140° C. in the microwave for 15 minutes. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(2-methoxyphenylamino)oxazole-4-carboxamide (0.0104 g, 0.030 mmol, 55%). 1H NMR (DMSO) δ 3.92 (3H, s), 6.99 (1H, ddd), 7.04 (1H, ddd), 7.12 (1H, dd), 7.35 (2H, t), 7.42 (2H, br. s), 7.64 (1H, m), 7.68 (1H, dd), 9.48 (1H, s). LCMS (2) Rt: 2.86 min; m/z (ES+) 346.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10].[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[Br:22])[C:16](Cl)=[O:17].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([Br:22])=[C:13]([CH3:12])[CH:14]=1
Reactant: COC(=O)c1ccccc1N
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1NC(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
To 2-amino-benzoic acid methyl ester (3.1 g) in dichloromethane (31 mL) under slight cooling was added 3-methyl-4-bromobenzoyl chloride ([21900-25-4], 4.8 g) followed by a triethylamine (3.15 mL). The temperature of the solution was kept below 40° C. and the reaction mixture was then stirred at room temperature for an hour. After such time, additional dichloromethane was added (50 mL) and the reaction mixture was washed with water. The aqueous phase was further extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (heptane-ethyl acetate: 0-50%) to yield 2-(4-bromo-3-methyl-benzoylamino)-benzoic acid methyl ester (7.1 g). MS (m/e): 348.3 (M+H+, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.Br[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[OH-].[Na+]>CN(C=O)C>[CH:23]1([CH2:22][N:13]2[C:14]3([CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:15][S:16][C:12]2=[N:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[CH3:1])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: BrCC1CCCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1CC1CCCCC1
Temperature: 45 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
To a solution of 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane (Method C2a; 0.10g, 0.3432 mmol) and bromomethylcyclohexane (1.00 mL) in DMF (1.00 mL) was added NaOH (approx. 0.13 g). The resulting mixture was stirred at 45° C. for 2 d during which it turned from deep red to bright orange. The reaction mixture was then cooled to room temp., filtered and concentrated under reduced pressure. The residual oil was purified by chromatography (SiO2; 5% EtOAc/hex) to afford 1-(cyclohexylmethyl)-2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane (0.042 g, 32%) mp 85-7° C.